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Capitanio M.,University of Florence | Canepari M.,University of Pavia | Maffei M.,University of Pavia | Beneventi D.,University of Florence | And 6 more authors.
Nature Methods | Year: 2012

We describe a dual-trap force-clamp configuration that applies constant loads between a binding protein and an intermittently interacting biological polymer. The method has a measurement delay of only ∼10 μs, allows detection of interactions as brief as ∼100 μs and probes sub-nanometer conformational changes with a time resolution of tens of microseconds. We tested our method on molecular motors and DNA-binding proteins. We could apply constant loads to a single motor domain of myosin before its working stroke was initiated (0.2-1 ms), thus directly measuring its load dependence. We found that, depending on the applied load, myosin weakly interacted (<1 ms) with actin without production of movement, fully developed its working stroke or prematurely detached (<5 ms), thus reducing the working stroke size with load. Our technique extends single-molecule force-clamp spectroscopy and opens new avenues for investigating the effects of forces on biological processes. © 2012 Nature America, Inc. All rights reserved. Source


Nava S.,University of Bologna | Ferrer M.,Thorax Institute | Esquinas A.,Intensive Care Unit | Scala R.,Respiratory Ward and Respiratory Intermediate Care Unit | And 8 more authors.
The Lancet Oncology | Year: 2013

Background: Despite best-possible medical management, many patients with end-stage cancer experience breathlessness, especially towards the end of their lives. We assessed the acceptability and effectiveness of non-invasive mechanical ventilation (NIV) versus oxygen therapy in decreasing dyspnoea and the amount of opiates needed. Methods: In this randomised feasibility study, we recruited patients from seven centres in Italy, Spain, and Taiwan, who had solid tumours and acute respiratory failure and had a life expectancy of less than 6 months. We randomly allocated patients to receive either NIV (using the Pressure Support mode and scheduled on patients' request and mask comfort) or oxygen therapy (using a Venturi or a reservoir mask). We used a computer-generated sequence for randomisation, stratified on the basis of patients' hypercapnic status (PaCO2 >45 mm Hg or PaCO2 ≤45 mm Hg), and assigned treatment allocation using opaque, sealed envelopes. Patients in both groups were given sufficient subcutaneous morphine to reduce their dyspnoea score by at least one point on the Borg scale. Our primary endpoints were to assess the acceptability of NIV used solely as a palliative measure and to assess its effectiveness in reducing dyspnoea and the amount of opiates needed compared with oxygen therapy. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00533143. Findings: We recruited patients between Jan 15, 2008, and March 9, 2011. Of 234 patients eligible for recruitment, we randomly allocated 200 (85%) to treatment: 99 to NIV and 101 to oxygen. 11 (11%) patients in the NIV group discontinued treatment; no patients in the oxygen group discontinued treatment. Dyspnoea decreased more rapidly in the NIV group compared with the oxygen group (average change in Borg scale -0·58, 95% CI -0·92 to -0·23, p=0·0012), with most benefit seen after the first hour of treatment and in hypercapnic patients. The total dose of morphine during the first 48 h was lower in the NIV group than it was in the oxygen group (26·9 mg [37·3] for NIV vs 59·4 mg [SD 67·1] for oxygen; mean difference -32·4 mg, 95% CI -47·5 to -17·4). Adverse events leading to NIV discontinuation were mainly related to mask intolerance and anxiety. Morphine was suspended because of severe vomiting and nausea (one patient in each group), sudden respiratory arrest (one patient in the NIV group), and myocardial infarction (one patient in the oxygen group). Interpretation: Our findings suggest that NIV is more effective compared with oxygen in reducing dyspnoea and decreasing the doses of morphine needed in patients with end-stage cancer. Further studies are needed to confirm our findings and to assess the effectiveness of NIV on other outcomes such as survival. The use of NIV is, however, restricted to centres with NIV equipment, our findings are not generalisable to all cancer or palliative care units. Funding: None. © 2013 Elsevier Ltd. Source


Nardone A.,University of Piemonte Orientale | Nardone A.,Scientific Institute of Veruno | Schieppati M.,University of Pavia | Schieppati M.,Scientific Institute of Pavia
European Journal of Physical and Rehabilitation Medicine | Year: 2010

This review addresses the issue whether instrumental evaluations of balance may be helpful in orienting the clinical decision regarding balance rehabilitation. The aptitude of instrumental assessment of balance in supporting decision making in patients with balance disorders connected with ageing and with neurological diseases is considered. Among instrumental evaluations, recording of body sway during quiet stance and dynamic conditions are described, together with manoeuvres for recording postural reactions to predictable or unpredictable postural perturbations. The posturography patterns encountered in elderly subjects and patients affected by Parkinson's disease, spasticity, peripheral neuropathy, cerebellar diseases, vestibular deficit and neck disorders are presented and discussed. Findings from instrumental assessments of balance are helpful in understanding the pathophysiology of balance disorders, in screening for balance disorders, and in evaluating the natural progression of the disease or the response to therapy, be it physical or pharmacological. Conversely, as far as the prediction of the risk of falling in one individual patient is concerned, the various posturography tests do not produce consistent results. Source


Siracusa A.,University of Perugia | Folletti I.,University of Perugia | Moscato G.,Scientific Institute of Pavia
Current Opinion in Allergy and Clinical Immunology | Year: 2013

Purpose of Review: Recently there has been growing interest in non-IgE-mediated and irritant-induced occupational rhinitis due to old and new low-molecular-weight and irritant agents. The purpose of this review is to summarize the scientific evidence on agents and work activities responsible for non-IgE-mediated and irritant-induced occupational rhinitis and work-exacerbated rhinitis published in 2011 and 2012. Recent Findings: Several epidemiological, surveillance and experimental studies, case reports and reviews showed that workers exposed to drugs, wood dust, chemicals, metals and biocides are at high risk of non-IgE-mediated and irritant-induced occupational rhinitis; among activities at risk are healthcare, antibiotic manufacturing and cleaning workers. Work-exacerbated rhinitis has not been specifically studied, but it is reasonable to expect that it is frequently associated with work-exacerbated asthma. Recently, work-related anosmia/microsmia, nasal polyps and sinusitis have also been described. Reducing or eliminating workplace exposure to the specific agent has been confirmed to be effective in preventing symptoms of nonallergic occupational rhinitis. Summary: In consideration of the relevance of non-IgE-mediated and irritant-induced work-related rhinitis, physicians should recognize work-related rhinitis symptoms due to old and new low-molecular-weight and irritant agents. The mechanisms of non-IgE-mediated and irritant-induced occupational rhinitis remain largely unclear and need to be studied further. Substitution of responsible agents, reduction or elimination of exposure at the workplace should be enforced as effective measures. Copyright © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Cannavino J.,University of Pavia | Brocca L.,University of Pavia | Sandri M.,Venetian Institute of Molecular Medicine | Sandri M.,University of Pavia | And 4 more authors.
Journal of Physiology | Year: 2015

Key points: Skeletal muscle atrophy occurs as a result of disuse. Although several studies have established that a decrease in protein synthesis and increase in protein degradation lead to muscle atrophy, little is known about the triggers underlying such processes. A growing body of evidence challenges oxidative stress as a trigger of disuse atrophy; furthermore, it is also becoming evident that mitochondrial dysfunction may play a causative role in determining muscle atrophy. Mitochondrial fusion and fission have emerged as important processes that govern mitochondrial function and PGC-1α may regulate fusion/fission events. Although most studies on mice have focused on the anti-gravitary slow soleus muscle as it is preferentially affected by disuse atrophy, several fast muscles (including gastrocnemius) go through a significant loss of mass following unloading. Here we found that in fast muscles an early down-regulation of pro-fusion proteins, through concomitant AMP-activated protein kinase (AMPK) activation, can activate catabolic systems, and ultimately cause muscle mass loss in disuse. Elevated muscle PGC-1α completely preserves muscle mass by preventing the fall in pro-fusion protein expression, AMPK and catabolic system activation, suggesting that compounds inducing PGC-1α expression could be useful to treat and prevent muscle atrophy. The mechanisms triggering disuse muscle atrophy remain of debate. It is becoming evident that mitochondrial dysfunction may regulate pathways controlling muscle mass. We have recently shown that mitochondrial dysfunction plays a major role in disuse atrophy of soleus, a slow, oxidative muscle. Here we tested the hypothesis that hindlimb unloading-induced atrophy could be due to mitochondrial dysfunction in fast muscles too, notwithstanding their much lower mitochondrial content. Gastrocnemius displayed atrophy following both 3 and 7 days of unloading. SOD1 and catalase up-regulation, no H2O2 accumulation and no increase of protein carbonylation suggest the antioxidant defence system efficiently reacted to redox imbalance in the early phases of disuse. A defective mitochondrial fusion (Mfn1, Mfn2 and OPA1 down-regulation) occurred together with an impairment of OXPHOS capacity. Furthermore, at 3 days of unloading higher acetyl-CoA carboxylase (ACC) phosphorylation was found, suggesting AMP-activated protein kinase (AMPK) pathway activation. To test the role of mitochondrial alterations we used Tg-mice overexpressing PGC-1α because of the known effect of PGC-1α on stimulation of Mfn2 expression. PGC-α overexpression was sufficient to prevent (i) the decrease of pro-fusion proteins (Mfn1, Mfn2 and OPA1), (ii) activation of the AMPK pathway, (iii) the inducible expression of MuRF1 and atrogin1 and of authopagic factors, and (iv) any muscle mass loss in response to disuse. As the effects of increased PGC-1α activity were sustained throughout disuse, compounds inducing PGC-1α expression could be useful to treat and prevent muscle atrophy also in fast muscles. © 2015 The Physiological Society. Source

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