Effetti della somministrazione di Vitamina D sul Sistema Renina Angiotensina Aldosterone in pazienti con Ipertensione Essenziale e Ipovitaminosi D

Negli ultimi 10 anni, la vitamina D ha suscitato un notevole interesse per i suoi possibili effetti sul sistema cardiovascolare. Infatti, essa è conosciuta principalmente per il ruolo chiave che svolge sul metabolismo calcio/fosforo e sul tessuto osseo, ma ultimamente stanno emergendo nuove funzioni extra-scheletriche e, tra queste, azioni cardioprotettive, antinfiammatorie ed anti-aterosclerotiche. Numerosi studi osservazionali hanno mostrato una relazione inversa fra livelli plasmatici di vitamina D e prevalenza di malattie cardiovascolari. Tale associazione è stata inoltre validata da studi in vitro e sull’animale, che hanno individuato numerosi meccanismi fisiopatologici in grado di rafforzare questa correlazione. È stato dimostrato che la somministrazione di vitamina D è in grado di modulare in senso negativo l’attività del sistema renina angiotensina aldosterone (RAAS), di migliorare l’attività del sistema dell’ossido nitrico, di ridurre gli effetti deleteri dei prodotti di glicosilazione terminale sull’endotelio e di ridurre i livelli dei mediatori dell’infiammazione. E’ sul sistema RAA che abbiamo concentrato la nostra attenzione. Lo studio ha avuto i seguenti obiettivi: - verificare l’esistenza di una relazione tra i valori plasmatici di vitamina D e il sistema RAA in pazienti con ipertensione arteriosa essenziale; - valutare gli effetti emodinamici e bioumorali sul RAAS della somministrazione di colecalciferolo in pazienti ipertesi essenziali e con ipovitaminosi D. La popolazione valutata nella nostra indagine è composta da un gruppo di 26 pazienti con ipertensione arteriosa essenziale. Di questi, ben 15 sono stati ammessi all’indagine in quanto hanno mostrato livelli plasmatici di 25(OH)vitamina D < 30 ng/ml. I pazienti reclutati, oltre ad essere ipertesi essenziali e ipovitaminosici, sono liberi da terapie interferenti con il sistema RAA (inibitori diretti della renina, ACE-inibitori e antagonisti del recettore di tipo 1 dell’angiotensina II), con il sistema nervoso simpatico (beta-bloccanti o beta-agonisti e clonidina) o con il metabolismo del calcio e del fosforo (diuretici). Lo studio ha previsto la somministrazione di 25000 UI di colecalciferolo una volta la settimana per otto settimane e un intake di sodio costante nella dieta per tutta la durata dell’indagine. In condizioni basali e alla fine dello studio sono stati valutati i componenti del RAAS (angiotensinogeno plasmatico, renina, PRA, angiotensina II, aldosterone e angiotensinogeno urinario), la pressione arteriosa e i livelli di vitamina D (25(OH)vitamina D). Dopo la somministrazione di colecalciferolo tutti i pazienti mostravano valori plasmatici di 25(OH)vitamina D normali. Alla fine dello studio è stata osservata una riduzione significativa (p<0,005) della renina plasmatica e dell’aldosterone e un decremento apprezzabile, seppur non rilevante ai fini statistici, di PRA e angiotensina II. Nessuna differenza è stata trovata nei valori di angiotensinogeno plasmatico e urinario. In conclusione, i nostri dati indicano che nei pazienti con ipertensione essenziale e con ipovitaminosi D, a dieta costante di sodio e liberi da terapie interferenti sul RAAS, la stimolazione cronica del recettore della vitamina D riduce l’attività del sistema RAA

Cerebral stroke in a teenage girl with paroxysmal nocturnal hemoglobinuria

We report a case of paroxysmal nocturnal hemoglobinuria (PNH) in a 14 year-old girl presenting a cerebral arterial thrombosis. The initial diagnosis was carential anemia due to menarche following identification of slight macrocytic anemia, leucopenia and mild thrombocytopenia at routine blood analysis. The child was eventually referred to a children’s hospital after the onset of progressive fatigue, anorexia and paleness. Severe anemia (hemoglobin 6 g/dL) with negative Coombs test, mild leucopenia (white blood cells 4.9×109/L) and thrombocytopenia (platelets 97×109/L) and high values of lactate dehydrogenase (2855 U/L) were identified; a packed red cells transfusion was administered. Her condition worsened and she subsequently presented complete right hemiplegia, aphasia and coma; magnetic resonance imaging revealed a massive ischemic lesion. A diagnosis of PNH was eventually made following high sensitivity flow cytometry, which identified a PNH clone (CD66b negative equal to 93.7% of granulocytes). Fast recovery from neurologic and hematological problems occurred in response to anticoagulant therapy and intravenous therapy with eculizumab. We are convinced that PNH should be included in the differential diagnosis of children presenting with cytopenia

Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue

BackgroundIn light of recent developments in nanotechnologies, interest is growing to better comprehend the interaction of nanoparticles with body tissues, in particular within the cardiovascular system. Attention has recently focused on the link between environmental pollution and cardiovascular diseases. Nanoparticles <50 nm in size are known to pass the alveolar¿pulmonary barrier, enter into bloodstream and induce inflammation, but the direct pathogenic mechanisms still need to be evaluated. We thus focused our attention on titanium dioxide (TiO2) nanoparticles, the most diffuse nanomaterial in polluted environments and one generally considered inert for the human body.MethodsWe conducted functional studies on isolated adult rat cardiomyocytes exposed acutely in vitro to TiO2 and on healthy rats administered a single dose of 2 mg/Kg TiO2 NPs via the trachea. Transmission electron microscopy was used to verify the actual presence of TiO2 nanoparticles within cardiac tissue, toxicological assays were used to assess lipid peroxidation and DNA tissue damage, and an in silico method was used to model the effect on action potential.ResultsVentricular myocytes exposed in vitro to TiO2 had significantly reduced action potential duration, impairment of sarcomere shortening and decreased stability of resting membrane potential. In vivo, a single intra-tracheal administration of saline solution containing TiO2 nanoparticles increased cardiac conduction velocity and tissue excitability, resulting in an enhanced propensity for inducible arrhythmias. Computational modeling of ventricular action potential indicated that a membrane leakage could account for the nanoparticle-induced effects measured on real cardiomyocytes.ConclusionsAcute exposure to TiO2 nanoparticles acutely alters cardiac excitability and increases the likelihood of arrhythmic events

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

Ispra Study on Methods Used in EISs for Annex I.9 Installations.

Abstract not availableJRC.(ISIS)-Institute For Systems, Informatics And Safet

Immune Response Failure in Paucisymptomatic Long-Standing SARS-CoV-2 Spreaders

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout the world. This disease has a spectrum of different clinical pictures with different outcomes. Herein, we report all the data from three paucisymptomatic patients during a hospital stay that might represent a paradigmatic example of the method by which SARS-CoV-2 is shed. We demonstrated the lack of an adequate qualitative and quantitative immune response by multiparametric flow cytometry analysis. Our data can provide a new perspective about the method by which SARS-CoV-2 is shed and the clinical weight of viral persistence. In all three cases, the long persistence of the virus and the consistent reduction in both innate and adaptative immune cells are not associated with greater disease severity. These patients might represent at least part of the population. In particular, one patient oscillated between positive and negative swab tests several times without presenting any immune response. In all three cases, the immune response failure was not associated with a clinically significant involvement, indicating that it is not the virus’s ability to impair the immune system, as well as its presence and persistence the fundamental mechanism that might causally lead to death. Finally, this kind of immune response in paucisymptomatic patients could pose a considerable danger to public health that questions the quarantine period. It is urgent to quantify the phenomenon with a large sample study

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume post-hemodiafiltration and 7 short-daily dialysis with the NxStage-One system. Instant dialysate/blood determinations were also performed at different times, and Kt was calculated as the product of the D/P ratio by volume of delivered dialysate plus UF. There were significant differences in single session and weekly Kt (whole dialysate and instant calculations) between methodologies, most notably for creatinine, phosphorus and beta2-microglobulin. Urea Kt messured in balance studies was almost equal to that derived from the usual plasma kinetic model-based Daugirdas' equation (eKt/V) and independent V calculation, indicating full correspondence. Non-urea solute Kt as a fraction of urea Kt (i.e. fractional removal relative to urea) showed significant differences between technologies, indicating non-proportional removal of non-urea solutes and urea. Instant Kt was higher than that in full balances, accounting for concentration disequilibrium between arterial and systemic blood, but measured and calculated quantitative solute removal were equal, as were qualitative Kt comparisons between technologies. Thus, we show that urea metrics may not reliably express removal efficiency of non-urea solutes, as indicated by Kt. Kt can easily be measured without whole dialysate collection, allowing to expand the metrics of dialytic efficiency to almost any non-urea solute removed by dialysis