9 research outputs found
Impaired oxygen extraction in metabolic myopathies: detection and quantification by near-infrared spectroscopy
No full textPatients with mitochondrial myopathies (MM) or myophosphorylase deficiency (McArdle's disease, McA) show impaired capacity for O(2) extraction, low maximal aerobic power, and reduced exercise tolerance. Non-invasive tools are needed to quantify the metabolic impairment. Six patients with MM, 6 with McA, 25 with symptoms of metabolic myopathy but negative biopsy (patient-controls, P-CTRL) and 20 controls (CTRL) underwent an incremental cycloergometric test. Pulmonary O(2) uptake (VO(2)) and vastus lateralis oxygenation indices (by near-infrared spectroscopy, NIRS) were determined. Concentration changes of deoxygenated hemoglobin and myoglobin (Delta[deoxy(Hb + Mb)]) were considered an index of O(2) extraction. Delta[deoxy(Hb + Mb)] peak (percent limb ischemia) was lower in MM (25.3 +/- 12.0%) and McA (18.7 +/- 7.3) than in P-CTRL (62.4 +/- 3.9) and CTRL (71.3 +/- 3.9) subjects. VO(2) peak and Delta[deoxy(Hb + Mb)] peak were linearly related (r(2) = 0.83). In these patients, NIRS is a tool to detect and quantify non-invasively the metabolic impairment, which may be useful in the follow-up of patients and in the assessment of therapies and interventions
Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication
No full textObjective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication
Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations
No full textTo determine the occurrence of neuroradiological abnormalities and to perform genotype-phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome).Alpha-subunit type A of voltage-gated sodium channel (SCN1A) mutational screening was performed by denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation probe amplification (MLPA). MRI inclusion criteria were: last examination obtained after the age of 4 years on 1.5-T systems; hippocampal cuts acquired perpendicular to the long axis of the hippocampus; qualitative assessment was performed on T(1)-weighted, T(2)-weighted, proton density, and 1-3 mm thick coronal FLAIR images.We collected 58 SMEI patients in whom last MRI was performed at or later than 4 years of age. SCN1A mutations occurred in 35 (60\%) cases. Thirteen (22.4\%) out of 58 patients showed abnormal MRIs. Eight patients showed cortical brain atrophy of which 3 associated to ventricles abnormalities, 1 to cerebellar atrophy, 1 to white matter hyperintensity; 3 patients had ventricles enlargement only; 1 patient showed hippocampal sclerosis (HS); 1 had focal cortical dysplasia. Genotype-phenotype analysis indicated that abnormal MRIs occurred more frequently in patients without SCN1A mutations (9/23; 39.1\%) compared to those carrying SCN1A mutations (4/35; 11.4\%) (p=0.02).Different brain abnormalities may occur in SMEI. Only one case with HS was observed; thus, our study does not support the association between prolonged febrile seizures and HS in SMEI. Abnormal MRIs were significantly more frequent in patients without SCN1A mutations. Prospective MRI studies will assess the etiological role of the changes observed in these patients
On the dynamics of planetesimals embedded in turbulent protoplanetary discs with dead zones
No full text. NJT was supported by the Jet Propulsion
Laboratory, California Institute of Technology, the NASA Origins
and Outer Planets programs, and the Alexander von Humboldt
Foundation
Insights into central and peripheral factors affecting the “oxidative performance” of skeletal muscle in aging
No full textMultidisciplinary, multicenter consensus for the care of patients affected with Sturge–Weber syndrome
No full textBackground: Sturge–Weber Syndrome (SWS) is a rare, sporadic neurocutaneous disorder affecting the skin, brain, and eyes, due to somatic activating mutations in GNAQ or, less commonly, GNA11 gene. It is characterized by at least two of the following features: a facial capillary malformation, leptomeningeal vascular malformation, and ocular involvement. The spectrum of clinical manifestations includes headache, seizures, stroke-like events, intellectual disability, glaucoma, facial asymmetry, gingival hyperplasia, etc. An early diagnosis is crucial to guarantee an appropriate care, which is best performed in reference centres by multidisciplinary teams. The aim of this study was to develop a multidisciplinary expert consensus for diagnosis, treatment, and follow-up of all disease manifestations, according to the recommendations of the Italian Law on Rare Disease Care. Results: Through a Delphi consensus methodology, 28 recommendations have been developed concerning (i) dermatological SWS manifestations and related treatment timing and modalities, (ii) neurological referral, diagnosis, pharmacological treatment of neurological signs and symptoms, neurosurgical indications, neurocognitive evaluation and related treatment, psychosocial support and patient follow-up, (iii) diagnosis of ophthalmological manifestations, medical and surgical treatment, and follow-up, (iv) maxillofacial surgical treatment, (v) oral cavity assessment, care and follow-up, and (vi) primary care paediatrician/general practitioner involvement. Conclusions: The present consensus developed by a multidisciplinary group of experts from Italian reference centres comprises practical recommendations for SWS global management, including currently controversial issues. Specific statements for all disease aspects, from skin manifestations and neurological and ocular signs and symptoms to oral and maxillofacial care, are provided. They can be exploited to uniform clinical practice in reference centres, but also in other hospitals and outpatient settings. Though this consensus has been developed taking primarily into account the Italian National Health System organization and rules on rare disorders, it could be translated also to other countries
Il principio di sussidiarietà orizzontale nella legislazione regionale
No full textIl saggio offre una panoramica critica della legislazione regionale relativa al principio di sussidiarietà.
L'analisi è articolata in fasi, relative rispettivamente all'introduzione del principio ad opera della l.59/1997, e poi alla sua costituzionalizzazione all'art. 118, co. 4, nel 2001. E ciò in ragione del fatto che il "clima" in cui maturano i diversi interventi, intrecciandosi con l'agenda delle regioni (si pensi al rinnovo degli statuti dopo la modifica costituzionale del 1999) detta forme, prospettive e temi distinti a quest'ultime.
L'attività dei legislatori regionali risulta però solo in parte differenziata, rivelando una incapacità di questi a dar corpo a letture proprie, e a interpretazioni organiche.
Esistono, naturalmente, importanti eccezioni.
Su queste il saggio si sofferma, evidenziando i tratti originali e le conseguenze che da questi discendono nella interpretazione complessiva di quello che può essere considerato ancora oggi il principio costituzionale più vago e indeterminato
Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival
No full textWe have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4+CD25- regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro, without needing cell-to-cell contact, and induced kidney allograft survival prolongation in-vivo. Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administered in-vivo, dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation
