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Milano, Italy

Tremolizzo L.,University of Milan Bicocca | Messina P.,Laboratory of Neurological Disorders | Conti E.,University of Milan Bicocca | Sala G.,University of Milan Bicocca | And 13 more authors.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2014

ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [3H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies. © 2014 Informa Healthcare. Source

Marin B.,French Institute of Health and Medical Research | Marin B.,University of Limoges | Marin B.,Limoges University Hospital Center | Marin B.,Mario Negri Institute for Pharmacological Research | And 10 more authors.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2016

Our objective was to assess non-self-sufficiency (NSS) in ALS as an outcome measure in therapeutic trials. Using data from the control arm of two randomized trials and an observational study, associations between NSS (score ≤2 in the ALSFRS-R items for swallowing, cutting food and handling utensils, or walking) and the total ALSFRS-R score, forced vital capacity (FVC), and survival at selected time-points until death or 48 weeks, were assessed. These measures were used as surrogates of relevant functional impairment. Of 82 self-sufficient (SS) patients at baseline, 32 (39.0%) became NSS at four weeks and increased to 72 (87.8%) at the end of follow-up. A significant association was found between NSS, ALSFRS-R score and FVC at 24, 36 and 48 weeks. Thirty-four subjects died (41.5%). Compared to SS patients (median survival, 27.9 months), individuals becoming NSS at four weeks were at increased risk to die (median survival, 23.6 months, p = 0.02). NSS status at four weeks predicted survival even after adjustment for ALSFRS-R total score, age, gender, site of onset, disease duration, BMI, and FVC. Walking was the only predictor of survival when adjusting for all covariates. In conclusion, NSS status is a possible endpoint to investigate short-term efficacy of treatments of ALS. © 2015 Taylor & Francis. Source

Tarella C.,Molecular Biotechnology Center | Rutella S.,Catholic University of the Sacred Heart | Gualandi F.,University of Genoa | Melazzini M.,Science Oncoematologia | And 13 more authors.
Cytotherapy | Year: 2010

Background and aims. The aim of this study was to evaluate and characterize the feasibility and safety of bone marrow-derived cell (BMC) mobilization following repeated courses of granulocytecolony stimulating factor (G-CSF) in patients with amyotrophic lateral sclerosis (ALS). Methods. Between January 2006 and March 2007, 26 ALS patients entered a multicenter trial that included four courses of BMC mobilization at 3-month intervals. In each course, G-CSF (5 μg/kg b.i.d.) was administered for four consecutive days; 18% mannitol was also given. Mobilization was monitored by flow cytometry analysis of circulating CD34+ cells and by in vitro colony assay for clonogenic progenitors. Co-expression by CD34+ cells of CD133, CD90, CD184, CD117 and CD31 was also assessed. Results. Twenty patients completed the four-course schedule. One patient died and one refused to continue the program before starting the mobilization courses; four discontinued the study protocol because of disease progression. Overall, 89 G-CSF courses were delivered. There were two severe adverse events: one prolactinoma and one deep vein thrombosis. There were no discontinuations as a result of toxic complications. Circulating CD34 + cells were monitored during 85 G-CSF courses and were always markedly increased; the range of median peak values was 4157/μL, with no significant differences among the four G-CSF courses. Circulating clonogenic progenitor levels paralleled CD34+ cell levels. Most mobilized CD34+ cells co-expressed stem cell markers, with a significant increase in CD133 co-expression. Conclusions. It is feasible to deliver repeated courses of G-CSF to mobilize a substantial number of CD34+ cells in patients with ALS; mobilized BMC include immature cells with potential clinical usefulness. © 2010 Informa UK Ltd. Source

Luigetti M.,Catholic University of the Sacred Heart | Fabrizi G.M.,University of Verona | Bisogni G.,Catholic University of the Sacred Heart | Romano A.,Catholic University of the Sacred Heart | And 6 more authors.
Clinical Neurology and Neurosurgery | Year: 2016

Objectives CMT is a group of heterogeneous motor and sensory neuropathies divided into demyelinating (CMT1) and axonal forms (CMT2). Distal Hereditary Motor Neuropathy (dHMN) is a motor neuropathy/neuronopathy which resembles CMT. Final genetic diagnosis is poor in CMT2 and in dHMN when compared with CMT1. Our aim is to report clinical, neurophysiological and genetic findings in a cohort of patients with axonal inherited neuropathies. Patients and methods We report clinical, neurophysiological and genetic findings from 45 patients with CMT2 or dHMN, coming from 39 unrelated families, observed in our Institute of Neurology over a 20-year period. Results Clinical and electrophysiological examinations showed that 38 patients had CMT2 and 7 patients presented dHMN. Extensive genetic evaluation showed 6 mutations in MFN2, 4 mutations in HSPB1, 2 mutations in BSCL2, 3 mutations in GJB1, 1 mutation in MPZ. Conclusion Since next-generation sequencing will not be easily accessible, epidemiological data and clinical "phenotyping" remain the best strategy for clinicians to reach a correct genetic diagnosis in CMT2 and dHMN patients. © 2016 Elsevier B.V. All rights reserved. Source

Pane M.,Catholic University | Fanelli L.,Catholic University | Mazzone E.S.,Catholic University | Olivieri G.,Catholic University | And 32 more authors.
Neuromuscular Disorders | Year: 2015

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years.All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year.At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001).The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels.Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. © 2015 The Authors. Source

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