The increased cortisol levels with preserved rhythmicity in aging and its relationship with dementia and metabolic syndrome.

BACKGROUND: In the aging process, the cumulative exposure to stress with increased cortisol levels is considered to be associated to the senescence itself and its related disorders. AIMS: To evaluate the role of cortisol in elderly subjects, with or without dementia, by the means of the AGICO study. METHODS: The AGICO study enrolled patients from ten Geriatric Units in Italy in 2012-2017 (Study Director Prof Paolo Falaschi, S. Andrea Hospital of Rome). Every subject received a comprehensive geriatric assessment (including the Mini-Mental State Examination, MMSE), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal). RESULTS: The MMSE was inversely related to the standardized diurnal and nocturnal urinary cortisol levels (p < 0.025 and p < 0.01, respectively) and the age was positively related (p < 0.01 and p < 0.001, respectively). The ratio between the standardized diurnal and nocturnal urinary cortisol levels was 1.50 ± 1.2 (mean ± standard deviation) and it was not modified by the age or dementia. The standardized diurnal and nocturnal urinary cortisol levels were significantly higher in patients with dementia (MMSE < 24) (p < 0.01). In the analysis of the subgroups with MetS, the highest concentrations of diurnal and nocturnal cortisol were found in patients with both dementia and MetS (p < 0.025 and p < 0.01, respectively). DISCUSSION: The AGICO study showed that the stress response significantly and progressively increases with age. CONCLUSION: The cortisol increase in aging is related to the presence of both dementia and metabolic syndrome.

Sleep quality as predictor of BMI in non-depressed caregivers of people with dementia.

PURPOSE: Although most cross-sectional and longitudinal studies of children and adolescents have found a link between short duration of sleep and obesity, the literature related to adults provides a non-consensual framework. The aim of the present study was to examine the association between sleep quality and BMI in a population of caregivers looking after people suffering from dementia, with a view to identifying the moderating role of depressive symptoms in the relationship between sleep problems and BMI. METHODS: A total of 117 subjects took part in the study, filling in a Sociodemographic Questionnaire, the Pittsburgh Sleep Quality Index, the Eating behavior Questionnaire and The Center for Epidemiologic Studies-Depression. RESULTS: Depressive symptoms were greater in females than in males. The sample was divided into two subgroups based on depressive-symptom scores. Only within the subsample with low depressive symptoms, higher sleep disturbances influenced BMI positively. Within this subsample of participants with low depressive symptoms, the variables that seem to play a pivotal role in explaining a high BMI are: female gender, sleep problems, and diet quality, while within the subsample with high depressive symptoms only the female gender factor was found to influence BMI. CONCLUSIONS: Depressive symptoms seem to act as moderators in the relationship between sleep and BMI. They should be evaluated to identify the risk of high BMI, and to differentiate clinical intervention, at least in this population, which experiences the stress of caregiving chronically, though not suffering from clinical eating disorders. LEVEL OF EVIDENCE: Level II, cross-sectional study.

Is poor sleep associated with obesity in older adults? A narrative review of the literature.

INTRODUCTION: To address the worldwide epidemic of obesity, a sizable literature implicates sleep problems in the onset of obesity in younger populations. However, less is known about how this process may operate among older adults, which is of concern, given demographic shifts that have resulted in a much higher proportion of developed nations around the world reaching late life. METHODS: We offer a current review of the literature studying older adults and examining associations between sleep quality and obesity in this population. We consider both subjective and objectively measured sleep as well as both cross-sectional and longitudinal studies offering stronger causal inference. RESULTS: We discuss seemingly contradictory literature showing that shorter sleep duration as well as longer sleep duration are associated with obesity risk, then review studies that tested for non-linear relationships and reported a U-shape pattern, suggesting that too much or too little sleep is detrimental. Besides sleep duration, we discuss evidence showing that other forms of sleep dysfunction related to night-time awakenings, REM sleep, slow-wave sleep, and daytime sleepiness, which are indicators of sleep quality, are also linked to obesity. Specific psychological and physiological mediators and moderators, suggesting possible mechanisms whereby sleep problems may affect obesity in older adults, are described. CONCLUSION: We conclude by discussing areas, where additional research could help clarify this association, considering such factors as medical comorbidities common in late life, and health-related behaviors that may stem from poor sleep (such as disordered eating behavior). Such insights will have great value for clinical practice. LEVEL OF EVIDENCE: Level V, narrative review.

[Mobbing: ten-year evaluation experience in a University Hospital]. / Mobbing: esperienza decennale di valutazione in un Policlinico Universitario.

OBJECTIVES: Bullying is a manifestation of occupational stress and can therefore be considered as a real "organizational pathology." Include the activities of the surgery dedicated to Mobbing, Unit of Occupational Medicine Sant'Andrea Hospital, which began operations in June 2001. METHODS: In over ten years of operation (July 2012), the sample, consisting of 50.7% for men and 49.3% women, is heterogeneous in age. The schooling of the sample is medium-high as more than 82% have higher education level. The business sector is the service sector accounted for most (84%) than in industry (9%) and agriculture (2%). RESULTS: Of the 1545 patients seen, 1320 completed the diagnostic path, while 225 have stopped. 814 users have been certified for compatibility bullying (63% of cases) with a net reduction of the awards from 2007 onwards. CONCLUSIONS: Considerations are expressed about the possible intervention strategies: the presence of dedicated experts at the counters of listening and professionals as the trusted advisor, to which workers in distress can call on for advice and guidance on how to defend itself from, in accordance with the implemented for years at the Ministry of Health, the establishment of such figures as the manager rehability that in other European countries, are scheduled for some time in work organization.

Recent advances in the role of cortisol and metabolic syndrome in age-related degenerative diseases.

The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11ß-hydroxysteroid dehydrogenase type 1, 11ß-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11ß-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).

Effects of escitalopram on serum BDNF levels in elderly patients with depression: a preliminary report.

BACKGROUND AND AIMS: Increasing evidence in the literature suggests a link between the brain-derived neurotrophic factor (BDNF) system and adult depression, supporting a role in the pathophysiology of the disease and response to therapy. Few studies have reported BDNF serum levels in elderly depressed subjects and their relationship with antidepressant therapy. The aim of the study was to evaluate BDNF serum levels in naive elderly depressed patients, before and after antidepressant treatment. METHODS: We enrolled n = 5 elderly naive patients affected by depression, according to the Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision criteria for major depressive episode. BDNF serum levels were evaluated through ELISA method. Cognitive functions were examined by Mini Mental State Examination (MMSE) and severity of depression was assessed by Geriatric Depression Scale (GDS). BDNF levels were measured at baseline (T0) and after 2 months (T2) of escitalopram. Ten healthy elderly subjects were enrolled as a control group. RESULTS: The serum BDNF levels in patients (T0) and controls were 11.5 ± 0.6 and 13.6 ± 3.4 ng/ml (m ± SD), respectively. At T2, the patients showed a significant improvement of depressive symptoms (p < 0.05), with a not significant increase of MMSE. The serum BDNF concentrations increased to 16.0 ± 2.7 ng/ml at T2 (p < 0.05), beyond the levels of BDNF in controls. The increase in BDNF levels was significantly related to the improvement in GDS scores of the patients (r = 0.9, p < 0.05). CONCLUSIONS: Serum BDNF levels may be considered as a marker of response to antidepressant treatment for depression in the elderly.

Guidelines for the management of osteoporosis and fragility fractures.

The purpose of this document, a result of the harmonisation and revision of Guidelines published separately by the SIMFER, SIOMMMS/SIR, and SIOT associations, is to provide practical indications based on specific levels of evidence and various grades of recommendations, drawn from available literature, for the management of osteoporosis and for the diagnosis, prevention, and treatment of fragility fractures. These indications were discussed and formally approved by the delegates of the Italian Scientific Associations involved in the project (SIE, SIGG, SIMFER, SIMG, SIMI, SIOMMMS, SIR, and SIOT).

Inverse correlation between morning plasma cortisol levels and MMPI psychasthenia and depression scale scores in victims of mobbing with adjustment disorders.

OBJECTIVES: Evidence in the literature suggests stress-related changes of hypothalamus-pituitary-adrenal (HPA) axis in mobbing. We investigated the association between HPA activity and psychological profiles in mobbing, using a multidisciplinary approach. DESIGN: Forty-eight victims of mobbing were evaluated by a working group of the Departments of Occupational Medicine, Psychiatry and Internal Medicine. After an informed consent, a detailed occupational history, a psychiatric interview with Minnesota Multiphasic Personality Inventory 2 (MMPI-2) administration and a blood sample (8:00 AM) for the determination of basal adrenocorticotropin (ACTH), cortisol and dehydroepiandrosterone sulphate (DHEAS) plasma levels were collected. Twenty-six patients received an overnight dexamethasone (dex) test. RESULTS: Mean ACTH, cortisol and DHEAS levels were within normal ranges. The dex-test response was normal, with a significant hormone suppression (ACTH p<0.001, cortisol p<0.001, DHEAS p<0.001). The correlations between basal hormones and the psychometric scales of MMPI-2 revealed that cortisol was significantly and negatively related to Psychasthenia (Pt, p=0.003) and Depression (D, p=0.006), while DHEAS showed a significant negative correlation to Hysteria (Hy, p=0.008). Basal ACTH levels were not significantly related to psychometric scales. CONCLUSION: A significant inverse correlation between morning plasma cortisol levels and psychometric parameters in victims of mobbing with adjustment disorders was observed. A larger group of patients is necessary to identify and validate a cut-off cortisol level that may become an innovative biological parameter for the diagnosis and follow-up in victims of mobbing.

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment.

The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential cross-reaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.

Association between human leukocyte antigen (HLA) and interferon- induced thyroid diseases in four patients with HCV-related chronic hepatitis.

OBJECTIVES: The interferon-alpha (IFN-alpha) therapy for HCV hepatitis may exacerbate or induce underlying thyroid disorders. Besides viral factors, the human leukocyte antigen (HLA) may be an independent risk factor. METHODS: We evaluated fifteen patients with HCV chronic hepatitis during a period of 40 months. At the enrollment, all the patients were negative for thyroid disorders, excluding one patient with subclinical hypothyroidism. Eleven patients received IFN-alpha therapy. The HLA system was examined in every patient, evaluating antigens (n=40) of locus A, B and Cw and alleles (n=19) of locus DRB1* and DQB1*. The HLA system was also examined in healthy subjects (n=107) as a control group. RESULTS: The HCV genotype distribution in patients was: 1b=20%, 2a=60%, 3a=20%. Four IFN-treated patients presented clinical thyroid disorders, including autoimmune hypothyroidism (n=2), transient thyrotoxicosis (n=1) and subacute thyroiditis (n=1). The HLA susceptibility to thyroid disorders (antigen/allele frequency) in the whole group of patients was not different in respect to controls and normal Italian population. The patients with HCV chronic hepatitis that developed thyroid diseases after IFN- treatment had a double and specific association with the HLA system (Mantel-Haenszel X(c)(2)=4.706, p<0.05). CONCLUSIONS: This case report suggests that HLA system examination is an important and promising diagnostic aspect that may be considered in order to evaluate the appearance of thyroid disorders during the IFN-alpha treatment for HCV-related chronic hepatitis.

The Prevention and Treatment of Delirium in Elderly Patients Following Hip Fracture Surgery.

Osteoporotic hip fracture needs a specific approach and treatment, since elderly patients are at high risk for adverse outcomes after surgery. In particular, delirium often occurs in the peri-operative period, and it is associated with death, hospital-acquired complications, persistent cognitive impairments, poor functional recovery after surgery and increased healthcare costs. The pre-operative assessment of the risk factors for delirium improves the preventive measures. The delirium diagnostic tools should be included in the standard of orthogeriatric cure for hip fracture. Given the increasing complexity of the clinical pictures, we present a review of the available treatment options for delirium in patients with hip fracture. The metabolic pre-operative disorders and the management of co-morbid diseases are specific targets of treatment in order to optimize the outcomes after surgery. In particular, elderly patients with Alzheimer's disease are highly vulnerable to hip fracture and delirium, and they are severely frail with reduced physiologic reserves. An integrated approach combining environmental and pharmacological strategies is useful in the delirium treatment, with a close collaboration between the orthopedic and geriatric team.

Tighter glycemic control is associated with ADL physical dependency losses in older patients using sulfonylureas or mitiglinides: Results from the DIMORA study.

BACKGROUND: There is growing evidence that tight glycemic control may be more harmful than beneficial in older persons with Type 2 diabetes (T2DM). It remains controversial if tight glycemic control (lower glycated hemoglobin A1c (A1c)) is associated with functional impairments in older frail patients with T2DM. We explored associations between A1c and losses in Activities of Daily Living (ADLs) in diabetic nursing home (NH) patients and tested for differences according to anti-diabetic treatment: diet, anti-diabetic oral drug (AOD), insulin, combined insulin+AOD. METHODS: We conducted a cross-sectional study on 1845 older NH patients with T2DM from 150 sites across Italy. Complete evaluations on ADLs, glycemic control, anti-diabetic treatments, comorbidities, and clinical data were recorded. ANOVA was applied to compare clinical characteristics across A1c tertiles. Multivariate regression models evaluated associations between A1c and ADL losses. RESULTS: Patients had a mean age [SD]=82 [8] years; BMI=25.5 kg/m(2) [4.7]; Fasting Plasma Glucose (FPG)=7.4 [3.0] mmol/l; Post-prandial glucose (PPG)=10.3 [3.6] mmol/l; A1c=7.0% (54 mmol/mol), ADL losses=3.7 [1.8]. Compared to higher A1c tertiles, patients in the lower tertile had greater ADL losses, were more likely to use AODs, while less likely to use insulin or insulin+AOD. After adjusting for multiple confounders, impairments in ADLs were associated with tighter A1c levels (B=-0.014; p=0.002). Regression models according to anti-diabetic treatment showed that tighter A1c levels continued as independent determinants of ADL losses in patients using AODs (B=-0.023; p=0.001), particularly in those using sulfonylureas (B=-0.043; p<0.001) or mitiglinides (B=-0.044; p=0.050). CONCLUSIONS: Tighter glycemic control was associated with ADL physical dependency losses, especially in those using sulfonylureas and mitiglinides.

Increased serum concentration of nerve growth factor in patients with microprolactinoma.

Nerve growth factor (NGF) is known to play a role as a circulating neurokine, integrating signals from the neuro-immuno-endocrine system. The ability of NGF to activate the pituitary-adrenocortical axis, together with the increase of its serum concentration in pregnancy and lactation, supports the hypothesis that NGF is secreted by the pituitary gland and plays a role as modulator of endocrine functions. Evidence obtained both in vitro and in vivo in experimental animal models suggests that lactotroph cells secrete both prolactin (PRL) and NGF. Furthermore, in previous studies we demonstrate that cell lines derived from dopamine (DA)-sensitive human prolactinomas express high levels of NGF messenger RNA and protein. On these basis, we studied serum NGF concentrations in female patients with microprolactinoma (n = 4) and in control women (n = 5). PRL and NGF were measured at the diagnosis, during the thyrotropin releasing hormone (TRH) test and after the therapy with DA D2 receptor agonist cabergoline (0.25 mg, twice a week). Results obtained suggested that hyperprolactinemia (70.3+/-8.4 ng/ml) paralleled markedly higher NGF levels (58.4+/-18.7 pg/ml) compared to controls (PRL 8.7+/-3.2 ng/ml, NGF 8.4+/-1.3 pg/ml). Serum concentrations of NGF and PRL during the TRH test were closely associated (r = 0.943, p < 0.01). Cabergoline therapy normalized PRL (7.9+/-3.6 ng/ml) and induced a significant decrease of NGF levels (12.5+/-4.9 pg/ml). In conclusions, data reported here indicated that, in human microprolactinomas, NGF is released in the bloodstream paralleling PRL-secretion and it is modulated by a neurotransmitter-regulated mechanism, since the normalization of PRL elicited by the DA D2 receptor agonist cabergoline induced a significant decrease of serum NGF as well.

The hypothalamic-pituitary-thyroid axis in subjects with subclinical thyroid diseases: the impact of the negative feedback mechanism.

OBJECTIVE: To evaluate the hypothalamus-pituitary-thyroid (HPT) axis in patients with subclinical thyroid dysfunction recently reported to have either symptoms or organ involvements with potential morbidity, in order to better differentiate these patients with respect to controls. PATIENTS: Sixtythree patients with subclinical hyperthyroidism (HyperT), 178 normal subjects (EuT) and 106 patients with subclinical hypothyroidism (HypoT) were enrolled; the groups presented normal thyroid hormone (FT4, FT3) levels and, respectively, reduced (HyperT), normal (EuT) and increased (HypoT) TSH levels. The negative feedback was simultaneously evaluated by multiple linear regression. RESULTS: The mean TSH, FT4 and FT3 levels were significantly different in the three groups. The negative correlation between thyroid hormones (FT4 and FT3) and TSH secretion was significant (p<0.001 in HyperT; p<0.01 in EuT; p<0.000001 in HypoT group). FT4 mostly contributed to the negative correlation with TSH. The normal ranges of TSH values was accurately defined on the basis of the regression equation in the EuT group, due to the combining influence of both thyroid hormones (FT3 and FT4). No patient of the HyperT or HypoT group fell inside the range of estimated values of the normal group. CONCLUSIONS: The HPT axis in patients with subclinical hyper- and hypo-thyroidism is significantly modified with respect to normal subjects. The status of the axis, as evaluated by the relationship between the three hormones (FT4, FT3, TSH) together considered, is characteristic of the normal or pathologic condition. A reliable method based on the regression analysis is proposed to correctly evaluate the status of the HPT axis.

Effects of mental stress on cardiovascular and endocrine response in Air Force Academy cadets.

OBJECTIVES: Pilots are exposed to the "stress of flight" and the chronically activated stress response may play an important role in circulatory system disease progression. We studied the effect of an experimental mental stress on cardiovascular and neuroendocrine activity, in Air Force Academy cadets, before and after one month intensive course. DESIGN: Nine cadets were submitted to a psychometric evaluation before Stroop test (ST), including Minnesota Multiphasic Personality Inventory, State and Trait Anxiety Inventory (STAI X1 and X2 form) and Reaction Scheme Test. After ST, subjects completed a STAI X1 form. Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) were monitored and serum prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH) and cortisol levels were determined, during ST. The protocol was repeated at the end of the course. RESULTS: No significant differences were evident in PRL, GH and ACTH levels. Cortisol concentrations were significantly higher before the course. ST did not modify hormone secretion. ST induced a significant and reproducible elevation of HR and SBP. Basal HR, SBP and DBP values were significantly elevated after the course. Two subjects presented a particular psychometric profile, a different cardiovascular response to ST and did not pass the course. CONCLUSIONS: acute mental stress significantly activated cardiovascular response without modifying endocrine responses, in relation to the psychological profiles. A significant increase of cardiovascular parameters was present after the course, with enhanced dichotomy between the endocrine and sympathetic system, suggesting a careful evaluation and follow-up for circulatory system diseases in cadets.

Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus.

Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6-phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported.

Treatment of insulin resistance in the neurodegeneration.

The association between diabetes and neurodegenerative diseases is increasing with aging. Several common mechanisms are involved in both these diseases. The endothelial cells of the blood brain barrier, neurons and glia express typical and different receptors of the glucose metabolism (glucose transporters, insulin receptors and glucagon-like peptide-1 receptors). The impairment in insulin signaling leads to an impairment of neuronal function and increases neurodegeneration, and, conversely, neurodegeneration causes a reduction of insulin signaling on neurons. Increased detailed knowledge of common physiological processes opens up the opportunities for developing new treatments that may prevent or reduce the onset of neurodegenerative diseases. The aim of the review is to discuss the potential neuroprotective effects of the antidiabetic drugs. The article presents some promising patents on the treatment of insulin resistance in the neurodegeneration.

Targets of anti-glucocorticoid therapy for stress-related diseases.

The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the hypothalamus-pituitary-adrenal (HPA) axis. Dysregulation in HPA activity (central and peripheral) has been reported in chronic diseases, like metabolic syndrome, type-2 diabetes mellitus, atherosclerosis-related disease, essential hypertension, dementia, depression, particularly during comorbid conditions. Different targets of anti-glucocorticoid treatment have been proposed, acting at supra-hypothalamic, HPA axis, glucocorticoid receptor and post-receptor levels. The recent promising patents on the therapy against glucocorticoid-mediated damage will be presented and discussed.