Preclinical Tests for Cerebral Stroke

Stroke is the second single highest cause of death in Europe. The low reliability of animal models in replicating the human disease is one of the most serious problems in the field of medical and pharmaceutical research about stroke. The standard models for the study of ischemic stroke are often poorly predictive as they simulate only partially the human disease. This work aims at investigating animal models with diseases typically associated with the onset of stroke in human patients. We have designed and realised a knowledge base for collecting, elaborating, and extracting analytical results of genomic, proteomic, biochemical, morphological investigations from animal models of cerebral stroke. Data analysis techniques are tailored to make the data available for processing and correlation, in order to increase the predictive value of the preclinical data, to perform biosimulation studies, and to support both academic and industrial research in the area of cerebral stroke therapy. A first statistical analysis of the retrieved information leads to the validation of our animal models and suggests a predictive and translational value for parameters related to a specific model. In particular, concerning gene expression data, we have applied a data analysis pipeline that initially takes into account an initial set of 64,000 genes and brings down the focus on a few tens of them

Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory

The Pierre Auger Collaboration has reported evidence for anisotropy in the distribution of arrival directions of the cosmic rays with energies $E>E_{th}=5.5\times 10^{19}$ eV. These show a correlation with the distribution of nearby extragalactic objects, including an apparent excess around the direction of Centaurus A. If the particles responsible for these excesses at $E>E_{th}$ are heavy nuclei with charge $Z$, the proton component of the sources should lead to excesses in the same regions at energies $E/Z$. We here report the lack of anisotropies in these directions at energies above $E_{th}/Z$ (for illustrative values of $Z=6,\ 13,\ 26$). If the anisotropies above $E_{th}$ are due to nuclei with charge $Z$, and under reasonable assumptions about the acceleration process, these observations imply stringent constraints on the allowed proton fraction at the lower energies

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Further delineation of Malan syndrome

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

Diabetic rat testes:morphological and functional alterations

Reproductive dysfunction is a consequence of diabetes, but the underlying mechanisms are poorly understood. This study investigated the histological and molecular alterations in the testes of rats injected with streptozotocin at prepuperal (SPI rats) and adult age (SAI rats) to understand whether diabetes affects testicular tissue with different severity depending on the age in which this pathological condition starts. The testes of diabetic animals showed frequent abnormal histology, and seminiferous epithelium cytoarchitecture appeared altered as well as the occludin distribution pattern. The early occurrence of diabetes increased the percentage of animals with high number of damaged tubules. The interstitial compartment of the testes was clearly hypertrophic in several portions of the organs both in SPI and SAI rats. Interestingly, fully developed Leydig cells were present in all the treated animals although abnormally distributed. Besides the above-described damages, we found a similar decrease in plasma testosterone levels both in SPI and SAI rats. Oxidative stress (OS) is involved in the pathogenesis of various diabetic complications, and in our experimental models we found that manganese superoxide dismutase was reduced in diabetic animals. We conclude that in STZ-induced diabetes, the altered spermatogenesis, more severe in SPI animals, is possibly due to the effect of OS on Leydig cell function which could cause the testosterone decrease responsible for the alterations found in the seminiferous epithelium of diabetic animals

Animal models of cerebral stroke

We have designed and realised a knowledge base for collecting, eleborating, and extracting analytical results of genomic, proteomic, biochemical, morphological investigations for animal models of cerebral stroke. Data analysis techniques are tailored to make the data available for processing and correlation, in order to increase the predictive value of the preclinical data, to perform biosimulation studies, and to support both academic and industrial research in the area of cerebral stroke therapy. The KB is conceived as a persistent tool, mantained and easy to update also with data of type different from initial project

Preclinical data for cerebral stroke: A Knowledge Base for collecting, processing and analysing biological data derived from animal models of cerebral stroke

We have designed and realised a knowledge base for collecting, elaborating, and extracting analytical results of genomic, proteomic, biochemical, morphological investigations from animal models of cerebral stroke. Data analysis techniques are tailored to make the data available for processing and correlation, in order to increase the predictive value of the preclinical data, to perform biosimulation studies, and to support both academic and industrial research in the area of cerebral stroke therapy. A first statistical analysis of the retrieved information leads to the validation of our animal models and suggests a greater predictive and translational value for parameters related to a specific model

Animal models of cerebral stroke += Proteomics data

Proteomics data has been added to the KB. We have designed and realised a knowledge base for collecting, eleborating, and extracting analytical results of genomic, proteomic, biochemical, morphological investigations for animal models of cerebral stroke. Data analysis techniques are tailored to make the data available for processing and correlation, in order to increase the predictive value of the preclinical data, to perform biosimulation studies, and to support both academic and industrial research in the area of cerebral stroke therapy. The KB is conceived as a persistent tool, mantained and easy to update also with data of type different from initial project