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.

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.

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.

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.

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.

Ultrasound inflammatory parameters and Treg/Th17 cell profiles in established rheumatoid arthritis.

BACKGROUND: Imbalance and disfuntion in regulatory T-cells (Tregs) and IL-17 producer lymphocytes (Th17) have been implicated in the pathogenesis of rheumatoid arthritis (RA). Gray scale synovial proliferation (GS), power Doppler signal (pD) and bone erosions seen on high resolution muskuloskeletal ultrasound (MSUS) are hallmarks of destructive articular disease. OBJECTIVE: To evaluate the association of peripheral Tregs and Th17 with MSUS findings in RA. METHODS: RA patients (1987 ACR criteria) treated with disease-modifying antirheumatic drugs (DMARDs) were included. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate regulatory FoxP3+ T cells and IL-17+ cells. MSUS (MyLab 60, Esaote, Genova, Italy, linear probe 6-18 MHz) was performed on hand joints, and a 10-joint US score was calculated for each patient. RESULTS: Data on lymphocytes subsets were avaiable for 90 patients. The majority of patients were Caucasian women with a median disease duration of 6 years (interquartile range: 2-13 years). Mean DAS28 was 4.28 (SD ± 1.64) and mean HAQ score was 1.11 (SD ± 0.83). There was no significant correlation of 10-joint GS score (rS = 0.122, 95% CI: - 0.124 to 0.336, P = 0.254) and 10-joint pD score (rS = 0.056, 95% CI: - 0.180 to 0.273, P = 0.602) with the mean percentage of peripheral Treg cells. Also, 10-joint GS score (rS = 0.083, 95% CI: - 0.125 to 0.302, P = 0.438) and 10-joint pD score 10 (rS = - 0.060, 95% CI: - 0.271 to 0.150, P = 0.575); did not correlate to Th17 profile. No association of bone erosions on MSUS with Treg and Th17 profiles (P = 0.831 and P = 0.632, respectively) was observed. CONCLUSION: In this first study addressing MSUS features and lymphocytes subtypes in established RA, data did not support an association of circulating Tregs and Th17 lymphocytes with inflammatory and structural damage findings on MSUS.

Characterization of senescence biomarkers in rheumatoid arthritis: relevance to disease progression.

Rheumatoid arthritis (RA) has been associated with early senescent features. However, the effects of disease progression on senescence markers are largely unknown. Here, we evaluated key senescence markers in RA, including telomere length and T cell differentiation stages as well as cytomegalovirus (CMV) serology, previously associated with premature aging. In a cross-sectional study, 44 patients with active (Ac-RA), 26 patients with controlled (Co-RA), and 30 healthy controls were recruited. Peripheral blood was collected and differentiation stages of T cells analyzed by multi-color flow cytometry. Enzyme-linked immunosorbent assays were used to evaluate the CMV serology. The telomere length was measured by multiplex quantitative PCR. Patients with Ac-RA presented lower percentage of intermediate-differentiated T cells (CD4+CD27-CD28+ and CD8+CD27-CD28+; p < 0.001). All patients had a reduced proportion of cytotoxic T cells, and higher CD4/CD8 ratio compared with controls (p < 0.001). A lower proportion of CMV IgG+ subjects was found in the Co-RA group, (P < 0.001), although no differences in the CMV IgG titers were observed between groups. The groups had similar leukocyte telomere length. In addition, age was negatively correlated with CD8+CD27+CD28+ T (early-differentiated) cells (P < 0.05). Positive correlations between CMV IgG titers and age (P < 0.05) and CD4+CD27-CD28- T (late-differentiated) cells (P < 0.01) were observed. Furthermore, disease duration was correlated with CD4+CD27+CD28+ T cells (r = - 0.318, p < 0.05) and CD4+CD27-CD28- T cells (r = 0.308, p < 0.05). Our findings indicate that CMV and age may have a similar impact on T cells in both RA patients and controls. KEY POINTS: • Patients and controls were homogenous regarding CMV IgG titers and TL. • A lower proportion of CMV IgG+ subjects was found in the Co-RA group. • Anti-CMV levels were positively correlated with age and percentage of CD4+CD27-CD28- (late-differentiated) T cells.

Ultrasound inflammatory parameters and Treg/Th17 cell profiles in established rheumatoid arthritis

Abstract Background: Imbalance and disfuntion in regulatory T-cells (Tregs) and IL-17 producer lymphocytes (Th17) have been implicated in the pathogenesis of rheumatoid arthritis (RA). Gray scale synovial proliferation (GS), power Doppler signal (pD) and bone erosions seen on high resolution muskuloskeletal ultrasound (MSUS) are hallmarks of destructive articular disease. Objective: To evaluate the association of peripheral Tregs and Th17 with MSUS findings in RA. Methods: RA patients (1987 ACR criteria) treated with disease-modifying antirheumatic drugs (DMARDs) were included. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate regulatory FoxP3+ T cells and IL-17+ cells. MSUS (MyLab 60, Esaote, Genova, Italy, linear probe 6-18 MHz) was performed on hand joints, and a 10-joint US score was calculated for each patient. Results: Data on lymphocytes subsets were avaiable for 90 patients. The majority of patients were Caucasian women with a median disease duration of 6 years (interquartile range: 2-13 years). Mean DAS28 was 4.28 (SD ± 1.64) and mean HAQ score was 1.11 (SD ± 0.83). There was no significant correlation of 10-joint GS score (rS = 0.122, 95% CI: - 0.124 to 0.336, P = 0.254) and 10-joint pD score (rS = 0.056, 95% CI: - 0.180 to 0.273, P = 0.602) with the mean percentage of peripheral Treg cells. Also, 10-joint GS score (rS = 0.083, 95% CI: - 0.125 to 0.302, P = 0.438) and 10-joint pD score 10 (rS = - 0.060, 95% CI: - 0.271 to 0.150, P = 0.575); did not correlate to Th17 profile. No association of bone erosions on MSUS with Treg and Th17 profiles (P = 0.831 and P = 0.632, respectively) was observed. Conclusion: In this first study addressing MSUS features and lymphocytes subtypes in established RA, data did not support an association of circulating Tregs and Th17 lymphocytes with inflammatory and structural damage findings on MSUS.

Features of Immunosenescence in Women Newly Diagnosed With Breast Cancer.

Adults exposed to childhood maltreatment have increased stress reactivity. This profile is associated with dysregulation of the immune system, including enhanced inflammatory reactions and accelerated senescence. Subjects exposed to ear stress have increased risk for several age-related diseases, including cardiovascular disease, type II diabetes, and cancer. Although previous studies have reported immune changes in advanced cancer, very little information is available regarding early stage breast cancer. Here, 29 patients with breast cancer were recruited: 15 with history of childhood maltreatment (CM+) and 14 without history (CM-). Twenty-seven healthy women without CM were selected as the control group. Peripheral blood was collected and lymphocyte subsets phenotyped by multi-color flow cytometry (B cells, CD4+ T, CD8+ T, natural killer cells, activated T cells, regulatory T cells, and senescence-associated T cells). Because human cytomegalovirus (CMV) was associated with signatures of early senescence, the CMV serology was determined by ELISA. None of the subjects had IgM reactivity to CMV, excluding acute viral infection. There was a higher proportion of patients with increased CMV IgG levels in the CM+ group as compared to CM- or controls. Different stages of T-cell differentiation can be determined based on the cell-surface expression of the costimulatory molecules CD27 and CD28: ear (CD27+CD28+), intermediate-differentiated (CD27-CD28+), and late-differentiated or senescent T cells (CD27-CD28-). After adjusting for age and education, ear T cells (CD27+CD28+) were found reduced in CM+ and CM- patients (p < 0.0001). In contrast, intermediate-differentiated T cells (CD27-CD28+; p < 0.0001), senescent T cells (CD27-CD28-; p < 0.0001), and exhausted T cells (CD8+CD27-CD28-PD1+; p < 0.0001) were found expanded in both CM+ and CM- groups. Our data suggest that features of immunosenescence are associated with newly diagnosed breast cancer, regardless of the CM history.

SALIVARY CORTISOL AND METABOLIC SYNDROME COMPONENT'S ASSOCIATION.

BACKGROUND: Actually the lifestyle exposes the population to several risk factors related to alimentary habits and less physical activity that contributes to chronic diseases appearance worldwide. AIM: To analyze the association between salivary cortisol and the components of metabolic syndrome. METHODS: This is a cross-sectional study. As part of it, 28 individuals aged 30-59 years presenting three or more of the following findings: CA: ≥88 cm for women and ≥102 cm for men; SBP>130 mmHg and DBP>85 mmHg; GL>100 mg/dl; TG>150 mg/dl; HDL<40 mg/dl for men and <50 mg/dl for women. Was performed analysis of salivary cortisol (by radioimmunoassay) from 25 salivary samples collected throughout the day, for evaluating changes in the circadian rhythm of this hormone (8AM, noon and 8PM). RESULTS: 28 evaluated individuals had a mean age of 51.9±7.5 years, mostly women (64.3%) and a mean of BMI 33.6±3.2 kg/m². The cortisol level from the 8AM averaged 18.7±4.8 ng/dlL. Individuals with FPG>110mg/dl, have significantly lower average levels of cortisol than ones with FPG <110 (12.8±5,2 vs. 17.3±4.2). Significant correlations were HOMA vs. WC (r=0,465; p˂0,005) and TG (r=0,473; p˂0,005), WC vs. FG (r=0,446; p˂0,005) and BMI (r=0,730; p˂0.0001); TG vs. HDL (r=0,441 p˂0,005) and FG (r=0,440; p˂0,005). CONCLUSION: Morning salivary cortisol in subjects with chronically elevated blood glucose can represent a downregulation of the hypothalamic-pituitary adrenal axis. This is an important finding not yet well investigated.

Serum IL-6 correlates with axial mobility index (Bath Ankylosing Spondylitis Metrology Index) in Brazilian patients with ankylosing spondylitis.

INTRODUCTION: Ankylosing spondylitis (AS) is a chronic disease featuring axial changes, peripheral arthritis and systemic involvement. Proinflammatory cytokines are probably involved in AS pathogenesis. The relationship of circulating cytokines with instruments of AS evaluation is an open field of research. OBJECTIVE: The aim of this study was to compare serum levels of cytokines in AS patients and healthy controls, and search for correlations of cytokines with indexes of disease activity and quality of life. PATIENTS AND METHODS: In this cross-sectional study, 32 AS patients and 32 age- and sex- matched controls were evaluated. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Funcional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis Disease Activity Score-C reactive protein (ASDAS-CRP), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), Ankylosing Spondylitis Quality of Life (ASQol) and Patient Global Assessment score were measured in AS patients. The soluble cytokines IL-6, IL-8, IL-1, IL-10, TNF-α, IL-12p70 and IL-17 were quantified by flow cytometry. IL-23 concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: Overall, AS patients were predominantly males (59.4%) and Caucasians (96.9%). Mean age was 46.9±10.7 years. Human leukocyte antigen B27 was present in 70% of cases. Concentrations of IL-6, IL-8, IL-10 and TNF-α were higher in AS cases than controls (p<0.05). Mean concentration of IL-6 correlated with the BASMI, an index of axial mobility (r=0.354, p=0.047). Anti-TNF intake (present in 21 patients, 65.6%) associated with a high BASMI (p=0.042) and lower quality of life as measured using the ASQol scale (p=0.009). CONCLUSION: A proinflammatory cytokine profile predominated in AS patients, but interestingly, the IL-10 concentrations were also elevated, pointing to a suppressive control of inflammation. A defined correlation of serum IL-6 with the BASMI suggests a role for this cytokine in axial disease. Anti-TNF users showed more axial activity and lower quality of life.

Cognitive impairment in rheumatoid arthritis: role of lymphocyte subsets, cytokines and neurotrophic factors.

To what extent the cognitive impairment of rheumatoid arthritis (RA) is modulated by autoimmune and/or inflammatory activity is largely unknown. The aim of this study was to investigate the role of peripheral inflammation on cognitive functions of patients with active (Ac-), controlled (Co-) RA and healthy controls. In a cross-sectional study, 102 RA patients and 30 matched healthy controls were recruited. B and T cell subsets were immunophenotyped by flow cytometry. Plasma cytokines and neurotrophins were measured by flow cytometry and ELISA, respectively. Cognitive performance, depression and stress were evaluated by structured clinical interviews. Generalized linear modeling (GzLM) was used to compare differences between groups and multiple linear regression models were used to explore the predictive value of immune variables on cognitive performance. RA patients had overall cognitive impairment. Of note, the Ac-RA had the poorest performance on digit span (DST) and N-back when compared to Co-RA and control group (DST 9.9 ± 2.1, 12.9 ± 4.2, 15.5 ± 4.7, respectively; N-back 49.2 ± 8.3, 55.5 ± 11.1, 60.8 ± 9.1, respectively, all p < 0.0001). RA patients had expansions of immature B cells (Ac-RA 11.2 ± 7.1, Co-RA: 9 ± 5.7, control 5.9 ± 2.1) and plasma cells (Ac-RA 5.2 ± 2.5, Co-RA 6.9 ± 3.7, control 2.8 ± 1.7) as compared to controls, all p < 0.05. RA patients (controlled and active disease) had higher plasma levels of TNF, IL-2, IL-4, IL-6 and IL-10 than controls (all p < 0.002). RA patients had higher BDNF levels (Ac-RA 17,354.4 ± 5357.3, Co-RA 13,841.2 ± 5953.7, control 11,543.3 ± 3772), but lower GDNF levels [median (interquartile range) Ac-RA 0 pg/ml (0.0), Co-RA 0 pg/ml (4.6) and control 4.7 pg/ml (18.1)] than controls (all p < 0.05). RA patients had global cognitive impairment, which was associated with disease activity and immune changes.

Salivary cortisol and metabolic syndrome component's association / Associação do cortisol salivar com os componentes da síndrome metabólica

ABSTRACT Background: Actually the lifestyle exposes the population to several risk factors related to alimentary habits and less physical activity that contributes to chronic diseases appearance worldwide. Aim: To analyze the association between salivary cortisol and the components of metabolic syndrome. Methods: This is a cross-sectional study. As part of it, 28 individuals aged 30-59 years presenting three or more of the following findings: CA: ≥88 cm for women and ≥102 cm for men; SBP>130 mmHg and DBP>85 mmHg; GL>100 mg/dl; TG>150 mg/dl; HDL<40 mg/dl for men and <50 mg/dl for women. Was performed analysis of salivary cortisol (by radioimmunoassay) from 25 salivary samples collected throughout the day, for evaluating changes in the circadian rhythm of this hormone (8AM, noon and 8PM). Results: 28 evaluated individuals had a mean age of 51.9±7.5 years, mostly women (64.3%) and a mean of BMI 33.6±3.2 kg/m². The cortisol level from the 8AM averaged 18.7±4.8 ng/dlL. Individuals with FPG>110mg/dl, have significantly lower average levels of cortisol than ones with FPG <110 (12.8±5,2 vs. 17.3±4.2). Significant correlations were HOMA vs. WC (r=0,465; p˂0,005) and TG (r=0,473; p˂0,005), WC vs. FG (r=0,446; p˂0,005) and BMI (r=0,730; p˂0.0001); TG vs. HDL (r=0,441 p˂0,005) and FG (r=0,440; p˂0,005). Conclusion: Morning salivary cortisol in subjects with chronically elevated blood glucose can represent a downregulation of the hypothalamic-pituitary adrenal axis. This is an important finding not yet well investigated.

RESUMO Racional: Atualmente o estilo de vida expõe a população a diversos fatores de risco relacionados a hábitos alimentares e à inatividade física, contribuindo para o surgimento de doenças crônicas. Objetivo: Analisar a associação entre o cortisol salivar e os componentes da síndrome metabólica. Métodos: Estudo transversal com 28 indivíduos, idade entre 30 e 59 anos apresentando três ou mais dos seguintes achados: circunferência abdominal ≥88 cm (mulheres) e ≥102 cm (homens); pressão arterial sistólica >130 mmHg e pressão arterial diastólica >85 mmHg; glicemia >100 mg/dl; triglicerídeo >150 mg/dl; lipoproteína de alta densidade <40 mg/dl (homens) e <50 mg/dl (mulheres). Foram realizadas coletas do cortisol salivar nos seguintes horários 8 h, 12 h e 20 h e analisadas por radioimunoensaio. Resultados: A média de idade foi 51,9±7,5 anos, 64,3% eram mulheres e a média do índice de massa corporal foi 33,6±3,2 kg/m². O nível de cortisol salivar às 8 h teve média de 18,7±4,8 ng/dl. Os indivíduos com glicemia de jejum >110 mg/dl, apresentaram níveis médios de cortisol significativamente menores que os com glicemia de jejum <110 mg/dl (12,8±5,2 vs. 17,3±4,2). As correlações significativas foram HOMA vs. circunferência abdominal (r=0,465; p˂0,005) e triglicerídeos (r=0,473; p˂0,005), circunferência abdominal vs. glicemia de jejum (r=0,446; p˂0,005) e índice de massa corporal (r=0,730; p˂0,0001), triglicerídeos vs. lipoproteína de alta densidade (r=0,441 p˂0,005) e glicemia de jejum (r=0,440; p˂0,005). Conclusão: O cortisol salivar pela manhã, em indivíduos com glicemia cronicamente elevada, pode representar uma contraregulação do eixo hipotálamo-hipófise-adrenal, sendo achado importante e pouco investigado.

Subclinical atherogenesis in patients with mild psoriasis: A role for IL-6? / Aterogênese subclínica em pacientes com psoríase leve: um papel para IL-6?

Summary Introduction: A link of psoriasis with subclinical atherosclerosis has been postulated and cytokine network might intermediate this association. Few data are available in patients with mild psoriasis. We evaluated carotid intima-media thickness (cIMT) in drug-free psoriatic individuals and controls. In parallel, we searched for associations of cIMT with disease activity indexes and serum interleukins (IL) in psoriatic patients. Method: An experienced radiologist performed the cIMT analyses. Cytokine concentrations were assessed by flow cytometry. Disease activity was evaluated based on psoriasis area and severity index (PASI) as well as body surface area (BSA). Results: Sixty-five (65) patients and 64 controls were studied. Mean age of patients (50.9 years) did not differ from controls (p=0.362). A low PASI and BSA (< 10) prevailed (69.2% and 56.9%, respectively). Median levels of IL-12p70, TNF-α, IL-1β and IL-10 were significantly lower in cases than in controls (adjusted p<0.05), while IL-6 and IL-8 medians did not differ between groups (adjusted p>0.05). Smoking habit and diabetes mellitus predominated in cases (p=0.002). An altered cIMT (≥ 0.9 mm) was more frequent in cases than in controls (23.8% versus 8.5%, adjusted p=0.045). Mean cIMT was higher in cases with a borderline significance (p=0.057). cIMT scores did not correlate to PASI (rs=0.066; p=0.250) or BSA (rs=0.175; p=0.185), but did correlate significantly with serum IL-6 (rs=0.26; p=0.005). Conclusion: Subclinical atherosclerosis was more frequent in patients with mild psoriasis than controls. cIMT in psoriatic individuals correlated with serum IL-6, pointing to an eventual proatherogenic role of IL-6 in these patients. Newer studies should clarify the connection of atherogenesis with cytokines in psoriasis.

Resumo Introdução: Foi postulada uma ligação entre psoríase e aterosclerose subclínica. A rede de citocinas pode intermediar essa associação. Poucos dados estão disponíveis em pacientes com psoríase leve. Avaliamos a espessura íntima-média carotídea (cIMT) em psoriáticos e controles livres de medicação. Paralelamente, pesquisamos a associação de cIMT com os índices de atividade de doença e interleucinas séricas (IL) em pacientes com psoríase. Método: Um radiologista experiente procedeu à análise do cIMT. As concentrações de citocinas foram avaliadas por citometria de fluxo. A atividade da doença foi avaliada pelo índice de gravidade (PASI) e pela área de superfície corporal (BSA). Resultados: Sessenta e cinco (65) pacientes e 64 controles foram estudados. A idade média dos pacientes (50,9 anos) não diferiu dos controles (p=0,362). PASI e BSA baixos (< 10) prevaleceram (69,2% e 56,9%, respectivamente). As medianas de IL-12p70, TNF-α, IL-1β e IL-10 foram significativamente menores nos casos do que nos controles (p<0,05 ajustado), enquanto as medianas de IL-6 e IL-8 não diferiram nos grupos (p>0,05 ajustado). Tabagismo e diabetes mellitus predominaram nos casos (p=0,002). Um cIMT alterado (≥ 0,9 mm) foi mais frequente nos casos do que nos controles (23,8% versus 8,5%, p=0,045 ajustado). A média de cIMT foi maior nos casos com significância borderline (p=0,057). Os escores de cIMT não se correlacionaram com o PASI (rs=0,066; p=0,250) ou o BSA (rs=0,175; p=0,185), mas se correlacionaram significativamente com a IL-6 sérica (rs=0,26; p=0,005). Conclusão: A aterosclerose subclínica foi mais frequente em pacientes com psoríase leve do que nos controles. Em psoriáticos, cIMT correlacionou-se com níveis de IL-6 no soro, apontando para um eventual papel pró-aterogênico para a IL-6 nesses pacientes. Novos estudos devem esclarecer a ligação da aterogênese com citocinas na psoríase.

Subclinical atherogenesis in patients with mild psoriasis: A role for IL-6?

INTRODUCTION: A link of psoriasis with subclinical atherosclerosis has been postulated and cytokine network might intermediate this association. Few data are available in patients with mild psoriasis. We evaluated carotid intima-media thickness (cIMT) in drug-free psoriatic individuals and controls. In parallel, we searched for associations of cIMT with disease activity indexes and serum interleukins (IL) in psoriatic patients. METHOD: An experienced radiologist performed the cIMT analyses. Cytokine concentrations were assessed by flow cytometry. Disease activity was evaluated based on psoriasis area and severity index (PASI) as well as body surface area (BSA). RESULTS: Sixty-five (65) patients and 64 controls were studied. Mean age of patients (50.9 years) did not differ from controls (p=0.362). A low PASI and BSA (< 10) prevailed (69.2% and 56.9%, respectively). Median levels of IL-12p70, TNF-α, IL-1ß and IL-10 were significantly lower in cases than in controls (adjusted p<0.05), while IL-6 and IL-8 medians did not differ between groups (adjusted p>0.05). Smoking habit and diabetes mellitus predominated in cases (p=0.002). An altered cIMT (≥ 0.9 mm) was more frequent in cases than in controls (23.8% versus 8.5%, adjusted p=0.045). Mean cIMT was higher in cases with a borderline significance (p=0.057). cIMT scores did not correlate to PASI (rs=0.066; p=0.250) or BSA (rs=0.175; p=0.185), but did correlate significantly with serum IL-6 (rs=0.26; p=0.005). CONCLUSION: Subclinical atherosclerosis was more frequent in patients with mild psoriasis than controls. cIMT in psoriatic individuals correlated with serum IL-6, pointing to an eventual proatherogenic role of IL-6 in these patients. Newer studies should clarify the connection of atherogenesis with cytokines in psoriasis.

Evidence for Immune Activation and Resistance to Glucocorticoids Following Childhood Maltreatment in Adolescents Without Psychopathology.

Early-life stress (ELS) increases the risk for psychopathology. Immune and endocrine changes have been reported in adults and are associated with maladaptation of stress-responsive systems. Here we investigated the effects of ELS on endocrine and immune pathways in adolescents without psychopathology. Thirty adolescents with a history of childhood maltreatment and 27 adolescents without ELS history were recruited. Blood and hair samples were obtained from all participants. Lymphocytes were isolated and stimulated in vitro. Flow cytometry was used to evaluate lymphocyte subsets, Th1/Th2/Th17 cytokines, mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathways, as well as lymphocyte sensitivity to dexamethasone. Brain-derived neurotrophic factor (BDNF) and hair cortisol were assessed with enzyme-linked immunosorbent assays (ELISAs). Adolescents with a history of ELS had increased percentages of T-cell activation markers (CD3+CD4+CD25+ and CD3+CD69+) and senescent T cells (CD8+CD28- and CD4+CD28-), as well as decreased percentages of NK (CD3-CD56+) and NK T cells (CD3+CD56+). Following stimulation, lymphocytes of ELS+ adolescents produced significantly more IL-2, IL-4, IFN-γ, and IL-17 and engaged more MAPK ERK and NF-κB signaling. ELS was associated with increased hair cortisol levels in parallel with increased lymphocyte resistance to dexamethasone and low plasma BDNF levels. These data provide the first indication of the presence of immune activation and pro-inflammatory profiles in healthy adolescents exposed to ELS, which could contribute to increased vulnerability of trauma-related psychopathology later in life. The underlying mechanisms of this impairment may include the enhanced activation of both MAPK and NF-κB signaling in parallel to partial resistance to glucocorticoids.

Autoantibodies against myelin sheath and S100ß are associated with cognitive dysfunction in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) has been associated with cognitive impairment and peripheral production of autoantibodies. Autoantibodies against central nervous system (CNS) proteins and S100 calcium-binding ß (S100ß) were found increased in diseases characterized by cognitive impairment like Alzheimer disease and Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). The aim of this study was to investigate the plasma levels of autoantibodies against myelin basic protein (anti-MBP), myelin oligodendrocyte glycoprotein (anti-MOG) and S100ß, and their relationships with cognitive performance in RA patients. Twenty patients with active rheumatoid arthritis and 19 age-, sex-, and schooling-matched healthy controls were recruited. Multiple dimensions of cognitive function were evaluated by structured clinical questionnaires. Autoantibodies and S100ß levels were assessed by ELISAs. Patients had significantly higher levels of anti-MBP IgG (17.51 ± 1.36 vs. 5.24 ± 0.53 ng/mL), anti-MOG IgG (5.68 ± 1.34 vs. 0.51 ± 0.49 ng/mL), and S100ß protein (2.24 ± 0.50 vs. 0.47 ± 0.06) than controls (all p < 0.0001). After adjusting for potential confounders, RA group presented worse cognitive performance involving the working memory and executive functions such as inhibition, flexibility, and mental control in parallel to higher autoantibodies and S100ß levels than healthy controls (all p < 0.001). Levels of anti-MBP were negatively associated with delayed verbal recall (DVR; r = -0.42, p = 0.005), Stroop Color-Word (r = -0.48, p = 0.004), and N-Back Total scores (r = -0.59, p < 0.0001) and positively with Trail Making Test B (TMB, r = 0.53, p = 0.001). Negative correlation was found between levels of anti-MOG and DVR (r = -0.64, p < 0.0001), N-Back Total scores (r = -0.35, p = 0.03), Stroop Color-Word (r = -0.51, p = 0.001), and positively with TMB (r = 0.50, p = 0.003). S100ß levels were associated with DVR (r = -0.51, p = 0.002), TMB (r = 0.46, p = 0.008), Stroop Color-Word (r = -0.67, p < 0.0001), and N-Back Total (r = -0.52, p = 0.003). RA is associated with impaired cognitive performance associated with higher levels of CNS-related autoantibodies and S100ß levels. Given the importance of myelin integrity to cognition, our data indicate that these autoantibodies may be harmful to proper cognitive function.

Envelhecimento saudável e atividade física: uma revisão sistemática sobre os efeitos do exercício nas doenças cardiovasculares / Healthy aging and physical activity: a systematic review on the effects of exercise on cardiovascular diseases

OBJETIVOS: Realizar uma revisão sistemática dos ensaios clínicos randomizados que avaliaram os benefícios do exercício físico (regular ou competitivo) para a saúde de idosos e a prevenção de doenças cardiovasculares. MÉTODOS: Foram investigados os registros no Pubmed, Web of Science, Library of Congress, Central de Registros Cochrane e as bases de dados com os registros dos ensaios clínicos de 2005 a 2016, juntamente com os anais das maiores conferências sobre doenças cardiovasculares no envelhecimento usando os termos definidos de acordo com a metodologia "paciente, intervenção, comparação e resultado". Os descritores utilizados foram physical effort, exercise, exercise therapy, physical activity, physical fitness, resistance training, cardiovascular disease, C-reactive protein, dyslipidemia, heart failure, cardiac insufficiency, revascularization, cardiac stent e heart transplant. Somente foram incluídos ensaios clínicos randomizados, com indivíduos acima de 60 anos de idade. Os artigos foram avaliados independentemente por dois avaliadores. RESULTADOS: Foram acessados um total de 3672 estudos e foram eleitos os 24 que preencheram os critérios de inclusão. A maioria desses estudos descreviam amostras reduzidas e apresentavam o exercício físico como um componente para a saúde. Apenas 16 estudos apresentavam relação da aderência à prática de exercícios físicos como prevenção cardiovascular. As medidas de resultados incluem fatores de qualidade de vida, capacidade física ou estado de condicionamento físico, força muscular, frequência cardíaca, aspectos psicológicos, marcadores inflamatórios e nutricionais e a progressão de doenças cardiovasculares. As evidências mais fortes apontam para os efeitos do exercício aeróbico na melhoria da capacidade física, força muscular e qualidade de vida de pacientes idosos com doença cardiovascular. CONCLUSÕES: Os benefícios do treinamento físico para pacientes idosos com doença cardiovascular estão bem estabelecidos, apoiando a prescrição de exercícios físicos nos seus tratamentos regulares. Intervenções que utilizam o exercício precisam ser progressivamente incluídas nos regimes dos centros de tratamento cardiovascular, embora o melhor protocolo de exercícios para pacientes com doença cardiovascular ainda não esteja completamente estabelecido.

AIMS: To perform a systematic review of randomized controlled trials that assess the benefits of physical exercise (regular or competitive) for the health of the elderly and prevention of cardiovascular diseases. Methods: Publications in PubMed, Web of Science, Library of Congress, Cochrane, and in databases with records of clinical trials between 2005 and 2016, and also in the proceedings of major congresses on cardiovascular diseases in the elderly were investigated using the terms defined in accordance with the "patient, intervention, comparison, and outcome" methodology. The following key words were used: physical effort, exercise, exercise therapy, physical activity, physical fitness, resistance training, cardiovascular disease, C-reactive protein, dyslipidemia, heart failure, cardiac insufficiency, revascularization, cardiac stent and heart transplant. Only randomized clinical trials with individuals aged over 60 years were included. The articles were assessed independently by two reviewers. RESULTS: A total of 3,672 studies were assessed and 24 that met the inclusion criteria were selected. Most of these studies had small sample sizes and showed physical exercise as health-promoting. Only 16 studies reported the relationship of adherence to physical exercise as a preventive factor against cardiovascular diseases. The outcome measures included quality of life, physical ability or fitness status, muscle strength, heart rate, psychological aspects, inflammatory and nutritional markers, and progression of cardiovascular diseases. There is strong evidence that aerobic exercise improves physical fitness, muscle strength, and the quality of life of elderly patients with cardiovascular disease. CONCLUSIONS: The benefits of exercise training for elderly patients with cardiovascular disease are well established, supporting the prescription of exercise training for their regular treatments. Interventions that use exercise need to be progressively included in cardiovascular treatment regimens, although the best exercise protocol for patients with cardiovascular disease is not yet fully established.

Distinct behavioral and immunoendocrine parameters during crack cocaine abstinence in women reporting childhood abuse and neglect.

AIM: To assess plasma levels of cortisol and cytokines between cocaine-dependent women with and without childhood maltreatment (CM) history during cocaine detoxification treatment. METHOD: We assessed immunoendocrine and clinical parameters of 108 crack cocaine female users during 3 weeks of inpatient detoxification treatment, and 24 healthy women to obtain reference values. Women with (CM+, n=53) or without (CM-, n=55) CM history were identified answering the Childhood Trauma Questionnaire (CTQ). Blood samples and clinical assessment were collected before lunch during the first, second and third week post-treatment admission. Flow cytometry was used to assess TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A plasma levels and ELISA assay was used to measure plasma cortisol levels. RESULTS: At baseline, lower Th1 and Th17-related cytokines levels and higher Th2 cytokines levels were observed in crack cocaine users compared with reference values. Cytokines levels of cocaine dependents gradually became closer to reference values along detoxification treatment. However, when CM+ and CM- groups were compared, increased levels of IL-6, IL-4 and TNF-α across time were observed in CM+ group only. Additionally, a Th1/Th2 immune imbalance was observed within CM+ group, which was negatively correlated with the severity of the crack withdrawal. Finally, loading trauma exposure severity, immunoendocrine and clinical parameters in factor analysis, we identified three clusters of observed variables during detoxification: (1) systemic immunity and trauma exposure, (2) pro-inflammatory immunity and (3) behavior CONCLUSION: Our results suggest the existence of an immunological phenotype variant associated with CM exposure during crack cocaine detoxification of women.

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.