Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients.

BACKGROUND: Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight. RESULTS: Hospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56+CD16-) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56+CD16+), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4+CD38+ cells than controls. Contrasting changes were reported in CD25+CD127low/neg regulatory T cells, with increased and decreased proportions found in CD4+ and CD8+ T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated - TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4+ and CD8+) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8+CD57+NKG2A+ cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19. CONCLUSIONS: These findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.

Ultrasound power Doppler synovitis is associated with plasma IL-6 in established rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: Cytokines have an important role in the pathogenesis of rheumatoid arthritis (RA). Although plasma levels of IL-6 have been related to musculoskeletal ultrasound (MSUS) synovitis in early DMARD-naïve RA, there are no similar studies in established disease. METHODS: 64 RA patients treated with non-biological DMARDs and 30 healthy controls were included in this prospective cross-sectional study. A blood sample was taken before evaluation of disease activity (DAS28) and ultrasonography (all tests performed in a blinded fashion). MSUS was performed by one of two ultrasound-trained rheumatologists on 10 joints of both hands. Gray scale (GS) and pD (power Doppler) synovitis were evaluated using a semi-quantitative scale (0-3) in individual joints, and their sum (score 10) was calculated. Plasma cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF, IFN-γ, and VEGF) were quantified by flow cytometry. RESULTS: Levels of all cytokines, excepting VEGF, were significantly higher in RA patients than in controls (P⩽0.05). In RA patients, IL-6, but not other cytokines, correlated positively with DAS28 and swollen joint count (P⩽0.01), as well as with 10-joint pD score, and GS and pD of both wrists (P<0.01 for all tests). In multiple linear regression, the association of IL-6 with 10-joint pD score was maintained even after adjustment for DAS28. However, there was no correlation of IL-6 with tender joint count, 10-joint GS score, or presence of erosions. CONCLUSION: We demonstrated an association of inflammatory findings on MSUS and plasma IL-6 independently of DAS28 in established RA.

Toll-like receptor expression and function in type I bipolar disorder.

Bipolar disorder (BD) has been associated with immune imbalance and low-grade inflammation. The underlying mechanisms remain largely obscure but may involve changes in cell signaling. Toll-like receptors (TLRs) are widely expressed by immune cells. Specific binding of TLRs to pathogen- or danger-associated signals leads to inflammatory responses. Here, we analyzed the frequencies of TLR-1, TLR-2, TLR-4, TLR-5 and TLR-6 in monocytes, regulatory T cells (Tregs) and activated T cells from type I BD euthymic patients and healthy controls (HCs). Monocytes were stimulated in vitro with specific TLR agonists (flagellin, LPS, LTA, BLP and PGN) and immunophenotyped. Cytokines (IL-8, IL-1beta, IL-6, IL-10, TNF-alpha and IL-12p70) were assessed with cytometric bead arrays. At baseline, increased percentages of TLR-1+ and TLR-2+ monocytes and reduced expression of TLR-5 were observed in BD. Following stimulation, the percentage of TLR-1+, TLR-2+, and TLR-6+ monocytes was higher in BD subjects than in HCs. Increased levels of IL-8, IL-12p70 and TNF were observed following stimulation with TLR-1, TLR-2 and TLR-6 agonists, suggesting increased signaling via these receptors in BD. In contrast to HCs, BD patients exhibited no changes in TLR-5 expression following stimulation. The percentage of TLR-2+ Treg cells as well as activated T cells expressing both TLR-2 and TLR-5 increased in BD patients. Given the importance of TLRs in triggering immune responses, our data indicate a role for these receptors in the low-grade inflammatory profile documented in BD.

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging.

Aging has been associated with increased generation of free radicals as well as immunosenescence. Previous studies have identified older individuals with inverted T CD4:CD8 cell ratio and increased immunity to cytomegalovirus (CMV). Here, we investigated markers of oxidative stress and antioxidant defences in older individuals with inverted CD4:CD8 T-cell ratio. Sixty-one subjects were identified with inverted CD4:CD8 ratio. Older individuals with a CD4:CD8 ratio <1 had increased levels of plasma advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP), but reduced levels of thiobarbituric acid reactive substances (TBARS) as compared to subjects with normal CD4:CD8 ratio. The CMV IgG serology was negatively correlated with CD4:CD8 ratio. These markers were more evident among elderly men than women. Our data suggest a close relationship between chronic CMV infection and oxidative profile in older individuals in the midst of its influence on the peripheral T-cell subsets.

Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) has been associated with premature immunosenescence and an increased prevalence of age-related morbidities including poor cognitive function. OBJECTIVE: We explored the relationships among lymphocyte subsets and memory in RA. METHODS: Thirty patients with RA and 19 age-matched healthy controls took part in this study. Cognitive function stress and depression scores were evaluated by structured clinical questionnaires. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate the following subsets: B cells, activated and naïve/memory T cells, regulatory FoxP3+ T (Treg) cells, Th17+ cells, NK cells and senescence-associated CD28- T cells. RESULTS: RA patients were more depressed than controls, but stress levels were similar in the 2 groups. Patients had impaired memory performance compared to controls, demonstrated by lower Mini-Mental State Examination scores and logical and working memories (all p < 0.0001). These group effects remained significant after correcting for depression and age. Patients had expansion of regulatory T cells, naïve CD4+ T cells and CD8+CD28- cells but reduced percentages of B cells and memory CD8+CD45RO+ T cells compared to controls. CD8+CD28- and CD8+CD45RO+ T cells were found to be negatively associated with memory. CONCLUSION: RA patients had reduced memory performance compared to healthy controls. Expansion of activated and senescence-associated T cells was correlated with poor memory performance.

Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders.

BACKGROUND: This study tested the hypothesis that the low-grade inflammation presented in patients with bipolar disorder (BD) is associated with expansion of activated T cells, and this activated state may be due to a lack of peripheral regulatory cells. METHODS: Specifically, we investigated the distribution of monocytes and lymphocyte subsets, and investigated Th1/Th2/Th17 cytokines in plasma by flow cytometry. Twenty-one BD type I patients and 21 age- and sex-matched controls were recruited for this study. RESULTS: BD patients had increased proportions of monocytes (CD14+). Regarding lymphocyte populations, BD patients presented reduced proportions of T cells (CD3+) and cytotoxic T cells (CD3+CD8+). BD patients also exhibited a higher percentage of activated T CD4+CD25+ cells, and a lower percentage of IL-10 expressing Treg cells. CONCLUSIONS: Our data shed some light into the underlying mechanisms involved with the chronic low-grade inflammatory profile described in BD patients.

Neurotrophic factors in women with crack cocaine dependence during early abstinence: the role of early life stress.

BACKGROUND: Neurotrophic factors have been investigated in the pathophysiology of alcohol and drug dependence and have been related to early life stress driving developmental programming of neuroendocrine systems. METHODS: We conducted a follow-up study that aimed to assess the plasma levels of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5) in crack users during 3 weeks of early abstinence in comparison with healthy controls. We performed a comprehensive clinical assessment in female inpatients with crack cocaine dependence (separated into 2 groups: participants with (CSA+) and without (CSA-) a history of childhood sexual abuse) and a group of nonuser control participants. RESULTS: Our sample included 104 women with crack cocaine dependence and 22 controls; of the women who used crack cocaine, 22 had a history of childhood sexual abuse and 82 did not. The GDNF plasma levels in the CSA+ group increased dramatically during 3 weeks of detoxification. In contrast, those in the CSA- group showed lower and stable levels of GDNF under the same conditions. Compared with the control group, BDNF plasma levels remained elevated and NGF levels were reduced during early abstinence. We found no differences in NT3 and NT4/5 between the patients and controls. However, within-group analyses showed that the CSA+ group exhibited higher levels of NT4/5 than the CSA- group at the end of detoxification. LIMITATIONS: Some of the participants were using neuroleptics, mood stabilizers or antidepressants; our sample included only women; memory bias could not be controlled; and we did not investigate the possible confounding effects of other forms of stress during childhood. CONCLUSION: This study supports the association between early life stress and peripheral neurotrophic factor levels in crack cocaine users. During early abstinence, plasmastic GDNF and NT4/5 were the only factors to show changes associated with a history of childhood sexual abuse.

The inverted CD4:CD8 ratio is associated with cytomegalovirus, poor cognitive and functional states in older adults.

BACKGROUND: Some premature features of immunosenescence have been associated with persistent viral infections and altered populations of T cells. In particular, the inverted T CD4:CD8 ratio has been correlated with increased morbidity and mortality across different age groups. OBJECTIVE: Here, we investigated the role of persistent viral infections, cognitive and functional states as predictors of inverted CD4:CD8 ratio of older adults in a developing country. METHODS: Three hundred and sixty community-dwelling older adults (aged 60-103 years) were recruited. Cognitive function was evaluated by the Instrument of Brief Neuropsychological Assessment and Mini-Mental State Examination inventory. Functional Activities Questionnaire was used to determine activities of daily living. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies were determined by ELISAs. Peripheral blood was assessed for lymphocyte subsets by flow cytometry (CD4+, CD8+, NK, NKT, B and CD8+CD28-). RESULTS: Fifty-nine individuals were identified with CD4:CD8 ratio <1, and had increased IgG titers to CMV (p < 0.01), but not to EBV, compared to subjects with CD4:CD8 ratio >1. The older adults with inverted CD4:CD8 ratio had impairments in some cognitive dimensions and had more functional disability and dependency (p = 0.01) than subjects with CD4:CD8 ratio >1. The lymphocyte subsets did not vary between groups. The increased CMV-IgG titers alone contributed to 8× higher chance to invert CD4:CD8 T cell ratio (OR 8.12, 95% CI 1.74-37.88, p < 0.01). CONCLUSION: Our data further indicate the role of CMV on circulating T cells, poor cognition and functional disability/dependency during aging.

Cytokines in bipolar disorder: paving the way for neuroprogression.

Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies.

Defining an Ageing-Related Pathology, Disease or Syndrome: International Consensus Statement.

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval. Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans. Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Decreased levels of circulating CD4+CD25+Foxp3+ regulatory T cells in patients with primary antiphospholipid syndrome.

INTRODUCTION: CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cell dysfunction has been documented in various autoimmune disorders, but not in antiphospholipid syndrome (APS) so far. METHODS: In this cross-sectional study, we aim to investigate CD4(+)CD25(+)Foxp3(+) Treg cells, CD3(+)CD19(-) T cells and CD3(-)CD19(+) B cells in patients with primary APS and healthy controls. Cell subtypes were immunophenotyped using specific monoclonal antibodies (anti-CD3 CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3, anti-CD19 PE) and flow cytometry. RESULTS: Twenty patients with APS and 20 age- and sex-matched controls were studied. The percentage of total lymphocytes, activated Th cells (CD4+CD25+), Treg cells and CD3(-)CD19(+) B cells were found significantly lower in APS patients as compared to controls (all p < 0.05). CONCLUSION: A dysfunction in CD4(+)CD25(+)Foxp3(+) Treg cells may represent one of the mechanisms leading to autoimmunity in APS patients. The decreased number of CD3(-)CD19(+) B cells of APS patients warrants further elucidation.

Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder.

Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation and increased pro-inflammatory cytokines. Immune activation is part of stress response, and psychosocial stress has been implicated in the pathogenesis of psychiatric disorders. Here, we investigated the neuroendocrine and immune responses to acute psychosocial stress challenge in BD. Thirteen euthymic participants with type 1 BD and 15 healthy controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST. Lymphocytes were isolated and stimulated in vitro to assess lymphocyte activation profile, lymphocyte sensitivity to dexamethasone, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling by flow cytometry. Heart rate and salivary cortisol levels were monitored across the task. BD participants exhibited blunted stress responses as shown by reduced heart rate and salivary cortisol levels in comparison to healthy controls. BD was also associated with reduction in the percentage of regulatory T cells, but with expansion of activated T cells. When compared to controls, patients showed increased lymphocyte MAPK p-ERK and p-NF-κB signaling after the stress challenge, but exhibited a relative lymphocyte resistance to dexamethasone. In conclusion, stress-related neuroendocrine responses are blunted, associated with increased immune activation and lower sensitivity to glucocorticoids in BD. An inability in reducing NF-κB and MAPK signaling following TSST could be underlying the immune imbalance observed in BD.

Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls. METHODS: Twenty-two euthymic female patients with BD type I and 17 age-matched healthy controls were selected for the study. A sample of blood was collected and mononuclear cells and DNA were isolated and TL measured. CMV immunoglobulin M (IgM) and IgG titers were measured using chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and NKT] were phenotyped by flow cytometry. RESULTS: Individuals with BD had shorter TLs but higher CMV IgG levels than controls (both p < 0.01). CMV IgG level was inversely correlated with TL. None of the subjects showed IgM reactivity for CMV, excluding acute viral infection. CMV IgG level was associated with expansion of senescent CD8+CD28- T cells and NK cells, which are involved in viral control. CONCLUSIONS: These data support the hypothesis of accelerated aging in BD, as shown by shortened telomeres, higher seropositivity for CMV, and expansion of senescent T cells.

Chemokines in bipolar disorder: trait or state?

Recent evidence has suggested that inflammatory and immune mechanisms may play a role in the pathophysiology of bipolar disorder (BD). Only a few studies have assessed the profile of chemokines, a family of chemotactic cytokines related to the recruitment of leukocytes, in BD. The objective of our study was to evaluate the plasma levels of chemokines in BD patients in different mood states in comparison with healthy controls. Seventy BD type I patients (35 in euthymia and 35 in mania), and 50 healthy controls matched by age, gender, and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL8, and CXCL10 were measured by enzyme-linked immunosorbent assay. BD patients presented higher plasma levels of CCL11 (1.69-fold increase; p < 0.001), CCL24 (1.40-fold increase; p = 0.02), CXCL10 (1.45-fold increase; p < 0.001) and decreased plasma levels of CXCL8 (8.68-fold decrease p < 0.001). Logistic regression stressed the main effect of increased plasma levels of CXCL10 (OR = 1.009, 95 % CI = 1.000-1.018, p = 0.042) and CCL11 (OR = 1.002, 95 % CI = 1.001-1.003, p = 0.003) and decreased plasma levels of CXCL8 (OR = 0.995, 95 % CI = 0.990-0.999, p = 0.013) to BD. This study reinforces the view that BD is associated with an immune dysfunction.

Accuracy of the triglyceride-glucose index as a surrogate marker for identifying metabolic syndrome in non-diabetic individuals.

OBJECTIVES: This study aimed to verify the performance of the triglyceride-glucose (TyG) index in predicting metabolic syndrome (MetS) using three different criteria in healthy individuals living in rural areas. In addition, it aimed to estimate the TyG index cutoff point in the prediction of MetS. METHODS: The study was a cross-sectional study of healthy individuals (aged ≥18 y) living in rural areas of southern Brazil. Individuals with diabetes mellitus were excluded. The variables investigated were waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, fasting glucose, and TyG index. MetS was defined using three criteria: harmonized, International Diabetes Foundation, and National Cholesterol Education Program Adult Treatment Panel III. The Poisson regression model was used for the multivariate analysis. The performance of the TyG index in identifying MetS was determined by receiver operating characteristic curves. RESULTS: A total of 133 individuals were included in this study, with a mean age of 49.0 ± 13.5 y; 54.1% were female. The TyG index performed better in predicting MetS through the harmonized criteria, with area under the curve (AUC) = 0.889 (95% confidence interval [CI], 0.829-0.949), followed by the International Diabetes Foundation criteria, with AUC = 0.877 (95% CI, 0.814-0.940), and the National Cholesterol Education Program criteria, with AUC = 0.867 (95% CI, 0.797-0.937). The TyG index cutoff points defined for the harmonized and International Diabetes Foundation criteria were ≥ 8.61, and ≥ 8.79 for the National Cholesterol Education Program Adult Treatment Panel III. CONCLUSIONS: The TyG index proved to be valid for diagnosing MetS. The largest AUC of the TyG index was identified for the harmonized criteria. Thus, the TyG index can be used to diagnose MetS in individuals living in rural areas.

cGAS-STING pathway as a potential trigger of immunosenescence and inflammaging.

Aging is associated with an increased incidence of autoimmune diseases, despite the progressive decline of immune responses (immunosenescence). This apparent paradox can be explained by the age-related chronic low-grade systemic inflammation (inflammaging) and progressive dysregulation of innate signaling. During cellular aging, there is an accumulation of damaged DNA in the cell's cytoplasm, which serves as ubiquitous danger-associated molecule, promptly recognized by DNA sensors. For instance, the free cytoplasmic DNA can be recognized, by DNA-sensing molecules like cGAS-STING (cyclic GMP-AMP synthase linked to a stimulator of interferon genes), triggering transcriptional factors involved in the secretion of pro-inflammatory mediators. However, the contribution of this pathway to the aging immune system remains largely unknown. Here, we highlight recent advances in understanding the biology of the cGAS-STING pathway, its influence on the senescence-associated secretory phenotype (SASP), and its modulation of the immune system during sterile inflammation. We propose that this important stress sensor of DNA damage is also a trigger of immunosenescence and inflammaging.

Caregiving of children with Down syndrome: impact on quality of life, stress, mental and oral health.

AIM: Parental caregivers of children with Down Syndrome (DS) have a greater burden of daily activities that may affect their health. The aim of this exploratory study was to evaluate the impact of caregiving of children with Down syndrome on parenting quality of life, stress, mental and oral health. METHODS: Fifty-four parental caregivers of children with DS and 51 parents of children without physical or mental disabilities participated of this study. All participants were clinically examined to evaluate the presence of dental caries, gingival conditions and answered a sociodemographic questionnaire. Depression, anxiety, quality of life and coping strategies were assessed using specific instruments. Hair cortisol level was assessed as biological marker of chronic stress. RESULTS: Psychological and quality of life parameters were similar between the groups of caregivers (p > .05). Caregivers of children with DS were older (48.6 vs. 41.5, p < .001), had longer caregiving period (> 10 vs < 10 years, p = .003), presented higher gingival bleeding index (6.1 vs. 4.7, p = .014) and higher cortisol levels (55.9 vs. 38.4, p = .07) as compared with parents of children without disabilities. Sociodemographic data has no influence on cortisol levels (p > .05). CONCLUSIONS: These findings suggest that the caregiving of children with DS has an impact on parenting oral health and stress.

Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder.

Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.

Interleukin-6 and verbal memory in recurrent major depressive disorder.

OBJECTIVE: To evaluate the possible association between peripheral levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) with immediate and delayed verbal recall in a group of recurrent depressed women. METHODS: Logical Memory Subtests of the Wechsler Memory Scale - Revised was administered to 30 patients with recurrent major depressive disorder with no clinical and psychiatric comorbidities. Blood samples were collected from 8:00 am to 9:00 am, before memory assessments.Plasma was stored and ELISA assay was used to detect IL-6 and TNF-alpha levels. RESULTS: There was a statistically significant association between IL-6 levels and immediate verbal recall (IVR) (B=-0.787, p=0.000) and delayed verbal recall (DVR) (B=-0.695, p=0.001) even after controlling for age, depression severity and body mass index. CONCLUSION: The results of this study indicated that low performances in IVR and DVR are associated with higher IL-6 levels in women with recurrent MDD. The results of this study suggest the existence of an association between inflammatory imbalance and cognitive impairment in MDD.

The Renin Angiotensin System and Bipolar Disorder: A Systematic Review.

Bipolar Disorder (BD) is a chronic a multifactorial psychiatric illness that affects mood, cognition, and functioning. BD is associated with several psychiatric conditions as well clinical comorbidities, particularly cardiovascular diseases. The neurobiology of BD is complex and multifactorial and several systems have been implicated. Considering that the Renin Angiotensin System (RAS) plays an important role in cardiovascular diseases and that recently evidence has suggested its role in psychiatric disorders, the aim of the present study is to summarize and to discuss recent findings related to the modulation of RAS components in BD. A systematic search of the literature using the electronic databases MEDLINE and LILACS was conducted through March 2019. The search terms were: "Bipolar Disorder"; "Renin Angiotensin System"; "Angiotensin 2"; "Angiotensin receptors"; "Angiotensin 1-7"; "ACE"; "ACE2"; "Mas Receptor". We included original studies assessing RAS in BD patients. Two hundred twenty-two citations were initially retrieved. Eleven studies were included in our systematic review. In the majority of studies (6 of 8), the ACE insertion/deletion (I/D) polymorphism did not differ between BD patients and controls. BD patients presented higher plasma renin activity in comparison with controls. The studies evaluating the RAS molecules in BD are very scarce and heterogeneous. The literature suggests a potential role of RAS in BD. Further studies are necessary to investigate this relationship.