Das Adapterprotein AKAP79/150 : Charakterisierung eines genetischen Polymorphismus und eines neuen Bindungspartners

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2012von Xenia Gorn

Oxidative Stress in Patients Undergoing Peritoneal Dialysis: A Current Review of the Literature

Peritoneal dialysis (PD) patients manifest excessive oxidative stress (OS) compared to the general population and predialysis chronic kidney disease patients, mainly due to the composition of the PD solution (high-glucose content, low pH, elevated osmolality, increased lactate concentration and glucose degradation products). However, PD could be considered a more biocompatible form of dialysis compared to hemodialysis (HD), since several studies showed that the latter results in an excess accumulation of oxidative products and loss of antioxidants. OS in PD is tightly linked with chronic inflammation, atherogenesis, peritoneal fibrosis, and loss of residual renal function. Although exogenous supplementation of antioxidants, such as vitamins E and C, N-acetylcysteine, and carotenoids, in some cases showed potential beneficial effects in PD patients, relevant recommendations have not been yet adopted in everyday clinical practice

Oxidative Stress in Hemodialysis Patients: A Review of the Literature

Hemodialysis (HD) patients are at high risk for all-cause mortality and cardiovascular events. In addition to traditional risk factors, excessive oxidative stress (OS) and chronic inflammation emerge as novel and major contributors to accelerated atherosclerosis and elevated mortality. OS is defined as the imbalance between antioxidant defense mechanisms and oxidant products, the latter overwhelming the former. OS appears in early stages of chronic kidney disease (CKD), advances along with worsening of renal failure, and is further exacerbated by the HD process per se. HD patients manifest excessive OS status due to retention of a plethora of toxins, subsidized under uremia, nutrition lacking antioxidants and turn-over of antioxidants, loss of antioxidants during renal replacement therapy, and leukocyte activation that leads to accumulation of oxidative products. Duration of dialysis therapy, iron infusion, anemia, presence of central venous catheter, and bioincompatible dialyzers are several factors triggering the development of OS. Antioxidant supplementation may take an overall protective role, even at early stages of CKD, to halt the deterioration of kidney function and antagonize systemic inflammation. Unfortunately, clinical studies have not yielded unequivocal positive outcomes when antioxidants have been administered to hemodialysis patients, likely due to their heterogeneous clinical conditions and underlying risk profile

Hemodialysis-related changes in phenotypical features of monocytes

Abstract Hemodialysis (HD) patients exhibit chronic inflammation and leukocyte activation. We investigated the surface-marker profile of monocytes by flow cytometry to assess the chronic effect of uremia and the acute effect of dialysis on their phenotypical and functional features in 16 healthy controls (CON) and 15 HD patients before and after a polysulfone-based dialysis session. Median fluorescence intensities were analyzed indicating expression of CD14, CD16, integrins (CD11b, CD18), chemokine receptors (CCR2, CX3CR1), scavenger receptors (CD36, CD163) and Toll-like receptor-2 (TLR2). Before and after dialysis, HD patients harbour 0.9-fold less CD14++CD16− (Mo1), 1.8-fold more CD14++CD16+ (Mo2) and CD14+CD16++ (Mo3) monocytes than CON. HD patients’ Mo1 showed elevated expression of CD11b (1.7-fold), CD18 (1.2-fold) and CD36 (2.1-fold), whereas CD163 expression was reduced in Mo1 and Mo2 (0.6-fold) compared to CON. These markers remained unaffected by dialysis. CX3CR1 expression on Mo2 and Mo3 was lower in HD patients before (0.8-fold) and further diminished after dialysis (0.6-fold). Stimulation of monocytes resulted in diminished responses in HD patients compared to CON. In conclusion, a systematic analysis of the expression of particular surface markers on distinct monocyte subsets may help to distinguish between uremia and/or dialysis induced effects and to evaluate the functionality of monocytes and biocompatibility of HD

Effects of AKAP5 Pro100Leu genotype on working memory for emotional stimuli.

Recent investigations addressing the role of the synaptic multiadaptor molecule AKAP5 in human emotion and behavior suggest that the AKAP5 Pro100Leu polymorphism (rs2230491) contributes to individual differences in affective control. Carriers of the less common Leu allele show a higher control of anger as indicated by behavioral measures and dACC brain response on emotional distracters when compared to Pro homozygotes. In the current fMRI study we used an emotional working memory task according to the n-back scheme with neutral and negative emotional faces as target stimuli. Pro homozygotes showed a performance advantage at the behavioral level and exhibited enhanced activation of the amygdala and fusiform face area during working memory for emotional faces. On the other hand, Leu carriers exhibited increased activation of the dACC during performance of the 2-back condition. Our results suggest that AKAP5 Pro100Leu effects on emotion processing might be task-dependent with Pro homozygotes showing lower control of emotional interference, but more efficient processing of task-relevant emotional stimuli

Effects of AKAP5 Pro100Leu on emotion processing (schematic overview).

<p>During emotional interference (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055613#pone.0055613-Richter1" target="_blank">[39]</a>), Pro homozygotes exhibit an increased OFC response (yellow) to task-irrelevant emotional distractors, possibly reflecting salience processing. Leu carriers, on the other hand, might suppress the emotional stimuli more efficiently as reflected by an increased ACC response (blue). When emotional stimuli are task-relevant (see results section), a different picture emerges, with Pro homozygotes exhibiting increased activity of the amygdala (and possibly a more extensive face processing network) and more efficient working memory performance.</p

Demographic and behavioral data of the fMRI experiment.

<p>Mean error rates in per cent and reaction times +/− standard deviation are shown.</p><p>Abbreviations: M: mean; SD: standard deviation; RT: reaction time.</p

Genotype-related differences in insula and dACC activation.

<p>(<b>A</b>) There was a complex interaction of genotype condition (0-back vs. 2-back X neutral versus emotional faces) in the left anterior insula, with the most pronounced between-group difference observed for the emotional 2-back condition. (<b>B</b>) Leu carriers exhibited higher dACC activation in the 2-back condition when compared to Pro homozygotes, irrespective of emotional salience. Bar plots depict contrasts of parameter estimates and standard errors.</p

Experimental design und corresponding functional MRI correlates of working memory for emotional stimuli.

<p>(<b>A</b>) Schematic illustration of the stimulation. Target stimuli in the 2-back condition are highlighted by red arrows. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055613#s2" target="_blank">Methods</a> section for details. <i>Note:</i> The face stimuli depicted in the figure were not presented in the original study and are displayed for illustrative purposes. The persons depicted gave written informed consent to have their photograph displayed here as outlined in the PLoS consent form. (<b>B</b>) Emotional stimuli elicited an amygdala response during 0-back performance, whereas no reliable amygdala activation was observed during the 2-back task across the whole cohort. Bar plots depict contrasts of parameter estimates and standard errors.</p

Neural correlates of working memory load.

<p>Activations related to working memory load (2-back vs. 0-back), separated by stimulus valence (neutral vs. emotional). All activations were whole-brain FWE-corrected (p<.05). Abbreviations: BA: Brodmann area; dACC: dorsal anterior cingulate cortex; PFC: prefrontal cortex.</p