Stefano Masiero

University of Padova, Padua, Veneto, Italy

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Publications (58)91.32 Total impact

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    ABSTRACT: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. EudraCT:2009-014484-39 .
    Journal of Translational Medicine 12/2015; 13(1):371. DOI:10.1186/s12967-014-0371-2 · 3.99 Impact Factor
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    Translational Myology in Aging and Neuromuscular Disorders (Spring Padua Muscle Days - 2015), Terme Euganee (Padua), Italy; 03/2015
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    ABSTRACT: Despite the ravages of long term denervation there is structural and ultrastructural evidence for survival of muscle fibers in mammals, with some fibers surviving at least ten months in rodents and 3-6 years in humans. Further, in rodents there is evidence that muscle fibers may regenerate even after repeated damage in the absence of the nerve, and that this potential is maintained for several months after denervation. While in animal models permanently denervated muscle sooner or later loses the ability to contract, the muscles may maintain their size and ability to function if electrically stimulated soon after denervation. Whether in mammals, humans included, this is a result of persistent de novo formation of muscle fibers is an open issue we would like to explore in this review. During the past decade, we have studied muscle biopsies from the quadriceps muscle of Spinal Cord Injury (SCI) patients suffering with Conus and Cauda Equina syndrome, a condition that fully and irreversibly disconnects skeletal muscle fibers from their damaged innervating motor neurons. We have demonstrated that human denervated muscle fibers survive years of denervation and can be rescued from severe atrophy by home-based Functional Electrical Stimulation (h-bFES). Using immunohistochemistry with both non-stimulated and the h-bFES stimulated human muscle biopsies, we have observed the persistent presence of muscle fibers which are positive to labeling by an antibody which specifically recognizes the embryonic myosin heavy chain (MHCemb). Relative to the total number of fibers present, only a small percentage of these MHCemb positive fibers are detected, suggesting that they are regenerating muscle fibers and not pre-existing myofibers re-expressing embryonic isoforms. Although embryonic isoforms of acetylcholine receptors are known to be re-expressed and to spread from the end-plate to the sarcolemma of muscle fibers in early phases of muscle denervation, we suggest that the MHCemb positive muscle fibers we observe result from the activation, proliferation and fusion of satellite cells, the myogenic precursors present under the basal lamina of the muscle fibers. Using morphological features and molecular biomarkers, we show that severely atrophic muscle fibers, with a peculiar cluster reorganization of myonuclei, are present in rodent muscleseven-months after neurectomy and in human muscles 30-months after complete Conus-Cauda Equina Syndrome and that these are structurally distinct from early myotubes. Beyond reviewing evidence from rodent and human studies, we add some ultrastructural evidence of muscle fiber regeneration in long-term denervated human muscles and discuss the options to substantially increase the regenerative potential of severely denervated human muscles not having been treated with h-bFES. Some of the mandatory procedures, are ready to be translated from animal experiments to clinical studies to meet the needs of persons with longterm irreversible muscle denervation. An European Project, the trial Rise4EU (Rise for You, a personalized treatment for recovery of function of denervated muscle in long-term stable SCI) will hopefully follow
    European Journal of Translational Myology 02/2015; 2(25):77-92. DOI:10.4081/bam.2015.2.77
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    ABSTRACT: Background We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Methods Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. Trial registration EudraCT:2009-014484-39 webcite.
    Journal of Translational Medicine 01/2015; 13(3). DOI:10.1186/s12967-014-0371-2. · 3.99 Impact Factor
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    ABSTRACT: Objective: To discover the anatomist who first identified the upper oesophageal sphincter. Method: The authors searched dozens of antique anatomy textbooks kept in the old section of the 'Vincenzo Pinali' Medical Library of Padua University, looking for descriptions of the upper oesophageal sphincter. Results: The oesophageal sphincter was drawn correctly only in 1601, by Julius Casserius, in the book De vocis auditusque organis historia anatomica… (which translates as 'An Anatomical History on the Organs of Voice and Hearing …'), and was properly described by Antonio Maria Valsalva in 1704 in the book De aure humana tractatus… ('Treatise on the Human Ear …'). Conclusion: Anatomists Casserius and Valsalva can be considered the discoverers of the 'oesophageal sphincter'.
    The Journal of Laryngology & Otology 10/2014; 128(10):1-5. DOI:10.1017/S0022215114002035 · 0.70 Impact Factor
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    Annals of Physical and Rehabilitation Medicine 05/2014; 57:e387. DOI:10.1016/j.rehab.2014.03.1408
  • Annals of Physical and Rehabilitation Medicine 05/2014; 57:e164-e165. DOI:10.1016/j.rehab.2014.03.594
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    Annals of Physical and Rehabilitation Medicine 05/2014; 40:S17–S18. DOI:10.1016/j.rehab.2014.03.652
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    ABSTRACT: Action observation activates the same motor areas as those involved in the performance of the observed actions and promotes functional recovery following stroke. Movement observation is now considered a promising tool for motor rehabilitation, by allowing patients to train their motor functions when voluntary movement is partially impaired. We asked chronic-stroke patients, affected by either left (LHD) or right hemisphere (RHD) lesions, to observe either a left or right hand, while grasping a small target (eliciting a precision grip) or a large target (eliciting a whole hand grasp directed towards a target object). To better understand the effects of action observation on damaged motor circuits, we used transcranial magnetic stimulation (TMS) to induce motor evoked potentials (MEP) from two muscles of the unaffected hand in 10 completely hemiplegic participants. Results revealed that LHD patients showed MEP facilitation on the right (contralesional) M1 during action observation of hand-object interactions. In contrast, results showed no facilitation of the left (contralesional) M1 in RHD patients. Our results confirm that action observation might have a positive influence on the recovery of motor functions after stroke. Activating the motor system by means of action observation might provide a mechanism for improving function, at least in LHD patients.
    04/2014; 2014:251041. DOI:10.1155/2014/251041
  • European Journal of Translational Myology 03/2014; 24(1). DOI:10.4081/bam.2014.1.41
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    ABSTRACT: Steroidogenic enzymes autoantibodies (SEAbs) are frequently present and are markers of autoimmune premature ovarian failure (POF) in females with autoimmune Addison's disease (AAD). The prevalence and the significance of SEAbs in males with AAD have not been yet defined. We studied the prevalence of SEAbs in a large cohort of males with AAD and assessed the relationship between SEAbs positivity and testicular function. 154 males with AAD (mean age 34yrs) were studied. SEAbs included autoantibodies to: steroid-producing-cells (StCA), detected by immunofluorescence; steroid 17α-hydroxylase (17α-OHAbs) and side-chain-cleavage enzyme (SCCAbs) measured by immunoprecipitation assays. Gonadal function was evaluated by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex-hormone-binding-globulin (SHGB), anti-Müllerian hormone (AMH), inhibin-B (I-B). 26 males, 10 SEAbs(+) and 16 SEAbs(-) were followed-up for a mean period of 7.6 years to assess the behavior of SEAbs and testicular function. SEAbs were found in 24.7% of males with AAD with the highest frequency in patients with APS-1. The levels of reproductive hormones in 30 SEAbs(+) males were in the normal range according to age and were not significantly different compared to 55 SEAbs(-) males (p>0.05). During follow-up, both SEAbs(+) and SEAbs(-) patients maintained normal testicular function. SEAbs were found with high frequency in males with AAD, however were not associated with testicular failure. This study suggests that the diagnostic value of SEAbs in males with AAD differs compared to females and this may be related to the immuno-privileged status of the testis.
    Clinical & Experimental Immunology 02/2014; 176(3). DOI:10.1111/cei.12303 · 3.28 Impact Factor
  • Gait & Posture 11/2013; 37:S23. DOI:10.1016/j.gaitpost.2012.12.051 · 2.30 Impact Factor
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    Biomedizinische Technik/Biomedical Engineering 09/2013; DOI:10.1515/bmt-2013-4016 · 2.43 Impact Factor
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    Biomedizinische Technik/Biomedical Engineering 09/2013; DOI:10.1515/bmt-2013-4034 · 2.43 Impact Factor
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    ABSTRACT: Addison's disease (AD) is a rare endocrine condition. we aimed to evaluate clinical, immunologic, adrenal imaging, and genetic features in 633 Italian patients with AD followed-up since 1967. adrenal-cortex autoantibodies, presence of other autoimmune and non-autoimmune diseases, non-adrenal autoantibodies, adrenal imaging and genetic profile for HLA-DR and AIRE were analyzed. 492(77.7%) patients were found to be affected by autoimmune AD(A-AD), 57(9%) tuberculous AD, 29(4.6%) genetic-associated AD, 10(1.6%) adrenal cancer, 6(0.94%) post-surgical AD, 4(0.6%) vascular disorder related, 3(0.5%) post-infectious AD, and 32(5.1%) were defined as idiopathic. Adrenal cortex antibodies were detected in the vast majority (88-100%) of patients with recent onset A-AD, but in none of those with non-autoimmune AD. Adrenal imaging revealed normal/atrophic glands in all A-AD patients. 88% of patients with A-AD had other clinical or autoimmune diseases or were positive for non-adrenal autoantibodies. BASED ON THE COEXISTENCE OF OTHER AUTOIMMUNE DISORDERS, 65.6% OF PATIENTS WITH A-AD WERE FOUND TO HAVE TYPE 2 AUTOIMMUNE POLYENDOCRINE SYNDROME (APS-2), 14.4% APS-1 AND 8.5% APS-4. CLASS II-HLA ALLELES DRB1*03 AND *04 WAS INCREASED, AND DRB1*01,07,13 WAS REDUCED IN APS-2 PATIENTS WHEN COMPARED TO CONTROLS. 96% OF THE PATIENTS WITH APS-1 REVEALED AIRE GENE MUTATIONS.CONCLUSIONS: A-AD is the most prevalent form of adrenal insufficiency in Italy, and approximately 90% of the patients are adrenal autoantibody positive at the onset. Assessment of patients with A-AD for the presence of other autoimmune diseases should be helpful in monitoring and diagnosing APS type 1, 2 or 4 and improving patients care.
    European Journal of Endocrinology 09/2013; DOI:10.1530/EJE-13-0528 · 3.69 Impact Factor
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    European Journal of Translational Myology 08/2013; 20(1-2). DOI:10.4081/bam.2010.1-2.33
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    ABSTRACT: Background Ankylosing spondylitis is a major chronic rheumatic disease that predominantly affects axial joints, determining a rigid spine from the occiput to the sacrum. The dorsal hyperkyphosis may induce the patients to stand in a stooped position with consequent restriction in patients’ daily living activities. The aim of this study was to develop a method for quantitatively and objectively assessing both balance and posture and their mutual relationship in ankylosing spondylitis subjects. Methods The data of 12 healthy and 12 ankylosing spondylitis subjects (treated with anti-TNF-α stabilized), with a mean age of 51.42 and 49.42 years; mean BMI of 23.08 and 25.44 kg/m2 were collected. Subjects underwent a morphological examination of the spinal mobility by means of a pocket compass needle goniometer, together with an evaluation of both spinal and hip mobility (Bath Ankylosing Spondylitis Metrology Index), and disease activity (Bath Ankylosing Spondylitis Disease Activity Index). Quantitative evaluation of kinematics and balance were performed through a six cameras stereophotogrammetric system and a force plate. Kinematic models together with a test for evaluating balance in different eye level conditions were developed. Head protrusion, trunk flexion-extension, pelvic tilt, hip-knee-ankle flexion-extension were evaluated during Romberg Test, together with centre of pressure parameters. Results Each subject was able to accomplish the required task. Subjects’ were comparable for demographic parameters. A significant increment was observed in ankylosing spondylitis subjects for knee joint angle with the target placed at each eye level on both sides (p < 0.042). When considering the pelvic tilt angle a statistically significant reduction was found with the target placed respectively at 10° (p = 0.034) and at 30° (p = 0.019) less than eye level. Furthermore in ankylosing spondylitis subjects both hip (p = 0.048) and ankle (p = 0.029) joints angles differs significantly. When considering the posturographic parameters significant differences were observed for ellipse, center of pressure path and mean velocity (p < 0.04). Goniometric evaluation revealed significant increment of thoracic kyphosis reduction of cervical and lumbar range of motion compared to healthy subjects. Conclusions Our findings confirm the need to investigate both balance and posture in ankylosing spondylitis subjects. This methodology could help clinicians to plan rehabilitation treatments.
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    ABSTRACT: OBJECTIVE: A higher prevalence (26.9% versus 8.3% of controls) of autoimmune thyroiditis (AIT) in polycystic ovary syndrome (PCOS) has been reported in one study to date. We aimed to evaluate the prevalence of clinical, subclinical, potential thyroid autoimmune diseases and other organ-specific autoimmunity in a group of Italian patients with PCOS. STUDY DESIGN: 113 consecutive patients referred to our endocrinology unit as outpatients over 18 months, and diagnosed with PCOS according to the Rotterdam criteria, were included in the study, and 100 age-matched healthy women were enrolled as controls. Each patient was evaluated for family and personal history of autoimmune and non-autoimmune diseases and tested for autoantibodies against thyroperoxidase, thyroglobulin, parietal cells, intrinsic factor, adrenal-cortex, 21-hydroxylase, steroid-producing cells, 17-alpha-hydroxylase, side-chain cleavage enzyme, islet-cells, glutamic-acid decarboxylase, nuclei and mitochondria. All patients had serum TSH, FT4 and FT3 tested and patients with thyroid autoantibodies and/or abnormal TSH levels had an ultrasound thyroid scan. An oral glucose tolerance test and measurements of serum anti-Mullerian hormone (AMH) and inhibin B levels were carried out. RESULTS: AIT was present in 30/113 (27%) patients compared with 8% of controls (p<0.001). Subclinical hypothyroidism was detected in 13/30 (43%) patients with AIT; the remaining patients had normal thyroid function. The prevalence of non-thyroid autoantibodies in PCOS patients was not different from controls. AMH concentration was higher in PCOS patients compared to controls, but there was no difference between AIT and non-AIT groups. CONCLUSIONS: The prevalence of AIT in patients with PCOS was significantly higher than in controls. No other autoimmune diseases were associated with PCOS. This observation suggests that PCOS patients should be screened for AIT.
    European journal of obstetrics, gynecology, and reproductive biology 03/2013; 169(2). DOI:10.1016/j.ejogrb.2013.03.003 · 1.63 Impact Factor
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    ABSTRACT: Background:Autoantibodies to tryptophan hydroxylase (TPHAbs) directed against serotonin-producing enterochromaffin cells (EC) have been reported in autoimmune-polyendocrine-syndrome type 1 (APS-1) patients with gastrointestinal dysfunction (GID). Serotonin plays a critical role in enteric function and its peripheral blood levels reflect serotonin release from the gastrointestinal tract.Aims:We test the hypothesis that TPHAbs mark a distinct autoimmune component of APS-1 characterized by an autoimmune attack toward EC, which results in clinical GID.Methods:TPHAbs were measured in 64 APS-1 patients. Endoscopy with gastric (antrum/body) and duodenal biopsy was carried in 16 TPHAbs+ patients (8 with and 8 without GID) and in 2 TPHAbs- patients (without GID). Immunohistochemistry of biopsy specimens was carried out using antibodies to serotonin, chromogranin-A, CD3, CD4, CD8, and CD20. Serotonin serum levels were measured in TPHAbs+ and TPHAbs- patients who had endoscopy.Results:Thirty-seven of 64 patients were TPHAbs+ (11/12 with GID and 26/52 without GID; P < .001). Gastric and duodenal biopsies in all 8 TPHAb+ patients with GID showed lymphocytic infiltration with increased CD3+CD8+ intraepithelial lymphocytes and absence of EC. Furthermore, mean serotonin serum levels were below the normal range in TPHAb+ patients with GID (P < .01). In 8 TPHAb+ patients without GID gastric and duodenal biopsies showed different grades of inflammatory infiltration and reduced number of EC. Mean serotonin serum levels were near the lower limit of the normal range. In all TPHAbs+ patients the biopsies showed a reduced number of chromogranin-A positive cells consistent with enteroendocrine cells depletion. TPHAbs- patients without GID showed normal gastrointestinal mucosa and serotonin serum levels.Conclusions:TPHAbs appear to be markers of a distinct autoimmune component of APS-1. Progressive involvement of the gastrointestinal EC leads to the transition from preclinical to clinical disease, characterized by GID and reduced serotonin serum levels.
    The Journal of Clinical Endocrinology and Metabolism 01/2013; 98(2). DOI:10.1210/jc.2012-2734 · 6.31 Impact Factor
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    ABSTRACT: Damage to the mutual and delicate articular relationships of the foot may lead to functional failure. A painful foot can be the heralding sign of inflammatory, metabolic or degenerative rheumatic disease that may cause severe disability if left untreated. Healthy tendons are brilliant white in colour, are fibroelastic in texture and can withstand huge mechanical loads. Pathological tendons are characterised by changes in cellular function, rupture of collagen bundles, increased production of the proteoglycan-water matrix and neurovascular proliferation. According to the underlying disease, tendinopathies may present with pain of variable duration and intensity and with functional impairment, or they may be an asymptomatic finding on imaging techniques. Pain is the most common presenting symptom in the inflammatory rheumatic diseases of the ankle and the foot and usually precedes ultrasound or radiographic changes; pain results from inflammatory changes of the synovia and soft tissue structures including bursae, tendons, fascias and peripheral nerves. The management of tendinopathies in inflammatory and non-inflammatory rheumatic patients includes "articular economy," pharmacological treatment, foot orthotics, cryotherapy, instrumental physiotherapy, rehabilitation and physical. This review highlights the differences between tendinopathies occurring in non-inflammatory rheumatic disorders compared to those appearing in the course of inflammatory rheumatic disorders and defines a conservative management framework that non-rheumatologists (orthopaedic surgeons) and rheumatologists could adhere for the management of foot tendinopathies.
    Clinical Rheumatology 12/2012; 32(5). DOI:10.1007/s10067-012-2158-2 · 1.77 Impact Factor