Zearalenone Effect on Uterine Weight of Rats

Mycotoxins are today considered one of the main contaminants of food and feed. Widespread zearalenone and its metabolites have potent estrogenic and anabolic activity, proven in numerous studies worldwide. The aim is to investigate influence of zearalenone on the uterine weight of rats depending on the applied dose and duration of the observation period. In a controlled experimental study, 63 adult female Wistar rats were divided into three groups, depending on the oral test dose of zearalenone applied: 0.1, 0.3 and 0.5 mg / kg of body weight. At the end of each of the four observation periods of seven days, animals were sacrificed under general anesthesia with ether, and after an autopsy the mass of the uterus was determined. Zearalenone in the dose of 0.1 mg / kg of body weight has caused a significant increase in uterine weight between the first and fourth observation interval. Doses of 0.3 and 0.5 mg zearalenone/ kg caused a decrease in uterine weight, which was at a dose of 0.5 mg / kg highly significant between all observational intervals. After 7 days of applying of the toxin, uterine weights did not differ significantly with respect to applied dose. After 14, 21 and 28 days, differences in uterine weight were highly significant, depending on the dose of zearalenone. The results show that prolonged application of large doses of zearalenone produced a significant decrease in uterine weights in experimental animals

Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer.

This is the published version. Copyright 1998 by American Society for Clinical Investigation.A soluble monomeric form of Alzheimer's amyloid-beta (1-40) peptide (sAbeta1-40) is present in the circulation and could contribute to neurotoxicity if it crosses the brain capillary endothelium, which comprises the blood-brain barrier (BBB) in vivo. This study characterizes endothelial binding and transcytosis of a synthetic peptide homologous to human sAbeta1-40 using an in vitro model of human BBB. 125I-sAbeta1-40 binding to the brain microvascular endothelial cell monolayer was time dependent, polarized to the apical side, and saturable with high- and low-affinity dissociation constants of 7.8+/-1.2 and 52.8+/-6.2 nM, respectively. Binding of 125I-sAbeta1-40 was inhibited by anti-RAGE (receptor for advanced glycation end products) antibody (63%) and by acetylated low density lipoproteins (33%). Consistent with these data, transfected cultured cells overexpressing RAGE or macrophage scavenger receptor (SR), type A, displayed binding and internalization of 125I-sAbeta1-40. The internalized peptide remains intact > 94%. Transcytosis of 125I-sAbeta1-40 was time and temperature dependent, asymmetrical from the apical to basolateral side, saturable with a Michaelis constant of 45+/-9 nM, and partially sensitive to RAGE blockade (36%) but not to SR blockade. We conclude that RAGE and SR mediate binding of sAbeta1-40 at the apical side of human BBB, and that RAGE is also involved in sAbeta1-40 transcytosis

Age-associated changes in the blood brain barrier: Comparative studies in human and mouse

Aims: While vascular pathology is a common feature of a range of neurodegenerative diseases, we hypothesised that vascular changes occur in association with normal ageing. Therefore we aimed to characterise age-associated changes in the blood brain barrier (BBB) in human and mouse cohorts. Methods: Immunohistochemistry and Evans Blue assays were used to characterise BBB dysfunction (tight junction protein expression and serum plasma protein accumulation), vascular pathology (pericyte loss and vascular density) and glial pathology (astrocyte and microglial density) in ageing neurological control human pre-frontal cortex (a total of 23 cases from 5 age groups representing the spectrum of young adult to old age: 20-30yrs, 31-45yrs, 46-60yrs, 61-75yrs and 75+) and C57BL/6 mice (3 month, 12 month, 18 month and 24 month, n=5/6 per group). Results: Quantification of the tight junction protein ZO-1 within the cortex and cerebellum of the mouse cohort showed a significant trend to both increased number (cortex p<0.001, cerebellum p<0.001) and length (cortex p<0.001, cerebellum p<0.001) of junctional breaks associated with increasing age. GFAP expression significantly correlated with ageing in the mice (p=0.037). In the human cohort assessment of human protein accumulation (albumin, fibrinogen and human IgG) demonstrated cells morphologically resembling clasmatodendritic astrocytes, indicative of BBB dysfunction. Semi-quantitative assessment of astrogliosis in the cortex expression revealed an association with age (p=0.003), while no age-associated changes in microglial pathology, microvascular density or pericyte coverage were detected. Conclusions: This study demonstrates BBB dysfunction in normal brain ageing, both in human and mouse cohorts

RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes

RAGE is a multiligand receptor of the immunoglobulin superfamily involved in regeneration of injured peripheral nerve and cell motility. RAGE is implicated in the development of various chronic diseases, such as neurodegenerative disorders, inflammatory responses, and diabetic complications. The correlation between RAGE endocytic trafficking and RAGE function is still uninvestigated. S100B is one of the ligands of RAGE. The molecular mechanisms responsible of S100B translocation in exocytic vesicles are still poorly investigated. In the present study we elucidate the role of RAGE endocytic trafficking in promoting S100B secretion in Schwann cells. Here we show that RAGE-induced secretion of S100B requires phosphorylated caveolin1-dependent endocytosis of RAGE. Endocytosis of RAGE in response to ligand binding promotes the fusion of endosomes with S100B-positive secretory vesicles. Src promotes the fusion of endosomes with S100B-secretory vesicles. Inhibition of src induces RAGE degradation. RAGE-mediated src activation induces cav1 phosphorylation and relocalization in the perinuclear compartment. RAGE signaling and recycling are required for S100-induced Schwann cells morphological changes and are inhibited by high-glucose, suggesting a possible link between diabetes and peripheral nerve injury. Indeed, high glucose inhibits RAGE-mediated src activation. Src inhibition blocks RAGE recycling, S100B secretion, and morphological changes. In summary, we identified a novel pathway of vesicular trafficking required for the amplification of RAGE signaling and cytoskeleton dynamics that is potentially involved in the regeneration of injured peripheral nerve. J. Cell. Physiol. 217: 60–71, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60463/1/21474_ftp.pd

Cerebral Amyloid Angiopathy: A Systematic Review

Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and less often capillaries and veins of the central nervous system. CAA occurs mostly as a sporadic condition in the elderly, its incidence associating with advancing age. All sporadic CAA cases are due to deposition of amyloid-β, originating from proteolytic cleavage of the Amyloid Precursor Protein. Hereditary forms of CAA are generally familial (and therefore rare in the general population), more severe and earlier in onset. CAA-related lobar intracerebral hemorrhage is the most well-studied clinical condition associated with brain amyloid deposition. Despite ever increasing understanding of CAA pathogenesis and availability of reliable clinical and diagnostic tools, preventive and therapeutic options remain very limited. Further research efforts are required in order to identify biological targets for novel CAA treatment strategies. We present a systematic review of existing evidence regarding the epidemiology, genetics, pathogenesis, diagnosis and clinical management of CAA

Relationship between mid-trimester ultrasound fetal liver length measurements and gestational diabetes mellitus

BackgroundThe aim of the present study was to investigate the relationship between mid-trimester ultrasound fetal liver length (FLL) and gestational diabetes mellitus (GDM) in a high-risk population. MethodsA prospective study was performed in 331 women with singleton pregnancies who were at high risk of GDM and were undergoing a mid-trimester ultrasound examination. The ultrasound scan at 23 weeks gestation was followed by a 100-g oral glucose tolerance test (OGTT) at 24 weeks gestation. Correlations between FLL and OGTT results at different time points were tested. Receiver operating characteristic (ROC) analysis of FLL as a potential prognostic factor for GDM was also performed. ResultsIn GDM patients, there was a significant positive correlation (P LT 0.01) between FLL and OGTT glycemia immediately before and 60, 120, and 180min after glucose intake. Mean FLL in GDM was significantly higher than in healthy subjects (41.04 vs 31.09mm, respectively; P LT 0.001). When tested as a potential prognostic factor for GDM, fetal liver measurements showed excellent diagnostic performance. The ROC analysis established a cut-off value of FLL of 39mm for the prediction GDM, with sensitivity of 71.76%, specificity 97.56%, positive predictive value 91.0%, and negative predictive value 90.9%. The usefulness of FLL measurements was supported by a high area under the ROC curve (90.5%). ConclusionIn conclusion, there is a strong correlation between FLL and OGTT results, with FLL possibly serving as a valid marker for the prediction of GDM in high-risk populations

A molecular atlas of cell types and zonation in the brain vasculature

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.Peer reviewe

Heat Shock Proteins and Amateur Chaperones in Amyloid-Beta Accumulation and Clearance in Alzheimer’s Disease

The pathologic lesions of Alzheimer’s disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular or extracellular misfolded proteins. The amyloid-β (Aβ) protein accumulates extracellularly in senile plaques and cerebral amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. “Professional chaperones”, such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent aggregation. “Amateur” chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions of AD, but may also be involved in conformational changes of Aβ, and in the clearance of Aβ from the brain via phagocytosis or active transport across the blood–brain barrier. Thus, both professional and amateur chaperones may be involved in the aggregation, accumulation, persistence, and clearance of Aβ and tau and in other Aβ-associated reactions such as inflammation associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention

Proving discriminatory violence at the European Court of Human Rights

Prominent European institutions and organisations frequently report on the incidence of discriminatory violence, motivated on such grounds as colour, association with a national minority, religion or sexual orientation, in various European States. This thesis explores the engagement of a fundamental European institution with the phenomenon of discriminatory violence, namely, the European Court of Human Rights. The main purpose of this thesis is to determine whether the evidentiary framework deployed by the European Court of Human Rights is adequate in discriminatory violence cases, and to offer suggestions for improvement where it is not. To reach that purpose, this study focuses on three evidentiary issues in cases of discriminatory violence. Firstly, it explores whether the Court’s application of the standard of proof ‘beyond reasonable doubt’ forms an obstacle in establishing the occurrence of discriminatory violence. Secondly, it explores the circumstances in which the burden of proof may shift from the applicant to the respondent State. Thirdly, the study looks at the types of evidentiary materials that may be used by the Court in order to establish discriminatory violence.</p