Novel and High Affinity Fluorescent Ligands for the Serotonin Transporter Based on (<i>S</i>)‑Citalopram

Novel rhodamine-labeled ligands, based on (<i>S</i>)-citalopram, were synthesized and evaluated for uptake inhibition at the human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) and for binding at SERT, in transiently transfected COS7 cells. Compound <b>14</b> demonstrated high affinity binding and selectivity for SERT (<i>K</i>_i = 3 nM). Visualization of SERT, using confocal laser scanning microscopy, validated compound <b>14</b> as a novel tool for studying SERT expression and distribution in living cells

Genome-Wide Association Study of Genetic Variants in LPS-Stimulated IL-6, IL-8, IL-10, IL-1ra and TNF-α Cytokine Response in a Danish Cohort

<div><p>Background</p><p>Cytokine response plays a vital role in various human lipopolysaccharide (LPS) infectious and inflammatory diseases. This study aimed to find genetic variants that might affect the levels of LPS-induced interleukin (IL)-6, IL-8, IL-10, IL-1ra and tumor necrosis factor (TNF)-α cytokine production.</p><p>Methods</p><p>We performed an initial genome-wide association study using Affymetrix Human Mapping 500 K GeneChip® to screen 130 healthy individuals of Danish descent. The levels of IL-6, IL-8, IL-10, IL-1ra and TNF-α in 24-hour LPS-stimulated whole blood samples were compared within different genotypes. The 152 most significant SNPs were replicated using Illumina Golden Gate® GeneChip in an independent cohort of 186 Danish individuals. Next, 9 of the most statistical significant SNPs were replicated using PCR-based genotyping in an independent cohort of 400 Danish individuals. All results were analyzed in a combined study among the 716 Danish individuals.</p><p>Results</p><p>Only one marker of the 500 K Gene Chip in the discovery study showed a significant association with LPS-induced IL-1ra cytokine levels after Bonferroni correction (<i>P</i><10⁻⁷). However, this SNP was not associated with the IL-1ra cytokine levels in the replication dataset. No SNPs reached genome-wide significance for the five cytokine levels in the combined analysis of all three stages.</p><p>Conclusions</p><p>The associations between the genetic variants and the LPS-induced IL-6, IL-8, IL-10, IL-1ra and TNF-α cytokine levels were not significant in the meta-analysis. This present study does not support a strong genetic effect of LPS-stimulated cytokine production; however, the potential for type II errors should be considered.</p></div

Top 9 SNPs showing the highest evidence of association with IL-6, IL-8, IL-10, IL-1ra and TNF-α LPS stimulated plasma levels among healthy individuals with the most associated <i>P</i>-values <5×10⁻⁵ in the discovery stage or <i>P</i>-values <0.05 in the first replication stage (<i>n</i> = 716).

<p>Chromosomal positions are from NCBI build 36 (hg 18).</p

Manhattan plots showing <i>P</i>-values of association of each of the SNPs in the analysis with LPS stimulated plasma cytokine levels.

<p>SNPs are plotted on the X-axis to their position on each chromosome against cytokine levels on the Y-axis (shown as –log₁₀<i>P</i>-value).</p

Forest plots of meta-analysis of each selected SNP on the cytokine production.

<p>The x-axis represents the estimated effect sizes in mean differences. The horizontal lines show the stage-specific estimated effect sizes and the corresponding 95% confidence intervals of the natural logarithmic mean differences. The solid vertical line at 0 means no difference in effect size.</p

Changes in personality scores in the escitalopram and the placebo group following four weeks of treatment.

a<p>) The distributions did not differ significantly from the normal distribution (Shapiro Wilkes test) and a t-test was used to compare the escitalopram and the placebo arm. P of Levene's test ranged from 0.11 to 0.80.</p>b<p>) The distributions differed from the normal distribution but judged from the graphical displays (histograms and probability distributions) they followed normal distributions with reasonable approximation, thus a t-test was also used.</p>c<p>) Eysenck: Escitalopram (n = 39), placebo (n = 37).</p>d<p>) NEO-PI-R: Escitalopram (n = 39), placebo (n = 38).</p

Flowchart consort for Agenda Trial Neuroticism.

<p>Flowchart consort for Agenda Trial Neuroticism.</p

Clinical and demographic characteristics of participants in the Agenda Trial.

<p>Clinical and demographic characteristics of participants in the Agenda Trial.</p

The untransformed cytokine levels (pg/ml) measured in supernatants after 24 hours LPS-stimulation from the healthy individuals included in this genome-wide association study.

<p><i>P</i>-values show significance of mean concentration difference between men and women by two-sample T-test of means.</p

Study design illustrating the genome-wide association (GWA) study approach.

<p>Study design illustrating the genome-wide association (GWA) study approach.</p