The role of clinical pharmacology and pharmacogenetics in electroconvulsive therapy : from safety to efficacy

Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly treatment resistant depression, acute mania, and schizophrenic syndromes. Safety of ECT increases the efficacy of therapy and provides fulfillment of a series of required treatments resulting in longer treatment effect of ECT. During the last few decades, researchers have been attempting to improve the effectiveness of ECT, to learn how and why it works, and to understand its risks and adverse side effects. As a result, the safety and efficacy of ECT has been improved and its indications have been relatively defined to increase the efficiency of outcome of therapy. While there has been considerable improvement in safety features, further investigation have been done to promote both the safety and efficacy of the treatment. Such efforts could increase our knowledge on the biological mechanisms involved in effectiveness of ECT that might result in discovery of new treatments. In this dissertation, we investigate how preprocedural medications could improve the safety and efficacy of ECT and further investigated the potential role of pharmacogenetics in the efficacy of ECT and procedural side effects such as cognitive disorders.UBL - phd migration 201

Impact of Vitamin D and Asthma on Preeclampsia Development: A Sequential Evidence-Based Approach to Genomic Analysis

The biologic evidence regarding the role for vitamin D in immunologic mechanisms and reproductive outcomes is strong. Epidemiologic studies have shown a high prevalence of vitamin D deficiency among pregnant women, especially among high-risk groups. Vitamin D has been also been linked to asthma attacks, another proposed risk factor for preeclampsia. Association of vitamin D and severe asthma has been studied in general population . Along with a clear genetic basis in atopic asthma, environmental factors, including early neonatal nutrition, may have an important influence on asthma development. Vitamin D may be an important environmental factor influencing asthma outcomes. A recent meta-analysis investigated the adverse perinatal outcomes in women with asthma and concluded that as much as a 50% increase risk of PE development in asthmatic pregnant women. Interestingly, in preeclampsia, epidemiologic studies have implicated alterations in vitamin D metabolism and low vitamin D status during pregnancy. The objective of this dissertation is to investigate the potential confounding/modulating effect of vitamin D in the association of asthma and preeclampsia as well as its role in gene expressions in early pregnancy of preeclamptic women. To achieve this goal, a sequential approach from abstracting available literature evidences, to epidemiologic and genomic analyses in proposed. Accordingly, in the introductory chapter one of this dissertation, we provide an evidence-based literature review on the role of vitamin D in asthma development or its severity, fetal development and healthy pregnancy as well as immunomodulation and conclude that vitamin D could have modulating effect on asthma and play important role in human development. In chapter two, we investigate the association between maternal asthma and serum level of vitamin D in early pregnancy with the risk of preeclampsia development, using data on the outcomes of pregnancy from the Vitamin D Antenatal Randomized Trial. In chapter three, we explore the influence of vitamin D on the expression of genes, potentially involved in the development of preeclampsia. Finally, in chapter four, the importance of our findings in the three previous chapters will be reviewed and the future perspective that this evidence based approach investigation proposes will be discussed

Transcriptome analysis of early pregnancy vitamin D status and spontaneous preterm birth.

BackgroundWe conducted a literature review on the studies that investigated the relationship of preterm birth, including spontaneous preterm birth (sPTB), with vitamin D status. Overall, these studies demonstrated that the incidence of sPTB was associated with maternal vitamin D insufficiency in early pregnancy. However, the potential mechanisms and biological pathways are unknown.ObjectivesTo investigate early pregnancy gene expression signatures associated with both vitamin D insufficiency and sPTB. We further constructed a network of these gene signatures and identified the common biological pathways involved.Study designWe conducted peripheral blood transcriptome profiling at 10-18 weeks of gestation in a nested case-control cohort of 24 pregnant women who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In this cohort, 8 women had spontaneous preterm delivery (21-32 weeks of gestation) and 17 women had vitamin D insufficiency (25-hydroxyvitamin D ResultAt 10-18 weeks of gestation, 146 differentially expressed genes (25 upregulated) were associated with both vitamin D insufficiency and sPTB in the discovery cohort (FDR ConclusionsOur gene expression study and network analyses suggest that the dysregulation of immune response pathways due to early pregnancy vitamin D insufficiency may contribute to the pathobiology of sPTB

Translation and Psychometric Evaluation of the Partners in Health Scale Among Iranian Adults With Chronic Diseases

Objectives: Characterizing the psychometric attributes of the Persian variant of partners in health (PIH) in multiple sclerosis (MS), Diabetes, and Low Back Pain (LBP) patients. Methods: In this cross-sectional study, 183 MS, diabetes, and LBP patients (70 male, 113 female) were treated with PIH post-forward-backward translation. Confirmatory factor analysis was used for studying the factor structure. Cronbach’s α and McDonald’s Ω coefficients were used to analyze PIH internal consistency. We used an interclass correlation coefficient to evaluate test-retest reliability. Criterion validity was determined by studying the correlation of PIH and Short Form (36) Health Survey (SF-36), Diabetes Self-Management Scale (DSMS), and Self-Efficacy in Chronic Disease Self-Management (SES6G). Results: The median age of the participants was 49.73±15.16 years, 113 (61.75%) of them were female, 64 (35.0%) had MS, 66 (36.1%) had diabetes, and 53 (29.0%) had LBP. Content validity was determined across all areas (clarity, relevancy, simplicity) by a content validity index ≥0.82. Additionally, all items were confirmed via a content validity ratio ≥0.78. The outcome of CFA depicts that the statistics presented as model fit were as follows: CFI= 0.938, NFI= 0.899, and RMSEA= 0.085. All PIH items exhibited valid internal consistency (0.886-0.893). The PIH showed sufficient test-retest reliability regarding its corresponding subscales (0.554-0.679). The construct validity was confirmed by the total scores of PIH correlated with the total score of SF-36, SES6G, and DSMS. Discussion: The Persian variant of the PIH showed sufficient validity and reliability as a measure to assess self-management in patients suffering from chronic disease (MS, diabetes, and LBP)

Role of nuclear factor of activated T cells 2 (NFATc2) in allergic asthma

Background: We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies. Objective: NFATc2 has been described to associate with IRF4 to induce interleukin-4, and to be inhibited by T-bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults. Methods: PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme-linked immunosorbent assay or multiplex analysis. RNA was then reverse-transcribed and NFATc1, NFATC2, IRF4, and T-bet mRNA were analyzed by real-time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study. Results: In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma. Conclusions: In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma. Clinical significance: Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects. Keywords: T cells; allergy processes; animals; eosinophils cells; human

Circulating MicroRNA: Incident Asthma Prediction and Vitamin D Effect Modification

Of children with recurrent wheezing in early childhood, approximately half go on to develop asthma. MicroRNAs have been described as excellent non-invasive biomarkers due to their prognostic utility. We hypothesized that circulating microRNAs can predict incident asthma and that that prediction might be modified by vitamin D. We selected 75 participants with recurrent wheezing at 3 years old from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Plasma samples were collected at age 3 and sequenced for small RNA-Seq. The read counts were normalized and filtered by depth and coverage. Logistic regression was employed to associate miRNAs at age 3 with asthma status at age 5. While the overall effect of miRNA on asthma occurrence was weak, we identified 38 miRNAs with a significant interaction effect with vitamin D and 32 miRNAs with a significant main effect in the high vitamin D treatment group in VDAART. We validated the VDAART results in Project Viva for both the main effect and interaction effect. Meta-analysis was performed on both cohorts to obtain the combined effect and a logistic regression model was used to predict incident asthma at age 7 in Project Viva. Of the 23 overlapped miRNAs in the stratified and interaction analysis above, 9 miRNAs were replicated in Project Viva with strong effect size and remained in the meta-analysis of the two populations. The target genes of the 9 miRNAs were enriched for asthma-related Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using logistic regression, microRNA hsa-miR-574-5p had a good prognostic ability for incident asthma prognosis with an area under the receiver operating characteristic (AUROC) of 0.83. In conclusion, miRNAs appear to be good biomarkers of incident asthma, but only when vitamin D level is considered

Increased expression of nuclear factor of activated T cells 1 drives IL-9–mediated allergic asthma

Nuclear factor of activated T cells (NFAT) is a family of transcription factors activated by dephosphorylation mediated by Ca++-activated calcineurin. NFAT coordinates different aspects of T-cell development and activation of T, B, natural killer, and mast cells and is the target of the immunosuppressive drug cyclosporin A.1 We reported recently that targeted deletion of NFATc1 in T cells resulted in inhibition of TH2 and TH17 differentiation