Publications by authors named "Giulia Ricci"

129 Publications

MEYE: Web-app for translational and real-time pupillometry.

eNeuro 2021 Sep 13. Epub 2021 Sep 13.

Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.

Pupil dynamics alterations have been found in patients affected by a variety of neuropsychiatric conditions, including autism. Studies in mouse models have used pupillometry for phenotypic assessment and as a proxy for arousal. Both in mice and humans, pupillometry is non-invasive and allows for longitudinal experiments supporting temporal specificity, however, its measure requires dedicated setups. Here, we introduce a Convolutional Neural Network that performs online pupillometry in both mice and humans in a web app format. This solution dramatically simplifies the usage of the tool for the non-specialist and non-technical operators. Because a modern web browser is the only software requirement, this choice is of great interest given its easy deployment and set-up time reduction. The tested model performances indicate that the tool is sensitive enough to detect both locomotor-induced and stimulus-evoked pupillary changes, and its output is comparable with state-of-the-art commercial devices.Alteration of pupil dynamics is an important biomarker that can be measured non-invasively and across different species. Even though pupil size is driven primarily by light, it can also monitor arousal states and cognitive processes. Here we show an open-source web app that, through Deep Learning, can perform real-time pupil size measurements in both humans and mice, with accuracy similar to commercial-grade eye trackers. The tool requires no installation and pupil images can be captured using infrared webcams, opening the possibility to perform pupillometry widely, cost-effectively, and in a high-throughput manner.
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http://dx.doi.org/10.1523/ENEURO.0122-21.2021DOI Listing
September 2021

A case of intravascular large B cell lymphoma with brain involvement mimicking progressive multifocal leukoencephalopathy.

Int J Neurosci 2021 Sep 1:1-5. Epub 2021 Sep 1.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Intravascular large B-cell lymphoma (IVLBCL) is a very rare form of extranodal lymphoma, characterized by the proliferation of neoplastic B cells within the lumen of small vessels. Due to its high aggressivity, for years the prognosis had been really poor with only anectodical cases of remission after traditional chemotherapy. More recently, new therapeutic protocols allowed a significant increase in overall survival. It can virtually involve every organ, being skin and central nervous system the most affected. The clinical presentation is often unspecific and insidious; therefore, diagnosis can be challenging. Tissue biopsy, in particular random deep skin biopsy, is the gold standard for definitive diagnosis. We describe the case of a 58-year-old woman with a previous diagnosis of myelofibrosis, who presented with a rapidly progressive neurological deterioration and a brain MRI suggestive of Progressive Multifocal Leukoencephalopathy. Due to the absence of BK and JC viruses in cerebrospinal fluid and the presence of severe myalgias and subcutaneous nodules, a skin and muscle biopsy was performed, allowing diagnosis of IVLBCL. We describe the diagnostic pitfalls of this case, briefly reviewing existing literature about IVLBCL.
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http://dx.doi.org/10.1080/00207454.2021.1972418DOI Listing
September 2021

Hard-to-heal wound treated with Integra Flowable Wound Matrix: analysis and clinical observations.

J Wound Care 2021 Aug;30(8):644-652

Department of Integrated Multi-Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

Skin healing defects severely impair the quality of life of millions of people and burden healthcare systems globally. The therapeutic approach to these pathologies still represents a challenge. Novel scaffolds, used as dermal substitutes, possibly represent a promising strategy in complex wound management. Integra Flowable Wound Matrix (IFWM) is composed of a lyophilised, micronised form of collagen/chondroitin sulphate matrix, already used in regenerative medicine and endorsed in the therapy of diabetic foot lesions. In this paper, IFWM was applied to a tunnelling hard-to-heal skin lesion in order to restore tissue integrity. Although the different phases of skin wound healing are well established, the molecular mechanism underpinning IFWM-induced tissue repair are almost unknown. Here, we report, for the first time, the comparative analysis of molecular, histological and clinical observations of the healing process of a hard-to-heal tunnelling skin wound. The therapeutic success of this clinical case allowed us to recommend the use of IFWM as a tissue substitute in this rare type of hard-to-heal wound in which the high inflammatory status hampered the natural healing process.
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http://dx.doi.org/10.12968/jowc.2021.30.8.644DOI Listing
August 2021

Expanding the clinical and genetic spectrum of pathogenic variants in STIM1.

Muscle Nerve 2021 Aug 8. Epub 2021 Aug 8.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Introduction/aims: Stromal interaction molecule 1 (STIM1) is a reticular Ca sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1.

Methods: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel.

Results: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients.

Discussion: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.
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http://dx.doi.org/10.1002/mus.27391DOI Listing
August 2021

Anti-HMGCR antibodies and asymptomatic hyperCKemia. A case report.

Acta Myol 2021 Jun 30;40(2):105-108. Epub 2021 Jun 30.

Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) related myositis is a form of immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR autoantibodies target HMGCR, a glycoprotein linked to the endoplasmic reticulum implied in the cholesterol synthesis pathway, and exert a pathogenic effect on skeletal muscle cells. More than 60% of patients affected by HMGCR-related myositis shares statin-exposure in their medical history. Patients commonly experience CK levels elevation, myalgia, muscle weakness and soreness at variable extent, which manifest acutely or sub acutely with a progressively worsening course, in some cases mimicking limb-girdle muscular dystrophies (LGMD) phenotype and treatment is based on an immunosuppressive strategy. Here we present the peculiar case of a previously statins-exposed 72 y.o. asymptomatic man with persistent moderate hyperCKemia and high levels of anti-HMGCR, in which pharmacotherapy has not been initiated yet, while a wait-and-see approach has been adopted instead.
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http://dx.doi.org/10.36185/2532-1900-050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290509PMC
June 2021

Management of motor rehabilitation in individuals with muscular dystrophies. 1 Consensus Conference report from UILDM - Italian Muscular Dystrophy Association (Rome, January 25-26, 2019).

Acta Myol 2021 Jun 30;40(2):72-87. Epub 2021 Jun 30.

Department of Clinical and Experimental Sciences, University of Brescia; NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy.

Muscular dystrophy (MD) is a group of neuromuscular diseases characterized by progressive muscle weakness due to various mutations in several genes involved in muscle structure and function. The age at onset, evolution and severity of the different forms of MD can vary and there is often impairment of motor function and activities of daily living. Although there have been important scientific advances with regard to pharmacological therapies for many forms of MD, rehabilitation management remains central to ensuring the patient's psychophysical well-being. Here we report the results of an Italian consensus conference promoted by UILDM (Unione Italiana Lotta alla Distrofia Muscolare, the Italian Muscular Dystrophy Association) in order to establish general indications and agreed protocols for motor rehabilitation of the different forms of MD.
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http://dx.doi.org/10.36185/2532-1900-046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290512PMC
June 2021

Cancer patient perspective in the arena of COVID-19 pandemic.

Psychooncology 2021 Jul 27. Epub 2021 Jul 27.

Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Ancona, Italy.

Objective: The coronavirus disease 2019 (COVID-19) outbreak has been declared a global pandemic of unprecedented proportions. Italy is a country which has been heavily affected. Cancer patients are at a higher risk owing to their intrinsic fragility related to their underlying disease and oncologic treatment. Against this backdrop, we conducted a survey to investigate how patients perceived their condition, clinical management and availability of information during the pandemic.

Methods: Between 15 April and 1 May 2020 a survey was submitted to cancer patients at oncology departments in the Marche region. Questions regarding the perception of personal safety, continuity of cancer care, information quality and psychological distress.

Results: Seven hundred patients participated in the survey; 59% were female and 40% were aged between 46 and 65. The majority of the participants perceived compliance with appropriate safety standards by cancer care providers and 80% were reassured about their concerns during the medical interview. 40% were worried of being at a higher risk of infection and 71% felt they were at a greater risk because of chemotherapy. 55% felt that postponing cancer treatment could reduce its efficacy, however 76% declared they did not feel abandoned at the time of treatment postponement. Patients between 46 and 65 years declared a significant reduction in sleep (p < 0.01) and in concentration (p = 0.03).

Conclusions: The emergency care offered to cancer patients has been deemed satisfactory in terms of both safety standards and care management. However, the majority of participants perceived the mutual negative influence between their oncologic disease and the risk of infection highlighting the need for special measures to ensure safe continuity of care.
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http://dx.doi.org/10.1002/pon.5774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420223PMC
July 2021

Acellular Dermal Matrix Used in Diabetic Foot Ulcers: Clinical Outcomes Supported by Biochemical and Histological Analyses.

Int J Mol Sci 2021 Jun 30;22(13). Epub 2021 Jun 30.

Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Miraglia 2, 80138 Naples, Italy.

Diabetic foot ulcer (DFU) is a diabetes complication which greatly impacts the patient's quality of life, often leading to amputation of the affected limb unless there is a timely and adequate management of the patient. DFUs have a high economic impact for the national health system. Data have indeed shown that DFUs are a major cause of hospitalization for patients with diabetes. Based on that, DFUs represent a very important challenge for the national health system. Especially in developed countries diabetic patients are increasing at a very high rate and as expected, also the incidence of DFUs is increasing due to longevity of diabetic patients in the western population. Herein, the surgical approach focused on the targeted use of the acellular dermal matrix has been integrated with biochemical and morphological/histological analyses to obtain evidence-based information on the mechanisms underlying tissue regeneration. In this research report, the clinical results indicated decreased postoperative wound infection levels and a short healing time, with a sound regeneration of tissues. Here we demonstrate that the key biomarkers of wound healing process are activated at gene expression level and also synthesis of collagen I, collagen III and elastin is prompted and modulated within the 28-day period of observation. These analyses were run on five patients treated with Integra sheet and five treated with the injectable matrix Integra Flowable, for cavitary lesions. In fact, clinical evaluation of improved healing was, for the first time, supported by biochemical and histological analyses. For these reasons, the present work opens a new scenario in DFUs treatment and follow-up, laying the foundation for a tailored protocol towards complete healing in severe pathological conditions.
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http://dx.doi.org/10.3390/ijms22137085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267704PMC
June 2021

The Relationship between Oscillations in Brain Regions and Functional Connectivity: A Critical Analysis with the Aid of Neural Mass Models.

Brain Sci 2021 Apr 12;11(4). Epub 2021 Apr 12.

Department of Electrical, Electronic and Information Engineering, Campus of Cesena, University of Bologna, 47521 Cesena, Italy.

Propagation of brain rhythms among cortical regions is a relevant aspect of cognitive neuroscience, which is often investigated using functional connectivity (FC) estimation techniques. The aim of this work is to assess the relationship between rhythm propagation, FC and brain functioning using data generated from neural mass models of connected Regions of Interest (ROIs). We simulated networks of four interconnected ROIs, each with a different intrinsic rhythm (in θ, α, β and γ ranges). Connectivity was estimated using eight estimators and the relationship between structural connectivity and FC was assessed as a function of the connectivity strength and of the inputs to the ROIs. Results show that the Granger estimation provides the best accuracy, with a good capacity to evaluate the connectivity strength. However, the estimated values strongly depend on the input to the ROIs and hence on nonlinear phenomena. When a population works in the linear region, its capacity to transmit a rhythm increases drastically. Conversely, when it saturates, oscillatory activity becomes strongly affected by rhythms incoming from other regions. Changes in functional connectivity do not always reflect a physical change in the synapses. A unique connectivity network can propagate rhythms in very different ways depending on the specific working conditions.
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http://dx.doi.org/10.3390/brainsci11040487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069852PMC
April 2021

Alpha and theta mechanisms operating in internal-external attention competition.

J Integr Neurosci 2021 Mar;20(1):1-19

Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna-Campus of Cesena, 47521 Cesena, Italy.

Attention is the ability to prioritize a set of information at expense of others and can be internally- or externally-oriented. Alpha and theta oscillations have been extensively implicated in attention. However, it is unclear how these oscillations operate when sensory distractors are presented continuously during task-relevant internal processes, in close-to-real-life conditions. Here, EEG signals from healthy participants were obtained at rest and in three attentional conditions, characterized by the execution of a mental math task (internal attention), presentation of pictures on a monitor (external attention), and task execution under the distracting action of picture presentation (internal-external competition). Alpha and theta power were investigated at scalp level and at some cortical regions of interest (ROIs); moreover, functional directed connectivity was estimated via spectral Granger Causality. Results show that frontal midline theta was distinctive of mental task execution and was more prominent during competition compared to internal attention alone, possibly reflecting higher executive control; anterior cingulate cortex appeared as mainly involved and causally connected to distant (temporal/occipital) regions. Alpha power in visual ROIs strongly decreased in external attention alone, while it assumed values close to rest during competition, reflecting reduced visual engagement against distractors; connectivity results suggested that bidirectional alpha influences between frontal and visual regions could contribute to reduce visual interference in internal attention. This study can help to understand how our brain copes with internal-external attention competition, a condition intrinsic in the human sensory-cognitive interplay, and to elucidate the relationships between brain oscillations and attentional functions/dysfunctions in daily tasks.
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http://dx.doi.org/10.31083/j.jin.2021.01.422DOI Listing
March 2021

Increased resistance towards fatigability in patients with facioscapulohumeral muscular dystrophy.

Eur J Appl Physiol 2021 Jun 1;121(6):1617-1629. Epub 2021 Mar 1.

Criams-Sport Medicine Centre Voghera, University of Pavia, Voghera, Italy.

Purpose: In facioscapulohumeral muscular dystrophy (FSHD) fatigue is a major complaint. We aimed to investigate whether during isometric sustained elbow flexions, performance fatigability indexes differ in patients with FSHD with respect to healthy controls.

Methods: Seventeen patients with FSHD and seventeen healthy controls performed two isometric flexions of the dominant biceps brachii at 20% of their maximal voluntary contraction (MVC) for 2 min and then at 60% MVC until exhaustion. Muscle weakness was characterized as a percentage of predicted values. Maximal voluntary strength, endurance time and performance fatigability indices (mean frequency of the power spectrum (MNF), muscle fiber conduction velocity (CV) and fractal dimension (FD)), extracted from the surface electromyogram signal (sEMG) were compared between the two groups.

Results: In patients with FSHD, maximal voluntary strength was 68.7% of predicted value (p < 0.01). Compared to healthy controls, FSHD patients showed reduced MVC (p < 0.001; r = 0.62) and lower levels of performance fatigability, characterized by reduced rate of changes in MNF (p < 0.01; r = 0.56), CV (p < 0.05; 0.37) and FD (p < 0.001; r = 0.51) and increased endurance time (p < 0.001; r = 0.63), during the isometric contraction at 60% MVC.

Conclusion: A decreased reduction in the slopes of all the considered sEMG parameters during sustained isometric elbow flexions suggests that patients with FSHD experience lower levels of performance fatigability compared to healthy controls.
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http://dx.doi.org/10.1007/s00421-021-04650-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144151PMC
June 2021

Diagnostic and prognostic value of CSF neurofilaments in a cohort of patients with motor neuron disease: A cross-sectional study.

J Cell Mol Med 2021 04 20;25(8):3765-3771. Epub 2021 Feb 20.

Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.

Motor neuron disease (MND) is a rare group of disorders characterized by degeneration of motor neurons (MNs). The most common form of MND, amyotrophic lateral sclerosis (ALS), is an incurable disease with a variable rate of progression. The search of robust biomarkers able to discriminate among different ALS forms is paramount to properly stratify patients, and to identify those who could most likely benefit from experimental therapies. Phosphorylated-neurofilament heavy chain (p-NfH) and neurofilament light chain (NfL) are neuron-specific components of the cytoskeleton and may represent reliable markers of neuronal injury in neurological disorders. In this study, we described our cohort of ALS patients in order to investigate whether and how cerebrospinal fluid (CSF) p-NfH and NfL levels may reflect progression rate, MN involvement and the extent of neurodegeneration. CSF p-NfH and NfL were significantly increased in ALS compared with healthy and disease controls, including patients with other forms of MND, and were higher in patients with more aggressive disease course, reflecting progression rate. We also evaluated neurofilament diagnostic accuracy in our centre, identifying with high sensitivity and 100% specificity cut-off values of 0.652 ng/mL for CSF p-NfH (P < .0001) and of 1261 pg/mL for NfL (P < .0001) in discriminating ALS from healthy controls. CSF neurofilaments were significantly correlated with ALS progression rate. Overall, CSF neurofilaments appear to reflect the burden of neurodegeneration in MND and represent reliable diagnostic and prognostic biomarkers in ALS.
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http://dx.doi.org/10.1111/jcmm.16240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051694PMC
April 2021

Next-generation sequencing application to investigate skeletal muscle channelopathies in a large cohort of Italian patients.

Neuromuscul Disord 2021 04 14;31(4):336-347. Epub 2020 Dec 14.

Neurology IV Unit, Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A, 3 in both CLCN1 and SCN4A, 1 in ATP2A1, 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1, p.K1302R in SCN4A, p.L208P in ATP2A1 and c.280-1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis.
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http://dx.doi.org/10.1016/j.nmd.2020.12.003DOI Listing
April 2021

Survival Pathways Are Differently Affected by Microgravity in Normal and Cancerous Breast Cells.

Int J Mol Sci 2021 Jan 16;22(2). Epub 2021 Jan 16.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed.
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http://dx.doi.org/10.3390/ijms22020862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829699PMC
January 2021

The role of angiogenetic single-nucleotide polymorphisms in thymic malignancies and thymic benign lesions.

J Thorac Dis 2020 Dec;12(12):7245-7256

Section of Pathological Anatomy and Histopathology - Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I - GM Lancisi - G Salesi, Ancona, Italy.

Background: We previously showed that selected single-nucleotide-polymorphisms (SNPs) of genes involved in angiogenesis influence the aggressiveness of thymic epithelial tumors (TETs). This study analyzes their role in TETs and in thymic benign lesions, in order to investigate potential correlation with risk and outcome.

Methods: Genomic DNA was extracted from paraffin-embedded tissue of 92 patients, undergoing surgery at our Institution. We investigated by Real-Time PCR the SNPs of the following genes: platelet-derived growth factor receptorα (α), hypoxia-inducible factor-1α (α), vascular endothelial growth factor (), vascular endothelial growth factor receptor-2 and 3 (), excision repair cross-complementation group-1 ().

Results: Fifty-seven TETs and 35 thymic benign lesions were included into the study. Frequency of SNPs was as follows: rs2057482 C, rs11158358 C and rs11549465 C polymorphisms of : thymomas < general population (P=0.008, P=0.007, and P=0.044 respectively). alleles: general population > study groups, rs1951795C SNP (P=0.026 for benign lesions and P=0.0007 for thymomas), rs10873142T SNP (P=0.008 and P=0.001 respectively), rs12434438 A SNP (P=0.034 and P=0.0007) and rs2301113A SNP (P=0.027 and P=0.010). rs699947C polymorphism of VEGF-A: benign lesions > general population (P=0.012).

Conclusions: This is the first study investigating the angiogenetic polymorphisms in thymic benign lesions and TETs. SNPs analysis may represent a further asset in identification of patients who could benefit from anti-angiogenetic therapy.
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http://dx.doi.org/10.21037/jtd-19-3720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797874PMC
December 2020

Large genotype-phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis.

Sci Rep 2020 12 10;10(1):21648. Epub 2020 Dec 10.

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9-10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9-10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9-10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9-10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9-10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype-phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.
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http://dx.doi.org/10.1038/s41598-020-78578-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730397PMC
December 2020

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, "Sapienza" University of Rome, 00161 Rome, Italy.

Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.
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http://dx.doi.org/10.3390/ijms21228669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698414PMC
November 2020

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .

Neurology 2020 12 3;95(24):e3163-e3179. Epub 2020 Nov 3.

From the Friedrich-Baur-Institute (J.S., B.S.-W., M.W.), Department of Neurology, LMU Munich, Germany; DNA Laboratory (P.L., P.S.), Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic; Neuromuscular Unit (D.K., A.K.), Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland; Dr. John T. Macdonald Foundation Department of Human Genetics (L.A., A.R., S.Z.), John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL; Neurogenetics Group (J.B., T.D., P.D.J.), Center for Molecular Neurology, University of Antwerp; Institute Born-Bunge (J.B., T.D., P.D.J.), University of Antwerp; Neuromuscular Reference Centre (J.B., P.D.J.), Department of Neurology, Antwerp University Hospital, Belgium; Department of Clinical Chemistry and Laboratory Medicine (C.B.), Jena University Hospital; Centogene AG (C.B.), Rostock, Germany; Department of Medical Genetics (G.J.B., H.H.), Telemark Hospital Trust, Skien, Norway; Neurology Department (D.B., A.L., J. Weishaupt), Ulm University, Germany; Department of Neurology (J.D., D. Walk), University of Minnesota, Minneapolis; Department of Neurology (L.D.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Sleep Medicine and Neuromuscular Diseases (B.D., A.S., P.Y.), University of Münster; Institute of Human Genetics (K.E., I.K.), Medical Faculty, RWTH Aachen University, Germany; Sydney Medical School (M.E., M.K., G.N.), Concord Hospital, Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, Australia; Department of Orthopaedics and Trauma Surgery (C.F., K.K., D. Weinmann, R.W., S.T., M.A.-G.), Medical University of Vienna, Austria; AP-HP (T.S.), Institut de Myologie, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, G-H Pitié-Salpêtrière, Paris, France; Department of Neurology (D.N.H.), University of Rochester, NY; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Department of Neurology (S.I.), Konventhospital der Barmherzigen Brüder Linz; Karl Chiari Lab for Orthopaedic Biology (K.K., D. Weinmann, S.T.), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Austria; Stanford Center for Undiagnosed Diseases (J.N.K.), Stanford, CA; Undiagnosed Diseases Network (UDN) (J.N.K., S.Z.); Centre for Medical Research (N.G.L., R.O., G.Ravenscroft), University of Western Australia, Nedlands; Harry Perkins Institute of Medical Research (N.G.L., R.O., G. Ravenscroft), Nedlands; Neurogenetic Unit (P.J.L.), Royal Perth Hospital, Perth, Australia; Department of Neurology (W.N.L., J. Wanschitz), Medical University of Innsbruck, Austria; Department of Neurosciences and Behavior (W.M.), Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Neurology (S.P.), Hannover Medical School, Germany; Department of Clinical and Experimental Medicine (G. Ricci), University of Pisa, Italy; Institute of Human Genetics (S.R.-S.), Medical University of Innsbruck, Austria; Department of Neurodegenerative Diseases Hertie-Institute for Clinical Brain Research and Center of Neurology (L.S., R.S., M.S.), University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (L.S., R.S., M.S.), Tübingen, Germany; AP-HP (B.F.), Laboratoire de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital de Bicêtre; Le Kremlin-Bicêtre, France; Institute of Human Genetics (T.M.S.), Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg; Institute for Human Genetics (T.M.S.), Technical University Munich; and Institut für Klinische Genetik (J. Wagner), Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Germany.

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.

Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.

Results: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance.

Conclusions: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.
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http://dx.doi.org/10.1212/WNL.0000000000011132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836667PMC
December 2020

Central Nervous System Involvement as Outcome Measure for Clinical Trials Efficacy in Myotonic Dystrophy Type 1.

Front Neurol 2020 7;11:624. Epub 2020 Oct 7.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Increasing evidences indicate that in Myotonic Dystrophy type 1 (DM1 or Steinert disease), an autosomal dominant multisystem disorder caused by a (CTG)n expansion in DMPK gene on chromosome 19q13. 3, is the most common form of inherited muscular dystrophy in adult patients with a global prevalence of 1/8000, and involvement of the central nervous system can be included within the core clinical manifestations of the disease. Variable in its severity and progression rate over time, likely due to the underlying causative molecular mechanisms; this component of the clinical picture presents with high heterogeneity involving cognitive and behavioral alterations, but also sensory-motor neural integration, and in any case, significantly contributing to the disease burden projected to either specific functional neuropsychological domains or quality of life as a whole. Principle manifestations include alterations of the frontal lobe function, which is more prominent in patients with an early onset, such as in congenital and childhood onset forms, here associated with severe intellectual disabilities, speech and language delay and reduced IQ-values, while in adult onset DM1 cognitive and neuropsychological findings are usually not so severe. Different methods to assess central nervous system involvement in DM1 have then recently been developed, these ranging from more classical psychometric and cognitive functional instruments to sophisticated psycophysic, neurophysiologic and especially computerized neuroimaging techniques, in order to better characterize this disease component, at the same time underlining the opportunity to consider it a suitable marker on which measuring putative effectiveness of therapeutic interventions. This is the reason why, as outlined in the conclusive section of this review, the Authors are lead to wonder, perhaps in a provocative and even paradoxical way to arise the question, whether or not the myologist, by now the popular figure in charge to care of a patient with the DM1, needs to remain himself a neurologist to better appreciate, evaluate and speculate on this important aspect of Steinert disease.
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http://dx.doi.org/10.3389/fneur.2020.00624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575726PMC
October 2020

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.

J Neurol Neurosurg Psychiatry 2020 11 11;91(11):1166-1174. Epub 2020 Sep 11.

Department of Neurology/Stroke Unit, Bolzano Hospital, Bolzano, Trentino-Alto Adige, Italy.

Objective: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).

Methods: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).

Results: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.

Conclusions: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.
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http://dx.doi.org/10.1136/jnnp-2020-323822DOI Listing
November 2020

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

Acta Myol 2020 Jun 1;39(2):57-66. Epub 2020 Jun 1.

Child and Adolescent Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic.

Methods: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials.

Results: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine.

Conclusions: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.
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http://dx.doi.org/10.36185/2532-1900-008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460733PMC
June 2020

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in in a Large Cohort of Italian Patients.

Front Neurol 2020 29;11:646. Epub 2020 Jul 29.

Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM ( < 0.01) and in Hyper/NormoPP than in HypoPP2 ( = 0.02). Cold-induced myotonia was more frequently observed in PMC ( = 34) than in SCM ( = 23) ( = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP ( = 4), SCM ( = 5), and PMC ( = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC ( < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
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http://dx.doi.org/10.3389/fneur.2020.00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403394PMC
July 2020

A 5-year clinical follow-up study from the Italian National Registry for FSHD.

J Neurol 2021 Jan 19;268(1):356-366. Epub 2020 Aug 19.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi 287, 41125, Modena, Italy.

Background: The natural history of facioscapulohumeral muscular dystrophy (FSHD) is undefined.

Methods: An observational cohort study was conducted in 246 FSHD1 patients. We split the analysis between index cases and carrier relatives and we classified all patients using the Comprehensive Clinical Evaluation Form (CCEF). The disease progression was measured as a variation of the FSHD score performed at baseline and at the end of 5-year follow-up (ΔFSHD score).

Findings: Disease worsened in 79.4% (112/141) of index cases versus 38.1% (40/105) of carrier relatives and advanced more rapidly in index cases (ΔFSHD score 2.3 versus 1.2). The 79.1% (38/48) of asymptomatic carriers remained asymptomatic. The highest ΔFSHD score (1.7) was found in subject with facial and scapular weakness at baseline (category A), whereas in subjects with incomplete phenotype (facial or scapular weakness, category B) had lower ΔFSHD score (0.6) p < 0.0001.

Conclusions: The progression of disease is different between index cases and carrier relatives and the assessment of the CCEF categories has strong prognostic effect in FSHD1 patients.
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http://dx.doi.org/10.1007/s00415-020-10144-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815626PMC
January 2021

Prognostic relevance of programmed cell death protein 1/programmed death-ligand 1 pathway in thymic malignancies with combined immunohistochemical and biomolecular approach.

Expert Opin Ther Targets 2020 09 23;24(9):937-943. Epub 2020 Jul 23.

Medical Oncology, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi , Ancona, Italy.

Background: The aim of the study was to investigate Programmed cell Death protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) and their mRNA expression in thymic epithelial tumors (TETs).

Research Design And Methods: We analyzed 68 samples of formalin-fixed paraffin-embedded tissue (63 thymomas and 5 thymic carcinomas). PD-1 and PD-L1 protein expression were evaluated by immunohistochemistry, and mRNA expression was evaluated by real-time PCR.

Results: M/F ratio was 33/35, and median age was 60.5 years. Twenty patients had Myasthenia Gravis (MG). In the subgroup with large tumors (>5 cm), PD-L1 mRNA overexpression was significantly associated with worse prognosis vs. patients with no mRNA overexpression (p = 0.0083) and simultaneous PD-L1 immunostaining (>1%); PD-L1 mRNA overexpression was significantly associated with worse prognosis, respect to patient with PD-L1 negative immunostaining, and no PD-L1 mRNA overexpression (p = 0.0178). The elderly patients (>60 years) with large tumors showed worse prognosis (p = 0.0395). PD-L1 immunostaining (>50%) resulted to be significantly associated with MG.

Conclusions: Our data suggest the potential involvement of the PD-1 and PD-L1 pathway in TETs' progression. According to our results, it may be helpful to design future trials with anti-PD-1 drugs to establish high-risk patients after surgery.
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http://dx.doi.org/10.1080/14728222.2020.1790529DOI Listing
September 2020

Neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous mutation with normal serum magnesium levels.

Acta Myol 2020 Mar 1;39(1):36-39. Epub 2020 Mar 1.

Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy.

Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in , previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.
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http://dx.doi.org/10.36185/2532-1900-007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315896PMC
March 2020

Cytokine Profile in Striated Muscle Laminopathies: New Promising Biomarkers for Disease Prediction.

Cells 2020 06 23;9(6). Epub 2020 Jun 23.

Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-β2) levels significantly discriminated Musc-LMNA from controls; interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.
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http://dx.doi.org/10.3390/cells9061532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348753PMC
June 2020

Transfer Entropy as a Measure of Brain Connectivity: A Critical Analysis With the Help of Neural Mass Models.

Front Comput Neurosci 2020 5;14:45. Epub 2020 Jun 5.

Department of Electrical, Electronic and Information Engineering, University of Bologna, Cesena, Italy.

Assessing brain connectivity from electrophysiological signals is of great relevance in neuroscience, but results are still debated and depend crucially on how connectivity is defined and on mathematical instruments utilized. Aim of this work is to assess the capacity of bivariate Transfer Entropy (TE) to evaluate connectivity, using data generated from simple neural mass models of connected Regions of Interest (ROIs). Signals simulating mean field potentials were generated assuming two, three or four ROIs, connected via excitatory or by-synaptic inhibitory links. We investigated whether the presence of a statistically significant connection can be detected and if connection strength can be quantified. Results suggest that TE can reliably estimate the strength of connectivity if neural populations work in their linear regions, and if the epoch lengths are longer than 10 s. In case of multivariate networks, some spurious connections can emerge (i.e., a statistically significant TE even in the absence of a true connection); however, quite a good correlation between TE and synaptic strength is still preserved. Moreover, TE appears more robust for distal regions (longer delays) compared with proximal regions (smaller delays): an approximate a priori knowledge on this delay can improve the procedure. Finally, non-linear phenomena affect the assessment of connectivity, since they may significantly reduce TE estimation: information transmission between two ROIs may be weak, due to non-linear phenomena, even if a strong causal connection is present. Changes in functional connectivity during different tasks or brain conditions, might not always reflect a true change in the connecting network, but rather a change in information transmission. A limitation of the work is the use of bivariate TE. In perspective, the use of multivariate TE can improve estimation and reduce some of the problems encountered in the present study.
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http://dx.doi.org/10.3389/fncom.2020.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292208PMC
June 2020

Exercise-Related Oxidative Stress as Mechanism to Fight Physical Dysfunction in Neuromuscular Disorders.

Front Physiol 2020 20;11:451. Epub 2020 May 20.

Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy.

Neuromuscular diseases (NMDs) are a group of often severely disabling disorders characterized by dysfunction in one of the main constituents of the motor unit, the cardinal anatomic-functional structure behind force and movement production. Irrespective of the different pathogenic mechanisms specifically underlying these disease conditions genetically determined or acquired, and the related molecular pathways involved in doing that, oxidative stress has often been shown to play a relevant role within the chain of events that induce or at least modulate the clinical manifestations of these disorders. Due to such a putative relevance of the imbalance of redox status occurring in contractile machinery and/or its neural drive in NMDs, physical exercise appears as one of the most important conditions able to positively interfere along an ideal axis, going from a deranged metabolic cell homeostasis in motor unit components to the reduced motor performance profile exhibited by the patient in everyday life. If so, it comes out that it would be important to identify a proper training program, suitable for load and type of exercise that is able to improve motor performance in adaptation and response to such a homeostatic imbalance. This review therefore analyzes the role of different exercise trainings on oxidative stress mechanisms, both in healthy and in NMDs, also including preclinical studies, to elucidate at which extent these can be useful to counteract muscle impairment associated to the disease, with the final aim of improving physical functions and quality of life of NMD patients.
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http://dx.doi.org/10.3389/fphys.2020.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251329PMC
May 2020

Correction to: Expectations and psychological issues before genetic counseling: analysis of distress determinant factors.

Hered Cancer Clin Pract 2020 19;18:11. Epub 2020 May 19.

1Clinica Oncologica, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona Umberto I G M Lancisi G Salesi, Ancona, Italy.

[This corrects the article DOI: 10.1186/s13053-020-00142-1.].
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http://dx.doi.org/10.1186/s13053-020-00143-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236283PMC
May 2020

Cardiac magnetic resonance in patients with muscular dystrophies.

Eur J Prev Cardiol 2020 May 16:2047487320923052. Epub 2020 May 16.

Fondazione Toscana Gabriele Monasterio, Italy.

Muscular dystrophies are inherited disorders sharing similar clinical features and dystrophic changes on muscle biopsy. Duchenne muscular dystrophy is the most common inherited muscle disease of childhood, and Becker muscular dystrophy is a milder allelic variant with a slightly lower prevalence. Myotonic dystrophy is the most frequent form in adults. Cardiac magnetic resonance is the gold standard technique for the quantification of cardiac chamber volumes and function, and also enables a characterisation of myocardial tissue. Most cardiac magnetic resonance studies in the setting of muscular dystrophy were carried out at single centres, evaluated small numbers of patients and used widely heterogeneous protocols. Even more importantly, those studies analysed more or less extensively the patterns of cardiac involvement, but usually did not try to establish the added value of cardiac magnetic resonance to standard echocardiography, the evolution of cardiac disease over time and the prognostic significance of cardiac magnetic resonance findings. As a result, the large and heterogeneous amount of information on cardiac involvement in muscular dystrophies cannot easily be translated into recommendations on the optimal use of cardiac magnetic resonance. In this review, whose targets are cardiologists and neurologists who manage patients with muscular dystrophy, we try to summarise cardiac magnetic resonance findings in patients with muscular dystrophy, and the results of studies evaluating the role of cardiac magnetic resonance as a tool for diagnosis, risk stratification and follow-up. Finally, we provide some practical recommendations about the need and timing of cardiac magnetic resonance examination for the management of patients with muscular dystrophy.
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http://dx.doi.org/10.1177/2047487320923052DOI Listing
May 2020
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