Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.

Epilepsia. 2007 Sep;48(9):1678-85. Epub 2007 Jun 11. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Marini C, Mei D, Temudo T, Ferrari AR, Buti D, Dravet C, Dias AI, Moreira A, Calado E, Seri S, Neville B, Narbona J, Reid E, Michelucci R, Sicca F, Cross HJ, Guerrini R. SourceEpilepsy, Neurophysiology and Neurogenetic Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy. Abstract PURPOSE: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations. METHODS: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients. RESULTS: We classified patients as: SMEI/SMEB = 55; GEFS+= 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations. CONCLUSION: We obtained a frequency of 71%SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes

Expresión del factor de crecimiento del endotelio vascular en carcinomas renales y su relación con la microdensidad vascular, la embolia tumoral y las metástasis a distancia

Los carcinomas renales de células claras derivan de las células epiteliales renales originadas en los túbulos contorneados proximales de las nefronas y se caracterizan por presentar una profusa vascularización. El funcionamiento aberrante del gen del VHL presente en gran parte de estos tumores, se traduce en la liberación de una serie de factores de crecimiento, entre ellos del factor de crecimiento del endotelio vascular (VEGF), implicado en el crecimiento y proliferación de las células tumorales, así como en el proceso de angiogénesis necesaria para el desarrollo de metástasis por vía hematógena. Varios trabajos han sostenido la hipótesis de que la marcación con VEGF podría ser de importancia como factor pronóstico. El objetivo del presente trabajo es determinar la distribución e intensidad de la inmunomarcación con VEGF en tumores renales de células calaras y su relación con la microdensidad vascular (MDV), la presencia de embolias tumorales y las metástasis a distancia.Facultad de Ciencias Médica

Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria–pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation

Cheese trademarks: Italian dairy firms’ practices during the 20th century

Trademarks have recently become a very useful sources for business historians. This longitudinal analysis of the twentieth-century trademarking activities of the most important Italian dairy firms of the era, namely Galbani, Invernizzi and Locatelli, demonstrates that trademarks were used both as a protective weapon against competitors and as an innovation carrier to open up new markets. This article also argues that trademark registrations had another dual purpose – not only were they used as buffers against negative shocks but they were also used to support periods of economic growth. A fundamental finding of this work is that trademarks, across various types of registrations, were closely connected to the features on which the companies based their sales strategies

Idiopathic epilepsies with seizures precipitated by fever: clinical and genetic study of 132 patients

Purpose: Mutations in the genes coding for subunits of ion channels have been associated with epilepsy. Of these known epilepsy genes SCN1A, coding for the α subunit of the sodium channel, is currently the most clinically relevant gene. The majority of SCN1A mutations lead to severe myoclonic epilepsy of infancy (SMEI) including borderline SMEI (SMEB) and to generalized epilepsy with febrile seizures plus (GEFS+). Both syndromes have febrile seizures (FS) as a common clinical feature. The aim of this study was to achieve a better definition of the spectrum of phenotypes that might be associated with SCN1A mutations. We aimed to performing phenotype-genotype correlations of SCN1A mutations with specific epilepsy syndromes. Methods: We selected 132 patients in whom most seizures occurred during febrile episodes. A clinical and genetic study focussing on SCN1A screening was performed. Results: Patients were classified as follow: SMEI/ SMEB = 55; GEFS+ spectrum= 25; sporadic myoclonic astatic epilepsy= 3; classical FS= 10; other phenotypes= 25. We identified 40 SCN1A mutations. Of the 40 mutations 37 were found in patients with SMEI in whom mutations were missense in 16 probands (2 familial) and truncating in 21 (2 familial). The remaining 3 missense mutations were associated with GEFS+. Missense mutations in the pore forming parts (S5-S6) of the Na+ channel occurred in 10 out of the 16 SMEI (62,5%) and only in one of the three GEFS+ patients. Mutations in the pore forming region seem to correlate in 70% with the classical SMEI type and only with 30% of the SMEB phenotype. Analysis of the age of seizures onset between SMEI patients with: a) SCN1A truncating mutations, b) SCN1A missense mutations and c) no SCN1A mutations showed that the differences of the age of FS onset was extremely significant between the three groups (p=0,0007, ANOVA test). Patients with truncating mutations had the earlier onset of FS, patients with missense mutations had an intermediate onset, and individuals without SCN1A mutations had the latest age of FS onset. Conclusion: We obtained a prevalence of about 70% of SCN1A mutations in SMEI and SMEB patients and of 12% in GEFS+ probands confirming the predominant and important role of SCN1A in patients with SMEI. None of the other patients with fever-provoked seizures carried mutations in SCN1A gene. The high correlation between SMEI and SCN1A mutations suggests a phenotypical specificity of SCN1A rather than a dysfunction of neurons exacerbated by high body temperatur