Sexual Dimorphisms of Protein-Coding Gene Profiles in Placentas From Women With Systemic Lupus Erythematosus.

Background: Systemic lupus erythematosus (SLE) may cause pathogenic changes in the placentas during human pregnancy, such as decreased placental weight, intraplacental hematoma, ischemic hypoxic change, placental infarction, and decidual vasculopathy, which contribute to high maternal and fetal mortality and morbidity. Sex-specific adaptations of the fetus are associated with SLE pregnancies. The present study aimed to determine the transcriptomic profiles of female and male placentas from women with SLE. Methods: RNA sequencing (RNA-seq) was performed to identify differentially expressed protein-coding genes (DEGs) in placentas from women with SLE vs. normal term (NT) pregnancies with female and male fetuses (n = 3-5/sex/group). Real-time-quantitative PCR was performed (n = 4 /sex/group) to validate the RNA-seq results. Bioinformatics functional analysis was performed to predict the biological functions and pathways of SLE-dysregulated protein-coding genes. Results: Compared with NT-female (NT-F) placentas, 119 DEGs were identified in SLE-female (SLE-F) placentas. Among these 119 DEGs, five and zero are located on X- and Y-chromosomes, respectively, and four are located on the mitochondrial genome. Compared with NT-male (NT-M) placentas, 458 DEGs were identified in SLE-male (SLE-M) placentas, among which 16 are located on the X-chromosome and zero on the Y-chromosome and mitochondrial genome. Twenty-four DEGs were commonly dysregulated in SLE-F and -M placentas. Functional analysis showed that SLE-dysregulated protein-coding genes were associated with diverse biological functions and pathways, including angiogenesis, cellular response to growth factor stimulus, heparin-binding, HIF (hypoxia-inducible factor)-1 signaling pathway, and Interleukin-17 (IL-17) signaling pathway in both SLE-F and -M placentas. Biological regulations were differentially enriched between SLE-F and -M placentas. Regulation of blood circulation, response to glucocorticoid, and rhythmic process were all enriched in SLE-F, but not SLE-M placentas. In contrast, tumor necrosis factor production, Th17 cell differentiation, and MDA (melanoma differentiation-associated gene)-5 signaling pathway were enriched in SLE-M but not SLE-F placentas. Conclusion: This report investigated the protein-coding gene profiles of placenta tissues from SLE patients using RNA-seq. The results suggest that the SLE-dysregulated protein-coding genes in placentas may contribute to the pathophysiological progress of SLE pregnancies in a fetal sex-specific manner, leading to adverse pregnancy outcomes.

Lifetime experience of multiple common mental disorders and 19-year mortality: results from a Canadian population-based cohort.

AIMS: To examine the impact of multiple psychiatric disorders over the lifetime on risk of mortality in the general population. METHODS: Data came from a random community-based sample of 1397 adults in Atlantic Canada, recruited in 1992. Major depression, dysthymia, panic disorder, generalised anxiety disorder and alcohol use disorders were assessed using the Diagnostic Interview Schedule (DIS). Vital status of participants through 2011 was determined using probabilistic linkages to the Canadian Mortality Database. Cox proportional hazard models with age at study entry as the time scale were used to investigate the relationship between DIS diagnoses and mortality, adjusted for participant education, smoking and obesity at baseline. RESULTS: Results suggested that mood and anxiety disorders rarely presented in isolation - the majority of participants experienced multiple psychiatric disorders over the lifetime. Elevated risk of death was found among men with both major depression and dysthymia (HR 2.56; 95% CI 1.12-5.89), depression and alcohol use disorders (HR 2.45; 95% CI 1.18-5.10) and among men and women who experienced both panic disorder and alcohol use disorders (HR 3.80; 95% CI 1.19-12.16). CONCLUSION: The experience of multiple mental disorders over the lifetime is extremely common, and associated with increased risk of mortality, most notably among men. Clinicians should be aware of the importance of considering contemporaneous symptoms of multiple psychiatric conditions.

Cyberbullying victimisation and internalising and externalising problems among adolescents: the moderating role of parent-child relationship and child's sex.

AIMS: Previous research has found links between cyberbullying victimisation and internalising and externalising problems among adolescents. However, little is known about the factors that might moderate these relationships. Thus, the present study examined the relationships between cyberbullying victimisation and psychological distress, suicidality, self-rated poor mental health and substance use among adolescents, and tested whether parent-child relationship and child's sex would moderate these relationships. METHODS: Self-report data on experiences of cyberbullying victimisation, self-rated poor mental health, psychological distress, suicidality and substance use were derived from the 2013 Ontario Student Drug Use and Health Survey, a province-wide school-based survey of students in grades 7 through 12 aged 11-20 years (N = 5478). Logistic regression models adjusted for age, sex, ethnicity, subjective socioeconomic status and involvement in physical fighting, bullying victimisation and perpetration at school. RESULTS: Cyberbullying victimisation was associated with self-rated poor mental health (adjusted odds ratio (OR) 2.15; 95% confidence interval (CI) 1.64-2.81), psychological distress (OR 2.41; 95% CI 1.90-3.06), suicidal ideation (OR 2.38; 95% CI 1.83-3.08) and attempts (OR 2.07; 95% CI 1.27-3.38), smoking tobacco cigarette (OR 1.96; 95% CI 1.45-2.65), cannabis use (OR 1.82; 95% CI 1.32-2.51), and binge drinking (OR 1.44; 95% CI 1.03-2.02). The association between cyberbullying victimisation and psychological distress was modified by parent-child relationship and child's sex (three-way interaction term p < 0.05). The association between cyberbullying victimisation and psychological distress was much stronger among boys who have a negative relationship with their parents. CONCLUSIONS: Findings suggest that cyberbullying victimisation is strongly associated with psychological distress in most adolescents with the exception of males who get along well with their parents. Further research using a longitudinal design is necessary to disentangle the interrelationship among child's sex, parent-child relationship, cyberbullying victimisation and mental health outcomes among adolescents in order to improve ongoing mental health prevention efforts.

Childhood adversity and subsequent mental health status in adulthood: screening for associations using two linked surveys.

AIMS: Accumulating evidence links childhood adversity to negative health outcomes in adulthood. However, most of the available evidence is retrospective and subject to recall bias. Published reports have sometimes focused on specific childhood exposures (e.g. abuse) and/or specific outcomes (e.g. major depression). Other studies have linked childhood adversity to a large and diverse number of adult risk factors and health outcomes such as cardiovascular disease. To advance this literature, we undertook a broad examination of data from two linked surveys. The goal was to avoid retrospective distortion and to provide a descriptive overview of patterns of association. METHODS: A baseline interview for the Canadian National Longitudinal Study of Children and Youth collected information about childhood adversities affecting children aged 0-11 in 1994. The sampling procedures employed in a subsequent study called the National Population Health Survey (NPHS) made it possible to link n = 1977 of these respondents to follow-up data collected later when respondents were between the ages of 14 and 27. Outcomes included major depressive episodes (MDE), some risk factors and educational attainment. Cross-tabulations were used to examine these associations and adjusted estimates were made using the regression models. As the NPHS was a longitudinal study with multiple interviews, for most analyses generalized estimating equations (GEE) were used. As there were multiple exposures and outcomes, a statistical procedure to control the false discovery rate (Benjamini-Hochberg) was employed. RESULTS: Childhood adversities were consistently associated with a cluster of potentially related outcomes: MDE, psychotropic medication use and smoking. These outcomes may be related to one another since psychotropic medications are used in the treatment of major depression, and smoking is strongly associated with major depression. However, no consistent associations were observed for other outcomes examined: physical inactivity, excessive alcohol consumption, binge drinking or educational attainment. CONCLUSIONS: The conditions found to be the most strongly associated with childhood adversities were a cluster of outcomes that potentially share pathophysiological connections. Although prior literature has suggested that a very large number of adult outcomes, including physical inactivity and alcohol-related outcomes follow childhood adversity, this analysis suggests a degree of specificity with outcomes potentially related to depression. Some of the other reported adverse outcomes (e.g. those related to alcohol use, physical inactivity or more distal outcomes such as obesity and cardiovascular disease) may emerge later in life and in some cases may be secondary to depression, psychotropic medication use and smoking.

A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis.

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

Déficit de vitamina D en pacientes post-menopáusicas y su relación con el metabolismo fosfocálcico y la osteoporosis / Vitamin D deficiency in post-menopausal patients and its relation with the mineral metabolism and the osteoporosis

La influencia de la hipovitaminosis D en la mujer post-menopáusica constituye un tema de gran importancia por las implicancias en el metabolismo fosfo-cálcico y su posible asociación en el desarrollo de otros tipos de patologías. Es por eso que el presente estudio tiene por objetivo conocer la prevalencia de la hipovitaminosis D en una población de mujeres post-menopáusicas y su asociación con los cambios en el metabolismo fosfocálcico y con el desarrollo de la osteoporosis. Se incluyó 67 mujeres post-menopáusicas procedentes de una consulta ambulatoria de reumatología. Se consideraron las siguientes variables clínicas (i.e. edad, peso), laboratorio (i.e. concentraciones de calcio, fosforo y PTH) y la presencia o ausencia de osteopenia u osteoporosis. El valor de la media de la edad de las pacientes fue de 66 ± 11,29 años y las concentraciones de vitamina D inferior a 30 ng/ml se observó en 50 (74,6%) pacientes. La osteopenia u osteoporosis se observó en una parte importante de nuestros pacientes. No se observó una correlación significativa entre las concentraciones de vitamina D y las concentraciones de calcio y fósforo. Se observó una correlación negativa en relación a las concentraciones de PTH (P= 0,049). Las pacientes con osteoporosis u osteopenia presentan con frecuencia hipovitaminosis D. Es por eso que existe la necesidad de realizar una detección y tratamiento temprano a fin de evitar las graves complicaciones que podrían acompañar a la pérdida de densidad ósea en este grupo de pacientes.

Maternal distress in early life predicts the waist-to-hip ratio in schoolchildren.

We report on life course stress determinants of overweight in children, using data from the longitudinal follow-up of the nested case-control arm of the SAGE (study of asthma genes and the environment) birth cohort in Manitoba, Canada. Waist and hip measurements were obtained during a clinic visit at age 9-11 years. Multiple linear regression was conducted to determine the relationship between the waist-to-hip ratio and maternal smoking during pregnancy, postpartum maternal distress and stress reactivity in children (cortisol, cortisol-DHEA [dihydroepiandrostrenone] ratio quartiles) following a clinic stressor at age 8-10 years. We found waist-to-hip risk at age 9-11 years to be elevated among boys and girls whose mothers had experienced distress in the postnatal period. This association varied by gender and asthma status. In healthy girls, postpartum distress increased waist-to-hip ratio by a factor of 0.034 (P < 0.01), independent of the child's stage of puberty and adrenarche, cortisol-DHEA ratio and duration of exclusive breastfeeding. Among girls with asthma, maternal smoking during pregnancy was associated with an increased waist-to-hip ratio, if the mother also experienced distress in the postpartum period (0.072, P = 0.038). Among asthmatic boys, an association between maternal distress and waist-to-hip ratio was evident at the highest cortisol-DHEA ratios. Stress-induced changes to leptin and infant over-eating pathways were proposed to explain the postnatal maternal distress effects. Drawing on the theories of evolutionary biology, our findings underscore the significance of postnatal stress in disrupting hypothalamic-pituitary-adrenal axis function in infants and increasing risk for child overweight.