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Objective: There are several models of staging in bipolar disorder (BD), but none has been validated. The aims of this study were to empirically investigate clinical variables that may be useful to classify patients in clusters according to stage and study the association with biomarkers as biological validators. Method: This was a historical cohort study. Patients (n = 115) diagnosed with BD and not in an acute episode and first-degree relatives of patients diagnosed with BD (n = 25) were recruited. Sociodemographic, clinical, and functional data were collected. Serum cytokines, brain-derived neurotrophic factor, and biomarkers of lipid and protein oxidation were assessed. Cluster analysis was carried out to build a model of staging, and logistic regression was conducted to study associations between the model and biomarkers. Results: Cluster analysis divided the sample into two equitable groups, denominated early and late stage, with empirical cutoffs for the Functioning Assessment Short Test score, number of episodes, age at onset of the disorder, and time elapsed since first episode. In the logistic regression, IL-6 was associated with late stage (P = 0.029). Conclusion: This study supports that clinical, functional, and biochemical variables may help to define a classification of staging in BD. Significant outcomes• A model of staging based on early and late stages according to functioning, number of episodes, age at onset of the disorder, and time elapsed since the first episode can be feasible and useful in bipolar disorder.• IL-6 is a valid biological biomarker for this proposal of staging in bipolar disorder. Limitations• Patients with subsyndromal symptoms were not excluded from the sample. • Biomarker assessment was carried out peripherally. • Lack of a prospective assessment hampers to test the validity of a model of staging.

Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2α-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2α-P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response. Thus, dysfunction in ER-related stress response may be associated with decreased cellular resilience in BD and illness progression.

Background: Stroke is the second leading cause of death after ischemic heart disease and the third leading cause of disability-adjusted life-years lost worldwide. There is a great need for developing more effective strategies to treat stroke and its resulting impairments. Among several neuroprotective strategies tested so far, the kynurenine pathway (KP) seems to be promising, but the evidence is still sparse. Methods: Here, we performed a systematic review of preclinical and clinical studies evaluating the involvement of KP in stroke. We searched for the keywords: (“kynurenine” or “kynurenic acid” or “quinolinic acid”) AND (“ischemia” or “stroke” or “occlusion) in the electronic databases PubMed, Scopus, and Embase. A total of 1,130 papers was initially retrieved. Results: After careful screening, forty-five studies were included in this systematic review, being 39 pre-clinical and six clinical studies. Despite different experimental models of cerebral ischemia, the results are concordant in implicating the KP in the pathophysiology of stroke. Preclinical evidence also suggests that treatment with kynurenine and KMO inhibitors decrease infarct size and improve behavioral and cognitive outcomes. Few studies have investigated the KP in human stroke, and results are consistent with the experimental findings that the KP is activated after stroke. Conclusion: Well-designed preclinical studies addressing the expression of KP enzymes and metabolites in specific cell types and their potential effects at cellular levels alongside more clinical studies are warranted to confirm the translational potential of this pathway as a pharmacological target for stroke and related complications.

Systemic toxicity is a relevant dimension of pathophysiology in bipolar disorder, and oxidative damage is one potential link between central and peripheral pathology. Although there is mounting evidence that chronic bipolar disorder is associated with oxidative stress, studies in the early stages of bipolar disorder are scarce, and heavily reliant on clinical in lieu of population studies. The objective of this study was to confirm leading hypotheses about the role of oxidative damage in bipolar disorder. To that end, we nested a case-control study in a population-based study of young adults aged 18-24 yr. After an initial psychopathology screen, all people with a lifetime history of (hypo)mania and matched controls underwent a structured diagnostic interview. This yielded a sample of 231 participants, in whom we measured serum protein carbonyl content (PCC) and thiobarbituric acid reactive substances (TBARS). People with bipolar disorder had higher PCC levels than healthy subjects. Those with major depression were not different from control subjects in either PCC or TBARS levels. Both bipolar disorder and major depression were associated with higher PCC levels in the a priori regression model controlling for possible confounders. These findings indicate that protein oxidative damage is present from early stages and can be seen as a sign of early illness activity in mood disorders.

Objective Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. Methods Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs—including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs—including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women. Results Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. Conclusion The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

Transcranial direct current stimulation (tDCS) has demonstrated effectiveness in reducing clinical and experimental measures of pain in patients with chronic pain; however, research examining the mechanisms of action for the effects of tDCS has been lacking. The present study investigated the effect of active tDCS on measures of inflammation and stress. Older adults (aged 50–70 years) with knee osteoarthritis (OA) were randomly assigned to receive daily 20-min sessions of either tDCS ( n = 20) or sham tDCS ( n = 20) for 5 consecutive days. Participants provided blood samples at baseline and the end of treatment. The following measures of immune function and stress were collected: interleukin (IL)-6 and 10, tumor necrosis factor-α (TNF-α), C-reactive protein, cortisol, and β-endorphin. Generalized linear modeling evaluated each posttreatment measure as a function of tDCS group, controlling for baseline (measuring residual change, analogous to analysis of covariance). Bayesian statistical inference was used to directly quantify the probability of the effect of active tDCS. IL-6, IL-10, TNF-α, and β-endorphin demonstrated lower levels of stress and inflammation in the active tDCS group. These findings provide preliminary evidence that active (relative to sham) tDCS is associated with reduced levels of inflammation.

Background Sex differences in COVID-19 are increasingly recognized globally. Although infection rates are similar between the sexes, men have more severe illness. The mechanism underlying these sex differences is unknown, but a differential immune response to COVID-19 has been implicated in several recent studies. However, how sex differences shape the immune response to COVID-19 remains understudied. Methods We collected demographics and blood samples from over 600 hospitalized patients diagnosed with COVID-19 from May 24th 2020 to April 28th, 2021. These patients were divided into two cohorts: Cohort 1 was further classified into three groups based on the severity of the disease (mild, moderate and severe); Cohort 2 patients were longitudinally followed at three time points from hospital admission (1 day, 7 days, and 14 days). MultiPlex and conventional ELISA were used to examine inflammatory mediator levels in the plasma in both cohorts. Flow cytometry was conducted to examine leukocyte responses in Cohort 2. Results There were more COVID+ males in the total cohort, and the mortality rate was higher in males vs. females. More male patients were seen in most age groups (in 10-year increments), and in most ethnic groups. Males with severe disease had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) than females; levels of IL-8, GRO, sCD40L, MIP-1β, MCP-1 were also significantly higher in severe vs. mild or control patients in males but not in females. Females had significantly higher anti-inflammatory cytokine IL-10 levels at 14 days compared to males, and the level of IL-10 significantly increased in moderate vs. the control group in females but not in males. At 7 days and 14 days, males had significantly more circulating neutrophils and monocytes than females; however, B cell numbers were significantly higher in females vs. males. Conclusion Sex differences exist in hospitalized patients with acute COVID-19 respiratory tract infection. Exacerbated inflammatory responses were seen in male vs. female patients, even when matched for disease severity. Males appear to have a more robust innate immune response, and females mount a stronger adaptive immune response to COVID-19 respiratory tract infection.