Current Practice in Pediatric Cow's Milk Protein Allergy-Immunological Features and Beyond.

Cow's milk protein allergy is one of the most common pediatric food allergies. It poses a significant socioeconomic burden in industrialized countries and has a profound effect on the quality of life of affected individuals and their families. Diverse immunologic pathways can lead to the clinical symptoms of cow's milk protein allergy; some of the pathomechanisms are known in detail, but others need further elucidation. A comprehensive understanding of the development of food allergies and the features of oral tolerance could have the potential to unlock more precise diagnostic tools and novel therapeutic approaches for patients with cow's milk protein allergy.

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.

Copper Content and Export in European Vineyard Soils Influenced by Climate and Soil Properties.

Copper-based fungicides (Cuf) are used in European (EU) vineyards to prevent fungal diseases. Soil physicochemical properties locally govern the variation of the total copper content (Cut) in EU vineyards. However, variables controlling Cut distribution at a larger scale are poorly known. Here, machine learning techniques were used to identify governing variables and to predict the Cut distribution in EU vineyards. Precipitation, aridity and soil organic carbon are key variables explaining together 45% of Cut distribution across EU vineyards. This underlines the effect of both climate and soil properties on Cut distribution. The average net export of Cu at the EU scale is 0.29 kg Cu ha-1, which is 2 orders of magnitude less than the net accumulation of Cu (24.8 kg Cu ha-1). Four scenarios of Cuf application were compared. The current EU regulation with a maximum of 4 kg Cu ha-1 year-1 may increase by 2% of the EU vineyard area, exceeding the predicted no-effect concentration (PNEC) in soil in the next 100 years. Overall, our results highlight the vineyard areas requiring specific remediation measures and strategies of Cuf use to manage a trade-off between pest control and soil and water contamination.

Defining healthstyles to plan behavior change interventions in representative samples of children and adults.

Based on Michie's COM-B model, we developed a survey methodology and segmentation procedure to identify groups of Hungarian school children and adults with distinctive characteristics, named healthstyles. We aimed to find interventions fitting to each healthstyle to generate behavioural change. For the segmentation of data, the latent class analysis method was applied. The analysis resulted in 8 healthstyles for the school children and 13 for the adults. Each healthstyle possess distinctive 'traits' and, therefore, special behavioural change methods and prevention strategies can be fitted for them. For demonstrating the advantages of using healthstyles, we discuss possible approaches for selecting behavioural change interventions, one for school children and one for adults.

DJ-1 can form ß-sheet structured aggregates that co-localize with pathological amyloid deposits.

The loss of native function of the DJ-1 protein has been linked to the development of Parkinson's (PD) and other neurodegenerative diseases. Here we show that DJ-1 aggregates into ß-sheet structured soluble and fibrillar aggregates in vitro under physiological conditions and that this process is promoted by the oxidation of its catalytic Cys106 residue. This aggregation resulted in the loss of its native biochemical glyoxalase function and in addition oxidized DJ-1 aggregates were observed to localize within Lewy bodies, neurofibrillary tangles and amyloid plaques in human PD and Alzheimer's (AD) patients' post-mortem brain tissue. These findings suggest that the aggregation of DJ-1 may be a critical player in the development of the pathology of PD and AD and demonstrate that loss of DJ-1 function can happen through DJ-1 aggregation. This could then contribute to AD and PD disease onset and progression.

Committor of elementary reactions on multistate systems.

In our study, we extend the committor concept on multi-minima systems, where more than one reaction may proceed, but the feasible data evaluation needs the projection onto partial reactions. The elementary reaction committor and the corresponding probability density of the reactive trajectories are defined and calculated on a three-hole two-dimensional model system explored by single-particle Langevin dynamics. We propose a method to visualize more elementary reaction committor functions or probability densities of reactive trajectories on a single plot that helps to identify the most important reaction channels and the nonreactive domains simultaneously. We suggest a weighting for the energy-committor plots that correctly shows the limits of both the minimal energy path and the average energy concepts. The methods also performed well on the analysis of molecular dynamics trajectories of 2-chlorobutane, where an elementary reaction committor, the probability densities, the potential energy/committor, and the free-energy/committor curves are presented.

The impact of environmental policy on soil quality: Organic carbon and phosphorus levels in croplands and grasslands of the European Natura 2000 network.

In this study, the Natura 2000 nature protection network of the European Union is assessed in the context of soil quality management. We explore the hypothesis that the soil quality of croplands and grasslands - as indicated by soil organic carbon and phosphorus levels - is better in terms of environmental parameters within the Natura 2000 network than outside it. The soil organic carbon and phosphorus content of 479 cropland and 450 grassland sites within Natura 2000 were compared with their nearest neighbours outside the network. The comparisons were repeated for pairs of both cropland and grassland sites by soil texture groups. The study revealed that organic carbon content was significantly higher in Natura 2000 sites than in non-protected areas for both croplands and grasslands. For croplands, this was true only for those with signs of ploughing, whereas for croplands without signs of ploughing there were no significant differences between Natura 2000 and non-protected areas. Areas with sand and loamy sand soils had significantly higher soil organic carbon content within the Natura 2000 network than outside it, for both croplands and grasslands. This was the only texture class that showed a significant difference in the case of croplands, whereas three further texture groups had higher soil organic carbon content in Natura 2000 grassland sites than on grassland sites outside this network. There was no significant difference in soil phosphorus content between areas within the Natura 2000 network and non-protected areas, except for grasslands with light textured soils, where soil phosphorus levels were significantly lower within Natura 2000 sites than outside them. The results suggest that the management of croplands and grasslands of Natura 2000 sites tends to perform better than that of adjacent areas with similar land cover in terms of soil carbon conservation. The difference is more evident for sites with certain soil characteristics. On the other hand, the nutrient input - as determined by phosphorus levels - of Natura 2000 croplands and grasslands generally does not appear to be less intensive than that of surrounding areas outside the network.

Monitoring soil for sustainable development and land degradation neutrality.

The adoption of the 17 sustainable development goals (SDGs) listed in the 2030 Agenda for Sustainable Development by the United Nations urged the scientific community to generate information for planning and monitoring socioeconomic development and the underlying environmental compartments. SDGs 2, 3, 6, 11, 13, 14, and 15 have targets which commend direct consideration of soil resources. There are five groups of SDGs and assigned SDG indicators where soil plays a central role. Frameworks of soil-related sustainable development goals and related indicators which can be monitored in current monitoring schemes are proposed.

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease.

DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, S-), oxidized (Cys106, SO2-), and over-oxidized (Cys106, SO3-) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

Baseline Characteristics and Disease Phenotype in Inflammatory Bowel Disease.

OBJECTIVES: Predicting short-term relapses and long-term prognosis is of utmost importance in paediatric inflammatory bowel disease (IBD). Our aim was to investigate the short-term disease outcome and medication during the first year in a paediatric incident cohort from Hungary. In addition, association laboratory markers and disease activity indices with short-term disease outcome and medication were analysed. METHODS: From January 1, 2008 to December 31, 2010, demographic data and clinical characteristics of newly diagnosed paediatric patients with IBD < 18 years of age were prospectively recorded. RESULTS: A total of 420 patients were identified (Crohn disease [CD] 266 and ulcerative colitis [UC] 124). Initially, 48% (124/256) of the patients with CD had moderate-to-severe disease (Pediatric Crohn's Disease Activity Index [PCDAI] > 31), and this rate decreased to 2.1% at 1-year follow-up. Proportion of patients with UC with moderate-to-severe disease (Pediatric Ulcerative Colitis Activity Index > 35) at diagnosis declined from 57.5% (69/120) to 6.8% at 1-year follow-up. Terminal ileal involvement correlated with higher initial C-reactive protein (CRP) (P = 0.021) and initial PCDAI (P = 0.026). In UC, elevated CRP (P = 0.002) was associated with disease extension. CRP and PCDAI at diagnosis were associated with the need for immunomodulators at 1 year in children with CD. Initial CRP was also associated with the need for immunomodulators in patients with UC at 1-year follow-up. CONCLUSIONS: At diagnosis, half of the patients with IBD had moderate-to-severe disease, and this rate decreased to <10% after 1 year. Initial CRP and PCDAI were related to the need for aggressive therapy in CD.

First detection of Pasteurella multocida type B:2 in Hungary associated with systemic pasteurellosis in backyard pigs.

This is the first report of Pasteurella multocida type B in Hungarian pigs. This disease was observed in backyard-raised pigs in three households within a small area. Neither the source of the infection nor the epidemiological connection between any of the premises could be determined. The most consistent lesion was dark red discolouration of the skin of the ventral neck and brisket, with accompanying oedema and haemorrhages. The morbidity was low and lethality relatively high, with three dead (50%) and two euthanised (33%) out of six affected animals. A total of three isolates of P. multocida (P55, P56 and P57) were cultured from these cases and examined in detail. These were identified as P. multocida ssp. multocida biovar 3. All were toxA negative and belonged to serotype B:2. Multilocus sequence typing was used to assign these to a new sequence type (ST61) that is closely related to other haemorrhagic septicaemia causing strains of P. multocida regardless of the host. M13 polymerase chain reaction and virulence-associated gene typing also show that type B strains form a highly homogeneous, distinct phylogenic group within P. multocida.

Detection of Small-Molecule Interactions with Fibrillar Tau Protein Aggregates Using Microscale Thermophoresis.

Aggregated fibrillar tau protein is a pathological hallmark of several neurodegenerative diseases. Small molecules that bind to tau fibrils may be applied for their detection and quantification. This is of great importance as they can potentially be used for earlier diagnosis of disease and disease progression. Microscale thermophoresis (MST) enables the detection of biomolecular interactions in an aqueous environment in which no immobilization of either reaction partner is required. Here, an MST assay methodology is described for the detection of the interaction between a variety of small molecules and tau fibrils. The results of this study demonstrate that MST is a practical methodology to quantify interactions between small molecules and tau fibrillar aggregates.

Long-term impact of unhealthy food tax on consumption and the drivers behind: A longitudinal study in Hungary.

Several countries have introduced public health product taxes with the objective of reducing the absolute amount of consumption of unhealthy food and tackling obesity. This study aims to estimate the long-term impact of the Hungarian public health product tax introduced in 2011. To achieve this, a unique consumer purchase dataset was analysed to examine daily fast-moving consumer goods purchases from a representative sample of 2,000 households from 2010 to 2018. The results indicate that the tax has been fully reflected in consumer prices. A decline in consumption was observed initially, consistent with previous experiences in Hungary and other countries. However, over time, the data suggests a recovery and even an increase in line with the growth of disposable income. The proportion of taxed products in total fast-moving consumer goods purchases increased from 5.9 % (95 % CI: 5.7 % to 6.0 %) in 2010 to 7.4 % (95 % CI: 7.3 % to 7.6 %) in 2018. Furthermore, the tax has contributed to increased inequality as low-income households spend a higher proportion of their total expenditure on it. Although taxes on unhealthy foods have proven effective in the short-term, they may not be adequate for reducing overall consumption in the long-term, particularly as disposable income increases. In conclusion, implementing complex interventions is necessary to achieve sustainable positive changes in dietary habits.

Examination of the Virulence of Actinobacillus pleuropneumoniae Serovar 16 in Pigs.

Different virulence variants of A. pleuropneumoniae are involved in the etiology of porcine pleuropneumonia. The purpose of the present trial was examination of the virulence of the Actinobacillus pleuropneumoniae A-85/14 strain, the type strain of serovar 16, in an animal challenge experiment. Thirty 12-week-old piglets seronegative for A. pleuropneumoniae were allocated into three trial groups each of 10 animals, and they were infected intranasally with 106, 107, or 108 colony forming units (cfu) of the strain, respectively. Clinical signs were recorded twice a day, and the animals were euthanized 6 days after the infection. Typical clinical signs and postmortem lesions of porcine pleuropneumonia were seen in the animals of each trial group; however, they were generally mild, and no significant differences could be seen between the three groups. Even 106 colony forming units of A. pleuropneumoniae A-85/14 strain could induce clinical signs and lesions. Based on these results, the type strain of serovar 16 of A. pleuropneumoniae must be regarded as a typical pathogenic strain of the species.

Estimation of influential points in any data set from coefficient of determination and its leave-one-out cross-validated counterpart.

Coefficient of determination (R (2)) and its leave-one-out cross-validated analogue (denoted by Q (2) or R cv (2) ) are the most frequantly published values to characterize the predictive performance of models. In this article we use R (2) and Q (2) in a reversed aspect to determine uncommon points, i.e. influential points in any data sets. The term (1 - Q (2))/(1 - R (2)) corresponds to the ratio of predictive residual sum of squares and the residual sum of squares. The ratio correlates to the number of influential points in experimental and random data sets. We propose an (approximate) F test on (1 - Q (2))/(1 - R (2)) term to quickly pre-estimate the presence of influential points in training sets of models. The test is founded upon the routinely calculated Q (2) and R (2) values and warns the model builders to verify the training set, to perform influence analysis or even to change to robust modeling.

Incidence, Paris classification, and follow-up in a nationwide incident cohort of pediatric patients with inflammatory bowel disease.

OBJECTIVES: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed. METHODS: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification. RESULTS: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/105 (95% confidence interval [CI] 6.34/105-8.83/105). The incidence for Crohn disease (CD) was 4.72/105 (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/105 (95% CI 1.71-3.09), and for IBD-unclassified 0.45/105 (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%. CONCLUSIONS: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

Identification of small-molecule binding pockets in the soluble monomeric form of the Aß42 peptide.

The aggregation of intrinsically disordered peptides and proteins is associated with a wide range of highly debilitating neurological and systemic disorders. In this work we explored the potential of a structure-based drug discovery procedure to target one such system, the soluble monomeric form of the Aß42 peptide. We utilised for this purpose a set of structures of the Aß42 peptide selected from clusters of conformations within an ensemble generated by molecular dynamics simulations. Using these structures we carried out fragment mapping calculations to identify binding "hot spots" on the monomeric form of the Aß42 peptide. This procedure provided a set of hot spots with ligand efficiencies comparable to those observed for structured proteins, and clustered into binding pockets. Such binding pockets exhibited a propensity to bind small molecules known to interact with the Aß42 peptide. Taken together these results provide an initial indication that fragment-based drug discovery may represent a potential therapeutic strategy for diseases associated with the aggregation of intrinsically disordered proteins.

The LUCAS topsoil database and derived information on the regional variability of cropland topsoil properties in the European Union.

Approximately 20,000 topsoil samples were collected in 25 European Union (EU) Member States (EU-27 except Bulgaria and Romania) with the aim to produce the first coherent pan-European physical and chemical topsoil database, which can serve as baseline information for an EU wide harmonized soil monitoring. The soil sampling was undertaken within the frame of the Land Use/Land Cover Area Frame Survey (LUCAS), a project to monitor changes in the management and character of the land surface of the EU. Soil samples have been analysed for basic soil properties, including particle size distribution, pH, organic carbon, carbonates, NPK, cation exchange capacity (CEC) and multispectral signatures. Preliminary studies show the outstanding potential of the dataset for enhancing the knowledge base on soils in the EU. The current paper provides an introduction to the LUCAS Topsoil 2009 project and provides an example of data applicability for cropland assessment by highlighting initial results for regional and national comparisons.

Patch seriation to visualize data and model parameters.

We developed a new seriation merit function for enhancing the visual information of data matrices. A local similarity matrix is calculated, where the average similarity of neighbouring objects is calculated in a limited variable space and a global function is constructed to maximize the local similarities and cluster them into patches by simple row and column ordering. The method identifies data clusters in a powerful way, if the similarity of objects is caused by some variables and these variables differ for the distinct clusters. The method can be used in the presence of missing data and also on more than two-dimensional data arrays. We show the feasibility of the method on different data sets: on QSAR, chemical, material science, food science, cheminformatics and environmental data in two- and three-dimensional cases. The method can be used during the development and the interpretation of artificial neural network models by seriating different features of the models. It helps to identify interpretable models by elucidating clusters of objects, variables and hidden layer neurons.