The Validation of the Finite Difference Method and Reciprocity for Solving the Inverse Problem in EEG Dipole Source Analysis

The performance of the finite difference reciprocity method (FDRM) to solve the inverse problem in EEG dipole source analysis is investigated in the analytically solvable three-shell spherical head model for a large set of test dipoles. The location error for a grid with 2 mm and 3 mm node spacing is in general, not larger than twice the internode distance, hence 4 mm and 6 mm, respectively. Increasing the number of scalp electrodes from 27 to 44 only marginally improves the location error. The orientation error is always smaller than 4° for all the test dipoles considered. We have also compared the sensitivity to noise using FDRM in EEG dipole source analysis with the sensitivity to noise using the analytical expression for the forward problem. FDRM is not more sensitive to noise than the method using the analytical expression.     

Treatment of in-stent restenosis with sirolimus-eluting-stents: results from the prospective German Cypher stent registry

Aims  Drug-eluting stents have been reported to effectively reduce in-stent restenosis (ISR). However, the effectiveness and safety have yet been investigated only in small trials or case series. The aim of this prospective large scale registry was to show that treatment of ISR with sirolimus eluting stents (SES) is safe, effective and feasible in daily routine. Methods and results  The German Cypher registry prospectively enrolled 6,555 patients undergoing implantation with SES for various indications, including 1,533 patients treated for ISR. Follow-up data (median 6.6 months) of this cohort was available for 1,531 patients (99.8%). Of these patients 75.8% were male. Of these patients 36.5% (n = 552) presented with acute coronary syndromes. In total, 1,932 SES were used with successful implantation in 98.9%. MI during hospitalization was observed in 0.7% (n = 11) while in-hospital mortality was only 0.1% (n = 2). MACE-rate at follow-up was 13.8% (n = 211) including a mortality of 1.3% (n = 20) and MI in 1.9% (n = 29). Total revascularization procedures including CABG (1.7%) were necessary in 12.3% (n = 186). Target vessel revascularization (TVR) rate was 9.3% (n = 139) and thus similar to patients with de novo lesions (8.1%, P = 0.69). Ten patients (0.65%) suffered from subacute stent thrombosis Vs. 0.24% observed in patients with de novo lesions (P = 0.03). Conclusion  This large registry confirms that treatment of ISR with sirolimus-eluting-stents is effective and save with good clinical results at index procedure and follow-up. TVR was not different from de novo lesions.     

Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis

OBJECTIVE: To investigate whether RGD peptide-exposing long circulating polyethylene glycol (PEG) liposomes (RGD-PEG-L) targeted to alphavbeta3 integrins expressed on angiogenic vascular endothelial cells (VECs) are able to bind VECs at sites of inflammation and whether such liposomes containing dexamethasone phosphate (DEXP) can be used as carriers to interfere with the development of experimental arthritis. METHODS: Binding and internalization of RGD-PEG-L were studied by fluorescence-activated cell sorting and confocal microscopy using fluorescently labeled liposomes. Radiolabeled liposomes were used to test in vivo pharmacokinetics and inflammation site targeting in lipopolysaccharide (LPS)-induced inflammation and adjuvant-induced arthritis (AIA) in rats. In vivo inflammation targeting was visualized by intravital microscopy using fluorescently labeled RGD-PEG-L. Therapeutic efficacy of DEXP-encapsulating RGD-PEG-L compared with nontargeted liposomes was evaluated in rats with AIA. RESULTS: RGD-PEG-L bound to and were taken up by proliferating human VECs in vitro. In vivo, increased targeting of radiolabeled RGD-PEG-L to areas of LPS-induced inflammation in rats was observed. Specific association with the blood vessel wall at the site of inflammation was confirmed by intravital microscopy. One single intravenous injection of DEXP encapsulated in RGD-PEG-L resulted in a strong and long-lasting antiarthritic effect in rat AIA. CONCLUSION: RGD-targeted PEG liposomes represent an endothelial cell-specific drug delivery system that targets VECs at sites of inflammation. Use of these liposomes to deliver DEXP to VECs at arthritis-affected sites proved efficacious in rat adjuvant arthritis. These data indicate that VECs have an essential role in the inflammation process and suggest the possibility of using VEC targeting for therapeutic intervention in inflammatory processes such as arthritis.     

Clericuzio type poikiloderma with neutropenia is distinct from Rothmund-Thomson syndrome

Two siblings from a consanguineous family presented with a poikiloderma of limbs and face, plantar keratoderma, and toenail pachyonychia. Neutropenia and neutrophil dysfunction with impairment of the respiratory burst and bacterial killing resulted in frequent respiratory tract infections. A bronchocentric granulomatous pneumonia was a fatal complication. The clinical presentation is consistent with Clericuzio type poikiloderma with neutropenia. Literature review identified several additional probable patients. Genetic linkage analysis excluded the locus of the RECQL4 gene, mutations in which have been described in some patients with the Rothmund-Thomson poikiloderma syndrome. This report confirms the clinical and genetic identity of the Clericuzio type of poikiloderma with neutropenia syndrome.     

The European Narcolepsy Network (EU‐NN) database

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease‐specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web‐based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post‐marketing medication side‐effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.     

Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2)

Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome‐linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations. © 2004 Wiley‐Liss, Inc.     

Effects of interleukin 4 on CD25+CD4+ regulatory T cell function

CD25+CD4+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance against self and non-self. The modulatory effects of cytokines, such as interleukin 4 (IL-4) on the function of Tregs have not been explored in detail. We here report that IL-4 prevents spontaneous apoptosis and the decline of foxp3 mRNA which were found to occur during culture of isolated Tregs. Tregs exposed to IL-4 were more potent in suppressing the proliferation of na?ve CD4+ T cells and they better inhibited IFN-gamma production by CD4+ T cells as compared to Tregs cultured in medium. IL-4 also enhanced membrane IL-2Ralpha (CD25) expression on Tregs above the levels observed on freshly isolated cells. IL-4-mediated effects on Treg function persisted in Tregs from Stat6-/- mice, pointing to a Stat6-independent intracellular transduction pathway. In conclusion, our data suggest that the anti-inflammatory function of IL-4 could partly be mediated by effects on Tregs function.     

Relationship between slow-wave EEG bursts and heart rate changes in preterm infants

The objective of the study is to explore interactions between cortical and autonomic functions in the first weeks of postnatal life. We investigated the behaviour of one-channel electroencephalogram (EEG) patterns and heart rate (HR) dynamics in preterm infants. In a group of 15 healthy preterm infants with a mean conceptional age (CA) of 36 weeks and a mean postnatal age of 17.5 days simultaneous registration of amplitude integrated EEG (aEEG) and HR pattern was performed during interfeeding intervals. Periods with a discontinuous EEG activity and a low heart-rate variability (HRV) were selected for further processing and averaging. It was found that spontaneous activity transients (SATs) or slow wave EEG bursts during "Tracé alternant" (TA) can be accompanied by an HR acceleration of 1-2% (mean: 1.9, range: 0.6-3.5 beats/min) lasting approximately 5s (mean, range: 3.6-7.1s). The aim of the study is to give evidence of a coherent behaviour of EEG bursts and HR in the developing nervous system of preterm infants.     

Tetrasomy 12pter-12p13.31 in a girl with partial Pallister-Killian syndrome phenotype

A dysmorphic patient was shown to carry a small supernumerary marker chromosome. Multicolor, centromere-multicolor and regular FISH experiments proved the marker to be an analphoid 12pter derived isochromosome. Microdissection of the marker followed by reverse painting and array CGH analysis showed that the isochromosome contains approximately 6 Mb of 12pter-12p13.31 derived sequence. This is only the second report of a marker with a neocentromere 12pter and the molecular fine mapping of the duplicated region further refines the 12p region defining the Pallister-Killian syndrome phenotype. In addition, we show the feasibility of using microdissected chromosomes or chromosomal fragments to molecularly map the chromosomal breakpoints on array CGH. This technology may aid in the identification of chromosomal translocation breakpoints.     

Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis

Recently, divergent reports on the role of mast cells (MC) in different glomerular diseases have brought our attention to their role in an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Genetically MC-deficient Kit(W)/Kit(W-v) mice, MC-reconstituted Kit(W)/Kit(W-v) mice and Kit+/+ control mice were subjected to anti-GBM GN. Kit(+/+) mice developed moderate proteinuria and glomerular damage following the induction of anti-GBM nephritis. In contrast, proteinuria and glomerular damage were dramatically increased in MC-deficient Kit(W)/Kit(W-v) mice. MC-reconstituted Kit(W)/Kit(W-v) mice showed proteinuria and glomerular damage comparable to Kit+/+ mice. A significant increase in infiltrating T cells and macrophages was detected in MC-deficient Kit(W)/Kit(W-v) mice as compared to Kit+/+ control mice and MC-reconstituted Kit(W)/Kit(W-v) mice. Accordingly, we observed an increase of TGF-beta1 mRNA in kidneys from Kit(W)/Kit(W-v) mice. Interestingly, we did not detect MC in the kidney using either Giemsa staining or RT-real-time PCR, but MC were found in the regional lymph nodes. Finally, mortality of Kit(W)/Kit(W-v) mice was significantly increased after the induction of anti-GBM GN due to uremia. Our report provides the first direct evidence that MC are protective in anti-GBM GN, possibly by modulating the influx of effector T cells and macrophages to inflammatory sites in the kidney.