Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

Franco Gemignani,1 Andrea Melpignano,1,2 Giulia Milioli,1,2 Silvia Riccardi,1,2 Liborio Parrino1,2 1Neurology Unit, Department of Neurosciences, University of Parma, Parma, Italy; 2Sleep Disorders Center, Department of Neurosciences, University of Parma, Parma, Italy Abstract: Restless legs syndrome (RLS) is a disorder of sensorimotor integration characterized by an urge to move the legs when at rest, especially at night or in the evening, which is relieved by movement. Sensory symptoms may be prominent, often exhibiting features consistent with neuropathic pain. Iron deficiency and genetic factors are implicated in RLS causation in most patients. The pathogenetic model of impaired circadian dopaminergic modulation of sensorimotor integration circuitry at the spinal level is fitting with the co-occurrence of movement disorders, sensory symptoms, and sleep disruption in RLS. Accordingly, levodopa and dopamine agonists are effective for RLS symptoms, which compensate for the impaired descending control by diencephalo-spinal dopa(min)ergic pathway. Dopamine agonists are usually indicated as the first-line therapy, but their use in long-term treatment is often complicated by augmentation and impulse control disorder, thus alpha-2-delta ligands also are now considered the first line of treatment. It has been recognized that endogenous opioid system is also involved in the mechanisms generating RLS, possibly through an impaired modulation of pain pathways. Opioids can be considered as an alternative therapy, particularly in patients with augmentation and/or refractory to other treatments. Recently introduced prolonged-release oxycodone–naloxone was efficacious for short-term treatment of patients with severe RLS inadequately controlled with previous treatment. It will be important to assess whether opioids, as well as other drugs, are especially effective in definite RLS subtypes such as the painful phenotype. Keywords: small fiber neuropathy, allodynia, hyperalgesi

Efficacy of conventional versus innovative therapies for treating skin wounds in veterinary medicine

open16siINTRODUCTION: The skin is the largest organ of mammals. The loss of skin integrity may induce important dysfunctions or even death. For superficial wounds, the endogenous healing mechanisms in combination with traditional wound care are sufficient to achieve functional repair. In contrast, in larger wounds, like third and fourth degree burns, chronic wound or deep ulcers it is difficult to obtain the restitutio ad integrum and fibrosis and/or scar tissue develops1,2. The aim of this study was to verify the efficacy of conventional and innovative topic treatments on skin regeneration, induced experimentally in sheep. To achieve this goal different types of investigations (clinical, molecular, histological, immunohistochemical) were performed. METHODS: Six skin lesions (4x4cm) were surgically created on the back of six healthy adult sheep; every single wound was destined, in a randomized way, to one of the following treatments: Acemannan gel, Manuka Honey, hyaluronic acid, Plasma3 (ionized gas), allogeneic mesenchymal stem cells isolated from peripheral blood (PB-MSCs). The sixth wound was the placebo. Biopsies were collected with a surgical punch (0,6x0,6 cm) at time T0, T15 and T40 days. Lesions were clinically evaluated considering the presence and color of wound fluid, the state of hydration, the wound surface/surroundings and other parameters. Histological examinations considered crust formation, re-epithelization and epidermal thickness, dermis edema, extension of granulation tissue, acute and chronic inflammation. Immunohistochemistry for evaluation of inflammation, vascularization and cell proliferation was performed using CD3, CD20, MHCII, von Willebrand factor (vWF) and KI67 antibodies. Furthermore, Real time-PCR investigated genes as V ascular endothelial growth factors (VEGF), Transforming growth factor beta 1(TGFβ1), Vimentin (VIM), Collagen 1α1 (Col1α1) and hair Keratin (hKER). RESULTS: Clinically, the lesions treated with plasma healed more rapidly respect to other treatments and a reduced bacterial load was observed. At T7 wounds treated with stem cells and plasma were less macerated than lesions treated with other therapies. At T15 the wounds treated with hyaluronic acid showed a normal state of hydration while lesions treated with Manuka Honey exhibited a normal hydration from the third week only (Acemannan gel at fourth week). From the second week onwards all wounds did not show presence of fluid and exhibited a dry and clean secondary layer. All lesions, excluded wounds treated with acemannan gel, presented a red (hyaluronic acid and plasma) and dark red (Manuka Honey, PB-MSCs) granulation tissue starting from the first week. Molecular analysis showed a correspondence between clinical and molecular/histologic results. For instance, VEGF mRNA expression confirms angiogenetic events observed at histological level while TGF-β, CD3 and CD20 mRNA/protein expression indicated the presence/absence of inflammation in the used treatments. DISCUSSION & CONCLUSIONS: Innovative therapies led to surprising results regarding regeneration of mammalian skin. Indeed, on the basis of clinical analysis, wounds treated with plasma and MSC healed more rapidly. Further examinations are ongoing in order to elucidate possible mechanisms explaining these differences. REFERENCES: 1S.Y. Broeckx, S. Maes, T. Martinello, et al (2014) Equine epidermis: a source of epithelial-like stem/progenitor cells with in vitro and in vivo regenerative capacities Stem Cells Dev, pp 1134-48. 2J.H. Spaas, C. Gomiero, S.Y. Broeckx, et al (2016) Wound healing markers after autologous and allogeneic epithelial-like stem cell treatment Cytotherapy 2016 (in press). 3E. Martines, M. Zuin, R. Cavazzana, et al. (2009) A novel plasma source for sterilization of living tissues, New J. Phys. 11, 115014.openPatruno, MARCO VINCENZO; Gomiero, Chiara; Martinello, Tiziana; Perazzi, Anna; Gemignani, F; DE BENEDICTIS, GIULIA MARIA; Ferro, Silvia; Zuin, M; Martines, E; Cordaro, Luigi; Brun, Paola; Maccatrozzo, Lisa; Broeckx, Sy; Spaas, Jh; Chiers, K; Iacopetti, IlariaPatruno, MARCO VINCENZO; Gomiero, Chiara; Martinello, Tiziana; Perazzi, Anna; Gemignani, F; DE BENEDICTIS, GIULIA MARIA; Ferro, Silvia; Zuin, M; Martines, E; Cordaro, Luigi; Brun, Paola; Maccatrozzo, Lisa; Broeckx, Sy; Spaas, Jh; Chiers, K; Iacopetti, Ilari

Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach

To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single-nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics, and a machine learning (ML) classifier to describe cases and controls in 3 different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P<0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both the datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a 7-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals and ML allows a fair prediction of case or control status based solely on the individual genetic background

Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52.

Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection

IL PROVVEDIMENTO SPORTIVO: DALLE ORIGINI, ALLE CONTROVERSE IPOTESI DI RISARCIBILITA' DELLE SITUAZIONI GIURIDICHE SOGGETTIVE.

La tesi approfondisce il tema del provvedimento sportivo emesso dal C.O.N.I o dalle Federazioni Nazionali, nonché i rapporti che intercorrono tra un tale atto (amministrativo?) e i meccanismi processuali che attengono la Giustizia sportiva e ordinaria. Dopo un breve excursus sulle origini e sull’organigramma dello Sport italiano, è esaltata la capacità del fenomeno sportivo di attualizzare i diritti e le libertà inviolabili di tutti i soggetti giuridici e in secundis, sono enunciati i caratteri di quell’ordinamento giuridico “speciale”, qual è quello sportivo; il focus ricade sull’autonomia normativa ( pur relativa) e sulla legge n°280 del 2003. Si disserta poi delle tipologie di provvedimento sportivo, degli artefici e della natura privatistica e/o amministrativistica del medesimo atto. Nel prosieguo si tratta delle difficoltà incontrate dalla giurisprudenza nell’individuazione e nell’eventuale statuizione della risarcibilità di situazioni giuridiche soggettive, intaccate dai provvedimenti sportivi: la crisi di sistema si ha con l’inquadramento del provvedimento sportivo disciplinare. Dal Febbraio 2011, la Corte Costituzionale (sentenza 49) individua una tutela meramente “demolitoria” assegnata ai Giudici sportivi, consistente nell’annullamento del provvedimento sportivo; dall’altra parte vi è una chance di tutela meramente risarcitoria affidata al Giudice Amministrativo in giurisdizione esclusiva, in relazione alla quale si illustrano i possibili sviluppi applicativi

L’utilizzo del perone vascolarizzato nella ricostruzione dell’arto inferiore in seguito a resezione intercalare

Negli ultimi decenni, grazie ai miglioramenti sopraggiunti nel campo delle metodiche diagnostiche e terapeutiche, la chirurgia di salvataggio dell’arto con preservazione dell’epifisi è divenuta la tecnica di scelta per la maggior parte dei pazienti con sarcoma delle ossa lunghe coinvolgente la regione metadiafisaria. Nel corso di questo studio saranno dunque di specifico interesse le perdite di sostanza ossea conseguenti la resezione intercalare di un tumore a livello degli arti inferiori e le metodiche ricostruttive utilizzate a tale livello, mettendo in risalto quelle che fanno utilizzo del perone vascolarizzato. VFG (vascularized fibular graft) senza l’utilizzo di innesti aggiuntivi, è generalmente usato nelle ricostruzioni degli arti superiori, mentre nell'arto inferiore, a causa delle maggiori sollecitazioni meccaniche, l'associazione di VFG con un allotrapianto è preferibile per migliorare la stabilità meccanica. La tecnica originale di associazione VFG (vascularized fibular graft) e allograft per la ricostruzione degli arti inferiori è stata descritta da Capanna et al. nel 1993. Questa tecnica combina un allograft con un innesto fibulare libero per la ricostruzione di ampi difetti ossei. Il razionale per l’utilizzo di questo approccio è che combina la forza meccanica dell’allograft con l’attività biologica del flap di osso vascolarizzato per promuovere la guarigione ossea, minimizzare il fallimento dell’allograft e facilitare l’uso funzionale dell’arto

Maladaptive Daydreaming and Its Relationship with Psychopathological Symptoms, Emotion Regulation, and Problematic Social Networking Sites Use: a Network Analysis Approach

The present study investigated the patterns of mutual associations between maladaptive daydreaming-related variables (MD, i.e., interference with life and somatosensory retreat), psychopathological symptoms (i.e., depression, anxiety, somatization, obsessive–compulsive, interpersonal sensitivity, psychoticism), emotion regulation strategies (i.e., cognitive reappraisal and expressive suppression), and problematic social networking sites use (PSNSU). A total of 531 young adults completed self-report measures through an online survey shared on social network groups. Two network models were performed on 297 young adults with probable MD (MDers) (Mage = 23.2, SD = 2.7) vs. 234 non-MDers (Mage = 23.4, SD = 2.6). Results showed that, compared to non-MDers, MDers showed significantly higher scores in all the study variables, except for cognitive reappraisal. Moreover, in the MDers network, the following patterns were identified: (i) no connections between the cluster of psychopathological symptoms, and neither cognitive reappraisal nor expressive suppression; (ii) a connection, through obsessive–compulsive (OC) symptoms, between the cluster of psychopathological symptoms and MD-interference with life; and (iii) a connection between PSNSU and MD-interference with life. Accordingly, the Network Comparison Test evidenced that the network structures of MDers vs. non-MDers were significantly different (M = .24; p = .01). Overall, higher scores on psychopathological symptoms in MDers provide support to the assumption that MD is a clinical condition, in which OC symptoms may play a critical role. Additionally, the association of PSNSU and MD-interference with life suggests that MDers might rely on PSNSU as a maladaptive emotion regulation strategy. Under this scenario, MD may be regarded as a potential vulnerability factor for PSNSU