Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects

OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND: Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS: Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS: The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS: Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infant's myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group.     

The variability of atlas-based targets in relation to surrounding major fibre tracts in thalamic deep brain stimulation

Background

In essential tremor (ET), the main target for deep brain stimulation (DBS) is the thalamic ventralis intermedius nucleus (Vim). This target cannot be identified on conventional magnetic resonance imaging (MRI). Therefore, targeting depends on probabilistic coordinates derived from stereotactic atlases. The goal of our study was to investigate the variability of atlas-based Vim targets in relation to surrounding major fibre tracts.

Methods

With the MRI and computed tomography (CT) scan data of ten patients who underwent DBS, we planned atlas based Vim targets in both hemispheres. We also performed deterministic fibre-tracking with diffusion tensor imaging (DTI) of the dentato-rubro-thalamic tract (DRTT), pyramidal tract (PT) and lemniscus medialis (LM) in all 20 hemispheres. Subsequently, we measured the distance from the atlas-based Vim target to each tract along the medial/lateral (x-coordinate), anterior/posterior (y-coordinate) and superior/inferior axis (z-coordinate).

Results

Seventeen out of 20 DRTTs could be depicted with our standardised DTI/fibre-tracking parameters. The PT and the LM could be displayed in all 20 hemispheres. The atlas-based Vim target was found inside the DRTT in 11 (concerning the x-coordinate) and 10 hemispheres (concerning the z-coordinate). Regarding the anterior/posterior direction, the target was posterior to the DRTT in 11 cases. In 19 hemispheres the Vim target was located medial and superior to the PT and in 17 hemispheres posterior to it. Concerning the LM, the Vim target was found inside the LM in 16 (regarding the x-coordinate) and in 14 cases (regarding the z-coordinate). In eight cases it was located inside and in 12 cases anterior to the LM concerning the y-coordinate.

Conclusions

We found a considerable variability of the location of atlas-based target points of the ventralis intermedius nucleus in relation to neighbouring major fibre tracts in individual patients. These results suggest that individualised targeting to structures not directly visible on conventional MRI is necessary.

     

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort.     

Modifying the Implicit Illness-Related Self-Concept in Patients with Somatoform Disorders May Reduce Somatic Symptoms

Background

According to dual process theories, not only do explicit but also implicit cognitive processes play a major role in the development and maintenance of somatoform disorders (SFDs). Recent evidence [1] suggests that patients with SFDs have a stronger implicit illness-related self-concept, which is related to the experience of medically unexplained symptoms.

Purpose

The current study was designed to investigate a possible causal link between biased implicit associations and symptoms in SFD patients by experimentally modifying the implicit illness-related self-concept.

Methods

Twenty-nine patients with SFDs (according to the DSM-IV) initially completed an Implicit Association Test (IAT) for assessing the implicit illness-related self-concept. Two weeks later, they underwent an evaluative conditioning task to modify the implicit self-concept.

Results

After this procedure, a change toward a healthier implicit self-concept was apparent in the follow-up IAT. A reduction in symptom severity and changes in health- and body-related cognitions were observed 13 days after the training in the follow-up questionnaires.

Conclusions

The findings suggest that a biased implicit self-concept may be causally relevant for symptom experiences in patients with SFDs. Existing cognitive behavioral treatments for SFDs might benefit from targeting implicit cognitive processes more directly.     

Neonatal blue light phototherapy increases café-au-lait macules in preschool children

Neonatal blue light phototherapy (NBLP) is an effective treatment for hyperbilirubinaemia. Concerning the influence on melanocytic nevi, conflicting studies have been published. To assess the role of NBLP according to the incidence of melanocytic nevi in preschool children, a cohort of 104 5- to 6-year-old children were included. The case group consisted of 52 NBLP-exposed children, while the control group (n?=?52) never had NBLP and was matched regarding age, gender, gestational age and skin phototype. Six dizygotic twins were included with one twin having received NBLP, respectively. The following parameters were recorded: nevi count, presence of freckles, café-au-lait macules, skin phototype and previous history of sun exposure. There was no significant association between nevi count and exposure to NBLP (median nevi count 17.0 compared to 18.5 in controls). No significant difference was also found in the dizygotic twin pairs with a median nevi count of 10.0 (with NBLP) compared to 14.5 (without NBLP). However, a significantly higher prevalence of café-au-lait macules was found in children with NBLP (mean count 0.5) than in children without NBLP (mean count 0.2; p?=?0.001). Significant predictors for the number of melanocytic nevi included skin phototype, sun exposure and vacations in the South. Conclusion: In this study, NBLP had no significant influence on the development of melanocytic nevi, but on café-au-lait macules which was a new finding. Differences with comparable studies regarding age, differentiation between nevi and other pigmented lesions as well as dose and type of NBLP need to be taken into account for further investigations.     

Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (KCa3.1) channels in vivo

Expression of the Ca²⁺ activated potassium channel 3.1 (K_Ca3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival. Therefore, a positron emission tomography (PET) tracer targeting this ion channel could serve as a potential diagnostic tool by imaging the K_Ca3.1 channel in vivo. It was envisaged to synthesize [¹⁸F]senicapoc ([¹⁸F]1) since senicapoc (1) shows high affinity and excellent selectivity towards the K_Ca3.1 channels. Because problems occurred during ¹⁸F-fluorination, the [¹⁸F]fluoroethoxy senicapoc derivative [¹⁸F]28 was synthesized to generate an alternative PET tracer targeting the K_Ca3.1 channel. Inhibition of the K_Ca3.1 channel by 28 was confirmed by patch clamp experiments. In vitro stability in mouse and human serum was shown for 28. Furthermore, biodistribution experiments in wild type mice were performed. Since [¹⁸F]fluoride was detected in vivo after application of [¹⁸F]28, an in vitro metabolism study was conducted. A potential degradation route of fluoroethoxy derivatives in vivo was found which in general should be taken into account when designing new PET tracers for different targets with a [¹⁸F]fluoroethoxy moiety as well as when using the popular prosthetic group [¹⁸F]fluoroethyl tosylate for the alkylation of phenols.

Expression of the Ca²⁺ activated potassium channel 3.1 (K_Ca3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival.