Fetal size and eating behaviour in childhood: a prospective cohort study.

BACKGROUND: Although studies showed that an adverse intrauterine environment increases the obesity risk in adulthood, little is known about consequences of fetal growth and birth size for eating behaviour. We examined whether fetal and birth size are associated with childhood eating behaviour. METHODS: Participants were 4350 mother-child dyads of the prospective cohort study Generation R. We assessed the relation between fetal and birth size measurements with child eating behaviour at age 4 years by maternal report on the Child Eating Behaviour Questionnaire. Child body mass index (BMI) was measured at age 2 years. RESULTS: Per one standard deviation (SD) larger birthweight, children scored lower on Satiety Responsiveness [-0.29 points; 95% confidence interval (CI): -0.39; -0.18], higher on Food Responsiveness (0.28 points; 95% CI: 0.17; 0.39) and on Enjoyment of Food (0.21 points; 95% CI: 0.12; 0.31) at age 4 years. Similar associations were found in late pregnancy. Per one SD increase in fetal growth from late pregnancy to birth, children scored lower on Satiety Responsiveness (-0.15 points; 95% CI: -0.26; -0.04). Children within the 10% highest birthweight scored higher on food approach and lower on food avoidant scales, whereas associations in children within the 10% lowest birthweights were absent. Although child BMI partly mediated the association, direct effects of birthweight on appetitive traits remained. CONCLUSIONS: This study indicates that fetal size, especially being large in utero, is associated with obesity-inducing eating behaviour. Our findings point to intrauterine influences on appetite and satiety, and contribute to understanding the complex aetiology of obesity.

Epigenetic evidence for involvement of the oxytocin receptor gene in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neurodevelopmental disorder that affects up to 3% of the general population. Although epigenetic mechanisms play a role in neurodevelopment disorders, epigenetic pathways associated with OCD have rarely been investigated. Oxytocin is a neuropeptide involved in neurobehavioral functions. Oxytocin has been shown to be associated with the regulation of complex socio-cognitive processes such as attachment, social exploration, and social recognition, as well as anxiety and other stress-related behaviors. Oxytocin has also been linked to the pathophysiology of OCD, albeit inconsistently. The aim of this study was to investigate methylation in two targets sequences located in the exon III of the oxytocin receptor gene (OXTR), in OCD patients and healthy controls. We used bisulfite sequencing to quantify DNA methylation in peripheral blood samples collected from 42 OCD patients and 31 healthy controls. RESULTS: We found that the level of methylation of the cytosine-phosphate-guanine sites in two targets sequences analyzed was greater in the OCD patients than in the controls. The higher methylation in the OCD patients correlated with OCD severity. We measured DNA methylation in the peripheral blood, which prevented us from drawing any conclusions about processes in the central nervous system. CONCLUSION: To our knowledge, this is the first study investigating DNA methylation of the OXTR in OCD. Further studies are needed to evaluate the roles that DNA methylation and oxytocin play in OCD.

Gender differences in the impact of daily sadness on 24-h heart rate variability.

Reduced heart rate variability (HRV) is proposed to mediate the relation between depressive symptoms and cardiovascular health problems. Yet, several studies have found that in women depression is associated with higher HRV levels, whereas in men depression is associated with lower HRV levels. So far, these studies have only examined gender differences in HRV levels using a single assessment. This study aimed to test the interactive effects of gender and sadness on ambulatory-assessed HRV levels. A sample of 60 (41 women) employees participated in an ambulatory study. HRV levels (mean of successive differences; MSD) were continuously measured for 24 h. During the daytime, hourly assessments of sadness and other mood states were taken, while depressive symptoms were assessed with the Center for Epidemiologic Studies Depression scale (CES-D). Gender differences were observed when examining the impact of average daily sadness on MSD. In women, but not in men, the total amount of sadness experienced during the day was associated with higher circadian MSD levels. These findings suggest that researchers need to take gender differences into account when examining the relation between sadness, HRV, and cardiovascular problems.

The association between cortisol and neighborhood disadvantage in a U.S. population-based sample of adolescents.

The association between neighborhood conditions and cortisol is rarely studied in children or adolescents and has been hampered by small sample size and racial/ethnic and geographic homogeneity. Our objective was to estimate the association between neighborhood disadvantage and salivary cortisol levels in a large, geographically and racially/ethnically diverse sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Salivary cortisol was collected before and after an interview administered in the adolescent's home. We used a propensity score approach to match adolescents living in disadvantaged neighborhoods with those in non-disadvantaged neighborhoods to create two similar groups based on the time and day of cortisol collection as well as demographic characteristics. Adolescents living in disadvantaged neighborhoods had higher pre-interview cortisol levels and steeper rates of decline in cortisol levels over the course of the interview than similar adolescents in non-disadvantaged neighborhoods. This bolsters the evidence base suggesting that place may influence the stress response system.

Plasma cortisol in first episode drug-naïve mania: differential levels in euphoric versus irritable mood.

BACKGROUND: Dysregulation of HPA axis has been widely described in subjects with bipolar disorder (BD), including changes in cortisol levels during mood episodes and euthymia. However, most of the studies were done with medicated BD patients with variable length of illness, which was shown to interfere on peripheral cortisol levels. Therefore, the present study aims to evaluate plasma cortisol levels in drug-naïve BD subjects during the first manic episode, as well as investigate the relationship between plasma cortisol levels and manic symptomatology. METHODS: Twenty-six drug-naïve patients were enrolled meeting criteria for a first manic episode in bipolar I disorder. Severity of mania was assessed using the Young Mania Rating Scale (YMRS). The control group included 27 healthy subjects matched by age and gender. Cortisol was quantified using a direct radioimmunoassay. RESULTS: Plasma cortisol levels were decreased during first manic episode compared to healthy controls. Higher cortisol levels were positively associated with the presence of irritability (dysphoria), while elated mania showed lower cortisol levels compared to controls. LIMITATION: Data including larger samples are lacking. CONCLUSION: Higher cortisol in dysphoric mania compared to predominantly elated/euphoric mania may indicate a clinical and neurobiological polymorphic phenomenon, potentially involving a higher biological sensitivity to stress in the presence of irritable mood. The present findings highlight the importance to add a dimensional approach to the traditional categorical diagnosis for future neurobiological studies in BD.

Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a prevalent psychiatric disorder of unknown etiology. However, there is some evidence that the immune system may play an important role in its pathogenesis. In the present study, two polymorphisms (rs1800795 and rs361525) in the promoter region of the cytokine tumor necrosis factor-alpha (TNFA) gene were genotyped in 183 OCD patients and in 249 healthy controls. The statistical tests were performed using the PLINK(®) software. We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic χ(2) association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the role of the immune system in its pathogenesis.

Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder / Estudo de associação entre polimorfismos funcionais do gene do TNF-alfa e transtorno obsessivo-compulsivo

Obsessive-compulsive disorder (OCD) is a prevalent psychiatric disorder of unknown etiology. However, there is some evidence that the immune system may play an important role in its pathogenesis. In the present study, two polymorphisms (rs1800795 and rs361525) in the promoter region of the cytokine tumor necrosis factor-alpha (TNFA) gene were genotyped in 183 OCD patients and in 249 healthy controls. The statistical tests were performed using the PLINK® software. We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic χ² association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the role of the immune system in its pathogenesis.

O transtorno obsessivo-compulsivo (TOC) é um quadro psiquiátrico de prevalência considerável na população e de etiologia desconhecida. No entanto, há evidências de que o sistema imunológico pode desempenhar um papel importante em sua patogênese. No presente estudo, dois polimorfismos (rs1800795 e rs361525), localizados na região promotora do gene que codifica a citocina conhecida como fator de necrose tumoral alfa (TNFA), foram genotipados em 183 pacientes com TOC e 249 controles saudáveis. Os testes estatísticos foram realizados utilizando-se o software PLINK®. Assim, evidenciou-se que o alelo A do polimorfismo rs361525 apresentava associação estatisticamente significante com o TOC (p=0,007). A presença de marcadores genéticos, tais como genes que codificam citocinas inflamatórias, associados com TOC, confere suporte adicional ao papel do sistema imunológico na patogênese desse transtorno.

Neuroendocrine and immune contributors to fatigue.

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body's stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF). This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.

Effects of the physical work environment on physiological measures of stress.

AIMS: In this study we investigated the effects of the physical work environment on two physiological measures of the stress response. METHODS AND RESULTS: Circadian variations in vagally mediated heart rate variability (HRV) and the morning rise in cortisol were evaluated in 60 participants working in a government building either in a traditional (individual offices and old cubicles; n=40) or a modern workspace (individualized cubicles with improved views and lighting; n=20). Results revealed significant linear (B=-1.03; confidence interval: -1.05 to -1.01, P<0.05) and quadratic (B=1.001; confidence interval: 1.0004-1.002, P<0.05) trends by office type interactions for indices of vagally mediated HRV. Individuals in the old office space had flatter slopes and thus less circadian variation including less HRV at night, and a larger rise in cortisol upon awakening compared with those in the new office space. CONCLUSION: These results indicate that physical features of the work environment may affect two aspects of the physiological stress response: circadian variations in HRV and the morning rise in cortisol. These findings have important social, economic, and public health implications for work environment risk factors on health.

Evaluation of stress systems by applying noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate variability and salivary cortisol.

The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.

Glucocorticoid dysregulations and their clinical correlates. From receptors to therapeutics.

Clinicians have long known that a substantial proportion of patients treated with high-dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic-pituitary-adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at-risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life-threatening.

Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study.

BACKGROUND: Major depressive disorder (MDD) is inconsistently associated with elevations in proinflammatory cytokines and neuropeptides. We used a skin sweat patch, recently validated in healthy control subjects, and recycling immunoaffinity chromatography to measure neuroimmune biomarkers in patients with MDD mostly in remission. METHODS: We collected blood at 8:00 am and applied skin sweat patches for 24 hours in 21- to 45-year-old premenopausal women (n = 19) with MDD (17/19 in remission) and age-matched healthy controls (n = 17) participating in the POWER (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study. RESULTS: Proinflammatory cytokines, neuropeptide Y, substance P, and calcitonin-gene-related peptide were significantly higher and vasoactive intestinal peptide, a marker of parasympathetic activity, was significantly lower in patients compared to controls, and depressive symptomatology strongly correlated with biomarker levels. All analytes were strongly correlated in the skin sweat patch and plasma in patients (r = .73 to .99; p < .0004). CONCLUSIONS: The skin sweat patch allows detection of disrupted patterns of proinflammatory cytokines and neuropeptides in women with MDD in clinical remission, which could predispose to medical consequences such as cardiovascular disease, osteoporosis, and diabetes. This method permits measurement of cytokines in ambulatory settings where blood collection is not feasible.

Inflammatory aspects of depression.

A bidirectional relation between depression and natural immunity has been identified: depressive episodes are associated to a relative immunodeficiency, conversely inflammatory activity has been implicated in the development of depressive symptoms and in the pathophysiology of depression. Depression has been associated with a decrease in the number and activity of NK lymphocytes and hence patients with depression may show immunodeficiency towards intracellular microorganisms and tumors. Paradoxically, depression is sometimes accompanied by an inflammatory state, developed from the peripheral stimuli (atopy) or central stimuli (chronic stress) and mediated by proinflammatory cytokines (IL-6, TNF and IL-1). These cytokines can play a role in the pathophysiology of depression and of various diseases, supporting the hypothesis that many chronic diseases are individual manifestations of a common proinflammatory denominator.

[Brain-immune interactions and implications in psychiatric disorders]. / Interações imunocerebrais e implicações nos transtornos psiquiátricos.

OBJECTIVE: This review will focus on the role of cytokines in the central nervous system and its implications to depressive disorder. We will then discuss the main findings of cytokine measurements in patients with major depressive disorder. METHOD: We searched Pubmed for studies published from 1999-2007, using the keywords depression and cytokine; and depressive disorder and cytokine. We have focused on pro-inflammatory cytokine measurements in patients with depression syndrome using DSM-criteria. RESULTS: Several lines of evidence suggest that cytokines have effects on depression, such as the induction of sickness behavior; clinical conditions related to cytokines that also overlap depressive symptoms; and immunotherapy that can lead to depressive symptoms attenuated by antidepressant treatment. Finally, patients with depression exhibit increased levels of pro-inflammatory cytokines, although conflicting results have been described. CONCLUSION: Cytokines may play a role in the pathophysiology of some cases of depression, although a causal link has not been established yet. Further longitudinal studies are needed to determine patterns of cytokine in patients with major depressive disorder, taking into account confounding factors closely associated with the activation of pro-inflammatory cytokines. In addition, simultaneous measurements of multiple biomarkers could provide critical insights into mechanisms underlying major depressive disorder and a variety of common cytokine-related diseases.

Interações imunocerebrais e implicações nos transtornos psiquiátricos / Brain-immune interactions and implications in psychiatric disorders

OBJETIVO: Nesta revisão será focado o papel das citocinas no sistema nervoso central e suas implicações para o quadro depressivo. Posteriormente, serão discutidos os principais achados sobre medidas de citocinas em pacientes com depressão maior. MÉTODO: Foi realizada uma pesquisa no Pubmed selecionando estudos entre 1999-2007, utilizando as seguintes palavras-chave: "depression, cytokine"; "depressive disorder, cytokine". Focou-se nos estudos de medidas de citocinas pró-inflamatórias em pacientes com síndrome depressiva que utilizaram critérios DSM. RESULTADOS: Várias linhas de evidência sugerem que as citocinas possam exercer um papel na depressão. Entre elas, destacam-se: citocinas induzindo a "comportamento doentio"; doenças clínicas relacionadas com citocinas também apresentam associação com quadros depressivos; uso de imunoterapia levando ao desenvolvimento de depressão. Além disso, níveis elevados de citocinas pró-inflamatórias em pacientes com depressão foram relatados, apesar de resultados contraditórios. CONCLUSÃO: O papel das citocinas na fisiopatologia em alguns casos de depressão é descrito; porém, uma relação causal não foi ainda estabelecida. Novos estudos são necessários para determinar padrões específicos de citocinas em pacientes com depressão, levando em consideração outros fatores associados à ativação imunológica. Além disso, medidas simultâneas de múltiplos marcadores biológicos podem gerar informações importantes para a compreensão dos mecanismos fisiopatológico da depressão e em doenças relacionadas à produção de citocinas.

OBJECTIVE: This review will focus on the role of cytokines in the central nervous system and its implications to depressive disorder. We will then discuss the main findings of cytokine measurements in patients with major depressive disorder. METHOD: We searched Pubmed for studies published from 1999-2007, using the keywords depression and cytokine; and depressive disorder and cytokine. We have focused on pro-inflammatory cytokine measurements in patients with depression syndrome using DSM-criteria. RESULTS: Several lines of evidence suggest that cytokines have effects on depression, such as the induction of sickness behavior; clinical conditions related to cytokines that also overlap depressive symptoms; and immunotherapy that can lead to depressive symptoms attenuated by antidepressant treatment. Finally, patients with depression exhibit increased levels of pro-inflammatory cytokines, although conflicting results have been described. CONCLUSION: Cytokines may play a role in the pathophysiology of some cases of depression, although a causal link has not been established yet. Further longitudinal studies are needed to determine patterns of cytokine in patients with major depressive disorder, taking into account confounding factors closely associated with the activation of pro-inflammatory cytokines. In addition, simultaneous measurements of multiple biomarkers could provide critical insights into mechanisms underlying major depressive disorder and a variety of common cytokine-related diseases.