National Neurological Institute C Besta

Milano, Italy

National Neurological Institute C Besta

Milano, Italy
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Binda E.,University of Milan Bicocca | Visioli A.,University of Milan Bicocca | Giani F.,University of Milan Bicocca | Lamorte G.,C o Instituto Mendel | And 15 more authors.
Cancer Cell | Year: 2012

In human glioblastomas (hGBMs), tumor-propagating cells with stem-like characteristics (TPCs) represent a key therapeutic target. We found that the EphA2 receptor tyrosine kinase is overexpressed in hGBM TPCs. Cytofluorimetric sorting into EphA2High and EphA2Low populations demonstrated that EphA2 expression correlates with the size and tumor-propagating ability of the TPC pool in hGBMs. Both ephrinA1-Fc, which caused EphA2 downregulation in TPCs, and siRNA-mediated knockdown of EPHA2 expression suppressed TPCs self-renewal ex vivo and intracranial tumorigenicity, pointing to EphA2 downregulation as a causal event in the loss of TPCs tumorigenicity. Infusion of ephrinA1-Fc into intracranial xenografts elicited strong tumor-suppressing effects, suggestive of therapeutic applications. © 2012 Elsevier Inc.

PubMed | Stemgen Spa., ISBReMIT Institute for Stem Cell Biology, Bioinformatic Unit, University of Milan Bicocca and 6 more.
Type: | Journal: Cancer research | Year: 2016

Brain invasion by glioblastoma (hGBM) determines prognosis, recurrence and lethality in patients, but no master factor coordinating the invasive properties of GBM has been identified. Here we report evidence favouring such a role for the non-canonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal GBM from poorly motile proneural and classical GBM. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly-infiltrating mesenchymal GBM cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal GBM TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical GBM TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of GBM, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in GBM patients.

PubMed | University of Bergen, University of Bologna, National Research Council Italy, Institute of Genetic Medicine and 6 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in 1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.

Thiele E.A.,Massachusetts General Hospital | Granata T.,National Neurological Institute C Besta | Matricardi S.,National Neurological Institute C Besta | Chugani H.T.,Wayne State University
Epilepsia | Year: 2014

Children with tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis all have complex but differing needs in the process of transition/transfer to adult care. All three may be associated with long-term normal intelligence or a varying degree of intellectual disability. In tuberous sclerosis complex, the emphasis of care in adulthood shifts from seizure control and developmental issues to renal and psychiatric disease and other issues. In Sturge-Weber syndrome, the emphasis shifts from seizure control and rehabilitation to management of disability and migraine. In Rasmussen encephalitis, transition may be particularly complex for those with adolescent onset. Those successfully operated on for childhood onset have a static problem and the potential to do well in life. © 2014 International League Against Epilepsy.

House E.D.,University of West Florida | Arruda J.E.,University of West Florida | Andrasik F.,University of Memphis | Grazzi L.,National Neurological Institute C Besta
Pain Practice | Year: 2012

Objectives: This study assessed the validity and reliability of the Visual Analog Mood Scales (VAMS) when administered to a non-English-speaking, headache population. Methods: The VAMS and another frequently administered measure of mood, the Profile of Mood States (POMS), were administered to sixty patients at a headache clinic in Milan, Italy. The VAMS and POMS were both administered before and after a regularly scheduled appointment at the clinic. Multitrait-multimethod analyses were conducted to assess the validity of each subscale comprising the VAMS. Results: All subscales comprising the VAMS possessed high test-retest reliability, and the "confused,""sad,""angry,""energetic," and "tired" subscales of the VAMS were shown to be valid when administered to a non-English-speaking pain population. Further, compared to age-matched controls (from available normative data), pain patients reported being significantly more confused, sad, and tense on the VAMS and significantly more tired, confused, depressed, and tense on the POMS. Discussion: Given the evidence of strong reliability and validity, the VAMS may be useful as a clinical diagnostic tool when administered to non-English-speaking pain populations. © 2012 The Authors. Pain Practice © 2012 World Institute of Pain.

Remiche G.,Free University of Colombia | Ronchi D.,University of Milan | Magri F.,University of Milan | Lamperti C.,National Neurological Institute C Besta | And 5 more authors.
Journal of Neurology | Year: 2014

Glycogen storage disease type II (GSDII) is a lysosomal storage disorder caused by acid alpha-1,4-glucosidase deficiency and associated with recessive mutations in its coding gene GAA. Few studies have provided so far a detailed phenotypical characterization in late onset GSDII (LO-GSDII) patients. Genotype-phenotype correlation has been previously attempted with controversial results. We aim to provide an in-depth description of a cohort (n = 36) of LO-GSDII patients coming from the north of Italy and compare our population's findings to the literature. We performed a clinical record-based retrospective and prospective study of our patients. LO-GSDII in our cohort covers a large variability of phenotype including subtle clinical presentation and did not differ significantly from previous data. In all patients, molecular analysis disclosed GAA mutations, five of them being novel. To assess potential genotype-phenotype correlations we divided IVS1-32-13T>G heterozygous patients into two groups following the severity of the mutations on the second allele. Our patients harbouring "severe" mutations (n = 21) presented a strong tendency to have more severe phenotypes and more disability, more severe phenotypes and more disability, higher prevalence of assisted ventilation and a shorter time of evolution to show it. The determination of prognostic factors is mandatory in order to refine the accuracy of prognostic information, to develop follow-up strategy and, more importantly, to improve the decision algorithm for enzyme replacement therapy administration. The demonstration of genotype-phenotype correlations could help to reach this objective. Clinical assessment homogeneity is required to overcome limitations due to the lack of power of most studies. © 2013 Springer-Verlag Berlin Heidelberg.

Usai S.,National Neurological Institute C Besta | Grazzi L.,National Neurological Institute C Besta | Andrasik F.,University of West Florida | Bussone G.,National Neurological Institute C Besta
Neurological Sciences | Year: 2010

Headache is one of the commonest conditions to affect children and adolescents in industrialized countries. Effective pharmacological treatments without side effects are still lacking. Ginkgolide B, an herbal constituent extract from ginkgo biloba tree leaves, is a natural antiplatelet activating factor (PAF). PAF is a potent proinflammatory and nociceptive agent released during the inflammation process. Therefore, Ginkgolide B can be considered a promising non-pharmacological tool for treatment of migraine with and without aura. We propose to determine the efficacy of Ginkgolide B as preventive treatment in a group of young patients suffering from migraine without aura. A small sample of 24 young patients suffering from migraine without aura entered the open-label prospective trial. Migraine without aura was diagnosed according to International Headache Society criteria. The treatment was well tolerated and the compliance was good. These preliminary data show that Ginkgolide B seems to be effective as preventive treatment in reducing migraine attack frequency and in attenuating the use of symptomatic medication in our small series of children with primary headache.

Andrasik F.,University of West Florida | Grazzi L.,National Neurological Institute C Besta | Usai S.,National Neurological Institute C Besta | Kass S.,University of West Florida | Bussone G.,National Neurological Institute C Besta
Cephalalgia | Year: 2010

Chronic migraine accompanied by medication overuse is particularly difficult to treat. The number of treatment investigations is limited, few have included follow-up beyond 6 months and almost none has examined whether treatment leads to concurrent improvements in disability and functional impairment. This open-label study addresses these limitations. We have been prospectively following an initial cohort of 84 chronic migraine patients with medication overuse, who at the time of this evaluation had been reduced to 58, for an extended period to assess longer-term maintenance of effects, using measurement procedures identical to those in the original investigation. Thus, the specific aim was to determine the clinical status, with respect to pain indices and disability level, of chronic migraine patients with medication overuse who were treated and followed prospectively for 5 years. All patients completed a brief inpatient treatment programme, in which they were withdrawn from their offending medications and subsequently placed on more appropriate preventive antimigraine medications. Both end-point, wherein missing data points were estimated, and continuer analyses, wherein data analysis was limited to the 58 individuals with complete datasets, revealed significant improvement on all measures studied-headache days per month, analgesic consumption and Migraine Disability Assessment (MIDAS) total score. The percentage reduction from baseline to 5 years for the MIDAS total score was 76.0%, while the percentage of individuals revealing improvements of clinically significant magnitude (≥ 50%) on the MIDAS was 91.9%. MIDAS total scores were lower at 5 years than at some of the intervening follow-up intervals. Comparisons of those who completed the 5-year follow-up (n = 58) with those who did not revealed no differences at baseline. This finding, coupled with the nearly identical results for the end-point and continuers analyses, suggests that attrition did not have a bearing on outcome. None of the patients completing the 5-year follow-up had relapsed since the prior 3-year follow-up assessment. High levels of maintenance were revealed at 5 years, with disability scores showing some continued improvement over time. The implications of these findings and the limitations of the study are discussed. © International Headache Society 2010.

Estienne M.,National Neurological Institute C Besta | Bugiani M.,VU University Amsterdam | Bizzi A.,National Neurological Institute C Besta | Granata T.,National Neurological Institute C Besta
Neurological Sciences | Year: 2011

Approaching an uncommon disease may result in diagnostic delay even in patients with typical clinical features. In this respect, diseases related to nutritional deficiencies may represent a diagnostic challenge. We describe a 2.5-year-old child with typical features of scurvy, who was referred for autistic-like behavior and severe muscle weakness and pain in lower limbs. Extensive investigations for non-nutrition-related disorders were first performed, including a muscle biopsy showing a selective type II fibers hypotrophy. Scurvy was eventually considered, after recalling the child's peculiar dietary habits. © Springer-Verlag 2011.

Lovati C.,Luigi Sacco Hospital | D'Amico D.,National Neurological Institute C Besta | Raimondi E.,Luigi Sacco Hospital | Mariani C.,Luigi Sacco Hospital | Bertora P.,Luigi Sacco Hospital
Expert Review of Neurotherapeutics | Year: 2010

Sleep and pain perception are two phylogenetically well-conserved functions, strictly influenced by environmental and psychological factors, and are able to interact reciprocally both in physiological and pathological situations. Sleep and head-pain perception share the involvement of several structures, such as the thalamus, the hypothalamus and brainstem nuclei, including the locus coeruleus and raphe nuclei. There ais clinical evidence indicating that sleep disorders can precede the appearance of certain headaches and that head pain, especially when frequent, can, in turn, affect sleep quality. In the present work the anatomy, physiology and pathology of sleep and head-pain perception will be reviewed with the aim of highlighting the points of contact and possible unifying treatment strategies. © 2010 Expert Reviews Ltd.

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