The Wnt signaling pathway in major depressive disorder: A systematic review of human studies.

Despite uncertainty about the specific molecular mechanisms driving major depressive disorder (MDD), the Wnt signaling pathway stands out as a potentially influential factor in the pathogenesis of MDD. Known for its role in intercellular communication, cell proliferation, and fate, Wnt signaling has been implicated in diverse biological phenomena associated with MDD, spanning neurodevelopmental to neurodegenerative processes. In this systematic review, we summarize the functional differences in protein and gene expression of the Wnt signaling pathway, and targeted genetic association studies, to provide an integrated synthesis of available human data examining Wnt signaling in MDD. Thirty-three studies evaluating protein expression (n = 15), gene expression (n = 9), or genetic associations (n = 9) were included. Only fifteen demonstrated a consistently low overall risk of bias in selection, comparability, and exposure. We found conflicting observations of limited and distinct Wnt signaling components across diverse tissue sources. These data do not demonstrate involvement of Wnt signaling dysregulation in MDD. Given the well-established role of Wnt signaling in antidepressant response, we propose that a more targeted and functional assessment of Wnt signaling is needed to understand its role in depression pathophysiology. Future studies should include more components, assess multiple tissues concurrently, and follow a standardized approach.

Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data.

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: A systematic review.

BACKGROUND: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically. METHODS: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk. RESULTS: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies. LIMITATIONS: Substantial heterogeneity among the studies precluded performing a meta-analysis. CONCLUSION: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder.

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Geographical approach analysis of the impact of air pollution on newborn intrauterine growth and cord blood DNA damage in Mexico City.

BACKGROUND: Few epidemiologic studies have focused on the specific source of ambient air pollution and adverse health effects in early life. Here, we investigated whether air pollutants from different emission sources were associated with decreased birth anthropometry parameters and increased DNA adduct formation in mother-child pairs residing in the Mexico City Metropolitan Area (MCMA). METHODS: This cross-sectional study included 190 pregnant women recruited during their last trimester of pregnancy from two hospitals at MCMA, and a Modeling Emissions Inventory (MEI) to calculate exposure to ambient air pollutants from different emissions sources (area, point, mobile, and natural) for two geographical buffers 250 and 750 m radii around the participants households. RESULTS: Contaminants were positively correlated with umbilical cord blood (UCB) adducts, but not with maternal blood (MB) adducts. PM10 emissions (area and point sources, overall emissions), PM2.5 (point sources), volatile organic compounds (VOC), total organic compounds (TOC) from point sources were positively correlated with UCB adducts. Air pollutants emitted from natural sources were correlated with a decrease in MB and UCB adducts. PM10 and PM2.5 were correlated (p < 0.05) with a decrease in birth weight (BW), birth length (BL) and gestational age at term (GA). In multivariate analyses adjusted for potential confounders, PM10 was associated with an increase in UCB adducts. PM10 and PM2.5 from overall emissions were associated with a decrease in BW, BL and GA at term. IMPACT: Results suggested higher susceptibility of newborns compared to mothers to damage related to ambient air pollution. PMs are associated with birth anthropometry parameters and DNA damage in adjusted models, highlighting the need for more strict regulation of PM emissions.

Age-Dependent Sex Differences in the Prevalence of Selective Serotonin Reuptake Inhibitor Treatment: A Retrospective Cohort Analysis.

Background: Antidepressants are among the most prescribed medications in the United States. The aim of this study was to explore the prevalence of antidepressant prescriptions and investigate sex differences and age-sex interactions in adults enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT) study. Materials and Methods: We conducted a retrospective analysis of the RIGHT study. Using electronic prescriptions, we assessed 12-month prevalence of antidepressant treatment. Sex differences and age-sex interactions were evaluated using multivariable logistic regression and flexible recursive smoothing splines. Results: The sample consisted of 11,087 participants (60% women). Antidepressant prescription prevalence was 22.24% (27.96% women, 13.58% men). After adjusting for age and enrollment year, women had significantly greater odds of antidepressant prescription (odds ratio = 2.29; 95% confidence interval = 2.07, 2.54). Furthermore, selective serotonin reuptake inhibitors (SSRIs) had a significant age-sex interaction. While SSRI prescriptions in men showed a sustained decrease with age, there was no such decline for women until after reaching ∼50 years of age. There are important limitations to consider in this study. Electronic prescription data were cross-sectional; information on treatment duration or adherence was not collected; this cohort is not nationally representative; and enrollment occurred over a broad period, introducing confounding by changes in temporal prescribing practices. Conclusions: Underscored by the significant interaction between age and sex on odds of SSRI prescription, our results warrant age to be incorporated as a mediator when investigating sex differences in mental illness, especially mood disorders and their treatment.

Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value.

BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Insulin resistance in bipolar disorder: A systematic review of illness course and clinical correlates.

BACKGROUND: Although insulin resistance (IR) and cardiometabolic syndrome are prevalent in patients with bipolar disorder (BD), only a few studies have attempted to precisely assess the degree and clinical impact of IR in BD. METHODS: A comprehensive search was conducted from multiple research databases through May 2022, following a pre-defined protocol (PROSPERO: CRD42022359259). We extracted neuroimaging, cognition, illness course, and treatment response findings from individuals with BD with evidence of IR compared with euglycemic BD individuals. RESULTS: Of 1436 identified articles, 10 reports fulfilling inclusion criteria were included (n = 1183). BD patients with IR displayed worse composite verbal memory scores and worse executive function and exhibited smaller hippocampal volumes along with prefrontal neurochemical alterations compared to euglycemic BD patients. Fixed-effect meta-analysis revealed that BD patients with impaired glucose metabolism (IGM) were more likely to develop a chronic and rapid cycling course when compared with euglycemic BD patients (k = 2, OR = 2.96, 95 % CI 1.69-5.17, OR = 2.88, 95 % CI 1.59-5.21, p < 0.001, respectively), with a trend for significantly lower Global Assessment of Functioning scores (k = 5, MD = -4, 95 % CI -8.23-0.23, p = 0.06). BD patients with IGM displayed a higher rate of poor response to mood stabilizers when compared with euglycemic BD patients (k = 2, OR = 6.74, 95 % CI 1.04-43.54, p = 0.04). LIMITATIONS: Cross-sectional design and small sample sizes of studies included limit the generalizability of results. CONCLUSION: IR is associated with worse clinical outcomes of BD and inadequate treatment response. Implementing strategies to prevent and treat IR in BD is crucial to improve the prognosis of such a difficult-to-treat population.

Pharmacotherapy exposure as a marker of disease complexity in bipolar disorder: Associations with clinical & genetic risk factors.

Individuals with bipolar disorder (BD) require chronic pharmacotherapy, typically including medication switches or polypharmacy due to persisting symptoms or intolerable side effects. Here, we quantified pharmacotherapy exposure (PE) of Mayo Clinic BD Biobank participants using the number of cross-sectional (at enrollment) and lifetime BD-specific medications and medication classes, to understand the relationship between PE and markers of disease severity or treatment failure, psychiatric comorbidities, and polygenic risk scores (PRS) for six major psychiatric disorders. Being female (p < 0.05), older (p < 0.01), having history of suicide attempts (p < 0.0001), and comorbid attention-deficit/hyperactivity disorder (p < 0.05) or generalized anxiety disorder (p < 0.05) were uniformly associated with higher PE. Lifetime exposure to unique medication classes among participants with BD-I was significantly lower than for those with schizoaffective disorder (estimate = -2.1, p < 0.0001) while significantly higher than for those with BD-II (estimate = 0.5, p < 0.01). Further, higher PRS for schizophrenia (SCZ) and anxiety resulted in greater lifetime medication counts (p < 0.01), both driven by antipsychotic (p < 0.001) and anxiolytic use (p < 0.05). Our results provide initial evidence of the utility of PE as a measure of disease complexity or treatment resistance, and that PE may be predicted by higher genetic risk for SCZ and anxiety.

Spatial organization of rat's behavior in a situation with three optional lever-pressing responses under continuous and fixed-interval schedules of food.

We assessed spatiotemporal distribution of behavior as a function of the spatial and temporal arrangement of food delivery. Eight food-deprived rats were exposed in an extended experimental chamber to a continuous reinforcement schedule (CRf) or to a fixed interval (FI) 30 s, with three levers contiguous to food dispenser or placed on separate panels. Responses on any of the levers were equally operative on the ongoing schedule. All rats moved mainly near to dispenser and levers when these were contiguous, under both, CRf and FI schedules, although distribution of responses on different levers was more variant under FI than under CRf. With separate levers, rats traveled through a larger area of the experimental space, especially under FI. Distribution of responses showed more variation under FI than under CRf schedule. Under FI, response patterns consisted in a post-meal pause followed by an acceleration towards the next food. Findings are discussed in the context of studies in which have been reported inconsistent patterns under FI schedules when are manipulated the number of operanda, dispensers, and their locations. It is highlighted the relevance of continuous analysis of rats' displacement, to account for the configuration of response patterns observed in this study.

CD38 a biomarker and therapeutic target in non-hematopoietic tumors.

The type II transmembrane glycoprotein CD38 has recently been implicated in regulating metabolism and the pathogenesis of multiple conditions, including aging, inflammation and cancer. CD38 is overexpressed in several tumor cells and microenvironment tumoral cells, associated to migration, angiogenesis, cell invasion and progression of the disease. Thus, CD38 has been used as a progression marker for different cancer types as well as in immunotherapy. This review focuses on describing the involvement of CD38 in various non-hematopoietic cancers.

Spatial distribution of behavior under concurrent random-time schedules of water.

A study was designed to explore the effects of concurrent random-time delivery of water on the spatial dimensions of behavior with five different continuous measures in time and space. Four water-deprived male-Wistar rats were exposed to two concurrent random time schedules of water delivered in two dispensers located at opposite walls of an enlarged experimental chamber. In five different phases, the scheduled frequency of water deliveries remained constant while their distribution in each of two dispensers varied systematically. The continuous record of rat location through the experimental chamber was analyzed in terms of the directionality, vigor, variation, preference, and persistence of behavior. Directionality and preference showed systematic variations as the number of dispensers providing water and their timing changed, vigor and variation remained relatively constant through the experimental phases, and persistence showed a slight decrease across phases. Results support the argument that molar continuous measures depict extended moment-to-moment changes in behavioral dimensions usually not considered in the typical procedures recording discrete repetitive responses.

Eritrocitosis secundaria a cardiopatía congénita como causa de pseudohipercalemia / Secundary erithrocitosis from congenital heart disease as a cause of pseudohiperkalemia

Resumen El potasio es, sin lugar a duda, uno de los componentes más importantes del balance hidroelectrolítico, además de ser uno de los exámenes de laboratorio más solicitados en el ámbito clínico. La hipercalemia se define por un valor sérico mayor a 5.5 mEq/L y su principal diagnóstico diferencial es la pseudohipercalemia o hipercalemia espuria. Esta se define como elevación del potasio solo en componente sérico y no plasmático con una diferencia mínima de 0.5 mEq/L. Entre las causas de pseudohipercalemia se encuentran factores mecánicos, químicos, contaminantes, temperatura y tiempo de procesamiento de la muestra. Se reporta el caso de un paciente masculino de 22 años de edad, con antecedentes de cardiopatía cianosante, que cursa con elevación espuria de potasio en suero, con aumento aislado severo del hematocrito y trombocitopenia concomitante, que luego mostraría valores normales en plasma.

Abstract Potassium is, without a doubt, one of the most important components of hydroelectrolitic balance, as well as being one of the most requested laboratory exams in the clinical setting. Hyperkalemia is defined as serum value above 5.5 mEq/L, and its main differential diagnosis is pseudohyperkalemia or spurious hyperkalemia. This conditioned is defined as an elevation of potassium levels exclusively in serum and not in plasma, with a minimal difference of 0.5 mEq/L between these measurements. Some of the causes of pseudohyperkalemia include mechanical factors, chemicals, contaminants, temperature and the time of sample processing. It is reported the case of a 22-year-old male with history of cyanotic heart disease that presented with a spurious elevation of serum potassium, with a severe increment in hematocrit and concomitant thrombocytopenia, that would later show normal levels in plasma.

Gene expression in peripheral blood in treatment-free major depression.

BACKGROUND: Peripheral gene expression of several molecular pathways has been studied in major depressive disorder (MDD) with promising results. We sought to investigate some of these genes in a treatment-free Latino sample of Mexican descent. MATERIAL AND METHODS: The sample consisted of 50 MDD treatment-free cases and 50 sex and age-matched controls. Gene expression of candidate genes of neuroplasticity (BDNF, p11, and VGF), inflammation (IL1A, IL1B, IL4, IL6, IL7, IL8, IL10, MIF, and TNFA), the canonical Wnt signaling pathway (TCF7L2, APC, and GSK3B), and mTOR, was compared in cases and controls. RNA was obtained from blood samples. We used bivariate analyses to compare subjects versus control mean mRNA quantification of target genes and lineal regression modelling to test for effects of age and body mass index on gene expression. RESULTS: Most subjects were female (66%) with a mean age of 26.7 (SD 7.9) years. Only GSK3B was differentially expressed between cases and controls at a statistically significant level (p = 0.048). TCF7L-2 showed the highest number of correlations with MDD-related traits, yet these were modest in size. DISCUSSION: GSK3B encodes a moderator of the canonical Wnt signaling pathway. It has a role in neuroplasticity, neuroprotection, depression, and other psychiatric phenotypes. We found that adding population diversity has the potential to elicit distinct peripheral gene expression markers in MDD and MDD-related traits. However, our results should only be considered as hypothesis-generating research that merits further replication in larger cohorts of similar ancestry.

Prenatal exposure to particulate matter and ozone: Bulky DNA adducts, plasma isoprostanes, allele risk variants, and neonate susceptibility in the Mexico City Metropolitan Area.

Mexico City's Metropolitan Area (MCMA) includes Mexico City and 60 municipalities of the neighbor states. Inhabitants are exposed to emissions from over five million vehicles and stationary sources of air pollutants such as particulate matter (PM) and ozone. MCMA PM contains elemental carbon and organic carbon (OC). OCs include polycyclic aromatic hydrocarbons (PAHs), many of which induce mutagenic and carcinogenic DNA adducts. Gestational exposure to air pollution has been associated with increased risk of intrauterine growth restriction, preterm birth or low birth weight risk, and PAH-DNA adducts. These effects also depend on the presence of risk alleles. We investigated the presence of bulky PAH-DNA adducts, plasma 8-iso-PGF2α (8-iso-prostaglandin F2α ) and risk allele variants in neonates cord blood and their non-smoking mothers' leucocytes from families that were living in a highly polluted area during 2014-2015. The presence of adducts was significantly associated with both PM2.5 and PM10 levels, mainly during the last trimester of gestation in both neonates and mothers, while the last month of pregnancy was significant for the association between ozone levels and maternal plasma 8-iso-PGF2α . Fetal CYP1B1*3 risk allele was associated with increased adduct levels in neonates while the presence of the maternal allele significantly reduced the levels of fetal adducts. Maternal NQO1*2 was associated with lower maternal levels of adducts. Our findings suggest the need to reduce actual PM limits in MCMA. We did not observe a clear association between PM and/or adduct levels and neonate weight, length, body mass index, Apgar or Capurro score. Environ. Mol. Mutagen. 60:428-442, 2019. © 2019 Wiley Periodicals, Inc.

Reinforcing and timing properties of water in the schedule-induced drinking situation.

A series of recent studies from our laboratory have added to the preceding literature on the potential role of water (in addition to food) as a positive reinforcer in the schedule-induced drinking situation, thus suggesting that adjunctive behaviors might have motivational properties that make their engagement a preferable alternative. It has also been suggested that adjunctive behaviors serve as a behavioral clock that helps organisms to estimate time, making their engagement motivational, so that they enable more accurate time adjustment under temporal schedules. Here, we review some of these experiments on conditioned reinforcement and concurrent chains, as well as on temporal learning. Data presented in this article suggest that adjunctive behaviors may be a part of the behavior patterns maintained by reinforcement, thus serving towards a better performance in temporal tasks.

Reparación endoscópica transnasal de la atresia de coanas. Estado del arte: resultados en 16 casos Hospital Universitario del Valle - Universidad del Valle. Cali, Colombia / Transnasal endoscopic repair of choanal atresia. State of the Art: results in 16 cases

Objetivo: Describir la epidemiologia local y la experiencia en el manejo de casos de atresia de coanas con la técnica de cirugía endoscópica transnasal e instrumental de poder. Diseño: Estudio retrospectivo. Metodología: Se toman 16 casos con diagnóstico de atresia de coanas, en los que fueron consideradas variables clínicas, método diagnóstico, lateralidad, tipo de atresia, manejo inicial y técnica quirúrgica. Se realizó análisis estadístico en Stata, versión 11.1. Resultados: En esta serie de casos, diez eran mujeres y seis hombres, con una relación mujer-hombre de 1,7:1; 56% de ellos fueron bilaterales, 56% de presentaron anomalías congénitas y la edad al diagnóstico fue postneonatal en el 81%. No se encontró asociación estadística entre sexo, tipo de atresia y lateralidad. El principal método diagnóstico fue la tomografía axial computarizada, en el 87,6% de los estudios. El 94% de los pacientes presentaron buen resultado quirúrgico funcional con la técnica endoscópica…

Objective: Describe the local epidemiology and the experience in the management of choanal atresia with endoscopic transnasal approach and power instruments. Methodology: Retrospective study of 16 cases with diagnosis of choanal atresia was considered variable clinics, diagnosis method, laterality, type of atresia, initial management and surgical technique. We performed statistical analysis in Stata, version 11.1. Results: In this series of cases, 10 was women and 6 was men, relation 1,7:1; 56% had associated congenital anomalies, the age of diagnosis was post neonatal 81%. There was no statistical association between sex, type of atresia and latelality. The main method diagnosis was the TAC in 87.6%. 94% of the patients showed a good surgical outcome with functional endoscopic technique. Conclusions: The experience observed in this series of cases with the use of technique endoscopic transnasal and power instrumentation (Shaver - Drill), represent a form of technique minimal invasive approach for this type of nasal congenital pathology with low degree of morbility, complications and excellent functional results…