IRCCS Fondazione Don Carlo Gnocchi

Milano, Italy

IRCCS Fondazione Don Carlo Gnocchi

Milano, Italy
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Pasetto L.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Pozzi S.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Castelnovo M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Basso M.,University of Trento | And 16 more authors.
Journal of Neuroscience | Year: 2017

Neuroinflammationis amajor hallmarkof amyotrophiclateral sclerosis (ALS), whichis currentlyuntreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients. © 2017 the authors.


Merati G.,University of Milan | Maggioni M.A.,University of Milan | Maggioni M.A.,Charite University of Medicine | Invernizzi P.L.,University of Milan | And 4 more authors.
European Journal of Applied Physiology | Year: 2015

Purpose: Endurance exercise is associated with high cardiac vagal tone, but how the cardiac autonomic control correlates with shorter anaerobic performances is unknown. Therefore, the aim of this study was to evaluate how autonomic modulations of heart rate (HR) variability (V) correlate with performances of short- (<1 min) and very short (<30 s) duration in elite athletes. Method: Thirteen male swimmers, national-level crawl specialists in short (100-m) and very short (50-m) distances, were enrolled. HR was recorded during 15-min supine rest: (1) in the morning after wake up, (2) in the afternoon before sprint-oriented training sessions, (3) few minutes after training (first recovery phase after swimming cooldown). Heart rate variability (HRV) vagal and sympatho/vagal indices were calculated in time, frequency and complexity domains. Correlations of best seasonal times on 100- or 50-m distances with HRV indices and the velocity at blood lactate accumulation onset (VOBLA) were calculated. Results and conclusion: Vagal indices were highest in the morning where they positively correlated with very short-distance times (higher the index, worse is the 50-m performance). Sympatho/vagal indices were highest after training where they negatively correlated with short-distance times (higher the index, better is the 100-m performance). VOBLA did not correlate with the performances. Therefore, autonomic HRV indices and not VOBLA predict short and very short, most anaerobic, performances. Results also suggest that a strong cardiac vagal control has no effect on short performances and is even detrimental to very short performances, and that the capacity to powerfully increase the sympathetic tone during exercise may improve short, but not very short performances. © 2014, Springer-Verlag Berlin Heidelberg.


Di Rienzo M.,IRCCS Fondazione Don Carlo Gnocchi | Vaini E.,IRCCS Fondazione Don Carlo Gnocchi | Castiglioni P.,IRCCS Fondazione Don Carlo Gnocchi | Merati G.,University of Milan | And 6 more authors.
Autonomic Neuroscience: Basic and Clinical | Year: 2013

Seismocardiogram (SCG) is the measure of the micro-vibrations produced by the heart contraction and blood ejection into the vascular tree. Over time, a large body of evidence has been collected on the ability of SCG to reflect cardiac mechanical events such as opening and closure of mitral and aortic valves, atrial filling and point of maximal aortic blood ejection. We recently developed a smart garment, named MagIC-SCG, that allows the monitoring of SCG, electrocardiogram (ECG) and respiration out of the laboratory setting in ambulant subjects. The present pilot study illustrates the results of two different experiments performed to obtain a first evaluation on whether a dynamical assessment of indexes of cardiac mechanics can be obtained from SCG recordings obtained by MagIC-SCG. In the first experiment, we evaluated the consistency of the estimates of two indexes of cardiac contractility, the pre-ejection period, PEP, and the left ventricular ejection time, LVET. This was done in the lab, by reproducing an experimental protocol well known in literature, so that our measures derived from SCG could have been compared with PEP and LVET reference values obtained by traditional techniques. Six healthy subjects worn MagIC-SCG while assuming two different postures (supine and standing); PEP was estimated as the time interval between the Q wave in ECG and the SCG wave corresponding to the opening of aortic valve; LVET was the time interval between the SCG waves corresponding to the opening and closure of the aortic valve. The shift from supine to standing posture produced a significant increase in PEP and PEP/LVET ratio, a reduction in LVET and a concomitant rise in the LF/HF ratio in the RR interval (RRI) power spectrum. These results are in line with data available in literature thus providing a first support to the validity of our estimates. In the second experiment, we evaluated in one subject the feasibility of the beat-by-beat assessment of LVET during spontaneous behavior. The subject was continuously monitored by the smart garment from 8. am to 8. pm during a workday. From the whole recording, three data segments were selected: while the subject was traveling to work (M1), during work in the office (O) and while traveling back home (M2). LVET was estimated on a beat-by-beat basis from SCG and the RRI influence was removed by regression analysis. The LVET series displayed marked beat-by-beat fluctuations at the respiratory frequency. The amplitude of these fluctuations changed in the three periods and was lower when the LF/HF RRI power ratio was higher, at O, thus suggesting a possible influence of the autonomic nervous system on LVET short-term variability. To the best of our knowledge this case report provides for the first time a representation of the beat-by-beat dynamics of a systolic time interval during daily activity. The statistical characterization of these findings remains to be explored on a larger population. © 2013 Elsevier B.V.


PubMed | University of Trento, Martin Luther University of Halle Wittenberg, Irccs Instituto Of Ricerche Farmacologiche Mario Negri, IRCCS Fondazione Don Carlo Gnocchi and 3 more.
Type: | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2016

Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and animal models of ALS, but have been proved disappointing, in part because effective targets have not yet been identified. Cyclophilin A (PPIA) as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in cerebrospinal fluid of SOD1We provide evidence that extracellular PPIA is a mediator of the neuroinflammatory reaction in ALS and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons and extended survival in the SOD1


Radaelli A.,Ospedale San Gerardo | Mancia G.,University of Milan Bicocca | Balestri G.,Ospedale Desio | Rovati A.,Ospedale San Gerardo | And 4 more authors.
Journal of Hypertension | Year: 2014

Objective: After myocardial infarction (MI), baroreflex function is impaired and heart rate (HR) variability is reduced. An impaired baroreflex has been observed also in coronary patients with no previous MI, leading to hypothesize alterations of HR variability also in these patients. The aim of the present work was, therefore, to study whether and to what extent cardiovascular variability is altered in coronary patients with no previous MI. Methods: Thirty-two individuals were studied: eleven patients with coronary artery disease but no previous MI [coronary artery disease (CAD)], eleven patients with a reduced left ventricular ejection fraction [congestive heart failure (CHF)] and ten age-matched controls (CNT). Results: Overall HR variability was significantly and similarly reduced in CAD (630±272 ms2) and CHF patients (594±395 ms2) with respect to CNT (1405±837 ms2), this being the case also for the low and high frequency spectral components. Low-frequency oscillations of blood pressure (BP) were also significantly and similarly less pronounced in CAD (0.7±0.7mmHg2) and CHF patients (0.7±0.7mmHg2) compared with CNT (1.8±1.4mmHg2). Moreover, both CAD and CHF patients showed a significantly reduced baroreflex function and an increased pulse-wave velocity with respect to CNT. Conclusion: Our study shows that in coronary patients with no MI and no left ventricular dysfunction, there is a profound alteration of both HR and BP variability as in CHF patients, presumably because of a marked impairment of the autonomic modulation of the heart and blood vessels.


Castiglioni P.,IRCCS Fondazione Don Carlo Gnocchi | Di Rienzo M.,IRCCS Fondazione Don Carlo Gnocchi | Radaelli A.,San Gerardo Hospital
Computing in Cardiology | Year: 2016

Heart rate variability (HRV) allows risk stratification in coronary artery disease (CAD) patients, but only few works evaluated HRV in CAD patients with preserved ejection fraction. Aim of this work is to describe spectral and fractal structures of HRV in CAD patients with normal ejection fraction. We recorded R-R intervals for 15 minutes in 10 CAD patients and in 10 matched controls with the same ejection fraction, estimating broadband power spectra, PSD(f), and the recently proposed temporal spectrum of scale coefficients, α(τ). In CAD patients, PSD(f) was significantly (p<0.05) lower over a low-frequency band (0.047-0.240 Hz) and over a very-low frequency band (0.007-0.022 Hz); α(τ) was significantly higher between 9 and 25 s (corresponding to low frequencies) but did not differ from controls at scales T corresponding to very-low frequencies. Therefore, in CAD patients, even when the ejection fraction is preserved, a low frequency spectral component with its own fractal signature is absent. In addition, fluctuations at lower frequencies are reduced but, in this case, the power reduction is not associated with an altered fractal dynamics. © 2015 CCAL.

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