Postnatal confirmation of prenatally diagnosed trisomy 20 mosaicism in a patient with linear and whorled nevoid hypermelanosis

Linear and whorled nevoid hypermelanosis (LWNH) is characterized by hyperpigmented reticulate macules in a Blaschko linear arrangement without atrophy or preceding inflammation. Underlying chromosomal mosaicism was often assumed, but has been verified in only a few published cases. We report a 7-year-old boy with LWNH associated with congenital ventricular septal defect and psychomotor retardation. Prenatal chromosomal analysis of amniocytes revealed trisomy 20 mosaicism, which was not confirmed in peripheral blood lymphocytes after birth. Histologic sections of skin biopsy specimens taken at age 6 years showed hyperpigmentation of the basal epidermal layer with prominent melanocytes and isolated melanophages in the upper dermis. Cytogenetic analysis of cultured skin fibroblasts revealed an extra chromosome 20 in 5 of the 30 metaphases studied (17%). Mosaic trisomy 20 is one of the most common autosomal mosaicisms identified in amniocytes and is, as a rule, compatible with normal pregnancy outcome. In postnatal analysis of peripheral blood lymphocytes, an extra chromosome 20 could never be detected. However, when confirmed in skin fibroblasts, trisomy 20 mosaicism may be associated with systemic anomalies. The present case shows for the first time an association of LWNH with trisomy 20 mosaicism and emphasizes the importance of analyzing skin fibroblasts in cases of prenatally diagnosed trisomy 20.     

Successful Treatment with Atomoxetine of an Adolescent Boy with Attention Deficit/Hyperactivity Disorder,Extreme Obesity,and Reduced Melanocortin 4 Receptor Function

ObjectiveRecent case reports suggest a link between reduced melanocortinergic tone and both obesity and attention deficit / hyperactivity disorder (ADHD). We present the case of a 13-year-old, male, obese MC4R mutation carrier with ADHD.Case ReportThe boy carries a heterozygous mutation in the melanocortin 4 receptor gene (MC4R; Met281Val), that leads to a reduced receptor function. Dominant mutations of this type represent major gene effects for obesity. He participated in a lifestyle intervention program for obesity and received treatment with the selective norepinephrine re-uptake inhibitor atomoxetine for 31 months. The boy markedly reduced his BMI from 47.2 to 29.6 kg/m².ConclusionAtomoxetine proved to efficiently reduce weight in a severely obese MC4R mutation carrier with ADHD. We briefly discuss possible mechanisms for our observation, including evidence for the functional connectivity between melanocortinergic, dopaminergic, and norepinephrinergic brain circuitries.Key Words: Pharmacogenetics, Brain-derived neurotrophic factor, Weight loss, Appetite control, Methylphenidate     

Influences of smoking and caffeine consumption on trigeminal pain processing

Background

Many human and animal studies have shown the influence of nicotine and caffeine on pain perception and processing. This study aims to investigate whether smoking or caffeine consumption influences trigeminal pain processing.

Methods

Sixty healthy subjects were investigated using simultaneous recordings of the nociceptive blink reflex (nBR) and pain related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). Thirty subjects were investigated before and after smoking a cigarette, as well as before and after taking a tablet of 400 mg caffeine.

Results

After smoking PREP showed decreased N2 and P2 latencies indicating central facilitation at supraspinal (thalamic or cortical) level. PREP amplitudes were not changed. NBR showed a decreased area under the curve (AUC) indicating central inhibition at brainstem level. After caffeine intake no significant changes were observed comparing nBR and PREP results before consumption.

Conclusions

Smoking influences trigeminal pain processing on supraspinal and brainstem level. In the investigated setting, caffeine consumption does not significantly alter trigeminal pain processing. This observation might help in the further understanding of the pathophysiology of pain disorders that are associated with excessive smoking habits such as cluster headache. Previous smoking has to be taken into account when performing electrophysiological studies to avoid bias of study results.     

Outcome and treatment quality of transfer primary percutaneous intervention in older patients with acute ST-elevation myocardial infarction (STEMI)

The aim of this study was to evaluate the outcome and treatment quality of transfer percutaneous coronary intervention (PCI) in older patients with acute STEMI. In this prospective study all patients with diagnosed acute (pain-to-balloon ≤ 12 h) STEMI transferred to our institution for primary PCI (n = 400) between January 2005 and October 2007 were under investigation. Overall 125 older patients with age ≥70 years were included (mean age 77.5 ± 4.9 years; 77 males). Pre-hospital delays were more common in older patients with longer pain-to-balloon: median (range) = 85 (5-629) vs. 66 (1-688) p = 0.031, and pain-to-first medical-contact-times: median: 206 (84-711) vs. 172 (45-720); p = 0.001. A trend towards a higher (non-significant) rate of major 5/125 (5%) vs. 5/275 (1.8%), p = 0.195 and minor 10/125 (8%) vs. 14/275 (5.1%). p = 0.256 bleeding complications in older patients was evident. In-hospital mortality was significantly higher in older patients compared to the younger patients group: 13/125, 10.4% vs. 8/275, 2.9%, p = 0.002). Overall mortality at 30-day follow-up was 11.2% in older and 3.3% in younger patients: 14/125 vs. 9/275, p = 0.002. Transfer PCI is an effective treatment strategy for older patients with acute ST-elevation myocardial infarction. Overall-30-day mortality in older STEMI-patients transferred for primary PCI is comparably low.     

Transient receptor potential canonical channel 1 impacts on mechanosignaling during cell migration

Cell migration is crucial for many important physiological and pathophysiological processes ranging from embryogenesis to tumor metastasis. It requires the coordination of mechanical forces generated in different regions of the migrating cell. It has been proposed that stretch-activated, Ca²⁺-permeable channels are involved in mechanosignaling during cell migration. To date, the molecular identity of these channels is only poorly defined. Here, we investigated the contribution of TRPC1 channels to mechanosignaling during cell migration. We used primary cultures of synovial fibroblasts from TRPC1^?/? mice and the wild-type littermates or Madin?CDarby canine kidney (MDCK-F) cells with increased or decreased TRPC1 expression. TRPC1^?/? fibroblasts have the same migratory phenotype as siTRPC1 MDCK-F cells, with a largely increased projected cell area and impaired directionality. Measurements of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) were combined with time-lapse video microscopic cell migration experiments. Cells were seeded on elastic silicone membranes. Uniaxial stretch elicits a graded elevation of the [Ca²⁺]_i in TRPC1-expressing cells. In contrast, TRPC1^?/? fibroblasts or siTRPC1 MDCK-F cells do not react to 0.4?%, and the response to 4?% stretch is attenuated. Similarly, siTRPC1 MDCK-F cells do not alter their direction of migration upon mechanical stimulation, which contrasts the behavior of TRPC1-overexpressing cells which turn into the direction of stretch. Impaired mechanosignaling in siTRPC1 MDCK-F cells leads to accelerated lamellipodial protrusions. Finally, artificially decreasing membrane tension with the detergent deoxycholate impairs the migration of TRPC1-overexpressing cells, but not of siTRPC1 cells. Taken together, our findings indicate that TRPC1 channels are linked to mechanosignaling during cell migration.     

Capture of cell culture-derived influenza virus by lectins: strain independent, but host cell dependent

Strategies to control influenza outbreaks are focused mainly on prophylactic vaccination. Human influenza vaccines are trivalent blends of different virus subtypes. Therefore and due to frequent antigenic drifts, strain independent manufacturing processes are required for vaccine production. This study verifies the strain independency of a capture method based on Euonymus europaeus lectin-affinity chromatography (EEL-AC) for downstream processing of influenza viruses under various culture conditions propagated in MDCK cells. A comprehensive lectin binding screening was conducted for two influenza virus types from the season 2007/2008 (A/Wisconsin/67/2005, B/Malaysia/2506/2004) including a comparison of virus-lectin interaction by surface plasmon resonance technology. EEL-AC resulted in a reproducible high product recovery rate and a high degree of contaminant removal in the case of both MDCK cell-derived influenza virus types demonstrating clearly the general applicability of EEL-AC. In addition, host cell dependency of EEL-AC was studied with two industrial relevant cell lines: Vero and MDCK cells. However, the choice of the host cell lines is known to lead to different product glycosylation profiles. Hence, altered lectin specificities have been observed between the two cell lines, requiring process adaptations between different influenza vaccine production systems.     

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.     

Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany

The association between common variants in the FTO gene with weight, adiposity and body mass index (BMI) has now been widely replicated. Although the causal variant has yet to be identified, it most likely maps within a 47 kb region of intron 1 of FTO. We performed a genome-wide association study in the Sorbian population and evaluated the relationships between FTO variants and BMI and fat mass in this isolate of Slavonic origin resident in Germany. In a sample of 948 Sorbs, we could replicate the earlier reported associations of intron 1 SNPs with BMI (eg, P-value=0.003, β=0.02 for rs8050136). However, using genome-wide association data, we also detected a second independent signal mapping to a region in intron 2/3 about 40–60 kb away from the originally reported SNPs (eg, for rs17818902 association with BMI P-value=0.0006, β=−0.03 and with fat mass P-value=0.0018, β=−0.079). Both signals remain independently associated in the conditioned analyses. In conclusion, we extend the evidence that FTO variants are associated with BMI by putatively identifying a second susceptibility allele independent of that described earlier. Although further statistical analysis of these findings is hampered by the finite size of the Sorbian isolate, these findings should encourage other groups to seek alternative susceptibility variants within FTO (and other established susceptibility loci) using the opportunities afforded by analyses in populations with divergent mutational and/or demographic histories.     

Executive brain functions after exposure to nocturnal traffic noise: effects of task difficulty and sleep quality

The after-effects of nocturnal traffic noise on cognitive performance and inhibitory brain activity were investigated. Twenty participants (18–30 years) performed an easy and a difficult visual Go/Nogo task with simultaneous EEG recording after a quiet night and then during three nights when aircraft noise was presented with equivalent noise levels of 39, 44, and 50 dBA, respectively, between 11 p.m. to 7 a.m. Based on subjective sleep quality rating, participants were separated into “good” versus “bad” sleepers. The performance and inhibition-related components (N2, P3) of event-related potentials were analysed. The N2 and P3 amplitudes were smaller and latencies were prolonged in the difficult than in the easy task. This effect was more pronounced for Nogo than for Go trials. The Nogo-P3 amplitude was smaller in Noise than in “Quiet” conditions in the difficult task only. In the difficult task, the Nogo-P3 latency was prolonged in bad sleepers than in good sleepers. The Nogo-P3 amplitude was reduced in Noise as compared to “Quiet” conditions in bad sleepers only. Sleep quality in bad sleepers worsened steadily with increasing noise levels. No effects of noise or subjective sleep quality on performance were found. Inhibitory processes appear to be selectively impaired after nocturnal noise exposure. The task difficulty and perceived sleep quality are important factors modulating noise effects. The results suggest that nocturnal traffic noise increase physiological costs for inhibitory functioning on the day even if no overt performance decrement is observed.