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1.
Artigo em Inglês | MEDLINE | ID: mdl-34355622

RESUMO

Objective: To evaluate how Amyotrophic Lateral Sclerosis (ALS) patients' mortality rates change, based on different levels of forced vital capacity (FVC) and disease duration, providing a scheme of mortality rates of a real population of ALS patients to improve the design of future RCTs. Methods: One random spirometry for each ALS patient was selected during four time intervals from disease onset: (1) ≤12 months; (2) ≤18 months; (3) ≤24 months; (4) ≤36 months. Date of spirometry corresponded to date of trial entry, while time interval onset-spirometry to disease duration at enrollment. Mortality rates from inclusion were computed at different time intervals. Based on progression rates, patients were stratified in slow, intermediate and fast progressors. Survival from recruitment was calculated depending on FVC, disease duration and progression rate. Results: We included 659 patients in group 1, 888 in group 2, 1019 in group 3 and 1102 in group 4. Mortality rates were higher in each group at reducing the FVC cutoff used for recruitment (p < 0.001). Median survival decreased when lowering FVC and disease duration cutoffs (p < 0.001); a higher median disease progression rate of included patients led to lower median survival from recruitment. The proportion of recruited fast progressors raised when shortening disease duration and lowering FVC cutoff. Conclusions: This is a simple model for setting eligibility criteria, based on mortality rates of patients depending on FVC and disease duration, to select the best population for RCTs, tailored to trials' primary endpoints and duration.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33879000

RESUMO

Objective: To investigate the impact of a novel heterozygous FUS mutation in the acceptor splice site of intron 14 (c.1542 - 1 g > t) on protein expression in Peripheral Blood Mononuclear Cells (PBMC) from a familial ALS patient. Methods: PBMC were isolated for mRNA analysis (cDNA synthesis, sequencing and one-step RT-PCR), Western Immunoblot (WI), and Immunofluorescence (IF). Results: cDNA analysis revealed the skipping of exon 15 and a premature stop codon at c.228. RT-PCR showed reduced FUS mRNA by more than half compared to a healthy control (HC) and an ALS patient without genetic mutations (wtALS). In WI FUS band intensity in the proband was 30-50% compared to HC and wtALS. An antibody expected to detect only the wild-type protein did not reveal any reduction of FUS band intensity compared to the other antibodies. IF showed no difference among HC, wtALS, and the proband. Discussion: The reduction of FUS mRNA and protein in PBMC suggests the absence of the truncated protein, probably due to nonsense-mediated decay, leading to loss of function.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33860702

RESUMO

Objective: To assess patients Quality of life (QoL) and the burden of their caregivers during Covid-19 pandemic and specifically the impact of two-month lockdown period. Methods: In April 2020, a total of 60 patients and 59 caregivers were administered by phone scales assessing patients' QoL (McGill QoL Questionnaire), general health status (EQ-5D-5L), and caregiver burden (Zarit Burden Interview). The administration was repeated one month after the end of lockdown measures, with the addition of a qualitative questionnaire (COVID-QoL Questionnaire) exploring family reorganization and personal perception of lock down. Results: QoL and perceived health status did not worsen during lockdown, while caregiver burden increased (p = 0.01). Patient's QoL and caregiver burden were inversely correlated at T1 (ZBI total score mildly correlated with Mc Gill existential subscore, p = 0.02, rho = 0.30 and with Mc Gill total score, p = 0.05, rho = 0.265). No significant correlations were found at T2. According to the COVID-QoL questionnaire, caregivers perceived lower family help compared to patients (p < 0.001). Conclusions: Restricted measures of lockdown period during COVID-19 pandemic did not result in a significant reduction of QoL in our cohort of ALS patients, while caregiver burden significantly increased. ALS motor impairment may have played a role in the unchanged life conditions of patients. Instead, the restriction of family help for primary caregivers could be responsible of their increased burden, reflecting the importance of a wide social support in the management of this clinical condition.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32924624

RESUMO

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.


Assuntos
Esclerose Amiotrófica Lateral/terapia , COVID-19 , Neurologia , Preferência do Paciente , Satisfação do Paciente , Psicologia , Telemedicina/métodos , Idoso , Esclerose Amiotrófica Lateral/fisiopatologia , Esclerose Amiotrófica Lateral/psicologia , Gerenciamento Clínico , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente , SARS-CoV-2 , Fonoterapia , Centros de Atenção Terciária
5.
Dis Model Mech ; 13(5)2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32188741

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.


Assuntos
Esclerose Amiotrófica Lateral/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Superóxido Dismutase-1/genética , Fatores de Transcrição/genética , Regulação para Cima/genética , Esclerose Amiotrófica Lateral/sangue , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Neurônios Motores/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/sangue , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Fatores de Transcrição/metabolismo , Ativação Transcricional/genética
6.
BMJ Open ; 10(3): e034049, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209625

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo. METHODS AND ANALYSIS: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+ cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER: Eudract 2014-002228-28.


Assuntos
Esclerose Amiotrófica Lateral , Filgrastim/uso terapêutico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Humanos , Itália , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Front Mol Neurosci ; 10: 99, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28428745

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.

8.
Neurotox Res ; 32(1): 1-7, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28337659

RESUMO

Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro-inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy.


Assuntos
Esclerose Múltipla/sangue , Doença de Parkinson/sangue , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Esclerose Amiotrófica Lateral/sangue , Feminino , Expressão Gênica , Humanos , Itália , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
9.
Anesth Analg ; 122(3): 624-32, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26599795

RESUMO

BACKGROUND: A central-to-radial arterial pressure gradient may occur after cardiopulmonary bypass (CPB), which, in some patients, may last for a prolonged time after CPB. Whenever there is a pressure gradient, the radial artery pressure measure may underestimate a more centrally measured systemic pressure, which may result in a misguided therapeutic strategy. It is clinically important to identify the risk factors that may predict the appearance of a central-to-radial pressure gradient, because more central sites of measurements might then be considered to monitor systemic arterial pressure in high-risk patients. The objective of this study was to assess preoperative and intraoperative risk factors for central-to-radial pressure gradient. METHODS: Seventy-three patients undergoing cardiac surgery using CPB were included in this prospective observational study. A significant central-to-radial arterial pressure gradient was defined as a difference of 25 mm Hg in systolic pressure or 10 mm Hg in mean arterial pressure for a minimum of 5 minutes. Preoperative data included demographics, presence of comorbidities, and medications. Intraoperative data included type of surgery, CPB and aortic clamping time, use of inotropic drugs, and vasodilators or vasopressors agents. The diameter of the radial and femoral artery was measured before the induction of anesthesia using B-mode ultrasonography. RESULTS: Thirty-three patients developed a central-to-radial arterial pressure gradient (45%). Patients with a significant pressure gradient had a smaller weight (71.0 ± 16.9 vs 79.3 ± 17.3 kg, P = 0.041), a smaller height (162.0 ± 9.6 vs 166.3 ± 8.6 cm, P = 0.047), a smaller radial artery diameter (0.24 ± 0.03 vs 0.29 ± 0.05 cm, P < 0.001), and were at a higher risk as determined by the Parsonnet score (30.3 ± 24.9 vs 17.0 ± 10.9, P = 0.007). In addition, a longer aortic clamping time (85.8 ± 51.0 vs 64.2 ± 29.3 minutes, P = 0.036), mitral and complex surgery (P = 0.007 and P = 0.017, respectively), and administration of vasopressin (P = 0.039) were identified as potential independent predictors of a central-to-radial pressure gradient. By using multivariate logistic regression analysis, the following independent risk factors were identified: Parsonnet score (odds ratio [OR], 1.076; 95% confidence interval [CI], 1.027-1.127, P = 0.002), aortic clamping time >90 minutes (OR, 8.521; 95% CI, 1.917-37.870, P = 0.005), and patient height (OR, 0.933, 95% CI, 0.876-0.993, P = 0.029). The relative risk (RR) estimates remained statistically significant for the Parsonnet score and the aortic clamping time ≥90 minutes (RR, 1.010; 95% CI, 1.003-1.018, P = 0.009 and RR, 2.253; 95% CI, 1.475-3.443, P < 0.001 respectively) while showing a trend for patient height (RR, 0.974; 95% CI, 0.948-1.001, P = 0.058). CONCLUSIONS: Central-to-radial gradients are common in cardiac surgery. The threshold for using a central site for blood pressure monitoring should be low in small, high-risk patients undergoing longer surgical interventions to avoid inappropriate administration of vasopressors and/or inotropic agents.


Assuntos
Pressão Arterial , Procedimentos Cirúrgicos Cardíacos/métodos , Complicações Intraoperatórias/epidemiologia , Artéria Radial/fisiopatologia , Idoso , Ponte Cardiopulmonar , Comorbidade , Constrição , Interações Medicamentosas , Eletrocardiografia , Feminino , Humanos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Vasoconstritores/efeitos adversos , Vasoconstritores/uso terapêutico , Vasopressinas/efeitos adversos , Vasopressinas/uso terapêutico
11.
J Neurol ; 261(11): 2178-83, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25178511

RESUMO

NADPH-oxidases (NOX) catalyze the formation of reactive oxygen species (ROS), which play a role in the development of neurological diseases, particularly those generated by the phagocytic isoform NOX2. Increased ROS has been observed in the amyotrophic lateral sclerosis (ALS) SOD1 transgenic mouse, and in this preclinical model the inactivation of NOX2 decreases ROS production and extends survival. Our aim was to evaluate NOX2 activity measuring neutrophil oxidative burst in a cohort of 83 ALS patients, and age- and gender-matched healthy controls. Oxidative burst was measured directly in fresh blood using Phagoburst™ assay by flow cytometry. Mean fluorescence intensity (MFI), emitted in response to different stimuli, leads to produce ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity (GeoMean). No difference was found between the MFI values in cases and controls. NOX2 activity was independent from gender and age, and in patients was not related to disease duration, site of onset (bulbar vs. spinal), or ALSFRS-R score. However, patients with a NOX2 activity lower than the median value showed a 1-year increase of survival from onset (p = 0.011). The effect of NOX2 was independent from other known prognostic factors. These findings are in keeping with the observations in the mouse model of ALS, and demonstrate the strong role of NOX2 in modifying progression in ALS patients. A proper modulation of NOX2 activity might hold therapeutic potential for ALS.


Assuntos
Esclerose Amiotrófica Lateral/enzimologia , Esclerose Amiotrófica Lateral/mortalidade , Glicoproteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Idoso , Esclerose Amiotrófica Lateral/diagnóstico , Ativação Enzimática/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 2 , Taxa de Sobrevida/tendências
12.
Neurobiol Aging ; 34(1): 357.e1-5, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22921269

RESUMO

The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.


Assuntos
Esclerose Amiotrófica Lateral , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/mortalidade , Proteína C9orf72 , Distribuição de Qui-Quadrado , Planejamento em Saúde Comunitária , Feminino , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Proteínas/genética , Adulto Jovem
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