Pharmacological inhibition of PKCθ counteracts muscle disease in a mouse model of duchenne muscular dystrophy

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease

Binge-like administration of alcohol mixed to energy drinks to male adolescent rats severely impacts on mesocortical dopaminergic function in adulthood: A behavioral, neurochemical and electrophysiological study

A growing body of evidence indicates that the practice of consuming alcohol mixed with energy drinks (ED) (AMED) in a binge drinking pattern is significantly diffusing among the adolescent population. This behavior, aimed at increasing the intake of alcohol, raises serious concerns about its long-term effects. Epidemiological studies suggest that AMED consumption might increase vulnerability to alcohol abuse and have a gating effect on the use of illicit drugs. The medial prefrontal cortex (mPFC) is involved in the modulation of the reinforcing effects of alcohol and of impulsive behavior and plays a key role in the development of addiction. In our study, we used a binge-like protocol of administration of alcohol, ED, or AMED in male adolescent rats, to mimic the binge-like intake behavior observed in humans, in order to evaluate whether these treatments could differentially affect the function of mesocortical dopaminergic neurons in adulthood. We did so by measuring: i) physiological sensorimotor gating; ii) voluntary alcohol consumption and dopamine transmission before, during, and after presentation of alcohol; iii) electrophysiological activity of VTA dopaminergic neurons and their sensitivity to a challenge with alcohol. Our results indicate that exposure to alcohol, ED, or AMED during adolescence induces differential adaptive changes in the function of mesocortical dopaminergic neurons and, in particular, that AMED exposure decreases their sensitivity to external stimuli, possibly laying the foundation for the altered behaviors observed in adulthood

Dallo studiolo alla città. La soglia di Via Santa Croce = From the 'studiolo' to the city. The threshold of Via Santa Croce

La soluzione della soglia d’ingresso alla sede della scuola sulla Via Santa Croce è prima di ogni altra cosa un tema urbano, solo in seconda battuta è un tema di allestimento. La strada che dalla Via Porcell conduce al bastione omonimo (e da qui alla “Torre dell’elefante”) è uno dei tracciati più significativi della città storica e lungo di esso si susseguono molteplici tasselli di straordinario valore storico e monumentale. «Essa si consolida tra la metà dell’Ottocento e il primo Novecento sul limite più esterno della rocca. Tracciata dalla metà del Cinquecento in avanti in relazione con le nuove opere bastionate, corre oggi in un luogo che nel medioevo si sarebbe potuto percorrere solo in volo, esterna al muro della città. Dal suo ingresso superiore, nuovo accesso urbano in corrispondenza con la via dei Genovesi, strada riqualificata da un apposito Piano redatto da Gaetano Cima nel 1857, la via Santa Croce dà accesso a palazzi (Cugia, già Carroz) e a molte architetture più a valle, spesso segnate da un elemento di mediazione con la strada [...]"The solution for the threshold to the school building in Via Santa Croce is, first of all, an urban topic. Consequently, it also became a theme of interior design. The road that leads from Via Porcell to the same name bastion (and from here to the “Torre dell’ Elefante”) is one of the most significant traces of the historic city, and along with it, there are numerous pieces of extraordinary historical and monumental value. “It consolidated between the mid-nineteenth and early twentieth centuries on the outermost edge of the fortress. Traced from the mid-sixteenth century onwards in connection with the new bastions, today it runs in a place that in the Middle Ages could have been experienced only by flight, outside the city wall. From its upper entrance, new urban access in correspondence with “Via dei Genovesi,” road redeveloped by a particular Plan drawn up by Gaetano Cima in 1857, via Santa Croce gives access to different palaces (Cugia, formerly Carroz) and many more architectures downstream, often marked by an element of mediation with the road [...]

Ret, GFRalpha-1; GFRalpha-2 and GFRalpha-3 receptors in the human hippocampus and fascia dentata

The immunohistochemical occurrence and localization of the receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and GDNF family receptor (GFR) alpha-1 to -3, is described in the human postmortem hippocampal formation at pre- and full-term newborn, and adult age. Two different antibodies for each of the four-receptor molecules were used.Western blot analysis indicates that the availability of GFRalpha receptor proteins may vary with age and post-mortem delay. The immunohistochemical detectability of GFRalpha-1, GFRalpha-2, GFRalpha-3 and Ret receptor molecules is shown in the rat up to 72 h postmortem. In the human specimens, labelled neuronal perikarya were detectable for each receptor protein at all examined ages, with prevalent localization in the pyramidal layer of the Ammon’s horn and hilus and granular layer of the fascia dentata. In the adult subjects, abundant punctate-like structures were also present. Labelled glial elements were identifiable. Comparison of the pattern of immunoreactive elements among young and adult subjects suggests that the intracellular distribution of the GDNF family ligands may vary between pre- and perinatal life and adult age. The results obtained suggest the involvement of the Ret and GFRalpha receptors signalling in processes subserving both the organization of this cortical region during development and the functional activity and maintenance of the mature hippocampal neurons

Radiotherapy for breast cancer: The predictable consequences of an unmet need

Radiotherapy has had a transformative impact on the treatment of breast cancer, but is unavailable to the majority of breast cancer patients in low- and middle-income countries. In these settings, where many women present with advanced disease at an age when they are often the primary caregiver for their families, the lack of access to radiotherapy is particularly devastating. Until recently, this disparity has been largely neglected in the medical literature and it had been difficult to convince governments, industry, and policymakers of the importance of investing in radiotherapy, as well as broader cancer control strategies, in low-resource settings. The Lancet Radiotherapy Commission report published in 2015 challenged many assumptions about the affordability of radiotherapy treatment. Data from the Commission is presented here to support radiotherapy investment for breast cancer and discuss how the morbidity and premature mortality among adult women caused by breast cancer has a huge detrimental effect on both the health sector and the economy. •Radiation therapy has had a transformative impact on breast cancer treatment.•Enormous worldwide inequalities in access created high mortality rates in LMICs.•Young age of onset in LMICs also generated profound long-term economic effects.•Strong medical and economic case for RT as essential for breast cancer care in LMICs

Le ceneri di Assandira. Identità, turismo e pastoralismo in Sardegna

Anche in Sardegna, come in diverse parti del mondo, i luoghi dell’attività pastorale sono da qualche decennio interessati dal fenomeno del turismo che, oltre ad assicurare una buona occasione economica, rappresenta anche uno stimolo a ripensare il processo produttivo ma anche un’occasione di incontro e di scambio culturale. Sono talvolta gli stessi pastori a trasformare le proprie strutture produttive orientandole alla recettività turistica e coniugando a queste una variegata produzione di forme di autorappresentazione identitaria che funga da richiamo e da filo conduttore all’esperienza degli ospiti. Il romanzo Assandira di Giulio Angioni e il film omonimo di Salvatore Mereu, che a esso si ispira, narrano di uno di questi modi di autorappresentazione che, pur nell’esasperazione specifica dell’invenzione letteraria, lascia intravvedere le trame più generali di quel processo onnipresente di produzione del passato culturale che ricorre spesso all’immaginazione e che Gérard Lenclud ha efficacemente interpretato come “filiazione inversa”, in cui è il presente a modellare il passato e le tradizioni, e non viceversa. L’obiettivo del presente saggio è quello di mostrare come le retoriche del comparto turistico internazionale, unitamente agli indirizzi delle dinamiche locali tese allo sviluppo economico del territorio e all’attrattività, ma anche le “immagini” mediatiche più diffuse, concorrano a influenzare i modi specifici delle autorappresentazioni identitarie di pastori e operatori turistici. Questi tendono per lo più verso una elaborazione standardizzata della propria cultura presente e passata, valorizzando ciò che il comune sentire contemporaneo percepisce come edificante, ed eliminando quanto avvertito come inappropriato o superfluo. Assandira di Angioni fissa una lettura in forma letteraria, seguita dalla sua ipertestualizzazione filmica, di queste di dinamiche

Early rehabilitation for severe acquired brain injury in intensive care unit: multicenter observational study

The increased survival after a severe acquired brain injury (sABI) raise the problem of making most effective the treatments in Intensive Care Unit (ICU)/Neurointensive Care Unit (NICU), also integrating rehabilitation care. Despite previous studies reported that early mobilization in ICU was effective in preventing complications and reducing hospital stay, few studies addressed the rehabilitative management of sABI patients in ICU/NICU

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

Prosafe: a european endeavor to improve quality of critical care medicine in seven countries

BACKGROUND: long-lasting shared research databases are an important source of epidemiological information and can promote comparison between different healthcare services. Here we present ProsaFe, an advanced international research network in intensive care medicine, with the focus on assessing and improving the quality of care. the project involved 343 icUs in seven countries. all patients admitted to the icU were eligible for data collection. MetHoDs: the ProsaFe network collected data using the same electronic case report form translated into the corresponding languages. a complex, multidimensional validation system was implemented to ensure maximum data quality. individual and aggregate reports by country, region, and icU type were prepared annually. a web-based data-sharing system allowed participants to autonomously perform different analyses on both own data and the entire database. RESULTS: The final analysis was restricted to 262 general ICUs and 432,223 adult patients, mostly admitted to Italian units, where a research network had been active since 1991. organization of critical care medicine in the seven countries was relatively similar, in terms of staffing, case mix and procedures, suggesting a common understanding of the role of critical care medicine. conversely, icU equipment differed, and patient outcomes showed wide variations among countries. coNclUsioNs: ProsaFe is a permanent, stable, open access, multilingual database for clinical benchmarking, icU self-evaluation and research within and across countries, which offers a unique opportunity to improve the quality of critical care. its entry into routine clinical practice on a voluntary basis is testimony to the success and viability of the endeavor