Intensity- and frequency-specific effects of transcranial alternating current stimulation are explained by network dynamics.

Transcranial alternating current stimulation (tACS) can be used to non-invasively entrain neural activity, and thereby cause changes in local neural oscillatory power. Despite an increased use in cognitive and clinical neuroscience, the fundamental mechanisms of tACS are still not fully understood. Here, we develop a computational neuronal network model of two-compartment pyramidal neurons and inhibitory interneurons which mimic the local cortical circuits. We model tACS with electric field strengths that are achievable in human applications. We then simulate intrinsic network activity and measure neural entrainment to investigate how tACS modulates ongoing endogenous oscillations. First, we show that intensity-specific effects of tACS are non-linear. At low intensities (<0.3 mV/mm), tACS desynchronizes neural firing relative to the endogenous oscillations. At higher intensities (>0.3 mV/mm), neurons are entrained to the exogenous electric field. We then further explore the stimulation parameter space and find that entrainment of ongoing cortical oscillations also depends on frequency by following an Arnold tongue. Moreover, neuronal networks can amplify the tACS induced entrainment via excitation-inhibition balance. Our model shows that pyramidal neurons are directly entrained by the exogenous electric field and drive the inhibitory neurons. Our findings can thus provide a mechanistic framework for understanding the intensity- and frequency- specific effects of oscillating electric fields on neuronal networks. This is crucial for rational parameters selection for tACS in cognitive studies and clinical applications.

Induced neural phase precession through exogeneous electric fields.

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.

Combining electrochemical and quantitative elemental analysis to investigate the sulfur poisoning process of ceria thin film fuel electrodes.

This work deals with the effect of sulfur incorporation into model-type GDC thin films on their in-plane ionic conductivity. By means of impedance measurements, a strongly deteriorating effect on the grain boundary conductivity was confirmed, which additionally depends on the applied electrochemical polarisation. To quantify the total amount of sulfur incorporated into GDC thin films, online-laser ablation of solids in liquid (online-LASIL) was used as a novel solid sampling strategy. Online-LASIL combines several advantages of conventional sample introduction systems and enables the detection of S as a minor component in a very limited sample system (in the present case 35 µg total sample mass). To reach the requested sensitivity for S detection using an inductively coupled plasma-mass spectrometer (ICP-MS), the reaction cell of the quadrupole instrument was used and the parameters for the mass shift reaction with O2 were optimised. The combination of electrical and quantitative analytical results allows the identification of a potential sulfur incorporation pathway, which very likely proceeds along GDC grain boundaries with oxysulfide formation as the main driver of ion transport degradation. Depending on the applied cathodic bias, the measured amount of sulfur would be equivalent to 1-4 lattice constants of GDC transformed into an oxysulfide phase at the material's grain boundaries.

Quantitative imaging of structured complex metal oxide thin films using online-LASIL-ICP-MS.

Online-laser ablation of solids in liquid (online-LASIL) coupled with ICP-MS detection was used as a new sampling strategy for the analysis of complex metal oxide (CMO) thin films. The in-house built and optimized online-LASIL ablation cell provides the unique possibility to correlate the signal intensities with the spatial origin of the signal at the sample. For that purpose a particle transport with as little particle dispersion as possible is crucial. To demonstrate the 2D imaging capability of this technique, geometrically structured samples with varying composition were prepared by pulsed laser deposition (PLD) and ion beam etching procedures. These thin films with a thickness of 220 nm were spatially resolved analysed. As a result, 2D intensity maps obtained by online-LASIL can be reported for the first time. Additionally a new approach for simultaneous online quantification was developed by adopting the standard addition concept allowing to correct for instrumental drifts of long time measurements.

Oxygen reduction via grain boundary transport in thin film platinum electrodes on yttria stabilized zirconia.

Model-type sputter deposited platinum microelectrodes with different grain sizes were investigated on single crystalline yttria stabilized zirconia (YSZ) by means of impedance spectroscopy. Measurements on single platinum microelectrodes could be continuously performed for > 100 h and from 250 to 800 °C without losing contact. From the temperature dependence, two parallel reaction pathways for oxygen reduction could be identified. Above 450 °C, a surface path with a rate determining step located at the three phase boundary is predominant. Its polarization resistance is independent of the Pt grain size and exhibits an activation energy of ca. 1.8 eV. In the low temperature regime (< 450 °C) a bulk path through Pt was verified, with an electrode polarization resistance depending on the Pt grain size. This resistance is only slightly thermally activated and the rate limiting step is most probably oxygen diffusion along Pt grain boundaries.

A novel approach for analyzing electrochemical properties of mixed conducting solid oxide fuel cell anode materials by impedance spectroscopy.

For application of acceptor-doped mixed conducting oxides as solid oxide fuel cell (SOFC) anodes, high electrochemical surface activity as well as acceptable electronic and ionic conductivity are crucial. In a reducing atmosphere, particularly the electronic conductivity of acceptor-doped oxides can become rather low and the resulting complex interplay of electrochemical reactions and charge transport processes makes a mechanistic interpretation of impedance measurements very complicated. In order to determine all relevant resistive and capacitive contributions of mixed conducting electrodes in a reducing atmosphere, a novel electrode design and impedance-based analysis technique is therefore introduced. Two interdigitating metallic current collectors are placed in a microelectrode, which allows in-plane measurements within the electrode as well as electrochemical measurements versus a counter electrode. Equivalent circuit models for quantifying the spectra of both measurement modes are developed and applied to simultaneously fit both spectra, using the same parameter set. In this manner, the electronic and ionic conductivity of the material as well as the area-specific resistance of the surface reaction and the chemical capacitance can be determined on a single microelectrode in a H2-H2O atmosphere. The applicability of this new tool was demonstrated in SrTi0.7Fe0.3O(3-δ) (STFO) thin film microelectrodes, deposited on single-crystalline yttria-stabilized zirconia (YSZ) substrates. All materials parameters that contribute to the polarization resistance of STFO electrodes in a reducing atmosphere could thus be quantified.

Subintimal revascularization of chronic iliac artery occlusions using a reentry-catheter.

PURPOSE: To demonstrate the value of a Reentry-Catheter for true lumen access after subintimal revascularization of chronic iliac artery occlusions. MATERIALS AND METHODS: Subintimal revascularization was performed in 5 patients (mean age: 67 ± 12 years; female: 3, male: 2) with total iliac artery occlusion (TASC B to D), but without gaining access to the true lumen distal to the occlusion. Subsequently, a Reentry-Catheter was used to establish reentry and a new subintimal tract. Patients were followed up after 6, 12 and 24 months for clinical re-evaluation to determine the Rutherford score and the ankle brachial index (ABI). In addition, duplex ultrasound was performed to evaluate vessel patency. RESULTS: The primary technical success rate was 100 %. In all cases angioplasty was followed by stent placement to establish the subintimal tract. The mean Rutherford score decreased from 3.6 ± 0.9 to 0.33 ± 0.57 after 24 months, while the ABI increased from 0.67 ± 0.06 to 1.2 ± 0. Vessel patency was observed in all patients available for follow-up examinations. CONCLUSION: The Reentry-Catheter reliably allowed access to the true lumen after subintimal revascularization of occluded iliac arteries. Results in this small patient cohort showed a significant reduction in the Rutherford score, increase in the ABI, and a good patency rate after two years.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Autologous blood donor screening indicated a lower prevalence of viral hepatitis in East vs West Germany: epidemiological benefit from established health resources.

Prevalence data concerning viral hepatitis and human immunodeficiency virus (HIV) in the general population are usually scarce. We aimed for a large cohort representative of the general population that required little funding. Autologous blood donors are relatively representative of the general population, and are tested for viral hepatitis and HIV in many countries. However, frequently these data are not captured for epidemiologic purposes. We analysed data from well over 35,000 autologous blood donors as recorded in 21 different transfusion centres for anti-hepatitis C virus (HCV), HBsAg and anti-HIV, as well as TPHA if available. We found a lower prevalence of hepatitis B virus and HCV in East vs West Germany, 0.2%vs 0.32% and 0.16%vs 0.32% respectively, which confirms earlier data in smaller cohorts, thus supporting the value of our approach. HIV was too rare to disclose significant differences, 0.01%vs 0.02%. TPHA was higher in East (0.34%) vs West Germany (0.29%) without significant differences. HCV was more frequent in women vs men. Transfusion institutes managing autologous blood donations should be used as a resource for epidemiological data relating to viral hepatitis and HIV, if such testing is performed routinely. This approach generates data relating to the general population with special emphasis on undiagnosed cases.

CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT.

The GVL effect following allo-SCT is one of the most prominent examples showing the ability of the immune system to eliminate malignant hematological diseases. Tumor-associated Ags (TAA), for instance WT1 and proteinase-3, have been proposed as targets for T cells to establish a GVL effect. Here, we examined an additional TAA (MUC1) as a possible T-cell target of GVL-related immune responses. We have defined new peptide epitopes from the MUC1 Ag to broaden patients' screening and to expand the repertoire of immunologic monitoring as well as for therapeutic approaches in the future. Twenty-eight patients after allo-SCT have been screened for T-cell responses toward TAA (proteinase-3, WT1, MUC1). We could detect a significant relationship between relapse and the absence of a TAA-specific T-cell response, whereby only 2/13 (15%) patients with TAA-specific CTL relapsed, in contrast to 9/15 (60%) patients without TAA-specific CTL responses (P<0.05). In conclusion, CD8(+) T-cell responses directed to TAA might contribute to the GVL effect. These observations highlight both the importance and the potential of immunotherapeutic approaches after allo-SCT.

[Autologous serum and alternative blood products for the treatment of ocular surface disorders]. / Eigenserum und alternative Blutprodukte zur Behandlung von Augenoberflächenerkrankungen.

Eye drops made from autologous serum have been increasingly used in the past decade to treat ocular surface disorders such as persistent epithelial defects and dry eye. Due to biologically active ingredients such as growth factors, vitamins, and nutrients, they can be used to lubricate the ocular surface and support epithelial wound healing. According to current legal requirements, they can be dispensed only for outpatient treatment if the producer has obtained a license from the appropriate local authorities. Therefore, the production and dispensing of autologous serum eye drops in Germany is currently limited to a very few institutions and their patients. We review the current evidence on the use of serum eye drops, recommend a standard protocol for their production, and describe a number of recently emerging alternative blood products for the treatment of ocular surface diseases along with their potential advantages and limitations.

Radiohybridization PET imaging of KRAS G12D mRNA expression in human pancreas cancer xenografts with [(64)Cu]DO3A-peptide nucleic acid-peptide nanoparticles.

There is a compelling need to image pancreas cancer at an early stage. Human pancreas cancer cells display elevated levels of KRAS protein due to high copy numbers of KRAS mRNA, and elevated levels of insulin-like growth factor 1 receptor (IGF1R) due to overexpression of IGF1R mRNA. Therefore we hypothesized that pancreas cancer could be detected in vivo with a single probe that targets both KRAS mRNA and IGF1R. Because positron emission tomography (PET) is a sensitive imaging technique, we designed a probe incorporating the positron-emitting nuclide (64)Cu. The KRAS-specific hybridization probe consisted of 1,4,7-tris(carboxymethylaza)cyclododecane-10-aza-acetyl (DO3A) on the N-terminus of a peptide nucleic acid (PNA) hybridization sequence (GCCATCAGCTCC) linked to a cyclized IGF1 peptide analog (d-Cys-Ser-Lys-Cys) on the C-terminus, for IGF1R-mediated endocytosis. A series of such KRAS radiohybridization probes with 0, 1, 2 or 3 mismatches to KRAS G12D mRNA, including exact matches to wild type KRAS mRNA and KRAS G12V mRNA, along with a double d(Ala) replacement IGF1 peptide control, were assembled by continuous solid phase synthesis. To test the hypothesis that KRAS-IGF1 dual probes could specifically image KRAS mRNA expression noninvasively in human IGF1R-overexpressing AsPC1 pancreas cancer xenografts in immunocompromised mice, [(64)Cu]PNA radiohybridization probes and controls were administered by tail vein. The [(64)Cu]KRAS-IGF1 radiohybridization probe yielded strong tumor contrast in PET images, 8.6 +/- 1.4-fold more intense in the center of human pancreas cancer xenografts than in the contralateral muscle at 4 h post-injection. Control experiments with single base KRASmismatches, an IGF1 peptide mismatch, and a breast cancer xenograft lacking KRAS activation yielded weak tumor contrast images. These experiments are consistent with our hypothesis for noninvasive PET imaging of KRAS oncogene expression in pancreas cancer xenografts. Imaging oncogene mRNAs with radiolabel-PNA-peptide nanoparticles might provide specific genetic characterization of preinvasive and invasive pancreas cancers for staging and choice of therapy.

Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption.

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. AIMS: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. METHODS: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. RESULTS: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. CONCLUSION: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.

Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus.

BACKGROUND: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering skin diseases usually treated with high-dose systemic corticosteroids and other immunosuppressants that may cause severe side-effects. Plasmapheresis also has been demonstrated to be of benefit in the treatment of pemphigus. In contrast to plasmapheresis, staphylococcal protein A immunoadsorption (PA-IA) specifically removes immunoglobulin from the circulation, allows treatment of larger plasma volumes, and does not require the substitution of plasma components. OBJECTIVES: To determine the effectiveness and side-effects of PA-IA in patients with severe pemphigus. METHODS: Five patients with severe pemphigus (PV, n = 4; PF, n = 1) were treated by PA-IA. Three of these patients had been refractory to various treatment regimens. In addition to PA-IA, methylprednisolone, 0.5 mg x kg-1 body weight day-1 was given initially and subsequently tapered. RESULTS: In all patients, a dramatic clinical improvement was seen within 2 weeks after initiation of therapy. Patients were free of lesions after 3, 4, 4, 10 and 21 weeks of treatment, respectively. Concurrently, autoantibody levels decreased rapidly. CONCLUSIONS: PA-IA is a rational, effective, and safe adjuvant therapy for severe pemphigus and warrants wider use for this indication. A controlled study should compare side-effects and effectiveness of PA-IA with other treatment options for pemphigus.

Anesthesiology and intensive care during epilepsy surgery in children and adolescents.

Thus far there are no known studies of the management of anesthesiology and intensive care in cases of implantation of subdural plates for the purpose of determining the epileptogenic areal and of subsequent epilepsy surgery. Such operative measures are still considered too risky, especially in the case of small children. The authors report on cases of 45 children and adolescents who underwent this kind of surgery between December 1992 and December 1997 in Gilead hospital. In order to judge the anesthesiological risk the children were divided into three age groups: A, 1-5 years (n = 12); B, 6-11 years (n = 14); C, 12-18 years (n = 19). In none of these groups were there complications which in retrospect would have shed a negative light on the operation.