Cytokines as mediators of the associations of prenatal exposure to phenols, parabens, and phthalates with internalizing behaviours at age 3 in boys: A mixture exposure and mediation approach.

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1ß, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways.

Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear. We conducted a multicentre case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) with those of patients diagnosed with other IRAEs. Methods: We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, four reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a P < 0.05 were included as covariates in a multivariate analysis. Results: Therefore, 167 ICI-AKI reports were compared with 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 versus 64.6 years; P = 0.0135), and chronic kidney disease was significantly more prevalent (12.0% versus 3.3%; P = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione [adjusted odds ratio (OR) 6.53, 95% confidence interval (95% CI) 2.21-19.31; P = 0.0007], a non-steroidal anti-inflammatory drug (NSAID, OR 3.18, 95% CI 1.07-9.4; P = 0.0368) or a proton-pump inhibitor (PPI, OR 2.18, 95% CI 1.42-3.34; P = 0.0004). Conclusion: This study is limited by a lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a 'second-hit' that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort.

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific "immuno-metabolic" profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry.

Early Life Exposure to Tumor Necrosis Factor Induces Precocious Sensorimotor Reflexes Acquisition and Increases Locomotor Activity During Mouse Postnatal Development.

Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories.

Identification of Serum Interleukin 6 Levels as a Disease Severity Biomarker in Facioscapulohumeral Muscular Dystrophy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles' pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics' efficacy. OBJECTIVES: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD. METHODS: We retrospectively measured the levels of 20 pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression. RESULTS: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression. CONCLUSIONS: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients.

Serum cytokines associated with behavior: A cross-sectional study in 5-year-old children.

Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used a penalized logistic regression method (Elastic Net), to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast, eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, C-C motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

Immune activity at birth and later psychopathology in childhood.

Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C-C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-ß with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life.

Deglutition manifestations in patients with oropharyngeal cancer subjected to conservative therapy: systematic review / Manifestações da deglutição em pacientes com câncer de orofaringe submetidos à terapia conservadora: revisão sistemática

ABSTRACT Objectives: To characterize scientific production and identify deglutition changes in individuals with oropharyngeal cancer subjected to conservative therapy. Methods: The search was applied to five electronic database [Scientific Electronic Library Online (Scielo), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), US National Library of Medicine National Institutes of Health (PubMed), Web of Science, and Scopus], besides the search of grey literature in the databases (OpenThesis e OpenGrey), avoiding selection and publication bias. Prospective longitudinal studies concerning the theme: deglutition disorders in individuals with oropharyngeal cancer subjected to conservative therapy were considered eligible. The risk of bias and the evaluation of individual methodological quality of the selected studies were measured by "The Joanna Briggs Institute Critical Appraisal tools for use in JBI Systematic Reviews" for prospective and longitudinal studies. Results: The search resulted in 899 records and after analysis four of them fulfilled the eligibility criteria. Among the studies included, all individuals presented some type of deglutition changes, the most common were: reduced of strength and retraction of the base of the tongue, delayed deglutition trigger, reduced laryngeal elevation, presence of residues on tongue and palate, in the pharyngeal area, valleculae, and posterior pharyngeal wall, as well as in the vestibules and in pyriform sinuses. Conclusion: The evidence from this systematic review suggests that conservative therapies cause deglutition changes or amplify the pre-existing ones, regardless of the type and magnitude of radiation, as well as tumor staging. However, there is little standardization in the research methodologies, making a meta-analysis study difficult to conduct.

RESUMEN Objetivos: Caracterizar la producción científica e identificar las alteraciones de deglución en personas con cáncer de orofaringe sometidas a tratamiento conservador. Métodos: Se realizó una búsqueda en cinco bases de datos electrónicas [Scientific Electronic Library Online (Scielo), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), US National Library of Medicine National Institutes of Health (PubMed), Web of Science y Scopus], además de la literatura gris en las bases de datos OpenThesis y OpenGrey, evitando sesgo de selección y publicación. Se consideraron elegibles los estudios longitudinales prospectivos sobre el tema: trastornos de deglución en pacientes con cáncer de orofaringe sometidos a tratamiento conservador. El riesgo de sesgo y la calidad metodológica individual de los estudios seleccionados se evaluaron mediante la herramienta de evaluación crítica del Instituto Joanna Briggs (JBI) para uso de sus revisiones sistemáticas, estudios prospectivos y longitudinales. Resultados: La búsqueda encontró 899 registros y, tras análisis, cuatro de ellos cumplieron los criterios de elegibilidad. Entre los estudios incluidos, todos los pacientes presentaron algún tipo de trastorno de la deglución. Los más frecuentes fueron: fuerza y retracción reducidas de la base de la lengua, retraso en el disparo de la deglución, elevación laríngea reducida, presencia de residuo en lengua y paladar, en región faríngea, valléculas y pared posterior de la faringe, así como en el interior de los vestíbulos y en los senos piriformes. Conclusión: Esta revisión sistemática sugiere que los tratamientos conservadores producen alteraciones de deglución o intensifican aquellas que ya existen, independientemente del tipo y de la intensidad de radiación, así como de la estadificación del tumor. Hay, sin embargo, poca estandarización en las metodologías de investigación, lo que hace difícil un estudio de metanálisis.

RESUMO Objetivos: Caracterizar a produção científica e identificar as alterações da deglutição em indivíduos com câncer de orofaringe submetidos à terapia conservadora. Métodos: Realizou-se uma busca em cinco base de dados eletrônicas [Scientific Electronic Library Online (Scielo), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), US National Library of Medicine National Institutes of Health (PubMed), Web of Science e Scopus], além da busca da literatura cinzenta nas bases de dados (OpenThesis e OpenGrey), evitando viés de seleção e publicação. Foram considerados elegíveis estudos longitudinais prospectivos sobre o tema: alterações de deglutição em indivíduos com câncer de orofaringe submetidos à terapia conservadora. O risco de viés e a qualidade metodológica individual dos estudos selecionados foram avaliados pela ferramenta de avaliação crítica do Joanna Briggs Institute (JBI) para uso de suas revisões sistemáticas, estudos prospectivos e longitudinais. Resultados: A busca resultou em 899 registros e, após análise, quatro deles atenderam aos critérios de elegibilidade. Entre os estudos incluídos, todos os indivíduos apresentaram algum tipo de alteração de deglutição; os mais frequentes foram: força e retração da base da língua reduzidas, atraso no disparo da deglutição, elevação laríngea reduzida, presença de resíduo em língua e palato, em região faríngea, valéculas e parede posterior da faringe, bem como no interior dos vestíbulos e em seios piriformes. Conclusão: Esta revisão sistemática sugere que as terapias conservadoras produzem distúrbios de deglutição ou intensificam os já existentes, independentemente do tipo e da intensidade de radiação, bem como do estadiamento do tumor. Há, no entanto, pouca padronização nas metodologias das pesquisas, dificultando um estudo de metanálise.

Meteorological and soil surface effects in gamma radiation time series - Implications for assessment of earthquake precursors.

Monitoring of environmental radioactivity for the purpose of earthquake prediction requires the discrimination of anomalies of non-tectonic origin from seismically-induced anomalies. This is a challenging task as time series of environmental radioactivity display a complex temporal pattern reflecting a wide range of different physical processes, including meteorological and surface effects. The present study is based on the detailed time series of gamma radiation from the Eastern North Atlantic (ENA) site in the Azores, and on very high resolution precipitation intensity and soil moisture time series. The results show that an abrupt shift in the average level of the gamma radiation time series previously reported as a potential earthquake precursor can also be explained by a corresponding abrupt change in soil moisture. It was concluded that the reduction of false positive earthquake precursors requires the detailed assessment of both precipitation and soil moisture conditions at high temporal resolution.

Naturally Acquired Binding-Inhibitory Antibodies to Plasmodium vivax Duffy Binding Protein and Clinical Immunity to Malaria in Rural Amazonians.

BACKGROUND: Antibodies to the cysteine-rich domain II of Plasmodium vivax Duffy binding protein (PvDBP) can inhibit binding of this parasite ligand to its receptor on red blood cells, the Duffy antigen/receptor for chemokines. These binding-inhibitory antibodies (BIAbs) also inhibit P. vivax invasion of reticulocytes in vitro. METHODS: To investigate whether naturally acquired anti-PvDBP antibodies are associated with reduced risk of clinical malaria in a population exposed to low levels of P. vivax transmission, we measured total levels of immunoglobulin G antibodies to 5 PvDBP variants and used a functional in vitro assay to quantify their binding-inhibitory activity in a cohort of 466 rural Amazonians followed up for up to 37 months. RESULTS: No association between total immunoglobulin G antibody responses to any PvDBP variant and risk of symptomatic, laboratory-confirmed vivax malaria was observed in this cohort. However, a Cox proportional hazards model, adjusted for age, sex, and genotype for the Duffy antigen/receptor for chemokines, showed a >40% decrease in the prospective risk of clinical vivax malaria in subjects with the strongest BIAb responses (upper and middle terciles). High BIAb responses were mostly PvDBP variant transcending and stable over time. CONCLUSIONS: Strong naturally acquired BIAb responses are associated with a reduced risk of clinical P. vivax malaria in rural Amazonians.

Versão Portuguesa da Escala Breve de Redes Sociais de Lubben (LSNS-6) / Portuguese version of the abbreviated Lubben Social Network Scale (LSNS-6)

A avaliação das redes sociais na investigação e prática gerontológica requer o uso de instrumentos válidos e eficazes que sejam simples, concisos e de fácil aplicação na população idosa. A Escala de Redes Sociais de Lubben (LSNS) é um dos instrumentos mais utilizados para avaliar a integração social e o risco de isolamento social em idosos residentes na comunidade. Este artigo debruça-se sobre a tradução e validação da versão abreviada da escala (LSNS-6) para o Português Europeu e expõe as suas principais características psicométricas.

The assessment of social networks in gerontological and research practice requires valid, concise and reliable short scales that can be easily used with older adults. The Lubben Social Network Scale (LSNS) is one of the most widely used instruments to assess social integration and to screen for social isolation among community-dwelling populations. This study presents the translation and validation process of the SNLS abbreviated version (LSNS-6) to European Portuguese. Main psychometric properties are discussed.