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Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

The stable presence of humans in the Alps dates back to the Bronze Age and peaked in the mid-19th century, deeply shaping the landscape and allowing the co-evolution of numerous plant and animal species. Since the 1950s, socio-economic changes have led to the gradual depopulation of mountain areas, and the consequent abandonment of traditional agro-pastoral activities. The rupture of the long-established balance between man and nature has triggered a process of transition, further exacerbated and accelerated by climate change. The Belmont Forum project ABRESO (Abandonment and rebound: Societal views on landscape and land-use change and their impacts on water and soils) started in 2021 and aims at advancing the understanding of mitigation and adaptation strategies to environmental change, through an international partnership involving five countries (the United States, France, Italy, Japan and Taiwan). Italy contributes to the project with three case studies: Gran Paradiso National Park, Val Grande National Park and the Tesino highlands are investigated in the Italian Alps. Using an interdisciplinary approach, the project aims to study the impact of the abandonment of traditional activities on ecosystem services provisioning, such as biodiversity conservation and soil sustainability, as well as the actual perception of the ongoing environmental changes by different stakeholders and its subsequent integration into local land management practices and policies. The land use and land cover change occurring due to land abandonment can have profound implications in the critical zone (CZ), inducing changes in soil, vegetation, carbon fluxes and water resources. This project integrates the natural and social sciences approaches to study the evolution of ecosystems in response to these factors. More specifically, advanced techniques that integrate Earth Observation, biogeochemical analyses and socio-economic investigation are used in the Italian sites to understand in which extent geo-biophysical and social landscapes reciprocally interact. The environmental variables collected for ecosystem monitoring and to study and upscale the ongoing dynamics in the CZ include snow cover and phenology parameters, soil organic carbon, and land use change maps extracted from time series of satellite imagery, validated via in situ measurements. Then, the observed processes will be compared to the perception of different stakeholders (local population, policy makers, tourists, business keepers, etc.) to unveil new insights into the way land use change in the mountain areas influence and is influenced by the local land management practices and policies.

The Coronavirus Disease 2019 (Covid-19) pandemic has profoundly affected the quality of life (QoL) and health of the general population globally over the past 2 years, with a clear impact on people with Parkinson's Disease (PwP, PD). Non-motor symptoms have been widely acknowledged to hold a vital part in the clinical spectrum of PD, and, although often underrecognized, they significantly contribute to patients' and their caregivers' QoL. Up to now, there have been numerous reports of newly emerging or acutely deteriorating non-motor symptoms in PwP who had been infected by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), while some of these symptoms, like fatigue, pain, depression, anxiety and cognitive impairment, have also been identified as part of the long-COVID syndrome due to their persistent nature. The subjacent mechanisms, mediating the appearance or progression of non-motor symptoms in the context of Covid-19, although probably multifactorial in origin, remain largely unknown. Such mechanisms might be, at least partly, related solely to the viral infection per se or the lifestyle changes imposed during the pandemic, as many of the non-motor symptoms seem to be prevalent even among Covid-19 patients without PD. Here, we summarize the available evidence and implications of Covid-19 in non-motor PD symptoms in the acute and chronic, if applicable, phase of the infection, with a special reference on studies of PwP.

The Coronavirus Disease 2019 (Covid-19) pandemic and the consequent restrictions imposed worldwide have posed an unprecedented challenge to research and training in Parkinson's disease (PD). The pandemic has caused loss of productivity, reduced access to funding, an oft-acute switch to digital platforms, and changes in daily work protocols, or even redeployment. Frequently, clinical and research appointments were suspended or changed as a solution to limit the risk of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spread and infection, but since the care and research in the field of movement disorders had traditionally been performed at in-person settings, the repercussions of the pandemic have even been more keenly felt in these areas. In this chapter, we review the implications of this impact on neurological research and training, with an emphasis on PD, as well as highlight lessons that can be learnt from how the Covid-19 pandemic has been managed in terms of restrictions in these crucial aspects of the neurosciences. One of the solutions brought to the fore has been to replace the traditional way of performing research and training with remote, and therefore socially distanced, alternatives. However, this has introduced fresh challenges in international collaboration, contingency planning, study prioritization, safety precautions, artificial intelligence, and various forms of digital technology. Nonetheless, in the long-term, these strategies will allow us to mitigate the adverse impact on PD research and training in future crises.

Dopamine agonists have been widely used to treat patients with Parkinson's disease, but concerns related to their well-known side effects might prevent their use even when indicated. In this review, the authors describe for the first time the concept of 'Dopamine Agonist Phobia', a pharmacophobia that the authors believe might affect clinicians, and they provide evidence of the benefits of dopamine agonists, focusing on non-motor symptoms.The authors performed an extensive literature research, including studies exploring the use of dopamine agonists for the treatment of non-motor symptoms. The authors indicate the highest level of evidence in each section.'Dopamine Agonist Phobia' may preclude valid therapeutic options in selected cases, specifically for the treatment of non-motor symptoms. Thus, the authors propose a personalized approach in Parkinson's disease treatment, and encourage a thoughtful use of dopamine agonists, rather than an overall nihilism.

This chapter reflects on the theoretical and operational implications of the concept of embeddedness applied to business strategies. Combining theoretical insights and case study analysis, the chapter shows that the corporate strategy as a whole (not only the location choice but also the marketing, the communication, and the corporate social responsibility) should be analyzed according to the degree of interaction the company establishes with the local territorial context.

Contains fulltext : 287510.pdf (Publisher’s version ) (Open Access) BACKGROUND: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. OBJECTIVE: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. METHODS: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. RESULTS: Significant between-group differences were observed for MDS-NMS NMF total scores (P 10 years this was 71.0% (P

Periodontitis triggers systemic repercussions, such as elevated levels of high-sensitive C-reactive protein (hs-CRP). This has never been studied within Parkinson’s Disease (PD). The aim of this study is to compare hs-CRP levels of self-reported periodontitis cases versus cases without periodontitis in PD patients. Data from the National Health and Nutrition Examination Survey (2015–2016 and 2017–2018 waves) were analyzed. PD cases were identified through medication regimens and periodontitis cases through a validated self-report questionnaire. 51 participants were included (24 females, 27 males, with mean age of 62.96 (14.71)). While the self-reported periodontitis group presented elevated levels of circulating hs-CRP (5.36 vs. 1.99 mg/L, p = 0.031), the self-reported without periodontitis group presented higher lymphocyte levels (29.35 vs. 28.03%, p = 0.007). Blood levels of hs-CRP were significantly higher in PD cases with self-reported periodontitis. Apart from the lymphocyte levels, there were no other significant differences according to the self-reported periodontal status. Future studies shall explore this association using clinical measures.

The paper presents the experimental attempt to apply the shift-share decomposition technique, mainly used in the economic field to analyse regional differentials, to the growth dynamics of infections during the first wave of the COVID-19 pandemic. Through a partial readjustment of the initial formulations of this technique, the regional patterns of the spread of the infections in Italy are analysed, taking into account the influence exercised by the demographic characteristics (age composition) of the region. In this reformulation, the shift-share analysis (SSA) allows to break down the daily variation of COVID-19 cases according to four effects resulting from: the distribution of the population by age groups (measured through the demographic and allocative effects), the tendency of the regional dynamics to follow the trend of the nation (measured by the national effect) and the rising of specific local dynamics (measured by the local effect). The application of our proposed reformulation studies the diffusion of infections in the Italian regions between March 9 and May 20, 2020, highlighting strengths and weaknesses of the methodology, offering ideas for further development and refinements to use SSA for applications in extra-economic realms (demographic, epidemiologic etc.), fruitfully. For example, the choice of the Italian case study was detrimental to the quality of the results obtained, since in Italy the population’s age distribution tends to be similar. For this reason, at the end of our study, it is suggested the opportunity to test the robustness of the proposed method using as case study other European nations (for example, France, Spain or Germany) characterised by more significant heterogeneity of the regional population than Italy.

The coronavirus disease (COVID-19) pandemic represented an unprecedented challenge for health care facilities, and innovative solutions were urgently required to overcome the high volume of critically ill infectious patients, limit in-hospital outbreaks, and limit the risk of occupational infection for health care workers (HCWs). Bergamo was the hardest-hit Italian province by COVID-19, and the local health care system had to undergo a profound and prompt reorganization. A COVID-19-only field hospital was rapidly set up meeting the standards for severe acute respiratory infection (SARI) treatment centers (https://apps.who.int/iris/handle/10665/331603). A zones partition, dedicated in-hospital pathways for HCWs, strict infection prevention and control (IPC) measures, and constant staff supervision were key components of our strategy to limit the risk of occupational infection for HCWs. Herein, we present the Bergamo field hospital layout enlightening fundamental IPC measures adopted as a valuable example of a SARI treatment center confronting COVID-19.

L'articolo si inserisce nel filone della letteratura che misura la resilienza economicaregionale a partire dalla dinamica dell'occupazione. Identificando nella crisi economicadel 2008 la principale discontinuità nei percorsi di crescita delle contemporanee economieregionali, l'articolo sostiene l'opportunità che le analisi comparative territoriali (o analisidi benchmarking) realizzate dopo tale evento assumano il concetto di resilienza comeprincipale riferimento teorico e metodologico. Significative appaiono a questo riguardoalcune recenti sperimentazioni tassonomiche condotte in ambito europeo, in cui la tenutaoccupazionale regionale è messa in relazione sia con la dinamica precedente alla crisi, siacon la dinamica aggregata (sensitività relativa). Muovendo da questi esempi, nell'articolo sipropone una modalità di analisi territoriale che, sfruttando la proprietà dell'analisi shiftsharedinamico-cumulativa di scomporre i tassi di crescita dell'occupazione in ragionedelle sue componenti costitutive (legate alla nazione di appartenenza, alla struttura dell'economiaregionale e alla competitività complessiva del sistema regionale), mette a confrontole dinamiche pre- e post-crisi delle singole regioni, e le legge in ragione della capacità occupazionale relativa, ossia dell'ammontare complessivo dei posti di lavoro creati o persi dopo il 2008 nella regione rispetto al Paese. Questa metodologia è quindi applicata al caso delle metroregioni italiane e il risultato che ne deriva è una geografia piuttosto ‘inedita' dei divari economici interni al Paese. Una geografia in cui il contributo più importante viene dalla peculiare capacità di risposta alla crisi della regione, indipendentemente dall'influenza esercitata dal contesto nazionale e dalla maggiore o minore tenuta occupazionale dei settori in cui è organizzata l'economia regionale.

L'impatto delle attività culturali nell'ultimo decennio è stato riconosciuto come una delle determinanti che creano benessere nella comunità locale e generano sviluppo economico (KEA, 2009), anche, ma non solo, in funzione del mercato turistico che contribuiscono a sostenere (Richards, 2014). In una prospettiva post-pandemica, diversi elementi costitutivi di queste attività (Lescure, 2013) ne lasciano presagire un ruolo chiave nello stimolo della crescita e nella costruzione di comunità "intelligenti" e resilienti (Polivka, 2015). In alcune città le attività culturali sono molto significative (Scott, 2000) e connotano la "città creativa", luogo con elevata concentrazione di capitale umano che rappresenta la "creative class" (Florida, 2002). Il caso di studio riguarda Torino, che da città operaia, con monocultura industriale, si è nel tempo evoluta verso una diversificazione economica, che vede anche una certa presenza di imprese culturali e creative, con professional della cultura che sono al servizio sia del comparto industriale, sia del fabbisogno culturale dei cittadini e dei turisti. Il nostro contributo elabora il database sulle imprese italiane creato presso Ircres-Cnr, da cui si estraggono le imprese culturali e creative sulla base della metodologia già individuata nella letteratura (Santagata, 2009; Santagata e Bertacchini 2012, Della Lucia e Segre, 2018), per ottenere la fotografia al 2018 della loro distribuzione settoriale, dimensionale e territoriale, nonché la dinamica di tale distribuzione nel corso del tempo (2008-2018). Quest'ultima consente di evidenziare l'impatto della crisi economica del 2008 sul settore, i processi di concentrazione economica (dimensione delle imprese) e geografica (localizzazione nei quartieri), i fattori di attrazione spaziale delle imprese (musei, teatri, enti pubblici, grandi imprese private, ecc.). I dati vengono esaminati alla luce dell'evoluzione avvenuta nei quartieri torinesi, che sono stati variamente oggetto di processi di deindustrializzazione, riqualificazione urbana, immigrazione e gentrificazione. Si individua anche il rapporto esistente tra "ciclo di vita" dei quartieri e caratteristiche delle imprese culturali ivi presenti, al fine di evidenziare eventuali specificità legate alla connotazione sociale, economica e demografica dei quartieri cittadini, e offrire primi spunti di riflessione su come esse potranno riposizionarsi nella nuova economia urbana che emergerà in seguito all'esperienza della pandemia.

L'articolo analizza le condizioni alle quali i prodotti agroalimentari tipici del territorio possano attivare, attraverso pratiche di community building, forme sostenibili di sviluppo locale. Nel fare ciò, l'articolo assume il caso di studio delle regioni di produzione dei vini Docg/Doc della Città metropolitana di Torino. Una delle ipotesi alla base dello studio è che la presenza nel territorio di una radicata connotazione produttiva vitivinicola faciliti la formazione di una specifica cultura del vino e, di conseguenza, la formazione di una specifica comunità del vino "spendibile" in processi di sviluppo eno-turistico.

Il volume, frutto della collaborazione AISRe-CREA, ripercorre le riflessioni sviluppate negli ultimi anni sui temi della sostenibilità e dell'innovazione dei sistemi agricoli locali, nelle aree interne del Paese. Nella prima parte si propone un inquadramento sugli scenari attuali di sviluppo e sul contesto di policy per le aree interne. La seconda parte del volume si focalizza sui sistemi locali in Italia e ripercorre alcune esperienze centrate sullo sviluppo agroalimentare dei territori, confluite in alcuni lavori presentati nel corso della XXXIX Conferenza annuale AISRe, di Bolzano nel 2018, che ha ospitato una sessione speciale su questo tema. I contributi proposti si inquadrano, quindi, in una lettura territoriale delle aree interne caratterizzate da una significativa distanza dai principali centri di offerta di servizi essenziali; una disponibilità elevata di importanti risorse ambientali e culturali; dinamiche di abbandono delle superfici agricole e ampi processi di spopolamento. Il volume manifesta una visione in cui le aree interne, rurali e remote, soggette ad un aggravio dei costi per le attività agricole connessi agli svantaggi morfologici ma anche ricche di biodiversità, sono un target ideale verso cui far convergere l'azione delle diverse policy territoriali. In particolare, è necessaria una governance della biodiversità in grado non solo di valorizzare le risorse agricole, ma di innestare meccanismi di crescita rurale rendendo attrattivi i territori dove risiede la biodiversità, tramite azioni specifiche di miglioramento dei servizi essenziali per le persone e di adeguamento delle infrastrutture fondamentali. Si è quindi molto vicini nel "Riportare la natura nella nostra vita" così come indicato dalla Commissione europea per la strategia della biodiversità per il 2030 e che nell'attuale periodo di transizione offre nuove opportunità di sviluppo

Nella lingua italiana, il termine radicamento identifica una condizione di stabile inserimento entro un dato contesto. La semantica del concetto riporta alla botanica. Nel processo di attecchimento delle piante che, appunto, mettono radici in modo saldo laddove trovano condizioni ecosistemiche favorevoli, a partire dal terreno e dal clima. Attraverso le radici la pianta estrae dal suolo i nutrimenti che le servono per vivere e, nello stesso tempo, ne modifica i caratteri fisici e chimici. Applicato alle scienze sociali, il radicamento presuppone quindi sempre una qualche forma di interazione tra l'oggetto considerato e l'ambiente ad esso esterno, contesto della sua localizzazione" [Bighi, Cotella e Rota "Torino e Piemonte fra locale e globale, Politiche di reti e ancoraggi territoriali" cap.2.3]. Applicato alle scienze economiche il concetto di embeddedness, introdotto per la prima volta dal sociologo-economista Karl Polany, spiega come l'agire economico non sia mai indotto da interessi esclusivamente economici: quando l'attore economico comincia ad interagire con altri attori, altri interessi entrano in gioco più strettamente connessi con la società, l'approvazione, lo status, il potere. Il contributo riflette sulle ricadute teoriche e operative del concetto di radicamento applicato all'analisi delle strategie di impresa. Combinando contributi di letteratura e case studies il messaggio veicolato è che nelle strategie aziendali non soltanto le scelte localizzative, ma anche quelle di marketing, comunicazione e RSI possano essere distinte in funzione del grado di maggiore o minore interazione che l'impresa stabilisce con il contesto territoriale, ossia in funzione della sua condizione di mera localizzazione, ancoraggio o radicamento territoriale.

Le present article contribue a la litterature relative aux reformes du secteur public en proposant l’analyse textuelle en tant que strategie de recherche utile pour examiner comment les archetypes de la reforme et les idees connexes sont deployes dans le debat parlementaire et les reformes qui font progresser les reglementations. L’administration publique (AP), le nouveau management public (NMP) et la gouvernance publique (GOV) peuvent etre decrits comme trois archetypes differents fournissant des idees et des concepts administratifs caracteristiques ainsi que des outils et pratiques connexes qui regissent les reformes. Nous utilisons l’analyse textuelle pour examiner plus de 20 ans de reformes comptables du gouvernement central italien et examiner comment les trois archetypes administratifs ont evolue, se sont entremeles et se sont mutuellement remplaces. L’analyse textuelle s’avere etre un outil utile pour etudier les processus de reforme, et nous permet de montrer que dans les pays neo-weberiens tels que l’Italie, le NMP et la GOV, loin d’etre des paradigmes revolutionnaires, peuvent representer des tendances passageres qui n’ont pas laisse de traces significatives dans la pratique et la rhetorique des reformes.Remarques a l’intention des praticiensDans des contextes fondes sur des traditions de droit civil, l’introduction de nouvelles reformes apparait lente et ardue, et elle est souvent plus efficace lorsqu’elle respecte les systemes d’AP existants, qui restent fortement enracines dans le secteur public. Les decideurs peuvent vouloir en tenir compte lorsqu’ils proposent ou mettent en œuvre de nouveaux changements. D’un point de vue organisationnel, ce qui precede souligne l’importance de rassurer les fonctionnaires et les politiciens quant a la coherence des « nouveaux » modeles proposes avec ceux auxquels ils sont habitues, et d’utiliser le langage traditionnel de l’AP pour expliquer et introduire de nouvelles idees et de nouveaux outils et les rendre plus acceptables. Cependant, cela doit etre contrebalance par un changement reel dans les anciens systemes et routines, en utilisant la continuite pour generer le changement et en evitant la reconstitution d’approches purement formelles.

This paper explores the deployment of rhetorical legitimation strategies during public-sector accounting reforms by investigating how organizational actors justify related changes in the central governments of the United Kingdom (UK), Italy and Austria. The study shows that changes are largely legitimated (and rarely delegitimated) by key actors, with authorization strategies dominating. Country differences and actors’ professional backgrounds also impact upon the use of legitimation strategies, with those from an accounting background and working in the UK being more likely to justify change in terms of rationalization and normalization. Italian and Austrian actors more frequently resort to authorization strategies to explain accounting change.

In the European literature on the regional and local development, the concept of resilience has progressively gained momentum, eventually overcoming that of competitiveness and posing a critical challenge for the future of territorial studies and the territorialisation of the policy discourse. In the current economic turmoil, the success of an urban and regional economy relies more and more on its capacity to react to sudden shocks in a positive and evolutionary perspective, i.e., in its resilience. Nevertheless, as a recent analysis of the employment dynamics of Italian metro-regions in the period before and after 2008 has demonstrated that the existing taxonomies may be distant from reality and hardly communicable. The paper proposes a taxonomy of regional resilience based on the consideration of the region&rsquo, s capacity of both improving its employment rate during the pre-crisis period and overcoming the concurrent performance of the nation. Via a shift-share analysis of the employment in Italian metro-regions, the paper investigates the contribution of the sectoral structure of the local labour market in terms of economic resilience. The result is twofold: a geography of the dynamism of the territorial systems in Italy that diverges from some &ldquo, classic&rdquo, interpretative frameworks, a novel taxonomic approach to regional resilience.

This article contributes to the literature on public sector reforms by proposing textual analysis as a useful research strategy to explore how reform archetypes and related ideas are deployed in the parliamentary debate and regulations advancing reforms. Public Administration (PA), New Public Management (NPM) and Public Governance (GOV) can be depicted as three different archetypes providing characteristic administrative ideas and concepts and related tools and practices, which lead reforms. We use textual analysis to look into more than 20 years of Italian central government accounting reforms and investigate how the three administrative archetypes have evolved, intertwined and replaced each other. Textual analysis proves a useful tool through which to investigate reform processes and allows us to show that in neo-Weberian countries, such as Italy, NPM and GOV, far from being revolutionary paradigms, may represent fashionable trends that have not left significant traces in the practice and rhetoric of reforms. Points for practitioners In contexts based on civil law traditions, the introduction of new reforms appears to be slow and difficult, and is often more successful when it respects extant PA systems, which remain well rooted in the public sector. Decision-makers may want to keep this into consideration when proposing or implementing new changes. From an organizational point of view, this underlines the importance of reassuring civil servants and politicians of the consistency of the ‘new’ proposed models with those they have been accustomed to, and of using the traditional language of PA to explain and introduce new ideas and tools and make them more acceptable. However, this has to be balanced by an actual change in the old systems and routines, using continuity to bring about change and avoiding the re-enactment of merely formalistic approaches.

Background and aim Time allowed for independent ethics committees (IECs) and administrative offices to assess and activate clinical trials is regulated by law. This study aims to describe time spent activating two multicentre non-profit trials supported by the Italian Medicines Agency (AIFA). Five non-AIFA supported (NAS) trials were used as a benchmark. Methods The two AIFA-supported trials were FATA-GIM3 (optimal adjuvant hormonal treatment for breast cancer) and TOSCA (duration of adjuvant FOLFOX in colorectal cancer). The five NAS trials focused on lung or ovarian cancer. The following were measured for all trials: date of submission of trial documentation to peripheral IEC, date of IEC opinion and date trial contracts were signed. Times are reported in months. Results 106 centres applied to participate in FATA-GIM3 and 137 in TOSCA. An IEC opinion was issued by 100/106 (1 negative opinion) and 137/137 (2 negative opinions) centres, with a median time from submission of 3.6 months (range 0.1–60.2). After a positive IEC opinion, the median time before signing the trial contract was 3.3 months (0.1–59.2). Contracts were signed with 93/99 and 135/135 centres, with a median time from submission of study documentation of 8.4 months (0.5–61.1). Times for NAS trials were not substantially different. Conclusions FATA-GIM3 and TOSCA centres were opened after a median of 8 months, consisting of nearly 4 months each for IEC opinion and administrative signature, similar to the NAS trials. The process of trial activation in Italy remains inefficient and takes far longer than legally allowed.

SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the "mixed" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain "in toto," even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.

Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.

Introduction The optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line. Patients and methods mCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS). Results About 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69–1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55–1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms. Conclusions This trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.

This paper studies the results of an unconventional cultural event, Paratissima (Turin, Italy), in the light of place-making theory and culture led-growth theories as well as also touching upon the literature on cultural policies. Using a qualitative and semi-quantitative method, the paper analyses the effects of the event produces in terms of individual and collective experiences, representations, and intentions at the local scale. As a result, the analysis shows that, although initially thought to be a critical ‘private’ initiative, the case of Paratissima progressively developed positive mutual relationships with the urban context – a neighbourhood effect – which allowed it to emerge as an interesting example of a cultural event that seems to contrast to the most renown findings of scholarly literature, as well as the conventional cultural policies. As such, the case study offers some insights on the role of cultural events in place-making.

The symposium focusses on the role of leadership to successfully manage inclusive organisational change, in ways that encourage the empowerment and contributions of all. To better understand the na...