Hepatotoxic Evaluation of N-(2-Hydroxyphenyl)-2-Propylpentanamide: A Novel Derivative of Valproic Acid for the Treatment of Cancer.

Valproic acid (VPA) is a drug that has various therapeutic applications; however, it has been associated with liver damage. Furthermore, it is interesting to propose new compounds derived from VPA as N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA). The HO-AAVPA has better antiproliferative activity than the VPA in different cancer cell lines. The purpose of this study was to evaluate the liver injury of HO-AAVPA by acute treatment (once administration) and repeated doses for 7 days under intraperitoneal administration. The median lethal dose value (LD50) was determined in rats and mice (females and males) using OECD Guideline 425. In the study, male rats were randomly divided into 4 groups (n = 7), G1: control (without treatment), G2: vehicle, G3: VPA (500 mg/kg), and G4: HO-AAVPA (708 mg/kg, in equimolar ratio to VPA). Some biomarkers related to hepatotoxicity were evaluated. In addition, macroscopic and histological studies were performed. The LD50 value of HO-AAVPA was greater than 2000 mg/kg. Regarding macroscopy and biochemistry, the HO-AAVPA does not induce liver injury according to the measures of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutathione peroxidase, glutathione reductase, and catalase activities. Comparing the treatment with HO-AAVPA and VPA did not show a significant difference with the control group, while malondialdehyde and glutathione-reduced levels in the group treated with HO-AAVPA were close to those of the control (p ≤ 0.05). The histological study shows that liver lesions caused by HO-AAVPA were less severe compared with VPA. Therefore, it is suggested that HO-AAVPA does not induce hepatotoxicity at therapeutic doses, considering that in the future it could be proposed as an antineoplastic drug.

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.

Childhood wheezing phenotypes and their association to perinatal factors: a longitudinal study.

INTRODUCTION: Multiple gestational and early life factors have been described as the variables that increase the risk for each phenotype of infantile wheezing. Our objective was to study the evolution of wheezing in a cohort of children followed up to 9-10 years of age and its relationship with different perinatal risk factors. METHODS: A longitudinal study was made on the evolution of wheezing, over time, in 1164 children from Salamanca (Spain) included in the International Study of Wheezing in Infants, when the children were 12 months old. They were classified into three phenotypes: transient early wheezing (last episode before 3 years of age), early persistent wheezing (start before 3 years age and persisting thereafter), and late-onset wheezing (first episode after 3 years of age). Univariate and multivariable analyses were performed to establish associations between the different phenotypes and perinatal factors. RESULTS: Data were obtained corresponding to a total of 531 children. Of these, 169 (31.8%) had experienced transient early wheezing, 100 (18.8%) early persistent wheezing, 28 (5.3%) late-onset wheezing, and 234 (44.1%) had never experienced wheezing. Cesarean delivery, early exposure to infections, the presence of atopic eczema, and a smoking father were associated with transient early wheezing. Early persistent wheezing was associated with a family history of allergy, smoking, and obstetric diseases. Exclusive breastfeeding was identified as a protective factor in both transient and persistent early wheezing. Late-onset wheezing was associated with the male gender and with maternal history of rhinitis and eczema. CONCLUSIONS: Wheezing phenotypes were associated with different risk perinatal factors. Knowledge in the field is essential in order to influence the modifiable factors.

Candidate pharmacological treatments for substance use disorder and suicide identified by gene co-expression network-based drug repositioning.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Brain Gene Expression Profiling of Individuals With Dual Diagnosis Who Died by Suicide.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.

Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results.

BACKGROUND: Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. OBJECTIVE: The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. METHODS: Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. RESULTS: We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. CONCLUSIONS: The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

Exploratory analysis of genetic variants influencing molecular traits in cerebral cortex of suicide completers.

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

Economic Downturns and Inequities in Birth Outcomes: Evidence From 149 Million US Births.

Using birth certificate data for nearly all registered US births from 1976 to 2016 and monthly data on state unemployment rates, we reexamined the link between macroeconomic variation and birth outcomes. We hypothesized that economic downturns reduce exposure to work-related stressors and pollution while increasing exposure to socioeconomic stressors like job loss. Because of preexisting inequalities in health and other resources, we expected that less-educated mothers and black mothers would be more exposed to macroeconomic variation. Using fixed-effect regression models, we found that a 1-percentage-point increase in state unemployment during the first trimester of pregnancy increased the probability of preterm birth by 0.1 percentage points, while increases in the state unemployment rate during the second/third trimester reduced the probability of preterm birth by 0.06 percentage points. During the period encompassing the Great Recession, the magnitude of these associations doubled in size. We found substantial variation in the impact of economic conditions across different groups, with highly educated white women least affected and less-educated black women most affected. The results highlight the increased relevance of economic conditions for birth outcomes and population health as well as continuing, large inequities in the exposure and impact of macroeconomic fluctuations on birth outcomes.

Complex relationships between vitamin D and allergic sensitization among Puerto Rican 2-year-old children.

BACKGROUND: In the United States, Puerto Ricans have a higher prevalence of asthma than other Latino ethnicities. Low vitamin D levels for children living in northern climates could be a factor. OBJECTIVE: To assess serum 25-hydroxyvitamin D [25(OH)D] distributions (a marker of vitamin D) and associations among vitamin D, allergic sensitization, early wheeze, and home/demographic factors. METHODS: Puerto Rican infants born in New York City, with a maternal history of atopy, were enrolled in a birth cohort. Blood was collected at age 2 years (n = 154; 82 males and 72 females). Serum 25(OH)D and immunoglobulin E (IgE) (indoor allergen-specific and total) were determined using immunoassays. Home/demographic characteristics and respiratory symptoms were assessed by questionnaire. RESULTS: The median concentration of 25(OH)D was 22.6 ng/mL; 32% were at risk of deficiency or inadequacy (<12 or 12-19 ng/mL). Serum 25(OH)D levels were lower in the heating (a surrogate for less sun exposure in colder months) compared with nonheating (26.1 vs 22.7 ng/mL, P = .02) season, but were not associated with allergen-specific IgE levels or with level of acculturation (measured by maternal birthplace). However, low 25(OH)D levels (below median) were associated with high total IgE >100 IU/mL (P = .01). Also, 25(OH)D concentrations differed between children who attended daycare and those who did not (21.8 vs 24.5 ng/mL; t test, P = .02). Serum 25(OH)D was not associated with wheeze or asthma by 2 years of age (P = .43). CONCLUSION: Vitamin D deficiency, possibly linked with allergic pathways, may partially explain the trajectory for disproportionate asthma burden among Puerto Ricans, especially those born and raised in colder climates.

The effects of a housing mobility experiment on participants' residential environments.

We used the Moving to Opportunity (MTO) housing experiment to inform how housing choice vouchers and housing mobility policies can assist families living in high-poverty areas to make opportunity moves to higher quality neighborhoods, across a wide range of neighborhood attributes. We compared the neighborhood attainment of the three randomly-assigned MTO treatment groups (Low Poverty voucher, Section 8 voucher, Control group) at 1997 and 2002 locations (4-7 years after baseline), by using survey reports, and by linking residential histories to numerous different administrative and population-based datasets. Compared to controls, families in Low-Poverty and Section 8 groups experienced substantial improvements in neighborhood conditions across diverse measures, including economic conditions, social systems (e.g., collective efficacy), physical features of the environment (e.g., tree cover) and health outcomes. The Low-poverty voucher group moreover achieved better neighborhood attainment compared to Section 8. Treatment effects were largest for New York and Los Angeles. We discuss the implications of our findings for expanding affordable housing policy.

Acetylcholinesterase is associated with a decrease in cell proliferation of hepatocellular carcinoma cells.

Acetylcholinesterase (AChE), the enzyme that rapidly splits acetylcholine into acetate and choline, presents non-cholinergic functions through which may participate in the control of cell proliferation and apoptosis. These two features are relevant in cancer, particularly in hepatocellular carcinoma (HCC), a very aggressive liver tumor with high incidence and poor prognosis in advanced stages. Here we explored the relation between acetylcholinesterase and HCC growth by testing the influence of AChE on proliferation of Huh-7 and HepG2 cell lines, addressed in monolayer cultures, spheroid formation and human liver tumor samples. Results showed a clear relation in AChE expression and cell cycle progression, an effect which depended on cell confluence. Inhibition of AChE activity led to an increase in cell proliferation, which was associated with downregulation of p27 and cyclins. The fact that Huh-7 and HepG2 cell lines provided similar results lent weight to the relationship of AChE expression with cell cycle progression in hepatoma cell lines at least. Human liver tumor samples exhibited a decrease in AChE activity as compared with normal tissue. The evidence presented herein provides additional support for the proposed tumor suppressor role of AChE, which makes it a potential therapeutic target in therapies against hepatocellular carcinoma.

Safety and risk factors for difficult endoscopist-directed ERCP sedation in daily practice: a hospital-based case-control study.

BACKGROUND: There are limited data concerning endoscopist-directed endoscopic retrograde cholangiopancreatography deep sedation. The aim of this study was to establish the safety and risk factors for difficult sedation in daily practice. PATIENTS AND METHODS: Hospital-based, frequency matched case-control study. All patients were identified from a database of 1,008 patients between 2014 and 2015. The cases were those with difficult sedations. This concept was defined based on the combination of the receipt of high-doses of midazolam or propofol, poor tolerance, use of reversal agents or sedation-related adverse events. The presence of different factors was evaluated to determine whether they predicted difficult sedation. RESULTS: One-hundred and eighty-nine patients (63 cases, 126 controls) were included. Cases were classified in terms of high-dose requirements (n = 35, 55.56%), sedation-related adverse events (n = 14, 22.22%), the use of reversal agents (n = 13, 20.63%) and agitation/discomfort (n = 8, 12.7%). Concerning adverse events, the total rate was 1.39%, including clinically relevant hypoxemia (n = 11), severe hypotension (n = 2) and paradoxical reactions to midazolam (n = 1). The rate of hypoxemia was higher in patients under propofol combined with midazolam than in patients with propofol alone (2.56% vs. 0.8%, p < 0.001). Alcohol consumption (OR: 2.674 [CI 95%: 1.098-6.515], p = 0.030), opioid consumption (OR: 2.713 [CI 95%: 1.096-6.716], p = 0.031) and the consumption of other psychoactive drugs (OR: 2.015 [CI 95%: 1.017-3.991], p = 0.045) were confirmed to be independent risk factors for difficult sedation. CONCLUSIONS: Endoscopist-directed deep sedation during endoscopic retrograde cholangiopancreatography is safe. The presence of certain factors should be assessed before the procedure to identify patients who are high-risk for difficult sedation.

The role of molecular structure of sugar-phosphate backbone and nucleic acid bases in the formation of single-stranded and double-stranded DNA structures.

Our previous DFT computations of deoxydinucleoside monophosphate complexes with Na(+)-ions (dDMPs) have demonstrated that the main characteristics of Watson-Crick (WC) right-handed duplex families are predefined in the local energy minima of dDMPs. In this work, we study the mechanisms of contribution of chemically monotonous sugar-phosphate backbone and the bases into the double helix irregularity. Geometry optimization of sugar-phosphate backbone produces energy minima matching the WC DNA conformations. Studying the conformational variability of dDMPs in response to sequence permutation, we found that simple replacement of bases in the previously fully optimized dDMPs, e.g. by constructing Pyr-Pur from Pur-Pyr, and Pur-Pyr from Pyr-Pur sequences, while retaining the backbone geometry, automatically produces the mutual base position characteristic of the target sequence. Based on that, we infer that the directionality and the preferable regions of the sugar-phosphate torsions, combined with the difference of purines from pyrimidines in ring shape, determines the sequence dependence of the structure of WC DNA. No such sequence dependence exists in dDMPs corresponding to other DNA conformations (e.g., Z-family and Hoogsteen duplexes). Unlike other duplexes, WC helix is unique by its ability to match the local energy minima of the free single strand to the preferable conformations of the duplex.

TRESK potassium channel in human T lymphoblasts.

TRESK (TWIK-related spinal cord K(+)) channel, encoded by KCNK18 gene, belongs to the double-pore domain K(+) channel family and in normal conditions is expressed predominantly in the central nervous system. In our previous patch-clamp study on Jurkat T lymphoblasts we have characterized highly selective K(+) channel with pharmacological profile identical to TRESK. In the present work, the presence of KCNK18 mRNA was confirmed in T lymphoblastic cell lines (Jurkat, JCaM, H9) but not in resting peripheral blood lymphocytes of healthy donors. Positive immunostaining for TRESK was demonstrated in lymphoblastic cell lines, in germinal centers of non-tumoral lymph nodes, and in clinical samples of T acute lymphoblastic leukemias/lymphomas. Besides detection in the plasma membrane, intracellular TRESK localization was also revealed. Possible involvement of TRESK channel in lymphocyte proliferation and tumorigenesis is discussed.

Future directions in research on institutional and interpersonal discrimination and children's health.

Research evidence indicates that 2 forms of racial discrimination-perceived interpersonal discrimination and racial/ethnic residential segregation (a form of institutional discrimination)-may influence children's health and disparities. Although research on these 2 forms of discrimination and health has primarily focused on adults, smaller bodies of work have documented that perceived interpersonal discrimination and segregation have a negative effect on infants' health, and that perceived interpersonal discrimination may negatively affect children's mental health. Three directions for research are (1) incorporating a life-course perspective into studies of discrimination and children's health, (2) linking residential segregation with geography-of-opportunity conceptual frameworks and measures, and (3) considering residential segregation along with segregation in other contexts that influence children's health (e.g., schools).

Sociocultural characteristics, obesity and inflammatory biomarkers in Puerto Rican toddlers born in New York City.

BACKGROUND: In the USA, Puerto Rican children have a higher prevalence of asthma than other Latino ethnicities, and acculturation is one of hypothesized reasons for this difference. We examined associations between sociocultural characteristics and serum leptin, high-sensitivity C-reactive protein (hsCRP), and body mass index (BMI), and further, among hsCRP, leptin levels, BMI percentiles, and allergic sensitization in 2-year-old children. METHODS: IgE antibodies, leptin, and hsCRP concentrations were measured in serum from Puerto Rican toddlers (n = 143) born in New York City with a maternal history of allergy and/or asthma. Demographic and home characteristics questionnaires were administered to the mother, postpartum and two years later. Children's weight and height were measured to determine BMI percentiles. RESULTS: More girls (60%) had leptin levels above the median compared with boys (37%) (p = 0.0063). Leptin was positively correlated with BMI (r = 0.25; p = 0.0042). Children in daycare were more likely to be obese (40% vs. 24% p < 0.06). Maternal birthplace was significantly associated with children's leptin but not with hsCRP. Leptin levels were lower for children whose mothers were born on the US mainland (GM = 2.5 ng/ml, 95% CI [2.2-2.7]) compared with those whose mothers were born in Puerto Rico or another country (GM = 3.2 ng/ml, 95% CI [2.2-3.9], t-test p = 0.01). Mothers born in another country were more likely than those born in the US mainland or Puerto Rico to have obese children (60% vs. 26% p < 0.02). Leptin, hsCRP, and BMI percentile were not associated with sensitization to any of the measured inhalant allergens or total IgE. CONCLUSION: Even at a very young age, some acculturation factors were associated with biomarkers and anthropometric measures of obesity among this Puerto Rican pediatric population. To our knowledge, this is the first study demonstrating the association of mother's birth place with child BMI and leptin as early as 24 months.

Coronary sinus aneurysm and left ventricular-coronary sinus fistula. Implantation of CRT device.

We describe a 72-year-old man referred for implantation of a cardiac resynchronization therapy device who had previously undergone repeated operations to replace the mitral valve. Retrograde venography of the coronary sinus (CS) to implant the left ventricular (LV) pacing lead revealed aneurysmal dilatation of the CS with LV-CS fistula that hindered-but did not prevent-complete implantation of the system.