Aberrant early in life stimulation of the stress-response system affects emotional contagion and oxytocin regulation in adult male mice

Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to mental illness later in life. Besides genetic predisposition, also environmental factors play a pivotal role in this process, through embodiment of the mother’s emotions, or via nutrients and hormones transferred through the placenta and the maternal milk. The aim of the current translational study was to mimic a severe stress condition by exposing female CD-1 mouse dams to abnormal levels of corticosterone (80 µg/mL) in the drinking water either during the last week of pregnancy (PreCORT) or the first one of lactation (PostCORT), compared to an Animal Facility Rearing (AFR) control group. When tested as adults, male mice from PostCORT offspring and somewhat less the PreCORT mice exhibited a markedly increased corticosterone response to acute restraint stress, compared to perinatal AFR controls. Aberrant persistence of adolescence-typical increased interest towards novel social stimuli and somewhat deficient emotional contagion also characterised profiles in both perinatal-CORT groups. Intranasal oxytocin (0 or 20.0 µg/kg) generally managed to reduce the stress response and restore a regular behavioural phenotype. Alterations in density of glucocorticoid and mineralocorticoid receptors, oxytocin and µ- and κ-opioid receptors were found. Changes differed as a function of brain areas and the specific age window of perinatal aberrant stimulation of the HPA axis. Present results provided experimental evidence in a translational mouse model that precocious adversity represents a risk factor predisposing to the development of psychopathological behaviour

Diagnostic predictors of immunotherapy response in head and neck squamous cell carcinoma

Programmed cell death ligand-1 (PD-L1) binds PD-1 on CD8+ lymphocytes, inhibiting their cytotoxic action. Its aberrant expression by head and neck squamous cell carcinoma (HNSCC) cells leads to immune escape. Pembrolizumab and nivolumab, two humanized monoclonal antibodies against PD-1, have been approved in HNSCC treatment, but similar to 60% of patients with recurrent or metastatic HNSCC fail to respond to immunotherapy and only 20 to 30% of treated patients have long-term benefits. The purpose of this review is to analyze all the fragmentary evidence present in the literature to identify what future diagnostic markers could be useful for predicting, together with PD-L1 CPS, the response to immunotherapy and its durability. We searched PubMed, Embase, and the Cochrane Register of Controlled Trials and we summarize the evidence collected in this review. We confirmed that PD-L1 CPS is a predictor of response to immunotherapy, but it should be measured across multiple biopsies and repeatedly over time. PD-L2, IFN-gamma, EGFR, VEGF, TGF-beta, TMB, blood TMB, CD73, TILs, alternative splicing, tumor microenvironment, and some macroscopic and radiological features are promising predictors worthy of further studies. Studies comparing predictors appear to give greater potency to TMB and CXCR9

Involvement of Bradykinin Receptor 2 in Nerve Growth Factor Neuroprotective Activity

Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer's disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells

Brainstem expression of SLC6A4, HTR2C, NGF, BDNF, TRKANGF, TRKBBDNF and P75NTR following paternal alcohol exposure in the male mouse

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Acute alcohol intoxication: a clinical overview

Alcohol is a legal and yet detrimental psychoactive substance, capable of establishing addiction and impacting the physical, mental, social, and economic health of people. Alcohol intake causes a large variety of tissue damages severely impacting the nervous system, digestive and cardiovascular systems and causing oral cavity, oropharyngeal, hypopharyngeal, esophageal, colon-rectal, laryngeal, liver and intrahepatic bile duct, and breast cancers. Alcohol can also play a role in the pathogenesis of diabetes mellitus, cardiomyopathy and hemorrhagic strokes. When drunk during pregnancy it is proved to be responsible for serious damage to fetuses causing a wide range of pathological conditions from miscarriage to Fetal Alcoholic Spectrum Disorder (FASD). Acute ethanol intoxication happens when the amount of alcohol consumed is greater than the disposal capacity of the liver, causing an accumulation of its metabolites displayed by initial dysphoria and disinhibition. Nausea, vomiting, memory loss could happen. Although, it can lead to more serious conditions like impaired speaking, impaired coordination, unstable gait, nystagmus, stupor, or coma. Respiratory depression and death could also happen in such cases. Unfortunately, diagnosis of acute alcohol intoxication is difficult because most of the drinkers deny or minimize their assumption. It is dramatically important to assess when the last intake happened to avoid withdrawal syndrome. Alcohol acute intoxication can be considered a serious harm to health and a relevant issue for healthcare provid-ers working in emergency rooms. Differential diagnosis is crucial to avoid serious outcomes. There is no consensus about therapies for acute intoxication, but supportive and symptomatic treatments were proved effective. The repercussions of alcohol misuse over drinkers' social, familiar, economical and working life enhance the importance of a multidisciplinary approach in such cases

Molecular pathology, oxidative stress, and biomarkers in obstructive sleep apnea

Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions

Ética de los agentes políticos

Concebido como instrumento de reflexión más que como «código de ética», el presente trabajo, realizado por un grupo de profesores de la Universidad Católica, se propone ofrecer criterios de discernimiento ético-político a los ciudadanos, en particular a los agentes políticos, los agentes de los medios de comunicación y los jóvenes. Las reflexiones están formuladas como patrones de conducta que se ordenan en torno a cuatro grandes desafíos: la verdad, la participación, la justicia y la espiritualidad

Oxidative stress inhibition by resveratrol in alcohol dependent mice

Objective uncontrolled ingestion of alcohol has dramatic consequences on the entire organism also associated with the oxidation process induced by alcohol by elevating radical oxygen species (ROS). Resveratrol, a non-flavonoid phenol, shows well-documented antioxidant properties. We investigated the potential antioxidant ability of this natural compound in a mouse model of alcohol addiction. Methods we administered (per os) for two months 10 mg/kg/day of resveratrol in alcoholic adult male mice. Oxidative stress was evaluated by measuring serum free oxygen radicals defense (FORD) and free oxygen radicals (FORT) levels. Resveratrol metabolites were measured in the serum of mice administered with resveratrol. Finally, the effect of resveratrol on alcohol-induced alteration of BDNF in the liver was investigated. Results prolonged consumption of resveratrol strongly counteracts serum ROS formation caused by chronic alcohol intake, without effects on natural, free oxygen radical defense. The presence of resveratrol metabolites only in the serum of animals supplemented with resveratrol potentiates the evidence that the antioxidant effect observed is due to the ingestion of the natural compound. Moreover, resveratrol supplementation can counteract alcohol-induced BDNF elevation in the liver, the main target of organ alcohol-induced damage. Conclusion the consumption of resveratrol through metabolite formation may play a protective role, by decreasing free radical formation, and by modulating BDNF involved in hepatic disruption induced by chronic alcohol consumption. Further investigation about the mechanism underlying the protective effect could reinforce the potential use of resveratrol as a dietary supplement to prevent damage associated with chronic alcohol abuse

Depression as a determinant of frailty in late life

Objectives Accumulating evidence shows depression as a risk factor for frailty, but studies are mainly population-based and widely differ in their assessment of either depression or frailty. We investigated the association between depression and frailty among geriatric outpatients using different assessment instruments for both conditions. Method Among 315 geriatric outpatients (mean age 72.1 years, 68.3% female sex) participating the MiMiCS-FRAIL cohort study, major and subthreshold depression were measured with psychiatric diagnostic interview according to DSM-5 criteria (SCID-5) as well as with instruments to screen and measure severity of depressive symptoms (GDS-15 and PHQ-9). Frailty was assessed according to a screening instrument (FRAIL-BR) and a multidimensional Frailty Index (FI-36 items). Multiple logistic and linear regression were performed to assess the association between depression (independent variable) and frailty (dependent variable) adjusted for confounders. Results Frailty prevalence in patients with no, subthreshold or major depressive disorder increases from either 14.5%, 46.5% to 65.1% when using the FRAIL-BR questionnaire, and from 10.2%, 20.9%, to 30.2% when using the FI-36 index. These association remain nearly the same when adjusted for covariates. Both the FRAIL-BR and the FI-36 were strongly associated with major depressive disorder, subthreshold depression, and depressive symptoms by PHQ-9 and GDS-15. Conclusion Late life depression and frailty are associated in a dose-dependent manner, irrespective of the used definitions. Nonetheless, to avoid residual confounding, future research on underlying biological mechanisms should preferably be based on formal psychiatric diagnoses and objectively assessment frailty status

Design and protocol of the multimorbidity and mental health cohort study in frailty and aging (MiMiCS-FRAIL):unraveling the clinical and molecular associations between frailty, somatic disease burden and late life depression

BACKGROUND: To explore the mutual relationship between multimorbidity, mental illness and frailty, we have set-up the Multimorbidity and Mental health Cohort Study in FRAILty and Aging (MiMiCS-FRAIL) cohort. At the population level, multimorbidity, frailty and late-life depression are associated with similar adverse outcomes (i.e. falls, disability, hospitalization, death), share the same risk factors, and partly overlap in their clinical presentation. Moreover, these three variables may share a common underlying pathophysiological mechanism like immune-metabolic dysregulation. The overall objectives of MiMiCS-FRAIL are 1) to explore (determinants of) the cross-sectional and longitudinal relationship between multimorbidity, depression, and frailty among non-demented geriatric outpatients; 2) to evaluate molecular levels of senoinflammation as a broad pathophysiological process underlying these conditions; and 3) to examine adverse outcomes of multimorbidity, frailty and depression and their interconnectedness. METHODS: MiMiCS-FRAIL is an ongoing observational cohort study of geriatric outpatients in Brazil, with an extensive baseline assessment and yearly follow-up assessments. Each assessment includes a comprehensive geriatric assessment to identify multimorbidity and geriatric syndromes, a structured psychiatric diagnostic interview and administration of the PHQ-9 to measure depression, and several frailty measures (FRAIL, Physical Phenotype criteria, 36-item Frailty Index). Fasten blood samples are collected at baseline to assess circulating inflammatory and anti-inflammatory cytokines, leukocytes' subpopulations, and to perform immune-metabolic-paired miRome analyses. The primary outcome is death and secondary outcomes are the number of falls, hospital admissions, functional ability, well-being, and dementia. Assuming a 5-year mortality rate between 25 and 40% and a hazard rate varying between 1.6 and 2.3 for the primary determinants require a sample size between 136 and 711 patients to detect a statistically significant effect with a power of 80% (beta = 0.2), an alpha of 5% (0.05), and an R2 between the predictor (death) and all covariates of 0.20. Local ethical board approved this study. DISCUSSION: Frailty might be hypothesized as a final common pathway by which many clinical conditions like depression and chronic diseases (multimorbidity) culminate in many adverse effects. The MiMiCS-FRAIL cohort will help us to understand the interrelationship between these variables, from a clinical perspective as well as their underlying molecular signature