Combined use of transcranial magnetic stimulation and metal electrode implants: a theoretical assessment of safety considerations

This paper provides a theoretical assessment of the safety considerations encountered in the simultaneous use of transcranial magnetic stimulation (TMS) and neurological interventions involving implanted metallic electrodes, such as electrocorticography. Metal implants are subject to magnetic forces due to fast alternating magnetic fields produced by the TMS coil. The question of whether the mechanical movement of the implants leads to irreversible damage of brain tissue is addressed by an electromagnetic simulation which quantifies the magnitude of imposed magnetic forces. The assessment is followed by a careful mechanical analysis determining the maximum tolerable force which does not cause irreversible tissue damage. Results of this investigation provide useful information on the range of TMS stimulator output powers which can be safely used in patients having metallic implants. It is shown that conventional TMS applications can be considered safe when applied on patients with typical electrode implants as the induced stress in the brain tissue remains well below the limit of tissue damage.

BIOCHEMICAL AND CELLULAR MECHANISMS OF RETINA AND RETINAL PIGMENT EPITHELIUM APOPTOSIS

Oxidative stress, intense light exposure and oxygen imbalances such as hypoxic or hyperoxic conditions perturb mitochondria, nuclear function and further lead to cellular damage of retina and retinal pigment epithelial (RPE) cells. Our major aim is to understand the various biochemical and proteomic events that occur during the progression of retina and RPE cell death. The comprehensive objectives of this dissertation are to understand the functional aspects of protein expression, posttranslational modifications, protein or lipid binding changes, phenotypic, morphological alterations and their regulation during the retina and RPE apoptosis under oxidative stress. The entire study is divided into four chapters Chapter 1 contains introduction and background on apoptotic signaling in retina and RPE cells. In chapter 2, we demonstrated that the oxidative stress biomarker prohibitin shuttles between mitochondria and nucleus as an anti-apoptotic molecule and acts as a transcriptional regulator by altering its lipid binding affinity and by posttranslational modifications during oxidative damage to the retina and RPE. In chapter 3, we demonstrated that oxidative and photo-oxidative stress induced nitric oxide regulates the RPE apoptosis by altering serine/threonine protein phosphatase 2A (PP2A) catalytic subunit, vimentin phosphorylation and Bcl xL expression regulation in the RPE cells in vitro. In chapter 4, we further analyzed the differential expression of prohibitin in the retina and RPE during oxidative stress, diabetic retinopathy (DR) and age-related macular degeneration (AMD) condition. Our analysis of postmortem retinas reveals that prohibitin is significantly increased in aged and AMD retina, and decreased in retinas of human diabetic retinopathy and RPE of AMD. Our study demonstrates that prohibitin levels determine the apoptotic signaling in the retina and RPE during retinal degenerative disease progression.

[Treatment of lymphangiomas with picibanil in the first year of life]

BACKGROUND: The therapeutic gold standard of cystic hygroma is its complete resection. Because of its growth pattern and its main location in the head and neck region complete resection is not always possible. An alternative is the local injection of Picibanil, but only few cases have been published about its use in infants. PATIENTS/METHOD: We retrospectively analyzed the data of 8 infants (age: 2 weeks-12 months) who got Picibanil therapy because of cystic hygroma in the time period 2002 until 2006. Follow up ranged from 3 months up to 3 years. RESULTS: During the postoperative period all patients had local swelling, in 4 cases accompanied with local inflammation and fever. Tumor reduction of >50% was obtained in 7 of 8 patients. CONCLUSIONS: Local injection of Picibanil in infants with cystic hygroma seems to be a safe alternative to surgical therapy, especially when complete tumor resection means damage of important neighbouring structures. Prospective trials are necessary to confirm the better outcome after therapy with Picibanil compare to primary surgery.

The role of the sinuses of Valsalva in aortic root flow dynamics and aortic root surgery: evaluation by magnetic resonance imaging

BACKGROUND AND AIM OF THE STUDY: Combined replacement of the aortic valve and ascending aorta using a composite graft represents the standard treatment for dilated aortic root with concomitant structural damage of the aortic valve, especially when the aortic valve cannot be preserved. Unfortunately, hemodynamic changes associated with prosthetic replacement of the aortic root have not been fully elucidated. The study aim was to compare hemodynamics within the replaced aortic root using either a prosthetic vascular graft with bulges mimicking the sinuses of Valsalva and including a stented pericardial valve, or a straight xenopericardial conduit and a stentless porcine valve. METHODS: Between July 2004 and March 2006, a total of 35 patients (mean age 65.2 years: range: 32-80 years) was enrolled into the present study. Aortic root replacement was performed in nine patients with a Valsalva graft (Gelweave Valsalva; Vascutek, Renfrewshire, UK) including a stented pericardial valve, and in 19 patients with a xenopericardial conduit containing a stentless porcine valve. All patients underwent postoperative magnetic resonance imaging (MRI). A control group of seven patients allowed for comparison with native aortic root hemodynamics. RESULTS: Maximum flow-velocity above the aortic valve as one marker of compliance of the aortic root was slightly higher in patients with a Valsalva graft compared to native aortic roots (1.9 m/s versus 1.3 m/s, p = 0.001), but was significantly lower than in patients with the xenopericardial graft without neo-sinuses (1.3 m/s versus 2.4 m/s, p < 0.001). CONCLUSION: The pre-shaped bulges in the prosthetic Valsalva graft effectively mimic the native sinuses of Valsalva, improve compliance of the aortic root, and result in a more physiologic flow pattern, as demonstrated by postoperative MRI.

Endangering of Businesses by the German Inheritance Tax? – An Empirical Analysis

This contribution addresses the substantial tax privilege for businesses introduced by the German Inheritance Tax Act 2009. Advocates of the vast or even entire tax exemption for businesses stress the potential damage of the inheritance tax on businesses, as those often lack liquidity to meet tax liability. This submission tackles this issue empirically based on data of the German Inheritance Tax Statistics and the SOEP. The results indicate that former German inheritance tax law has not endangered transferred businesses. Hence, there is no need for the tremendous tax privilege for businesses in current German inheritance tax law. An alternative flat inheritance tax without tax privileges, which meets revenue neutrality per tax class according to current tax law, provokes in some cases relative high tax loads which might trouble businesses.

Seasonality and magnitude of floods in Switzerland under future climate change

The flood seasonality of catchments in Switzerland is likely to change under climate change because of anticipated alterations of precipitation as well as snow accumulation and melt. Information on this change is crucial for flood protection policies, for example, or regional flood frequency analysis. We analysed projected changes in mean annual and maximum floods of a 22-year period for 189 catchments in Switzerland and two scenario periods in the 21st century based on an ensemble of climate scenarios. The flood seasonality was analysed with directional statistics that allow assessing both changes in the mean date a flood occurs as well as changes in the strength of the seasonality. We found that the simulated change in flood seasonality is a function of the change in flow regime type. If snow accumulation and melt is important in a catchment during the control period, then the anticipated change in flood seasonality is most pronounced. Decreasing summer precipitation in the scenarios additionally affects the flood seasonality (mean date of flood occurrence) and leads to a decreasing strength of seasonality, that is a higher temporal variability in most cases. The magnitudes of mean annual floods and more clearly of maximum floods (in a 22-year period) are expected to increase in the future because of changes in flood-generating processes and scaled extreme precipitation. Southern alpine catchments show a different signal, though: the simulated mean annual floods decrease in the far future, that is at the end of the 21st century. Copyright © 2013 John Wiley & Sons, Ltd.

Investigation of potential causes for the development of porcine ear necrosis: different study designs--comparable results?

During the last years two studies for the investigation of the etiology of porcine ear necrosis were carried out at the Clinic for Swine of the University of Veterinary Medicine Vienna. In study 1, parameters, which are discussed in this context, were collected by veterinary practitioners by completing specially designed questionnaires in farms with symptoms of the porcine ear necrosis syndrome. In study 2, samples of piglets and feed were collected for laboratory analysis of the most important infectious agents as well as mycotoxins. In the present manuscript, the results of both projects were compared. Even if the selection criteria of both studies differed, the affected age class was comparable (5.5 to ten weeks of life in study 1 and six to ten weeks of life in study 2). The herd-specific prevalence of the porcine ear necrosis syndrome varied considerably with percentages between 2 and 10, respectively, to 100%. The evaluation of questionnaires in study 1 showed that 51% of the farms had problems with cannibalism. Particles of plant material, which were frequently seen on the histologic slides of study 2, could have got into the tissue by chewing the ears of the pen mates or cannibalism. Whereas in study 1 the negative effect of parameters as high pig density, suboptimal climate, missing enrichment material and bad quality of feed and water were considered, in study 2 all these factors were checked at sample collection and ruled out as precursor for cannibalism. In both studies bacterial agents proved to be a crucial co-factor for the expansion of the necroses to deeper tissue layers, whereas viral pathogens were classified less important. In both projects it was not possible to estimate the direct impact of infectious agents and mycotoxins as direct trigger of the necroses as well as their participation as co-factors or precursor in the sense of an immunosuppression or previous damage of blood vessels or tissue.

Herbivores equalize the seedling height growth of three dominant tree species in an African tropical rain forest

Determining the impact of insect herbivores on forest tree seedlings and saplings is difficult without experimentation in the field. Moreover, this impact may be heterogeneous in time and space because of seasonal rainfall and canopy disturbances, or ‘gaps’, which can influence both insect abundance and plant performance. In this study we used fine netting to individually protect seedlings of Microberlinia bisulcata, Tetraberlinia bifoliolata and Tetraberlinia korupensis trees (Fabaceae = Leguminosae) from insects in 41 paired gap-understorey locations across 80 ha of primary rain forest (Korup, Cameroon). For all species, growth in height and leaf numbers was negligible in the understorey, where M. bisulcata had the lowest survival after c. 2 years. In gaps, however, all species responded positively with pronounced above-ground growth across seasons. When exposed to herbivores their seedling height growth was similar, but in the absence of herbivores, M. bisulcata significantly outgrew both Tetraberlinia species and matched their leaf numbers. This result suggests that insect herbivores might play an important role in maintaining species coexistence by mitigating sapling abundance of the more palatable M. bisulcata, which in gaps was eaten the most severely. The higher ratio in static leaf damage of control-to-caged M. bisulcata seedlings in gaps than understorey locations was consistent with the Plant Vigour Hypothesis. This result, however, did not apply to either Tetraberlinia species. For M. bisulcata and T. korupensis, but not T. bifoliolata (the most shade-tolerant species), caging improved relative seedling survival in the understory locations compared to gaps, providing restricted support for the Limiting Resource Model. Approximately 2.25 years after treatments were removed, the caged seedlings were taller and had more leaves than controls in all three species, and the effect remained strongest for M. bisulcata. We conclude that in this community the impact of leaf herbivory on seedling growth in gaps is strong for the dominant M. bisulcata, which coupled to a very low shade-tolerance contributes to limiting its regeneration. However, because gaps are common to most forests, insect herbivores may be having impacts upon functionally similar tree species that are also characterized by low sapling recruitment much more widely than currently appreciated. An implication for the restoration and management of M. bisulcata populations in forests outside of Korup is that physical protection from herbivores of new seedlings where the canopy is opened by gaps, or by harvesting, should substantially increase its subcanopy regeneration, and thus, too, its opportunities for adult recruitment.

Holocene flood frequency across the Central Alps – solar forcing and evidence for variations in North Atlantic atmospheric circulation

The frequency of large-scale heavy precipitation events in the European Alps is expected to undergo substantial changes with current climate change. Hence, knowledge about the past natural variability of floods caused by heavy precipitation constitutes important input for climate projections. We present a comprehensive Holocene (10,000 years) reconstruction of the flood frequency in the Central European Alps combining 15 lacustrine sediment records. These records provide an extensive catalog of flood deposits, which were generated by flood-induced underflows delivering terrestrial material to the lake floors. The multi-archive approach allows suppressing local weather patterns, such as thunderstorms, from the obtained climate signal. We reconstructed mainly late spring to fall events since ice cover and precipitation in form of snow in winter at high-altitude study sites do inhibit the generation of flood layers. We found that flood frequency was higher during cool periods, coinciding with lows in solar activity. In addition, flood occurrence shows periodicities that are also observed in reconstructions of solar activity from C-14 and Be-10 records (2500-3000, 900-1200, as well as of about 710, 500, 350, 208 (Suess cycle), 150, 104 and 87 (Gleissberg cycle) years). As atmospheric mechanism, we propose an expansion/shrinking of the Hadley cell with increasing/decreasing air temperature, causing dry/wet conditions in Central Europe during phases of high/low solar activity. Furthermore, differences between the flood patterns from the Northern Alps and the Southern Alps indicate changes in North Atlantic circulation. Enhanced flood occurrence in the South compared to the North suggests a pronounced southward position of the Westerlies and/or blocking over the northern North Atlantic, hence resembling a negative NAO state (most distinct from 4.2 to 2.4 kyr BP and during the Little Ice Age). South-Alpine flood activity therefore provides a qualitative record of variations in a paleo-NAO pattern during the Holocene. Additionally, increased South Alpine flood activity contrasts to low precipitation in tropical Central America (Cariaco Basin) on the Holocene and centennial time scale. This observation is consistent with a Holocene southward migration of the Atlantic circulation system, and hence of the ITCZ, driven by decreasing summer insolation in the Northern hemisphere, as well as with shorter-term fluctuations probably driven by solar activity. (C) 2013 Elsevier Ltd. All rights reserved.

Floods at the northern foothills of the Tatra Mountains — A Polish-Swiss research project

The present paper introduces the topical area of the Polish-Swiss research project FLORIST (Flood risk on the northern foothills of the Tatra Mountains), informs on its objectives, and reports on initial results. The Tatra Mountains are the area of the highest precipitation in Poland and largely contribute to flood generation. The project is focused around four competence clusters: observation-based climatology, model-based climate change projections and impact assessment, dendrogeomorphology, and impact of large wood debris on fluvial processes. The knowledge generated in the FLORIST project is likely to have impact on understanding and interpretation of flood risk on the northern foothills of the Tatra Mountains, in the past, present, and future. It can help solving important practical problems related to flood risk reduction strategies and flood preparedness.

Characterisation of flash floods in small ungauged mountain basins of Central Spain using an integrated approach

One of the main problems of flood hazard assessment in ungauged or poorly gauged basins is the lack of runoff data. In an attempt to overcome this problem we have combined archival records, dendrogeomorphic time series and instrumental data (daily rainfall and discharge) from four ungauged and poorly gauged mountain basins in Central Spain with the aim of reconstructing and compiling information on 41 flash flood events since the end of the 19th century. Estimation of historical discharge and the incorporation of uncertainty for the at-site and regional flood frequency analysis were performed with an empirical rainfall–runoff assessment as well as stochastic and Bayesian Markov Chain Monte Carlo (MCMC) approaches. Results for each of the ungauged basins include flood frequency, severity, seasonality and triggers (synoptic meteorological situations). The reconstructed data series clearly demonstrates how uncertainty can be reduced by including historical information, but also points to the considerable influence of different approaches on quantile estimation. This uncertainty should be taken into account when these data are used for flood risk management.

Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors.

BACKGROUND Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. METHODS [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys40(Ahx-DTPA-natIn)NH2]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. RESULTS Combination of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys40(Ahx-DTPA-111In)NH2]-exendin-4. CONCLUSION The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.

Bacterial meningitis: insights into pathogenesis and evaluation of new treatment options: a perspective from experimental studies.

ABSTRACT  Bacterial meningitis is associated with high mortality and morbidity rates. Bacterial components induce an overshooting inflammatory reaction, eventually leading to brain damage. Pathological correlates of neurofunctional deficits include cortical necrosis, damage of the inner ear and hippocampal apoptosis. The hippocampal dentate gyrus is important for memory acquisition and harbors a neuronal stem cell niche, thus being potentially well equipped for regeneration. Adjuvant therapies aimed at decreasing the inflammatory reaction, for example, dexamethasone, and those protecting the brain from injury have been evaluated in animal models of the disease. They include nonbacteriolytic antibiotics (e.g., daptomycin), metalloproteinase inhibitors and modulators of the immunological response, for example, granulocyte colony-stimulating factor. Increasing research interest has recently been focused on interventions aimed at supporting regenerative processes.

Monitoring the temporal development of natural hazard risks as a basis indicator for climate change adaptation.

The potential effects of climatic changes on natural risks are widely discussed. But the formulation of strategies for adapting risk management practice to climate changes requires knowledge of the related risks for people and economic values. The main goals of this work were (1) the development of a method for analysing and comparing risks induced by different natural hazard types, (2) highlighting the most relevant natural hazard processes and related damages, (3) the development of an information system for the monitoring of the temporal development of natural hazard risk and (4) the visualisation of the resulting information for the wider public. A comparative exposure analysis provides the basis for pointing out the hot spots of natural hazard risks in the province of Carinthia, Austria. An analysis of flood risks in all municipalities provides the basis for setting the priorities in the planning of flood protection measures. The methods form the basis for a monitoring system that periodically observes the temporal development of natural hazard risks. This makes it possible firstly to identify situations in which natural hazard risks are rising and secondly to differentiate between the most relevant factors responsible for the increasing risks. The factors that most influence the natural risks could be made evident.

Continuum damage interactions between tension and compression in osteonal bone

Skeletal diseases such as osteoporosis impose a severe socio-economic burden to ageing societies. Decreasing mechanical competence causes a rise in bone fracture incidence and mortality especially after the age of 65 y. The mechanisms of how bone damage is accumulated under different loading modes and its impact on bone strength are unclear. We hypothesise that damage accumulated in one loading mode increases the fracture risk in another. This study aimed at identifying continuum damage interactions between tensile and compressive loading modes. We propose and identify the material constants of a novel piecewise 1D constitutive model capable of describing the mechanical response of bone in combined tensile and compressive loading histories. We performed several sets of loading–reloading experiments to compute stiffness, plastic strains, and stress-strain curves. For tensile overloading, a stiffness reduction (damage) of 60% at 0.65% accumulated plastic strain was detectable as stiffness reduction of 20% under compression. For compressive overloading, 60% damage at 0.75% plastic strain was detectable as a stiffness reduction of 50% in tension. Plastic strain at ultimate stress was the same in tension and compression. Compression showed softening and tension exponential hardening in the post-yield regime. The hardening behaviour in compression is unaffected by a previous overload in tension but the hardening behaviour in tension is affected by a previous overload in compression as tensile reloading strength is significantly reduced. This paper demonstrates how damage accumulated under one loading mode affects the mechanical behaviour in another loading mode. To explain this and to illustrate a possible implementation we proposed a theoretical model. Including such loading mode dependent damage and plasticity behaviour in finite element models will help to improve fracture risk analysis of whole bones and bone implant structures.