Evoluzione storica di ECMAScript Un cammino tra le sue feature

Con la presente dissertazione è mio scopo illustrare come sia cambiato negli anni ECMAScript (la versione ufficiale di JavaScript, standardizzata dall'associazione ECMA) attraverso un'analisi di alcune delle sue funzionalità principali. Vuole essere un’indagine non solo teorica, ma anche pratica per scoprire se l’evoluzione abbia portato effettivamente a un progresso dal punto di vista del codice e dell’efficienza del risultato. In conclusione, a livello di programmazione mi sono trovata progressivamente meglio nell’impiego dei costrutti via via più recenti: sono risultati più comodi, visivamente puliti e logici. Anche gli esiti delle valutazioni mi hanno confermato come il bilancio evolutivo di ECMAScript, secondo quanto analizzato, sia positivo

A real opportunity to modify cardiovascular risk through primary care and prevention: A pilot study

Cardiovascular diseases (CVDs) represent a major threat to health and primary prevention outstands as the most effective instrument to face this issue, addressing multiple risk factors at a time and influencing behavioral patterns. Community nurses have been involved in many interdisciplinary prevention activities, resulting in effective control of CV risk factors. We conducted a pilot study aiming at describing the impact on the CV risk profile of an 18-month interdisciplinary intervention on lifestyle habits. From September 2018 to May 2020, four general practitioners (GPs) working in the Roman neighborhood of Torresina recruited patients having a cardiovascular risk score (CRS) equal to or higher than 3% and lower than 20%; those patients were included in a nutritional, physical, and psychological counseling program. Assessments of patients' health status were led at baseline, 6, 12, and 18 months by a nutritionist, a physiotherapist, a psychologist, their GPs, and a community nurse. The CRS was estimated at every examination, based on the Italian Progetto Cuore algorithm. A total of 76 patients were included (mean age of 54.6 years; 33 men and 43 women). Mean CRS showed a significant reduction between baseline and 12 months (from 4.9 to 3.8); both total cholesterol and systolic blood pressure (SBP) significantly decreased at 6 months of follow-up (respectively, from 211.1 to 192 and from 133.1 to 123.1). Nonetheless, the reduction was later maintained only for SBP. However, during the last 6 months of the intervention, the COVID-19 pandemic broke out, thus, it is not possible to know how much the results achieved at 18 months were influenced by the restrictive measures introduced by the Italian government. When stratifying according to the presence of hypertension/diabetes and physical activity, no differences in the CRS could be highlighted between the two groups. Our pilot study proved that an interdisciplinary counseling intervention program can improve CV risk profile and could be further spread to people that, according to their CRS, would benefit more from changes in lifestyles

Is personal identity something that does not matter? An inquiry into Derek Parfit and Alfred N. Whitehead

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Chora and Identity: Whitehead's Re-Appropriation of Plato's Receptacle

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Il ruolo dell'Inflammosoma nella progressione del danno epatico

Contesto e obiettivo: La steatosi epatica non alcolica (NAFLD) è la forma più comune di malattia epatica cronica. L’inflammosoma NLRP3 può suscitare una risposta pro-infiammatoria, quando attivato, ma regola anche l'omeostasi intestinale e la composizione del microbiota intestinale. L’inflammosoma NLRP3 è stato implicato nella patogenesi di obesità, di diabete e nella progressione del danno epatico cronico, ma il suo ruolo nella NAFLD è controverso. Pertanto, lo scopo di questo studio è stato quello di indagare il ruolo dell’inflammosoma NLRP3 in NAFLD. Metodi:I topi Nlrp3 - /- e topi wild-type C57BL/6 sono stati alimentati con una dieta ricca di grassi con il fruttosio (HFHC), o con una dieta di controllo (chow) per 12 settimane. Risultati: I topi Nlrp3-/- alimentati con HFHC ha mostrato una riduzione della spesa energetica e questo ha portato ad un aumento del peso corporeo, ad una superiore massa grassa e ad una maggiore espressione del fattore di necrosi tumorale a livello del tessuto adiposo (TNF-α). I topi Nlrp3-/- nutriti con HFHC hanno sviluppato più steatosi epatica, misurato dal contenuto di trigliceridi, rispetto ai topi WT alimentati con HFHC a causa della aumentata attività epatica di SCD-1 (un regolatore di lipogenesi epatica) e dell’elevata espressione di PPARɣ2 (che regola l'assorbimento e stoccaggio dei lipidi). Un’aumentata ossidazione mitocondriale degli acidi grassi e una ridotta espressione della NRF2, il "principale regolatore" della risposta antiossidante, hanno portato ad un aumento della produzione di superossido nei topi Nlrp3-/- alimentati con HFHC. In seguito ad un’alimentazione ipercalorica HFHC, la mancanza di inflammosoma NLRP3 era associata ad un significativo cambiamento del microbiota intestinale (un più alto rapporto Firmicutes/Bacteroidetes, e un aumento dei livelli dei batteri muco degradanti Akkermansia e Desulfovibrio), che è stato associato ad una barriera intestinale permeabile. Allo stesso tempo, l’espressione epatica del TLR4 e TLR9, dei macrofagi infiammatori nel fegato, e il punteggio NAS sono aumentati nei topi Nlrp3-/- alimentati con HFHC, indicando un aumento della risposta infiammatoria e del danno epatico. La sterilizzazione intestinale mediante antibiotici ha determinato una riduzione del peso corporeo, della traslocazione batterica e del danno epatico nei topi Nlrp3-/- nutriti con HFHC. Conclusioni: La mancanza di inflammosoma NLRP3 è legata a gravi alterazioni metaboliche e alla progressione del danno epatico forse a causa della traslocazione di prodotti batterici.Background and aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease. The NLRP3-inflammasome can elicit a pro-inflammatory response when activated but it also regulates intestinal homeostasis and gut microbiota composition. The NLRP3-inflammasome has been implicated in the pathogenesis of obesity, diabetes and in the progression of chronic liver injury, but its role in NAFLD is controversial. Therefore, the aim of this study was to investigate the role of NLRP3-inflammasome in NAFLD. Methods: Nlrp3-/- and wild-type (WT) C57BL/6 mice were fed with a high-fat diet with fructose in drinking water (HFHC), or a chow diet, for 12 weeks. Results: Nlrp3-/- HFHC showed reduced energy expenditure and this led to increased body weight, higher fat mass and adipose tissue TNF-α expression. Nlrp3-/- HFHC developed more hepatic steatosis, measured by triglyceride content, compared to WT HFHC because of augmented SCD-1 activity (a regulator of hepatic lipogenesis) and PPARγ2 expression (that regulates lipid uptake and storage). Increased mitochondrial fatty acid oxidation and reduced expression of NRF2, the “master regulator” of antioxidant response, led to increased superoxide production in Nlrp3-/- HFHC. After HFHC, lack of NLRP3-inflammasome was associated with significant alteration in intestinal microbiota (higher Firmicutes/Bacteroidetes ratio, and increased levels of mucus-degrading bacteria Akkermansia and Desulfovibrio) which was associated to a “leaky” intestinal barrier. Concomitantly, hepatic TLR4 and TLR9 expression, inflammatory macrophages in the liver, and NAS score were increased in Nlrp3-/- HFHC mice, indicating increased inflammatory response and liver injury. Gut decontamination by antibiotics reduced body weight, bacterial translocation and liver injury in Nlrp3-/- HFHC mice. Conclusions: Lack of NLRP3-inflammasome is linked to severe metabolic alterations and development of NASH possibly due to translocation of bacterial products

HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD

Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD.

Abstract Non-Alcoholic Fatty Liver Disease (NAFLD) represents the most common form of chronic liver injury and can progress to cirrhosis and hepatocellular carcinoma. A “multi-hit” theory, involving high fat diet and signals from the gut-liver axis, has been hypothesized. The role of the NLRP3-inflammasome, which senses dangerous signals, is controversial. Nlrp3−/− and wild-type mice were fed a Western-lifestyle diet with fructose in drinking water (HFHC) or a chow diet. Nlrp3−/−-HFHC showed higher hepatic expression of PPAR γ2 (that regulates lipid uptake and storage) and triglyceride content, histological score of liver injury and greater adipose tissue inflammation. In Nlrp3−/−-HFHC, dysregulation of gut immune response with impaired antimicrobial peptides expression, increased intestinal permeability and the occurrence of a dysbiotic microbiota led to bacterial translocation, associated with higher hepatic expression of TLR4 (an LPS receptor) and TLR9 (a receptor for double-stranded bacterial DNA). After antibiotic treatment, gram-negative species and bacterial translocation were reduced, and adverse effects restored both in liver and adipose tissue. In conclusion, the combination of a Western-lifestyle diet with innate immune dysfunction leads to NAFLD progression, mediated at least in part by dysbiosis and bacterial translocation, thus identifying new specific targets for NAFLD therapy

Treatment with CDAA+CCl₄ induces development of HCC after 9 months.

<p><b>A</b>) Mice sacrificed after 1 and 3 months from the beginning of the treatment do not show any nodular lesions in the parenchyma. Conversely, mice sacrificed after 6 months of treatment show few nodular lesions compatible with HCC. After 9 months of treatment mice show a liver parenchyma completely damaged. B) Histochemical staining for H&E and Sirius Red show respectively no fat deposition and absence of collagen content into the nodules. C) After 6 months of treatment, about 30% of mice show HCC development both with CDAA and CDAA+CCl₄. After 9 months of treatment, 100% of mice from the CDAA+CCl₄ group show at least one nodule into the liver parenchyma. D) After 6 months, the average of nodules dimension in the group of CDAA mice is significantly lower in comparison to that of the group of CDAA+CCl₄ mice. After 9 months, the average of nodules dimension in the group of CDAA+CCl₄ mice results of 9 mm, in comparison to 3 mm of the group of mice treated with CDAA alone. Data represent mean ± SD; *p<0.05 vs CDAA.</p