Scientific Institute of Milan

Milano, Italy

Scientific Institute of Milan

Milano, Italy
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Bussotti M.,Scientific Institute of Milan | Gremigni P.,University of Bologna | Pedretti R.F.E.,Scientific Institute of Milan | Pedretti R.F.E.,Scientific Institute of Tradate | And 6 more authors.
Cardiovascular and Hematological Disorders - Drug Targets | Year: 2017

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterised by a severe impairment of functional status and quality of life (QoL). Use of rehabilitative programmes may help to improve outcomes. The aim of this pre/post test case series was to evaluate the impact of a training program, including sessions of aerobic and resistance exercise, inspiratory muscle reinforcement, slow breathing, relaxation, and psychological support, on functional outcomes. Methods: Fifteen patients affected by PAH, in World Health Organization (WHO) Functional Class (FC) II or III and in stable clinical condition, were included in a 4-week cardiorespiratory training programme conducted in outpatient service. Patients were tested during a routine control visit (T0), one month later at the beginning of the training programme (T1), and at study end (T2). Between T0 and T1, patients continued their normal activities and therapies. At each step, patients underwent respiratory and functional evaluation by spirometry, 6-minute walk test (6-MWT), maximal cardiopulmonary exercise testing (CPET), echocardiography, and levels of brain natriuretic peptide (BNP). QoL was also assessed at T1 and T2 using the Hospital Anxiety and Depression Scale and the EuroQoL-5D questionnaire. The primary endpoint was the effect of training on peak oxygen consumption (peak V̇O2). Results: There were no significant differences in BNP levels, or in any of the respiratory or echocardiographic parameters measured, between T0 and T1. Between T1 and T2, significant improvements were recorded in QoL (HADS-Anxiety mean change 3.5 ± 3.3 and HADS-Depression mean change 1.6 ± 2.0, all p < 0.01). Significant improvements were also observed in functional capacity with distance walked at 6-MWT increasing from 455 ± 115 to 487 ± 120 (+8%, p < 0.01), workload (WR) of CPET increased of 22% (from 73 ± 22 to 87 ± 21 watt, p < 0.001), peak V̇O2 increasing from 17.3 ± 4.2 to 19.9 ± 4.5 mL/kg/min (p < 0.001) and pulse O2 increasing from 7.8 ± 1.8 to 8.8 ± 2.4 mL/beat (p < 0.01). No adverse events or deterioration in clinical status were observed during the training sessions. Conclusion: Cardiorespiratory training in a outpatient service is a suitable option for patients with PAH in WHO FC II/III thanks to improved exercise capacity and QoL, which may allow them to achieve better outcomes. © 2017 Bentham Science Publishers.

Chio A.,University of Turin | Battistini S.,University of Siena | Calvo A.,University of Turin | Caponnetto C.,University of Genoa | And 14 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.

Chio A.,University of Turin | Borghero G.,University of Cagliari | Pugliatti M.,University of Sassari | Calvo A.,University of Turin | And 41 more authors.
Archives of Neurology | Year: 2011

Objective: To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations. Design: Population-based, prospective cohort study. Patients: A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients. Intervention: Patients underwent mutational analysis for SOD1, FUS, and TARDBP. Results: Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G > A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness. Conclusions: The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor. ©2011 American Medical Association. All rights reserved.

Frazzitta G.,Moriggia Pelascini Hospital | Frazzitta G.,Scientific Institute of Montescano | Balbi P.,Scientific Institute of Milan | Maestri R.,Scientific Institute of Montescano | And 3 more authors.
American Journal of Physical Medicine and Rehabilitation | Year: 2013

In the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease. Copyright © 2013 by Lippincott Williams & Wilkins.

PubMed | Federal University of São Paulo, University Paris - Sud, University of Rome La Sapienza, Queen's University and 5 more.
Type: | Journal: International journal of cardiology | Year: 2015

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coexistence increases morbidity and mortality. The intercept of ventilation (VEint) on the VE vs. carbon dioxide production (VCO2) relationship during exercise has been found to vary in proportion with dead space (VD) in HF. Considering that increased VD is the key pathophysiological abnormality in COPD but a secondary finding in HF we hypothesized that a high VEint would be useful in suggesting COPD as HF co-morbidity. Our aim was to assess whether an elevated VEint suggests the presence of COPD in HF.In a multicenter retrospective study, the VE-VCO2 relationship was analyzed both as slope and intercept in HF (n = 108), HF-COPD (n = 106) and COPD (n = 95). Patients with pulmonary arterial hypertension (PAH) (n = 85) and healthy subjects (HF) (n = 56) served as positive and negative controls relative to VE-VCO2 abnormalities, respectively.Slope and VEint varied in opposite directions in all groups (p < 0.05) being VE-VCO2 slope highest and lowest in PAH and healthy subjects, respectively. No slope differences were observed among HF, HF-COPD and COPD (32 7, 31 7, and 31 6, respectively). VEint was higher in HF-COPD and COPD compared to HF, PAH and controls (4.8 2.4 L/min, 5.9 3.0 L/min, 3.0 2.6L/min, 2.3 3.3 L/min and 3.9 2.5L/min, respectively; p < 0.01). A VEint 4.07 L/min identified patients with high probability of having COPD or HF-COPD (sensitivity of 71.6% and specificity of 72.0%).These data provide novel evidence that a high VEint ( 4.07 L/min) should be valued to suggest coexistent COPD in HF patients.

PubMed | University Utrecht, Massey University, University of Edinburgh, University of Piemonte Orientale and 8 more.
Type: Journal Article | Journal: The Lancet. Neurology | Year: 2014

Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process.We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register.We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=095, Ireland r(2)=099, Italy r(2)=095, the Netherlands r(2)=099, and Scotland r(2)=097; overall r(2)=099. All five registers gave similar estimates of the linear slope ranging from 45 to 51, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 48 (95% CI 45-50), with similar estimates for men (46, 43-49) and women (50, 45-55).A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues.UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).

Chio A.,University of Turin | Calvo A.,University of Turin | Mazzini L.,University of Piemonte Orientale | Cantello R.,University of Piemonte Orientale | And 14 more authors.
Neurology | Year: 2012

Objective: To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases. Methods: Thestudy population includes allALScases diagnosed in Piemonte, Italy, from January2007to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, andC9ORF72have been assessed. Results: Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012). Conclusions: We have found that ̃11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease. © 2012 American Academy of Neurology.

Franchignoni F.,Scientific Institute of Veruno | Mora G.,Scientific Institute of Milan | Giordano A.,Scientific Institute of Veruno | Volanti P.,Scientific Institute of Mistretta | Chio A.,University of Turin
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2013

Objective: To examine dimensionality, reliability and validity of the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) using traditional classical test theory methods and Rasch analysis in order to provide a rationale for possible improvement of its metric quality. Methods: Methodological research on ALSFRS-R collected in a consecutive sample of 485 patients with amyotrophic lateral sclerosis (ALS) attending three tertiary ALS centres. Results: The ALSFRS-R items showed good internal consistency but dimensionality analysis argues against the use of ALSFRS-R as a single score because the scale lacks unidimensionality. Parallel analysis and exploratory factor analysis revealed three factors representing the following domains: (1) bulbar function; (2) fine and gross motor function; and (3) respiratory function. Rasch analysis showed that all items in each domain fitted the respective constructs to measure, except for item No 9 'climbing stairs' and item No 12 'respiratory insufficiency'. Rating categories did not comply with the criteria for category functioning. Collapsing the scale's 5 level ratings into 3 levels improved its metric quality. Conclusions: The ALSFRS-R fails to satisfy rigorous measurement standards and should be, at least in part, revised. At present, ALSFRS-R should be considered as a profile of mean scores from three different domains (bulbar, motor and respiratory functions) more than a global total score. Further studies on ALSFRS-R using modern psychometric methods are warranted to confirm our findings and refine the metric quality of this scale, through a step by step process.

Chio A.,University of Turin | Chio A.,University of Genoa | Calvo A.,University of Turin | Calvo A.,University of Genoa | And 21 more authors.
Neurology | Year: 2015

Objective: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). Methods: PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007-2012 period (discovery cohort); controls were 509 neurologically healthy age-and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy. Results: In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p 5 0.0001; odds ratio 14.8, 95% confidence interval 1.9-110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3-2.2; polyQ <31, 2.7 years, IQR 1.6-5.1; p 5 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5-3.4; polyQ <31, 3.2 years, IQR 2.0-6.4; p 5 0.007). Conclusions: ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Diseasemodifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS. © 2014 American Academy of Neurology.

PubMed | Scientific Institute of Milan, Italy Eastern Piedmont University, University of Turin, Scientific Institute of Veruno NO and 2 more.
Type: Journal Article | Journal: Journal of neurology, neurosurgery, and psychiatry | Year: 2016

To assess the prognostic influence of premorbid smoking habits and vascular risk profile on amyotrophic lateral sclerosis (ALS) phenotype and outcome in a population-based cohort of Italian patients.A total of 650 patients with ALS from the Piemonte/Valle dAosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid cigarette smoking habits and chronic obstructive pulmonary disease (COPD) were collected at the time of diagnosis.Current smokers had a significantly shorter median survival (1.9years, IQR 1.2-3.4) compared with former (2.3years, IQR 1.5-4.2) and never smokers (2.7years, IQR 1.8-4.6) (p=0.001). Also COPD adversely influenced patients prognosis. Both smoking habits and CODP were retained in Cox multivariable model.This study has demonstrated in a large population-based cohort of patients with ALS that cigarette smoking is an independent negative prognostic factor for survival, with a dose-response gradient. Its effect is not related to the presence of COPD or to respiratory status at time of diagnosis. The understanding of the mechanisms, either genetic or epigenetic, through which exogenous factors influence disease phenotype is of major importance towards a more focused approach to cure ALS.

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