Psychological Alterations in Youths with Type I Diabetes: Associations with Salivary Cortisol Concentration.

Background and Objectives: Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children and adolescents, and is associated with stress and other psychological alterations. This study aims to assess psychological and sleep disorders and health-related quality of life in young people with T1DM and to determine the relationship between these parameters and levels of salivary cortisol, a hormone widely associated with stress and several psychological symptoms. Materials and Methods: In our cross-sectional study performed in 60 Moroccan children and adolescents with T1DM, detailed psychological evaluations were performed to assess symptoms of anxiety, attention-deficit hyperactivity disorder (ADHD), sleep quality and diabetes-specific quality of life (using the RCMAS-2, ADHD rating scale, Pittsburgh scale and the DQoL scale, respectively), and cortisol concentration was measured from saliva samples taken mid-morning. Results: A total of 60 children and adolescents with T1DM were recruited. The mean age was 11.05 ± 0.35 (6-17). The mean salivary cortisol level in ng/mL was 4.7 ± 0.49 (0.7-20.2) and was significantly associated with an anxiety RCMAS2 score for the Worry subdomain and DQoL subdomain "Anxiety". Linear regression analysis showed that salivary cortisol was significantly higher in girls compared to boys (p = 0.004) (beta coefficient: 3.384 CI95%: 1.137-5.630) and with Hb1AC level as a continuous variable (p = 0.0001) (beta coefficient: 1.135 CI95%: 0.509-1.760). The other variables included in the model were not significant (p > 0.05). There was an association between salivary cortisol concentration with anxiety RCMAS2 score for Worry subdomain and QoL sub-domain "Anxiety". Still, a significant (p = 0.018) association emerged for anxiety RCMAS2 score Worry subdomain and QoL anxiety subdomain (p = 0.044). Conclusions: Children and adolescents with T1DM experienced significantly elevated symptoms of anxiety and sleep disturbances, particularly in girls, and frequent symptoms of ADHD, particularly in boys. Salivary cortisol concentration collected in the morning is associated with anxiety burden but not with other psychological alterations. Further studies are needed to clarify the associations between salivary cortisol concentration and anxiety in type 1 diabetes in order to propose the hormone as a biomarker for interventions aimed to reduce anxiety levels in these patients.

The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients.

BACKGROUND: Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. METHODS: PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. RESULTS: In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. CONCLUSIONS: These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response.

Impaired release of corticosterone from adrenals contributes to impairment of circadian rhythms of activity in hyperammonemic rats.

Patients with liver cirrhosis may present impaired sleep-wake and circadian rhythms, relative adrenal insufficiency and altered hypothalamus-pituitary-adrenal gland (HPA) axis. The underlying mechanisms remain unclear. Circadian rhythms are modulated by corticosteroids which secretion is regulated by HPA axis. Hyperammonemia alters circadian rhythms of activity and corticosterone in rats. The aims were: (1) assessing whether corticosterone alterations are responsible for altered circadian rhythm in hyperammonemia: (2) to shed light on the mechanism by which corticosterone circadian rhythm is altered in hyperammonemia. The effects of daily corticosterone injection at ZT10 on circadian rhythms of activity, plasma corticosterone, adreno-corticotropic hormone (ACTH) and hypothalamic corticotropic releasing hormone (CRH) were assessed in control and hyperammonemic rats. ACTH-induced corticosterone release was analyzed in cultured adrenal cells. Corticosterone injection restores the corticosterone peak in hyperammonemic rats and their activity and circadian rhythm. Plasma ACTH and CRH in hypothalamus are increased in hyperammonemic rats. Corticosterone injection normalizes ACTH. Chronic hyperammonemia impairs adrenal function, reduces corticosterone content and ACTH-induced corticosterone release in adrenals, leading to reduced feedback modulation of HPA axis by corticosterone which contributes to impair circadian rhythms of activity. Impaired circadian rhythms and motor activity may be corrected in hyperammonemia and hepatic encephalopathy by corticosterone treatment.

Hair Cortisol Concentration as a Biomarker of Symptoms of Depression in the Perinatal Period.

Pregnancy is a sensitive period when women experience major hormonal and psychological changes. A high prevalence of the symptoms of depression and manifested major depression rates have been reported during this period, leading to negative outcomes both for mothers and the offspring. Despite its prevalence, the aetiology of depression is not yet fully understood. Nonetheless, alterations in cortisol levels have been proposed as a reliable biomarker to identify pregnant women at risk of perinatal depression. Hair cortisol has recently been extensively used in bio-psychological studies as a suitable non-invasive biomarker for several neuropsychiatric disorders. Various studies have published evidence regarding the relationship between cortisol fluctuations during the perinatal period, measured both in hair and in other substrates, and the onset of perinatal symptoms of depression. This current review provides an overview of cortisol level changes measured in women's hair during pregnancy or the postpartum period and its association with perinatal symptoms of depression. Further studies, including repetitive measurement of both hair cortisol and depression throughout the prenatal period, must be performed to clarify the relationship between cortisol levels and perinatal symptoms of depression.

Hair cortisol concentration associates with insomnia and stress symptoms in breast cancer survivors.

Stress, depressive symptoms and sleep quality are important and modifiable determinant of health and their association with hair cortisol concentrations (HCC) in breast cancer survivors has not been evaluated. We selected a random sample of 65 participants (mean age 57.9 years old, range 44-75 years) recruited from local patients' associations of breast cancer survivors. Each provided a hair sample at enrollment and basic clinical data and psychological evaluation regarding self-perceived stress (PSS-scale), depressive (GDS scale) and insomnia symptoms (Athens scale). We observed a direct and significant (p = 0.001) association between HCC and stress-levels. Depressive symptoms associated significantly (p < 0.01) with stress levels but not with HCC. There were also a significant and direct correlation between hair cortisol concentration and totals core of insomnia symptoms (p = 0.002), and the subdimension of sleep difficulty symptoms (p = 0.002), and with daytime sleepiness symptoms (p = 0.016). Further investigations into the association between stress and insomnia and changes in HCC in breast cancer survivors are warranted in order to validate this biomarker for diagnosis of psychological alterations and to tailor the effects of interventions aimed to reduced stress and improve sleep quality in these women.

Hair Cortisol Concentration as a Biomarker of Sleep Quality and Related Disorders.

Cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and its production is increased mainly in stressful situations or in chronic disorders accompanied by stress enhancement. Altered cortisol concentrations have been reported in a number of neuropsychiatric diseases and sleep disorders. Cortisol concentrations have been measured using several methods, and in several matrixes, such as blood, saliva, and urine. However, lately, hair cortisol, for several reasons, has emerged as a promising biomarker of long-term retrospective HPA activation. Several experimental approaches for cortisol measurement with the corresponding concentration reference ranges and a summary of findings from scientific literature on this field are presented. There is evidence of a close relationship between HPA functional alteration and the development of neuropsychiatric disorders. Sleep disorders are the most common manifestation in several neuropsychiatric conditions, and have also been associated to cortisol alterations in both adults and children. Many studies indicate that hair cortisol constitutes a valuable tool for further contributing to existing data on salivary, plasma, or urinary cortisol concentrations in patients with sleep disorders.

Circadian Rhythm and Concentration of Melatonin in Breast Cancer Patients.

BACKGROUND: Melatonin is a biomarker of the central circadian clock and its chronobiotic actions entraining circadian rhythms to the light-dark cycle are well known. Reduction in melatonin levels and altered circadian rhythms have been associated with a high risk of breast cancer. Melatonin has also been shown to display anti-proliferative effects on breast cancer growth and proliferation. Evaluation of melatonin circadian rhythm alterations in patients bearing breast cancer may have interesting prognostic and therapeutic applications. OBJECTIVE: To review studies evaluating the circadian rhythm of melatonin in breast cancer patients. The effects of surgery and chemotherapy on melatonin secretion were also reviewed. METHODS: Electronic databases, including PubMed/MEDLINE and Scopus, were searched from their inception to May 2020, using the keywords "Melatonin", "Circadian rhythm" and "Breast cancer". RESULTS: Patients with breast cancer maintain a circadian rhythm of melatonin secretion with relatively high levels during the night and low levels during the day, however, a reduction in nocturnal melatonin peak and decreased amplitude of melatonin circadian rhythms in these patients have also been reported. Melatonin levels can influence estrogen receptor concentrations in hormone-dependent estrogen- positive breast cancer. Chemotherapy alters melatonin levels and breast surgery tends to alter melatonin secretion at first-day post-operation. Melatonin levels correlate with clinical and psychological symptoms of breast cancer, such as sleep quality and depression severity. CONCLUSION: Circadian rhythm and the concentration of melatonin in the blood are altered in patients with breast cancers, and it can modify not only the sleep-wake cycle and, thus, patients' quality of life but due to melatonin's antioxidant effects, the effect of therapies can be modulated. Due to the heterogonous protocols used to assess melatonin and variable environmental factors during sampling, further studies need to control, such variables in order to tailor clinical trials based on melatonin rhythm adjustment and/or supplementation in breast cancer patients.

Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum.

Reduced function of the glutamate--nitric oxide (NO)--cGMP pathway is responsible for some cognitive alterations in rats with hyperammonemia and hepatic encephalopathy. Hyperammonemia impairs the pathway in cerebellum by increasing neuronal nitric oxide synthase (nNOS) phosphorylation in Ser847 by calcium-calmodulin-dependent protein kinase II (CaMKII), reducing nNOS activity, and by reducing nNOS amount in synaptic membranes, which reduces its activation following NMDA receptors activation. The reason for increased CaMKII activity in hyperammonemia remains unknown. We hypothesized that it would be as a result of increased tonic activation of NMDA receptors. The aims of this work were to assess: (i) whether tonic NMDA activation receptors is increased in cerebellum in chronic hyperammonemia in vivo; and (ii) whether this tonic activation is responsible for increased CaMKII activity and reduced activity of nNOS and of the glutamate--NO--cGMP pathway. Blocking NMDA receptors with MK-801 increases cGMP and NO metabolites in cerebellum in vivo and in slices from hyperammonemic rats. This is because of reduced phosphorylation and activity of CaMKII, leading to normalization of nNOS phosphorylation and activity. MK-801 also increases nNOS in synaptic membranes and reduces it in cytosol. This indicates that hyperammonemia increases tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate--NO--cGMP pathway.

Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.

Patients with liver cirrhosis may present hepatic encephalopathy with a wide range of neurological disturbances and alterations in sleep quality and in the sleep-wake circadian rhythm. Hyperammonemia is a main contributor to the neurological alterations in hepatic encephalopathy. We have assessed, in an animal model of chronic hyperammonemia without liver failure, the effects of hyperammonemia per se on the circadian rhythms of motor activity, temperature, and plasma levels of adrenal corticosteroid hormones. Chronic hyperammonemia alters the circadian rhythms of locomotor activity and of cortisol and corticosterone levels in blood. Different types of motor activity are affected differentially. Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly ambulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammonemia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammonemia abolished completely the circadian rhythm of corticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in control rats at the start of the dark period. The data reported show that chronic hyperammonemia, similar to that present in patients with liver cirrhosis, alters the circadian rhythms of corticosteroid hormones and of motor activity. This suggests that hyperammonemia would be a relevant contributor to the alterations in corticosteroid hormones and in circadian rhythms in patients with liver cirrhosis.

Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.