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A biochemical and ultrastructural evaluation of the type 2 Gaucher mouse

Gaucher mice, created by targeted disruption of the glucocerebrosidase gene, are totally deficient in glucocerebrosidase and have a rapidly deteriorating clinical course analogous to the most severely affected type 2 human patients. An ultrastructural study of tissues from these mice revealed glucocerebroside accumulation in bone marrow, liver, spleen, and brain. This glycolipid had a characteristic elongated tubular structure and was contained in lysosomes, as demonstrated by colocalization with both ingested carbon particles and cathepsin D. In the central nervous system (CNS), glucocerebroside was diffusely stored in microglia cells and in brainstem and spinal cord neurons, but not in neurons of the cerebellum or cerebral cortex. This rostralcaudal pattern of neuronal lipid storage in these Gaucher mice replicates the pattern seen in type 2 human Gaucher patients and clearly demonstrates that glycosphingolipid catabolism and/or accumulation varies within different brain regions. Surprisingly, the cellular pathology of tissue from these Gaucher mice was relatively mild, and suggests that the early and rapid demise of both Gaucher mice and severely affected type 2 human neonates may be the result of both a neurotoxic metabolite, such as glucosylsphingosine, and other factors, such as skin water barrier dysfunction secondary to the absence of glucocerebrosidase activity

Determination of parameters for the evaluation of Phosphorus/Calcium metabolism in adult normal dogs

Diseases that facilitate alterations in the metabolism of calcium (Ca) and phosphorus (Pi) are\ndiverse. Knowing and interpreting normal parameters is fundamental to making a diagnosis.\nIn this study both minerals were evaluated in the blood and urine of 52 healthy adult dogs in\nthree age ranges in years old (group A: from 1 to 5, group B: from 6 to 10, and group C: older\nthan 10).\nCalcium levels exhibited no significant difference across age groups. A significant increase (p = 0.03)\nin phosphorus was found in group C in relation to the other two groups.\nBased on the elimination of both minerals through the urine, evaluated from the fractional\nexcretion (DIP and DICa) and the relation Ca or Pi / Creatinine, a non-significant tendency\nof a lower elimination of Pi through urine was observed, according to DIP values of group C\n(p = 0.055).\nThe values of DIP and DICa were correlated with the ones in Pi or Ca/Cr in urine (r = 0.9, p < 0.0001).\nThese results allow us to infer that the mineral/Cr relation can be used when evaluating\nelimination by urine. The age range must be taken into account when interpreting results of\nphosphorus in blood and urine, since groups older than 10 years old have higher minimum\nand maximum threshold levels than the other two groups.Fil: Martiarena, B. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Castillo, V. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Endocrinología; ArgentinaFil: Regonat, M. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Patología Clínica; ArgentinaFil: Regonat, M. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Laboratorio; ArgentinaFil: Quintana, H. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Nutrición; ArgentinaFil: Quintana, H. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Nutrición; ArgentinaFil: Brandi, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Patología Clínica; ArgentinaFil: Brandi, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Laboratorio; ArgentinaFil: Lamarca, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Molina, E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animlaes. Unidad de Nefrología y Urología; ArgentinaFil: Ruidiaz, V. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Visintini, A. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaLas enfermedades que alteran el metabolismo fósforo (Pi)/calcio (Ca) son variadas. Para\ndiagnosticarlas es necesario conocer e interpretar parámetros normales. Se estudiaron ambos\nminerales, en sangre y orina, en 52 perros adultos sanos, agrupados según rango etario en años:\nGA de 1 a 5; GB de 6 a 10 y GC ? de 10.\nNo se encontraron diferencias significativas para la calcemia entre los grupos. Hubo un\nincremento significativo para la fosfatemia (p 0.03) y el producto Ca x Pi (p 0.02) en el GC\nrespecto al resto.\nDe la eliminación de ambos minerales en orina, evaluada mediante la excreción fraccional (DIP\ny DICa) y por la relación Calcio o fósforo/creatinina, se observó una tendencia, no significativa,\na una menor eliminación de fósforo, según los valores de DIP en el grupo C (p 0.055). Los\nvalores de DIP y DICa se correlacionaron con los de Fósforo o Calcio/Creatinina (r 0.9, p < 0.0001),\nhaciendo que dichas relaciones pueden ser utilizadas para evaluar la excreción urinaria.\nEl rango etario debe tenerse en cuenta para interpretar resultados del fósforo en sangre y orina,\ndado que los valores de cortes mínimos y máximos son más elevados en los mayores de 10 años

A Comparison of Stimulus Set Size on Tact Training for Children with Autism Spectrum Disorder

Previous studies on skill acquisition have taught targets in stimulus sets composed of different numbers of stimuli. Although the rationale for selection of a stimulus set size is not clear, the number of target stimuli trained within a set is a treatment decision for which there is limited empirical support. The current investigation compared the efficiency of tact training in 4 stimulus set sizes, each of which included 12 stimuli grouped into (a) 4 sets of 3 stimuli, (b) 3 sets of 4 stimuli, (c) 2 sets of 6 stimuli, and (d) 1 set of 12 stimuli. Results of all 4 participants with autism spectrum disorder show tact training with larger (i.e., 6 and 12) stimulus set sizes was more efficient than training with smaller (i.e., 3 and 4) stimulus set sizes

A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia

<p>Abstract</p> <p>Background</p> <p>Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the <it>NR1H3 </it>and <it>NR1H2 </it>genes and preeclampsia.</p> <p>Methods</p> <p>We assessed associations between single nucleotide polymorphisms of <it>NR1H3 </it>(rs2279238 and rs7120118) and <it>NR1H2 </it>(rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.</p> <p>Results</p> <p>We found no association between <it>NR1H3 </it>SNPs and the disease, but the <it>NR1H2 </it>polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; <it>p </it>= 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; <it>p </it>= 0.049).</p> <p>Conclusions</p> <p>This study provides the first evidence of an association between the <it>NR1H2 </it>gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.</p

GEP100/Arf6 Is Required for Epidermal Growth Factor-Induced ERK/Rac1 Signaling and Cell Migration in Human Hepatoma HepG2 Cells

BACKGROUND: Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-△PH, a pleckstrin homology (PH) domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-△PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1-T17N) also largely abolished EGF-induced cell migration. CONCLUSIONS/SIGNIFICANCE: Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF-induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone

Analysis of Interactions of Salmonella Type Three Secretion Mutants with 3-D Intestinal Epithelial Cells

The prevailing paradigm of Salmonella enteropathogenesis based on monolayers asserts that Salmonella pathogenicity island-1 Type Three Secretion System (SPI-1 T3SS) is required for bacterial invasion into intestinal epithelium. However, little is known about the role of SPI-1 in mediating gastrointestinal disease in humans. Recently, SPI-1 deficient nontyphoidal Salmonella strains were isolated from infected humans and animals, indicating that SPI-1 is not required to cause enteropathogenesis and demonstrating the need for more in vivo-like models. Here, we utilized a previously characterized 3-D organotypic model of human intestinal epithelium to elucidate the role of all characterized Salmonella enterica T3SSs. Similar to in vivo reports, the Salmonella SPI-1 T3SS was not required to invade 3-D intestinal cells. Additionally, Salmonella strains carrying single (SPI-1 or SPI-2), double (SPI-1/2) and complete T3SS knockout (SPI-1/SPI-2: flhDC) also invaded 3-D intestinal cells to wildtype levels. Invasion of wildtype and TTSS mutants was a Salmonella active process, whereas non-invasive bacterial strains, bacterial size beads, and heat-killed Salmonella did not invade 3-D cells. Wildtype and T3SS mutants did not preferentially target different cell types identified within the 3-D intestinal aggregates, including M-cells/M-like cells, enterocytes, or Paneth cells. Moreover, each T3SS was necessary for substantial intracellular bacterial replication within 3-D cells. Collectively, these results indicate that T3SSs are dispensable for Salmonella invasion into highly differentiated 3-D models of human intestinal epithelial cells, but are required for intracellular bacterial growth, paralleling in vivo infection observations and demonstrating the utility of these models in predicting in vivo-like pathogenic mechanisms

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

| Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted