MacHado L.R.,University of Leicester |
Hardwick R.J.,University of Leicester |
Hardwick R.J.,Wellcome Trust Sanger Institute |
Bowdrey J.,University of Leicester |
And 5 more authors.
American Journal of Human Genetics | Year: 2012
Both sequence variation and copy-number variation (CNV) of the genes encoding receptors for immunoglobulin G (Fcγ receptors) have been genetically and functionally associated with a number of autoimmune diseases. However, the molecular nature and evolutionary context of this variation is unknown. Here, we describe the structure of the CNV, estimate its mutation rate and diversity, and place it in the context of the known functional alloantigen variation of these genes. Deletion of Fcγ receptor IIIB, associated with systemic lupus erythematosus, is a result of independent nonallelic homologous recombination events with a frequency of approximately 0.1%. We also show that pathogen diversity, in particular helminth diversity, has played a critical role in shaping the functional variation at these genes both between mammalian species and between human populations. Positively selected amino acids are involved in the interaction with IgG and include some amino acids that are known polymorphic alloantigens in humans. This supports a genetic contribution to the hygiene hypothesis, which states that past evolution in the context of helminth diversity has left humans with an array of susceptibility alleles for autoimmune disease in the context of a helminth-free environment. This approach shows the link between pathogens and autoimmune disease at the genetic level and provides a strategy for interrogating the genetic variation underlying autoimmune-disease risk and infectious-disease susceptibility. © 2012 by The American Society of Human Genetics. All rights reserved.
Rovere-Querini P.,San Raffaele Scientific Institute |
Clementi E.,Scientific Institute IRCCS Eugenio Medea |
Clementi E.,National Research Council Italy |
Brunelli S.,San Raffaele Scientific Institute |
Brunelli S.,University of Milan Bicocca
European Journal of Pharmacology | Year: 2014
Muscular dystrophies comprise an heterogeneous group of diseases characterised by primary wasting of skeletal muscle, in the most severe forms leading to progressive paralysis and death. Current therapies for these conditions are extremely limited and based on corticosteroids that bear significant side effects. Several studies have proposed possible alternative strategies, ranging from cell and gene therapy to more classical pharmacological approaches. Nitric oxide is a gaseous messenger involved in many mechanisms responsible for preserving muscle function and stimulating muscle repair. We herein review the most recent pre-clinical and clinical findings that open new prospective for the development of nitric oxide as a therapeutic tool for muscular dystrophies. © 2013 Elsevier B.V.
Perrotta C.,University of Milan |
Cervia D.,University of Milan |
Cervia D.,University of Tuscia |
De Palma C.,University of Milan |
And 5 more authors.
Apoptosis | Year: 2015
Autophagy, the main intracellular process of cytoplasmic material degradation, is involved in cell survival and death. Autophagy is regulated at various levels and novel modulators of its function are being continuously identified. An intriguing recent observation is that among these modulators is the sphingolipid metabolising enzyme, Acid Sphingomyelinase (A-SMase), already known to play a fundamental role in apoptotic cell death participating in several pathophysiological conditions. In this review we analyse and discuss the relationship between autophagy and A-SMase describing how A-SMase may regulate it and defining, for the first time, the existence of an A-SMase-autophagy axis. The imbalance of this axis plays a role in cancer, nervous system, cardiovascular, and hepatic disorders. © 2015 Springer Science+Business Media.
Cazzato D.,University of Milan |
Assi E.,University of Milan |
Moscheni C.,University of Milan |
Brunelli S.,University of Milan Bicocca |
And 7 more authors.
Experimental Cell Research | Year: 2014
The muscle-specific variant of neuronal nitric oxide (NO) synthase (NOS-I), is developmentally regulated in mouse suggesting a role of NO during myogenesis. In chick embryo, a good model of development, we found that the expression of NOS-I is up-regulated, but only in the early phase of development. Through a pharmacological intervention in ovo we found that NO signalling plays a relevant role during embryonic development. The inhibition of NOS-I decreased the growth of embryo, in particular of muscle tissue, while the restoring of physiological NO levels, via administration of a NO donor, reversed this effect. We found a selective action of NO, produced by NOS-I, on regulatory factors involved in myogenic differentiation in the early phase of chick embryo development: inhibition of NO generation leads to a decreased expression of the Myocyte enhancer factor 2a (Mef2a), Mef2c, Myogenin and Myosin, which was reversed by the administration of a NO donor. NO had no effects on Myf5 and MyoD, the myogenic regulatory factors necessary for myogenic determination. The action of NO on the myogenic regulatory factors was mediated via generation of cyclic GMP (cGMP) and activation of the cGMP-dependent protein kinase G (PKG). Finally we found in myoblasts in vitro that the activation of Mef2c was the key event mediating the NO-induced modulation of myogenesis.Our results identify NO produced by NOS-I as a key messenger in the early phase of embryonic development of chicken, acting as a critical determinant of myogenesis through its physiological cGMP/PKG pathway. © 2013 Elsevier Inc.
De Palma C.,University of Milan |
Perrotta C.,University of Milan |
Pellegrino P.,University of Milan |
Clementi E.,University of Milan |
And 3 more authors.
Frontiers in Aging Neuroscience | Year: 2014
Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterised by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity and chronic local inflammation leading to substitution of myofibres by connective and adipose tissue. DMD patients suffer of continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. The autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels it can be detrimental and contribute to muscle wasting; at low levels it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular levels, the Akt axis is one of the key disregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signalling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting. © 2014 De_palma, Perrotta, Pellegrino, Clementi and Cervia.
Pozzi M.,Scientific Institute IRCCS Eugenio Medea |
Piccinini L.,Scientific Institute IRCCS Eugenio Medea |
Gallo M.,University of Milan |
Motta F.,Childrens Hospital V Buzzi |
And 3 more authors.
Orphanet Journal of Rare Diseases | Year: 2014
Current therapies for the Lesch-Nyhan Syndrome (OMIM: 300322) are off-label and experimental, often leading to inconsistent outcomes. We here report the effects of an intrathecal baclofen therapy, carried out at the Scientific Institute Eugenio Medea (Lecco, Italy), on three patients who no longer received benefit from previous therapies. This treatment, as expected, ameliorated the motor symptoms and, unexpectedly, it also improved behavioural components. This result may involve a functional interaction between baclofen and dopamine, complemented by an anxiolytic effect. Our observations provide the rationale for the use of intrathecal baclofen administration in the therapy of the Lesch-Nyhan Syndrome. © 2014 Pozzi et al.
Lorusso M.L.,Scientific Institute IRCCS Eugenio Medea |
Civati F.,Scientific Institute IRCCS Eugenio Medea |
Molteni M.,Scientific Institute IRCCS Eugenio Medea |
Turconi A.C.,Scientific Institute IRCCS Eugenio Medea |
And 3 more authors.
Child Neuropsychology | Year: 2013
A group of 42 Italian boys with Duchenne Muscular Dystrophy was compared with a control group of 10 boys with Spinal Muscular Atrophy and Osteogenesis Imperfecta on tests assessing general intellectual ability, language, neuropsychological functions, and reading skills with the aim of describing a comprehensive profile of the various functions and investigating their interrelationships. The influence of general intellectual level on performance was analyzed. Further, correlations between various neuropsychological measures and language performances were computed for the group with Duchenne Muscular Dystrophy, as well as the correlations between reading scores and other cognitive and linguistic measures. A general lowering in VIQ, PIQ, and FSIQ scores was found to characterize the group with Duchenne Muscular Dystrophy. Expressive language skills were within the normal range, while syntactic and grammatical comprehension were significantly impaired. The presence of below-average reading performances was further confirmed. However, unlike previous studies on irregular orthographies, the present results show that (a) the mild reading difficulties found in the sample essentially concern speed rather than accuracy; (b) they concern word rather than nonword reading; (c) lower reading performances are related to lower scores in general IQ; (d) no correlations emerge with phonological abilities, verbal short-term memory, or working memory, but rather with long-term memory and lexical skills. This may suggest that language-specific effects modulate the cognitive expressions of Duchenne Muscular Dystrophy and raises the possibility that the dysfunctions underlying the reading difficulties observed in affected readers of regular orthographies involve different neurocognitive systems than the cortico-cerebellar circuits usually invoked. © 2013 Taylor & Francis Group, LLC.
Lerna A.,Scientific Institute Irccs Eugenio Medea |
Esposito D.,Scientific Institute Irccs Eugenio Medea |
Conson M.,The Second University of Naples |
Russo L.,Scientific Institute Irccs Eugenio Medea |
Massagli A.,Scientific Institute Irccs Eugenio Medea
International Journal of Language and Communication Disorders | Year: 2012
Background: The Picture Exchange Communication System (PECS) is a common treatment choice for non-verbal children with autism. However, little empirical evidence is available on the usefulness of PECS in treating social-communication impairments in autism. Aims: To test the effects of PECS on social-communicative skills in children with autism, concurrently taking into account standardized psychometric data, standardized functional assessment of adaptive behaviour, and information on social-communicative variables coded in an unstructured setting. Methods & Procedures: Eighteen preschool children (mean age = 38.78 months) were assigned to two intervention approaches, i.e. PECS and Conventional Language Therapy (CLT). Both PECS (Phases I-IV) and CLT were delivered three times per week, in 30-min sessions, for 6 months. Outcome measures were the following: Autism Diagnostic Observation Schedule (ADOS) domain scores for Communication and Reciprocal Social Interaction; Language and Personal-Social subscales of the Griffiths' Mental Developmental Scales (GMDS); Communication and Social Abilities domains of the Vineland Adaptive Behavior Scales (VABS); and several social-communicative variables coded in an unstructured setting. Outcomes & Results: Results demonstrated that the two groups did not differ at Time 1 (pre-treatment assessment), whereas at Time 2 (post-test) the PECS group showed a significant improvement with respect to the CLT group on the VABS social domain score and on almost all the social-communicative abilities coded in the unstructured setting (i.e. joint attention, request, initiation, cooperative play, but not eye contact). Conclusions & Implications: These findings showed that PECS intervention (Phases I-IV) can improve social-communicative skills in children with autism. This improvement is especially evident in standardized measures of adaptive behaviour and measures derived from the observation of children in an unstructured setting. © 2012 Royal College of Speech and Language Therapists.
Losito L.,Scientific Institute Irccs Eugenio Medea
Journal of child neurology | Year: 2013
The diagnosis of Moebius syndrome, a rare congenital disorder, is primarily based on congenital facial and abducent nerve palsy. Involvement of other cranial nerves is also common. Occasionally the V, X, XI, and XII cranial nerves are involved, resulting in a difficulty to chew, swallow, and cough, which often leads to respiratory complications. Mental retardation and autism have been reported in some cases. Moebius syndrome can be associated with orofacial anomalies and limb malformations. The authors describe a patient with a confirmed diagnosis of Moebius syndrome associated with hydrosyringomyelia. No case of Moebius syndrome involving primarily the spinal cord has been reported so far. This patient did not present with other factors directly linked to syringomyelia.
PubMed | University of Trento, Vita-Salute San Raffaele University, Scientific Institute IRCCS Eugenio Medea and IRCCS Eugenio Medea
Type: | Journal: Journal of neurophysiology | Year: 2017
Motor planning is not a monolithic process, and distinct stages of motor planning are responsible for encoding different levels of abstractness. However, how these distinct components are mapped into different neural substrates remains an open question. We studied one of these high-level motor planning components, defined as second-order motor planning, in a patient (R.G.) with an extremely rare case of cerebellar agenesis but without any other cortical malformations. Second-order motor planning dictates that when two acts have to be performed sequentially, planning of the second act can influence the execution of the first. We used an optoelectronic system for kinematic analysis to compare R.G.s performance with age-matched controls in a second-order motor planning task. The first act was to reach for an object and the second was to place it into a small or large container. Our results showed that despite the expected difficulties in fine-motor skills, second-order motor planning (i.e., the ability to modulate the first act as a function of the nature of the second act) was preserved even in the patient with congenital absence of the cerebellum. These results open new intriguing speculations about the role of the cerebellum in motor planning abilities. Although prudence is imperative when suggesting conclusions based on single-case findings, this evidence suggests fascinating hypotheses about the neural circuits that support distinct stages of the motor planning hierarchy, and regarding the functional role of second-order motor planning in motor cognition and its potential dysfunction in autism.