Magnetic resonance imaging 3t and total fibrotic volume in autosomal dominant polycystic kidney disease

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Several authors have attempted to identify a kidney damage marker for predicting the prognosis and the effectiveness of therapy in ADPKD. The aim of this study was to identify and quantify in ADPKD, through a novel MR protocol with 3 Tesla (MRI 3Tesla), the presence of parenchymal fibrotic tissue at early stage of disease, able to correlate the glomerular filtrate and to predict the loss of the function renal. MATERIAL AND METHODS: 15 ADPKD patients undergone to renal MRI 3Tesla at T0 and revaluated after follow up (T1) of 5 years. We have evaluated renal function, plasma aldosterone concentration (PAC), insulin resistance and surrogate markers of atherosclerosis (carotid intima media thickness (IMT), ankle/brachial index (ABI) and left ventricular mass index (LVMI). RESULTS: Our study showed a significant negative correlation between total kidney volume and estimated glomerular filtration rate (eGFR) during observational observation (p<0.02). Moreover, we showed a negative correlation between eGFR with Total Fibrotic Volume (TFV) (p<0.04) and Total Perfusion Volume/Total kidney Volume(<0.02). Moreover TFV was correlated positively with PAC (p<0.05), insulin values (p<0.05), ABI (p <0.05) and LVMI(p<0.01). CONCLUSIONS: The MRI 3Tesla, despite the high costs, could be considered an useful and non-invasive method in the evaluation of fibrotic tissue and progression of the disease in ADPKD patients. Further clinical trials on larger group are due to confirm the results of this pilot study, suggesting that MRI 3Tesla can be useful to evaluate the effectiveness of new therapeutic strategies. This article is protected by copyright. All rights reserved

DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p<0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Reddish metagranites from the Gennargentu Igneous Complex (Sardinia, Italy) : insight into metasomatism induced by magma mingling

The mineralogy of thermometamorphic granites is relatively simple, making it possible to track the spatial distribution of chemical and mineralogical variations in these rocks and investigate the processes that underpin these metamorphic reactions. We have undertaken a detailed investigation of metagranites from the contact aureole that fringes a quartz diorite intrusion of Late Permian age, emplaced into Carboniferous peraluminous granites of the Gennargentu Igneous Complex (Sardinia, Italy). New data are presented including the petrography of metagranites within a 500 m zone adjacent to the quartz diorite intrusion, the compositions of minerals and bulk-rocks, and the oxygen isotope compositions of separated minerals. We have used these data to assess the mobility of elements, expressed as Δoxide, in the aureole, and the physical conditions of fluid-assisted thermometamorphism. Modal variations and the oscillatory zoning of plagioclase demonstrate that the shallow (P ≤200 MPa) quartz diorite intrusion was emplaced through a number of magmatic injections. The border zone of the quartz diorite intrusion presents evidence of two main processes: hybridization between andesite and rhyolite magmas and volatile saturation of the mingled magma. Modal differences in the contact zone with respect to the protolith (i.e. peraluminous granite), variations in mineral composition, temperature constraints and ΔK₂O, ΔNa₂O, ΔSiO₂ and ΔAl₂O₃ indicate that a relatively large volume of the host granite (up to 400 m from the contact) was metasomatized by high-temperature (650–350℃) fluids derived from the mingled zone of the quartz diorite intrusion. In detail, the metasomatic K₂O-rich fluid reacted with albite to form K-feldspar, and triggered the recrystallization of quartz and plagioclase to higher calcium concentrations. The progressive increase in the MgO/(MgO + FeO) of chlorite closer to the contact indicates that this phase also recrystallized. The iron released during chlorite recrystallization was buffered by hematite formation in the pores of metasomatic K-feldspar. The Gennargentu metagranites provide evidence that metasomatic fluids can play a major role in driving metamorphic reactions in contact aureoles. For instance, the expected increase of Ca in plagioclase owing to thermal equilibration was not achieved in the high-T zone of the aureole because of fluid-assisted removal of cations. We conclude that caution should be taken when interpreting the processes that underpin contact metamorphism in terms of thermally driven, ionic diffusion alone, because the role of fluids may be significant, if not overwhelming, in the domains closest to the magmatic source.21 page(s

Magma-carbonate interaction: An experimental study on ultrapotassic rocks from Alban Hills (Central Italy)

The Alban Hills ultrapotassic volcanic district is one of the main districts emplaced during Quaternary time along the Tyrrhenian margin of Italy. Alban Hills lava flows and scoria clasts are made up essentially of clinopyroxenes and leucites and their chemical composition is mostly K-foiditic. Differentiated products (MgO < 3 wt.%) are characterised by low SiO2 concentration (< 50 wt.%) and geochemical features indicate that this unique differentiation trend is driven by crystal fractionation plus carbonate crust interaction. Notably, the Alban Hills Volcanic District was emplaced into thick limestone units. With the aim of constraining the magmatic differentiation, we performed experiments on the Alban Hills parental composition (plagioclase-free phono-tephrite) under anhydrous, hydrous, and hydrous-carbonated conditions. Experiments were carried out at 1 atm, 0.5 GPa and 1 GPa, temperatures ranging from 1050 to 1300 degrees C, and H2O and CaCO3 in the starting material up to 2 and 7 wt.%, respectively The experiments performed at 0.5 GPa are the most representative of the Alban Hills plumbing system. Clinopyroxene and leucite are the main phases occurring under all the investigated conditions and the liquidus phases. Nevertheless, our experimental results demonstrate that the occurrence of CaCO3 in the starting material strongly affects phase relations. Experiments performed under hydrous conditions crystallize magnetite and phlogopite at relatively high temperature. This early crystallization drives the glass composition towards a silica enrichment, resulting in a differentiation trend moving from phono-tephritic (Alban Hills parental composition) to phonolitic compositions. This is in contrast with micro-textural evidence showing late crystallization of magnetite and phlogopite in the natural products and with the composition of the juvenile products. On the contrary, in the CaCO3-bearing experiments (i.e., simulating magma-carbonate interaction) the magnetite and phlogopite stability fields are strongly reduced. As a consequence, the melt differentiation is mainly controlled by the cotectic crystallization of clinopyroxene and leucite, resulting in a differentiation trend moving towards K-foiditic compositions. These experimental results are in agreement with micro-textural features and chemical compositions of Alban Hills natural products and with the magmatic differentiation model inferred by geochemical data. Magma-carbonate interaction is not a rare process and its occurrence has been demonstrated for different plumbing systems. However, the uniqueness of the Alban Hills liquid line of descent suggests that the efficacy of the carbonate contamination process is controlled by different factors, the dynamics of the plumbing system being one of the most important. (c) 2007 Elsevier B.V. All rights reserved

Drug dosing in children with obesity: a narrative updated review

Childhood obesity and its associated comorbidities are highly prevalent diseases that may add to any other possible health problem commonly affecting the pediatric age. Uncertainties may arise concerning drug dosing when children with obesity need pharmacologic therapies. In general, in pediatric practice, there is a tendency to adapt drug doses to a child's total body weight. However, this method does not consider the pharmacological impact that a specific drug can have under a two-fold point of view, that is, across various age and size groups as well. Moreover, there is a need for a therapeutic approach, as much as possible tailored considering relevant interacting aspects, such as modification in metabolomic profile, drug pharmacokinetics and pharmacodynamics. Taking into account the peculiar differences between children with overweight/obesity and those who are normal weight, the drug dosage in the case of obesity, cannot be empirically determined solely by the per kg criterion. In this narrative review, we examine the pros and cons of several drug dosing methods used when dealing with children who are affected also by obesity, focusing on specific aspects of some of the drugs most frequently prescribed in real-world practice by general pediatricians and pediatric subspecialists

Carbonate assimilation in magmas: A reappraisal based on experimental petrology

The main effect of magma-carbonate interaction on magma differentiation is the formation of a silica-undersaturated, alkali-rich residual melt. Such a desilication process was explained as the progressive dissolution of CaCO3 in melt by consumption of SiO2 and MgO to form diopside sensu stricto. Magma chambers emplaced in carbonate substrata, however, are generally associated with magmatic skarns containing clinopyroxene with a high Ca-Tschermak activity in their paragenesis. Data are presented from magma-carbonate interaction experiments, demonstrating that carbonate assimilation is a complex process involving more components than so far assumed. Experimental results show that, during carbonate assimilation, a diopside-hedenbergite-Ca-Tschermak clinopyroxene solid solution is formed and that Ca-Tschermak/diopside and hedenbergite/diopside ratios increase as a function of the progressive carbonate assimilation. Accordingly, carbonate assimilation reaction should be written as follows, taking into account all the involved magmatic components:. CaCO3solid + SiO2melt + MgOmelt + FeOmelt + Al2O3melt → (Di-Hd-CaTs)sssolid + CO2fluid. The texture of experimental products demonstrates that carbonate assimilation produces three-phases (solid, melt, and fluid) whose main products are: i) diopside-hedenbergite-Ca-Tschermak clinopyroxene solid solution; ii) silica-undersaturated CaO-rich melt; and iii) C-O-H fluid phase. The silica undersaturation of the melt and, more importantly, the occurrence of a CO2-rich fluid phase, must be taken into account as they significantly affect partition coefficients and the redox state of carbonated systems, respectively. © 2009 Elsevier B.V. All rights reserved