Rethinking Benefits in Health Research, Reflections of an Ethics Committee.

The principle of beneficence in health research implies the effort of researchers to minimize risk to participants and maximize benefits to participants and society, which could be considered an abstract definition. Therefore, the benefits are not easily conceived by researchers who fail to achieve their goal, which is to privilege the well-being of participants. The purpose of this work was to describe and discuss the theoretical elements that support the principle of beneficence so that their knowledge allows designing and granting adequate benefits to participants. The present document defines the principle of beneficence. It also analyzes the maximization of benefits, the distinctions between different classifications of benefits, and the differentiation from compensations or incentives. With all this information, researchers must do a critical deliberation to select adequate benefits for participants of their studies, considering the type of study, potential participants, probability of risk, among others. These benefits should not be understood as a charity that researchers grant to the participant; they should be conceived as any form of action in favor of the well-being of participants. Participants must always be considered as moral agents, responsible for deciding whether the benefits would outweigh the possible negative unintended consequences of a particular study. Finally, no risk should be taken if it is not commensurate or proportional to the benefit of the research study.

Integrative DNA Methylation and Gene Expression Analysis in the Prefrontal Cortex of Mexicans Who Died by Suicide.

BACKGROUND: Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. METHODS: In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. RESULTS: We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing. CONCLUSION: Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.

Suicidal ideation and planning among Mexican adolescents are associated with depression polygenic risk scores.

Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA individuals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N = 1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N = 437, 20-25 years, 63% women). At both assessments, individuals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.

Inflammatory Profiles in Depressed Adolescents Treated with Fluoxetine: An 8-Week Follow-up Open Study.

Changes in cytokine levels in major depression and during treatment have been reported in adults. However, few studies have examined cytokine levels in an adolescent sample despite this being a common age of onset. Methods. We measured proinflammatory (IL-2, IFN-γ, IL-1ß, TNF-α, IL-6, IL-12, and IL-15) and anti-inflammatory (IL-4, IL-5, IL-13, IL-1Ra, and IL-10) cytokine serum levels in 22 adolescents with major depression and 18 healthy volunteers. Cytokines were measured by multiplex bead-based immunoassays at baseline, and 4 and 8 weeks after commencement of fluoxetine administration in the clinical group. Results. Compared to healthy volunteers, adolescents with major depression at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1Ra and IL-10. Significant changes were observed in fluoxetine treatment compared to baseline: proinflammatory cytokines IFN-γ, IL-1ß, TNF-α, IL-6, IL-12, and IL-15 were decreased only at week 4 whereas IL-2 was increased only at week 8; anti-inflammatory cytokines IL-4 and IL-5 were increased at week 8 while IL-1Ra was reduced only at week 4. There were no significant correlations between cytokine levels and symptomatic improvement in HDRS. Discussion. The results suggest a significant interplay between cytokine levels, the depressive state, and the stage of treatment with an SSRI. To the best of our knowledge, this is the first report in depressed adolescents with elevated IL-12, IL-13, and IL-15 levels. Further studies are necessary to clarify the role and mechanisms of altered cytokine levels in the pathogenesis and physiopathology of major depressive disorder.

Genetic and epigenetic regulation of the brain-derived neurotrophic factor in the central nervous system.

The BDNF is required for the development and proper function of the central nervous system, where it is involved in a variety of neural and molecular events relevant to cognition, learning, and memory processes. Although only a functional mature protein is synthesized, the human BDNF gene possesses an extensive structural complexity, including the presence of multiple promoters, splicing events, and 3´UTR poly-adenylation sites, resulting in an intricate transcriptional regulation and numerous messengers RNA. Recent data support specific cellular roles of these transcripts. Moreover, a central role of epigenetic modifications on the regulation of BDNF gene transcription is also emerging. The present essay aims to summarize the published information on the matter, emphasizing their possible implications in health and disease or in the treatment of different neurologic and psychiatric disorders.

Associations of externalizing polygenic scores with externalizing disorders among Mexican youth.

Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.

After a disaster: Validation of PTSD checklist for DSM-5 and the four- and eight-item abbreviated versions in mental health service users.

Posttraumatic stress disorder (PTSD) is a common and disabling condition developing in one of four survivors after an earthquake. Brief and self-reported validated measures for assessing PTSD symptom severity are necessary to improve care access and assess disorder progress and treatment response. Therefore, we evaluated the psychometric properties of the PTSD-Checklist for the DSM-5 (PCL-5) of 20-, 8- and 4-item in patients that sought specialized mental health services after a catastrophic earthquake that stroke Mexico on September 19th, 2017. The internal consistency of 20-, 8- and 4-item PCL-5 was adequate (≥.7). Using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) as a reference, signal detection analyses revealed a PCL-5 score of 27 as optimal (sensitivity = .96, specificity = .73) for identifying probable PTSD cases. The shortened versions highly correlated with the full PCL-5 and had comparable diagnostic utility. Our results indicate that the 20-item PCL-5 and the abridged versions can effectively identify possible PTSD cases. The 8-item version has better psychometric properties and more consistent diagnostic utility across time and civil populations. These measures must be evaluated in independent samples to corroborate their utility in different populations and regarding diverse traumatic events.

BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents.

BACKGROUND: The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence. METHODS: Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence. RESULTS: Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a "refractory" or resilient phenotype to the noticeable influence of CAs. CONCLUSION: Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures.

Estudio de la variabilidad genética del DRD4 y del DAT1 en individuos habitantes de la Ciudad de México / Genetic variability study of DRD4 and DAT1 in the urban population of Mexico City

Family, twin and adoption studies suggest that genetics plays an important role in the etiology of many psychiatric disorders. It has been proposed that the dopaminergic brain system could be affected in schizophrenia, substance abuse and attention deficit hyperactivity disorder. The most studied genes are two VNTR polymorphic systems; one located in the exon 3 of the dopamine D4 receptor (DRD4) gene, and the other in the 3' untranslated region of the dopamine transporter (DAT1 or SCLA6A3) gene. It has been reported that allele frequencies of these polymorphisms varied between populations and this could affect the results in the association studies. Due to the previous findings, the objective of the present study was to determine the allele frequencies of DRD4 and DAT1 in an epidemiological sample of the adolescent population of México City. We found that the frequencies presented in our study were in between those reported for Caucasians and those reported for the American Indigenous population, this result are consistent with Euro-Indigenous inbreeding that has occurred in Mexico. Moreover, the results presented in the present study could explain the lack of consistency in the association analysis and make necessary to develop these investigations in our population.

Existe evidencia fehaciente de la influencia genética en los trastornos psiquiátricos y se ha propuesto que el sistema dopáminergico cerebral puede ser uno de los afectados en diversos trastornos como la esquizofrenia, el abuso de sustancias y el trastorno por déficit de atención e hiperactividad. En este sentido, los sistemas genéticos más estudiados son 2 VNTRs; uno localizado en el exón 3 del gen del Receptor a dopamina D4 (DRD4) y el otro en la región 3' no traducida del transportador a dopamina (DAT1 o SCL6A3). Se ha reportado que las frecuencias alélicas de estos polimorfismos difieren significativamente entre poblaciones y que esto puede afectar los resultados en los estudios de asociación. Debido a lo anterior, el objetivo del presente trabajo fue determinar las frecuencias alélicas del DRD4 y del DAT1 a partir de una muestra epidemiológica de la población adolescente de la Ciudad de México. Las frecuencias alélicas reportadas en el presente estudio son intermedias a las reportadas en caucásicos y poblaciones indígenas de América, lo que concuerda con la historia de mestizaje ocurrida en México. Estás diferencias pueden ayudar a explicar la falta de consistencia en diferentes estudios de asociación y hacen necesario realizarlos en población mexicana.

Thrombocytosis induced in mice after subacute and subchronic V2O5 inhalation.

Reports about vanadium (V) inhalation toxicity on the hematopoietic system, specifically about coagulation are limited. Therefore, we decided to evaluate the effects of V with a complete blood count and morphologic analysis of platelets on blood smears. CD-1 male mice inhaled V2O5 0.02 M 1 h twice weekly over 12 weeks. Blood samples were obtained by direct heart puncture; Wright stained smears were used for platelet quantification. An increase in platelet count from the third week of exposure was observed, as well as the presence of megaplatelets. Our results demonstrate, for the first time, that V induces thrombocytosis and it might correlate with some thromboembolic diseases. Further analysis is needed to evaluate the functionality of these platelets as well as the cause of its increase.

Inhaled vanadium pentoxide decrease gamma-tubulin of mouse testes at different exposure times.

Vanadium is an important environmental and industrial pollutant whose concentrations have increased in the last decades. Due to its status as reproductive toxicant and a microtubule damaging agent, the present study investigated by immunohistochemistry the effect of the inhalation of vanadium pentoxide on gamma-tubulin within somatic and testicular germ cells. Male mice inhaled vanadium pentoxide (V2O5) (0.02 M) 1 h/twice a week for 12 weeks. Our results demonstrated that vanadium accumulates in the testes starting with the initial inhalation (24 h), and this pattern remained until the last week of treatment. In general, vanadium was capable of significantly decreasing the percentage of gamma-tubulin in all analyzed testicular cells (Sertoli, Leydig and germ cells) starting with the first week of treatment. For all cell types studied, regression analysis revealed a negative and significant relationship between the percentage of immunopositive cells to gamma-tubulin and exposure time, showing a time dependent response in all cases. Our findings suggest that alterations on this protein might imply changes in microtubule-involved function such as cell division, which in the testes might lead to damage in the spermatogenesis, leading probably to infertility.