Patient's thoughts and expectations about centres of expertise for PKU

Background: In the Netherlands (NL) the government assigned 2 hospitals as centres of expertise (CE) for Phenylketonuria (PKU), while in the United Kingdom (UK) and Germany no centres are assigned specifically as PKU CE's. Methods: To identify expectations of patients/caregivers with PKU of CEs, a web-based survey was distributed through the national Phenylketonuria societies of Germany, NL and UK. Results: In total, 105 responded (43 patients, 56 parents, 4 grandparents, 2 other) of whom 59 were from NL, 33 from UK and 13 from Germany. All participants (n = 105) agreed that patients and/or practitioners would benefit from CEs. The frequency patients would want to visit a CE, when not treated in a CE (n = 83) varied: every hospital visit (24%, n = 20), annual or bi-annual (45%, n = 37), at defined patient ages (6%, n = 5), one visit only (22%, n = 18), or never (4%, n = 3). Distance was reported as a major barrier (42%, n = 35). 78% (n = 65) expected CE physicians and dieticians to have a higher level of knowledge than in non-CE centres. For participants already treated in a CE (n = 68), 66% requested a more extensive annual or bi-annual review. In general, psychology review and neuropsychologist assessment were identified as necessary by approximately half of the 105 participants. In addition, 66% (n = 68) expected a strong collaboration with patient associations. Conclusion: In this small study, most participants expected that assigning CEs will change the structure of and delivery of Phenylketonuria care

Conceptual framework for scenarios development in the Water futures and Solutions project

The major purpose of the Water Futures & Solutions (WFaS) initiative is to develop a set of adaptable resilient and robust solutions and a framework to facilitate access to and guidance through them by decision makers facing a variety of water-related challenges to sustainable evelopment, and a set of optional pathways to achieve plausible sustainable development goals by 2050. The WFaS Initiative addresses the multidimensional aspects of the water system and is guided by stakeholders representing these various aspects. The Initiative views freshwater systems as being strongly interweaved with human activities (Economy, Society) and Nature as a whole. Dynamics and health of freshwater systems is critical to human well- being. The Initiative will go beyond scenario production and model comparisons and will focus on exploring solutions and necessary innovations to address the growing water challenges. Solutions can be combinations of technological innovations, regulatory approaches, manageent or institutional changes that improve the balance of water supply and demand, improve water quality, or reduce water-related risks for society. Solutions will often be embedded in and cut across all sectors of social and economic activities. In order to represent the aspirations and interdependencies as described above, the conceptual framework has been developed, to communicate project results to the target audiences. This document describes this conceptual framework that will be used: -to support development of qualitative water scenarios -to identify and select critical dimensions of the water scenarios -to guide integration of scenarios with quantitative models -to guide integration of information from various data sources into the scenarios -to support development and assessment of solutions -to support collaboration between project and stakeholder groups -to facilitate presentation of results to target audiences The WFaS conceptual framework is developed using the 'concept maps' technique (Caqas and Carff, 2005; Novak and Caqas, 2006b). Concept maps method was develop to represent knowledge in an organized way. It allows practitioners to represent concepts and specific relationships between concepts. It is flexible enough to adapt to different knowledge domains to support better understanding and communication between individuals and groups from different backgrounds

Building global water use scenarios

The Water Future and Solutions Initiative (WFaS) develops consistent, multi-model global water scenaros with the aim to analyze the water-food-energy-climate- environment nexus and identify future hotspots of water insecurity and related impacts on food and energy security. WFaS coordinates its work with on-going scenario development in the fifth assessment review of the Intergovernmental Panel on Climate Change (IPCC), which has developed climate scenarios based on the Representative Concentration pathways (RCPs) and alternative futures of societal developments described in the Shared Socio-economic Pathways (SSPs). In its 'fast-track' scenario assessment WFaS applies available multi-model ensembles of RCP climate scenarios and population, urbanization, and economic development quantifications of the SSPs. Here we interpret SSP narratives to indicate direct or indirect consequences for key water dimensions. Criical scenario assumptions are assessed for different conditions in terms of a country or regions ability to cope with water-related risks and its exposure to complex hydrologcal conditions. For this purpose a classification of hydro-economic challenges across countries has been developed. Scenario assumptions were developed for defined categories of hyro-economic development challenges and relevant features of SSPs. In this way we systematically assess qualitatively key scenario drivers required for global water models We then provide quantifications of assumptions for technological and structural changes for the industry and domestic sector. For the quantification of global scenarios of future water demand, we applied an ensemble of three global water models (H08, PCR-GLOBWB, WaterGAP). Ensemble results of global industrial water withdrawal highlight a steep increase in almost all SSP scenarios. Global amounts across the three models show a wide spread with the highest amounts reaching almost 2000 km^3 yr^-1 by 2050, more than doubled compared to the present industrial water use intensity (850 km^3 yr^-1). Increases in world population result in global domestic water withdrawals by 2050 reaching 700-1500 km^3 yr^-1 depending on scenario and water model. This is an increase of up to 250% compared to the present domestic water use intensity (400-450 km^3 yr^-1). We finally suggest improvements for future water use modelling

Metal-responsive gene regulation and metal transport in Helicobacter species

Helicobacter species are among the most successful colonizers of the mammalian gastrointestinal and hepatobiliary tract. Colonization is usually lifelong, indicating that Helicobacter species have evolved intricate mechanisms of dealing with stresses encountered during colonization of host tissues, like restriction of essential metal ions. The recent availability of genome sequences of the human gastric pathogen Helicobacter pylori, the murine enterohepatic pathogen Helicobacter hepaticus and the unannotated genome sequence of the ferret gastric pathogen Helicobacter mustelae has allowed for comparitive genome analyses. In this review we present such analyses for metal transporters, metal-storage and metal-responsive regulators in these three Helicobacter species, and discuss possible contributions of the differences in metal metabolism in adaptation to the gastric or enterohepatic niches occupied by Helicobacter species

Acquired demyelination but not genetic developmental defects in myelination leads to brain tissue stiffness changes

Changes in axonal myelination are an important hallmark of aging and a number of neurological diseases. Demyelinated axons are impaired in their function and degenerate over time. Oligodendrocytes, the cells responsible for myelination of axons, are sensitive to mechanical properties of their environment. Growing evidence indicates that mechanical properties of demyelinating lesions are different from the healthy state and thus have the potential to affect myelinating potential of oligodendrocytes. We performed a high-resolution spatial mapping of the mechanical heterogeneity of demyelinating lesions using atomic force microscope-enabled indentation. Our results indicate that the stiffness of specific regions of mouse brain tissue is influenced by age and degree of myelination. Here we specifically demonstrate that acquired acute but not genetic demyelination leads to decreased tissue stiffness, which could influence the remyelination potential of oligodendrocytes. We also demonstrate that specific brain regions have unique ranges of stiffness in white and grey matter. Our ex vivo findings may help the design of future in vitro models to mimic the mechanical environment of the brain in healthy and diseased states. The mechanical properties of demyelinating lesions reported here may facilitate novel approaches in treating demyelinating diseases such as multiple sclerosis

Simulations of lattice animals and trees

The scaling behaviour of randomly branched polymers in a good solvent is studied in two to nine dimensions, using as microscopic models lattice animals and lattice trees on simple hypercubic lattices. As a stochastic sampling method we use a biased sequential sampling algorithm with re-sampling, similar to the pruned-enriched Rosenbluth method (PERM) used extensively for linear polymers. Essentially we start simulating percolation clusters (either site or bond), re-weigh them according to the animal (tree) ensemble, and prune or branch the further growth according to a heuristic fitness function. In contrast to previous applications of PERM, this fitness function is {\it not} the weight with which the actual configuration would contribute to the partition sum, but is closely related to it. We obtain high statistics of animals with up to several thousand sites in all dimension 2 <= d <= 9. In addition to the partition sum (number of different animals) we estimate gyration radii and numbers of perimeter sites. In all dimensions we verify the Parisi-Sourlas prediction, and we verify all exactly known critical exponents in dimensions 2, 3, 4, and >= 8. In addition, we present the hitherto most precise estimates for growth constants in d >= 3. For clusters with one site attached to an attractive surface, we verify the superuniversality of the cross-over exponent at the adsorption transition predicted by Janssen and Lyssy. Finally, we discuss the collapse of animals and trees, arguing that our present version of the algorithm is also efficient for some of the models studied in this context, but showing that it is {\it not} very efficient for the `classical' model for collapsing animals.Comment: 17 pages RevTeX, 29 figures include

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence

Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H 2 O 2 . OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100&nbsp;µM, but not 50&nbsp;µM, of H 2 O 2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100&nbsp;µM H 2 O 2 leading to upregulation of TLR4 signaling and IL-1β. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once