Diabetic kidney disease. new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "the natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function"

Recent epidemiological studies have disclosed heterogeneity in diabetic kidney disease (DKD). In addition to the classical albuminuric phenotype, two new phenotypes have emerged, i.e., “nonalbuminuric renal impairment” and “progressive renal decline”, suggesting that DKD progression toward end-stage kidney disease in diabetic patients may occur through two distinct pathways heralded by a progressive increase in albuminuria and decline in renal function independent of albuminuria, respectively. Besides the natural history of DKD, also the management of hyperglycemia in patients with type 2 diabetes and reduced renal function has profoundly changed in the last two decades. New anti-hyperglycemic drugs have become available for treatment of these individuals and the lowest estimated glomerular filtration rate safety thresholds for some of the old agents have been reconsidered. This joint document of the Italian Diabetes Society (SID) and the Italian Society of Nephrology (SIN) reviews the natural history of DKD in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents in DKD patients

Panethnic differences in blood pressure in Europe : a systematic review and meta-analysis

Background: People of Sub Saharan Africa (SSA) and South Asians(SA) ethnic minorities living in Europe have higher risk of stroke than native Europeans(EU). Study objective is to provide an assessment of gender specific absolute differences in office systolic(SBP) and diastolic(DBP) blood pressure(BP) levels between SSA, SA, and EU. Methods and Findings: We performed a systematic review and meta-analysis of observational studies conducted in Europe that examined BP in non-selected adult SSA, SA and EU subjects. Medline, PubMed, Embase, Web of Science, and Scopus were searched from their inception through January 31st 2015, for relevant articles. Outcome measures were mean SBP and DBP differences between minorities and EU, using a random effects model and tested for heterogeneity. Twenty-one studies involving 9,070 SSA, 18,421 SA, and 130,380 EU were included. Compared with EU, SSA had higher values of both SBP (3.38 mmHg, 95% CI 1.28 to 5.48 mmHg; and 6.00 mmHg, 95% CI 2.22 to 9.78 in men and women respectively) and DBP (3.29 mmHg, 95% CI 1.80 to 4.78; 5.35 mmHg, 95% CI 3.04 to 7.66). SA had lower SBP than EU(-4.57 mmHg, 95% CI -6.20 to -2.93; -2.97 mmHg, 95% CI -5.45 to -0.49) but similar DBP values. Meta-analysis by subgroup showed that SA originating from countries where Islam is the main religion had lower SBP and DBP values than EU. In multivariate meta-regression analyses, SBP difference between minorities and EU populations, was influenced by panethnicity and diabetes prevalence. Conclusions: 1) The higher BP in SSA is maintained over decades, suggesting limited efficacy of prevention strategies in such group in Europe;2) The lower BP in Muslim populations suggests that yet untapped lifestyle and behavioral habits may reveal advantages towards the development of hypertension;3) The additive effect of diabetes, emphasizes the need of new strategies for the control of hypertension in groups at high prevalence of diabetes

Dopamine receptor D5 signaling plays a dual role in experimental autoimmune encephalomyelitis potentiating Th17-mediated immunity and favoring suppressive activity of regulatory T-cells

Indexación: Scopus.This work was supported by grants FONDECYT-1170093 (to RP) and FONDECYT-3160383 (to CP) from ‘‘Fondo Nacional de Desarrollo Científico y Tecnológico de Chile’’, AFB170004 (to RP) from ‘‘Comisión Nacional de Investigación Científica y Tecnológica de Chile (CONICYT)’’ and DI-1224-16/R (to RP) from Universidad Andres Bello.A number of studies have shown pharmacologic evidence indicating that stimulation of type I dopamine receptor (DR), favors T-helper-17 (Th17)-mediated immunity involved in experimental autoimmune encephalomyelitis (EAE) and in some other inflammatory disorders. Nevertheless, the lack of drugs that might discriminate between DRD1 and DRD5 has made the pharmacological distinction between the two receptors difficult. We have previously shown genetic evidence demonstrating a relevant role of DRD5-signaling in dendritic cells (DCs) favoring the CD4+ T-cell-driven inflammation in EAE. However, the role of DRD5-signaling confined to CD4+ T-cells in the development of EAE is still unknown. Here, we analyzed the functional role of DRD5-signaling in CD4+ T-cell-mediated responses and its relevance in EAE by using a genetic approach. Our results show that DRD5-signaling confined to naive CD4+ T-cells exerts a pro-inflammatory effect promoting the development of EAE with a stronger disease severity. This pro-inflammatory effect observed for DRD5-signaling in naive CD4+ T-cells was related with an exacerbated proliferation in response to T-cell activation and to an increased ability to differentiate toward the Th17 inflammatory phenotype. On the other hand, quite unexpected, our results show that DRD5-signaling confined to Tregs strengthens their suppressive activity, thereby dampening the development of EAE manifestation. This anti-inflammatory effect of DRD5-signaling in Tregs was associated with a selective increase in the expression of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), which has been described to play a critical role in the expansion of Tregs. Our findings here indicate a complex role for DRD5-signaling in CD4+ T-cells-driven responses potentiating early inflammation mediated by effector T-cells in EAE, but exacerbating suppressive activity in Tregs and thereby dampening disease manifestation in late EAE stages. © 2018 Osorio-Barrios, Prado, Contreras and Pacheco.https://www.frontiersin.org/articles/10.3389/fncel.2018.00192/ful

Clathrin light chains' role in selective endocytosis influences antibody isotype switching

Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules

Current trends in oxysterol research

In this short review we provide a synopsis of recent developments in oxysterol research highlighting topics of current interest to the community. These include the involvement of oxysterols in neuronal development and survival, their participation in the immune system, particularly with respect to bacterial and viral infection and to Th17-cell development, and the role of oxysterols in breast cancer. We also discuss the value of oxysterol analysis in the diagnosis of disease

Impact of Blood Pressure Variability on Cardiac and Cerebrovascular Complications in Hypertension

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Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophage

Franco Tosi, Legnano : riqualificazione urbana del comparto sud

LAUREA MAGISTRALEIl progetto riguarda la riqualificazione di un’area industriale situata a Legnano, che è rimasta inutilizzata dagli anni ‘80. L’intervento prevede sia il recupero con rifunzionalizzazione della maggior parte degli edifici, simbolo del retaggio industriale del paese, sia limitate parte realizzate ex-novo. L’area oggetto di tesi viene introdotta da una breve descrizione della storia più recente di Legnano, utile a comprendere le dinamiche della città ed il contesto nel quale sorge la ditta Franco Tosi. Tali conoscenze risultano estremamente importanti per le fasi successive del progetto, in particolare per individuare le parti più significative del progetto e quindi nelle decisioni sulle porzioni da conservare e quelle da demolire. Inoltre la ricerca storica ha permesso di comprendere l’eccezionale ruolo che ha ricoperto la ditta nel corso degli anni. L’area è estremamente grande, si estende per circa 100.000 mq e si trova in prossimità del centro storico, ragion per cui questa porzione di territorio abbandonata e inaccessibile, una sorta di buco nero della città, deve assolutamente essere restituito ai suoi abitanti. Il recupero di siti industriali dismessi é un tema piuttosto diffuso ai tempi nostri, in cui molte città possiedono aree industriali più o meno vaste che, dopo un periodo di grande sviluppo in cui si investivano enormi quantità di risorse nel settore, risultano attualmente abbandonate a causa delle trasformazioni delle città e della società. Spazi che, in alcuni casi, rappresentano delle opportunità per la città e quindi necessitano di essere rigenerati. Seppur sia relativamente semplice trasformare un’area cementificata in un’area verde, solitamente pubblica, e seppur in molti casi la riqualificazione è intesa in questi termini nel progetto in esame non è stato fatto solo questo. L’obiettivo principale del progetto è quello di riattivare il complesso dal punto di vista sociale ed economico, inserendo funzioni rivolte ai cittadini e rendendo così l’area parte attiva della città. La trasformazione quindi di gran parte dell’area in parco è fatta per contribuire al raggiungimento di quest’obiettivo. Riassumendo, i temi portanti su cui poggia il progetto sono: la conservazione della memoria, l’integrazione con la città, il recupero fisico e sociale dei manufatti. Particolare attenzione è stata posta sull’aspetto tecnologico-ambientale, sul rispetto delle normative vigenti e sulla fattibilità tecnico-economica.The project concerns the refurbishment of an industrial area located in Legnano (Milano), which has remained unused since the '80s. The intervention includes both the recovery with repurposing of most buildings, a symbol of the industrial heritage of the country, and limited part realized ex-novo. The area object of the thesis is introduced by a brief description of the most recent history of Legnano, useful for understanding the dynamics of the city and the context in which the company Franco Tosi rises. These are important for the later phases of the project, in particular to identify the most significant parts of the project and therefore in decisions about conservations and demolitions. Furthermore, the research has allowed to understand the exceptional role that the company has played over the years. The area is extremely large, covers about 100,000 square meters and is located near the historic center, which is why this portion of abandoned and inaccessible territory, a sort of black hole in the city, must absolutely be returned to its inhabitants. The recovery of abandoned industrial sites is a rather widespread issue in our time, in which many cities have more or less extensive industrial areas that, after a period of great development in which huge amounts of resources was invested in the sector, are currently abandoned due to of the transformations of cities and society. Spaces that, in some cases, represent opportunities for the city and therefore need to be regenerated. Although it is relatively simple to transform a cemented area into a green area, usually public, and although in many cases the redevelopment is intended in these terms, this project has not been done in this project. The main objective of the project is to reactivate the complex from a social and economic point of view, including functions aimed at citizens and thus making the area an active part of the city. The transformation of most of the area into a park is therefore made to contribute to achieving this goal. In summary, the main themes on which the project is based are: conservation of memory, integration with the city, physical and social recovery of artefacts. Particular attention was paid to the technologicalenvironmental aspect, compliance with current regulations and technical-economic feasibility

ACE-Inhibitors in High Vascular Risk: From Experimental Medicine to Clinical Trials

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Comparative assessment of angiotensin receptor blockers in different clinical settings

Cardiovascular and renal disease can be regarded as progressing along a sort of continuum which starts with cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, etc), evolves with progression of atherosclerotic lesions and organ damage, and then becomes clinically manifest with the major clinical syndromes (myocardial infarction, stroke, heart failure, end-stage renal disease). The blood pressure control remains a fundamental mechanism for prevention of cardiovascular disease. The renin–angiotensin system is believed to play an important role along different steps of the cardiovascular disease continuum. Convincing evidence accumulated over the last decade that therapeutic intervention with angiotensin receptor blockers (ARBs) is effective to slow down or block the progression of cardiovascular disease at different steps of the continuum, with measurable clinical benefits. However, despite the shared mechanism of action, each ARB is characterized by specific pharmacological properties that may influence its clinical efficacy. Indeed, important differences among available ARBs emerged from clinical studies. Therefore, generalization of results obtained with a specific ARB to all available ARBs may be misleading. The present review provides a comparative assessment of the different ARBs in their efficacy on major clinical endpoints along the different steps of the cardiovascular disease continuum