Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data

The treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18-66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated

Plasma p-Cresol Lowering Effect of Sevelamer in Peritoneal Dialysis Patients: Evidence from a Cross-Sectional Observational Study.

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate, that represents more than 95% of circulating p-cresol, causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies able to reduce plasma p-cresol levels are highly demanded but unfortunately not available yet. Because it has been reported that the phosphate binder sevelamer also sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis patients, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. When we compared total p-cresol plasma concentrations in these different groups of patients, we, we found that plasma p-cresol levels were significantly lower in patients receiving sevelamer than in subjects receiving lanthanum or no drug. Patients assuming sevelamer had also lower high sensitivity C-reactive protein serum concentrations compared to patients not assuming this drug. Multiple linear regression analysis showed that Conversely, no difference either in residual glomerular filtration rate, total weekly dialysis dose or serum phosphate levels were observed among the different groups. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect the cardiovascular risk because of its anti-inflammatory effect

Evidence That p-Cresol and IL-6 Are Adsorbed by the HFR Cartridge: Towards a New Strategy to Decrease Systemic Inflammation in Dialyzed Patients?

Introduction Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate. Methods We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UFin) and at the outlet (UFout) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD. Results p-Cresol and IL-6 were lower in UFout than in UFin both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UFout collected at the end than with UFin collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro-inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures. Conclusions This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels. Trial Registration ClinicalTrials.gov NCT0186577

Determination of plasmatic microRNA levels by ddPCR as peripheral biomarkers for IDH-wild type glioblastomas: a pilot study

BACKGROUND: Glioblastoma (GBM) is the most frequent malignant brain tumour in adults with a dismal prognosis. Peripheral biomarkers may be useful and effective in managing patients affected by GBM. The aim of our study was to analyse the plasmatic levels of three miRNAs as possible GBM-specific biomarkers. We focused on miR-21-5p – an onco-miR overexpressed in blood, tumour tissue and cell cultures derived from patients affected by GBM – miR-23b-3p – overexpressed in GBM, especially under hypoxic conditions – and miR-34a-5p – a tumour suppressor miR downregulated in tumour tissue and serum of patients with GBM. MATERIALS AND METHODS: Eight patients presenting with firstly-diagnosed IDH-wild type GBM and 10 age- and gender-matched healthy volunteers (hV) have been enrolled in the study. Peripheral blood samples were collected at diagnosis and one month after surgery. Total RNA was isolated from plasma by means of miRNeasy Serum/Plasma Kit (Qiagen), according to the manufacturer’s instructions. Digital droplet PCR (ddPCR) was performed for each miRNA according to the QX200 EvaGreen ddPCR protocol. RESULTS: The circulating concentrations of miR-21-5p were in mean 24.00 (28.44) and 72.40 (147.88) copies/L in patients with GBM at diagnosis and one month after surgery (p=0.38), respectively, compared with 98.74 copies/L ( 123.60) quantified in hV (p=0.09; p=0.69). The mean peripheral levels of miR-23b-3p were 0.49 copies/L (0.49) at diagnosis and 3.02 copies/L (6.88) one month after surgery (p=0.32) in patients with GBM, and 2.56 copies/L (5.57) in hV (p=0.31; p=0.88). Analysing plasmatic expression of miR-34a-5p, 1.11 (1.55) and 1.85 copies/L (1.87) were measured on average at diagnosis and one month after surgery in patients with GBM (p=0.41), while 0.73 copies/L (0.85) in hV (p=0.52; p=0.11). CONCLUSIONS: We preliminarily reported higher concentrations of circulating miR-21-5p, miR-23b-3p and miR-34a-5p in plasma of patients affected by IDH-wild type GBM one month after surgery compared to the levels at diagnosis

Plasmatic microRNA levels by ddPCR as peripheral biomarkers for IDH-wild type glioblastomas: a pilot study

BACKGROUND: Glioblastoma (GBM) is the most frequent malignant brain tumour in adults with a dismal prognosis and peripheral biomarkers may be useful and effective in managing patients with GBM. The main aim of our study was the use of ddPCR to assess the absolute quantification of the plasmatic levels of three miRNAs as possible GBM-specific biomarkers. We focused on: miR-21-5p, an onco-miR overexpressed in blood, tumour tissue and cell cultures derived from patients affected by GBM, miR-23b-3p and miR-34a-5p, tumour suppressor miRs dysregulated in GMB. MATERIALS AND METHODS: Eight patients presenting with firstly-diagnosed IDH-wild type GBM and 10 age- and gender-matched healthy control donors (hC) have been enrolled in the study. Peripheral blood samples were collected at diagnosis and one month after surgery. Total RNA was isolated from plasma by means of miRNeasy Serum/Plasma Kit (Qiagen), according to the manufacturer’s instructions. Digital droplet PCR (ddPCR) was performed to assess the absolute quantification of each miRNA level according to the QX200 ddPCR protocol. RESULTS: The expression analysis revealed: i) different levels of each miRNA in hC: 98.74 copies/L (±123.60), 2.56 copies/L (±5.57), 0.73 copies/L (±0.85) for miR-21-5p, miR-23b-3p and miR-34a-5p, respectively; ii) a trend of downregulation of miR-21-5p and miR-23b-3p in GMB patients at diagnosis compared to hC; iii) a trend of upregulation of each miRNA in GMB patients one month after surgery compared with the levels measured at diagnosis, in particular 3.02, 6.2 and 1.7 fold increase for miR-21-5p, miR-23b-3p and miR-34a-5p, respectively. CONCLUSIONS: In this pilot study we reported higher amounts of circulating miR-21-5p, miR-23b-3p and miR-34a-5p in plasma of patients affected by IDH-wild type GBM one month after surgery compared to the levels at diagnosis

Local variability of the ground shaking during the 2009 L’Aquila earthquake (April 6, 2009—Mw 6.3): the case study of Onna and Monticchio villages

The 2009 Mw 6.3 L’Aquila event caused extensive damage in the city of L’Aquila and in some small towns in its vicinity. The most severe damage was recognized SE of L’Aquila town along the Aterno river valley. Although building vulnerability and near-source effects are strongly responsible for the high level of destruction, site effects have been invoked to explain the damage heterogeneities and the similarities between the 2009 macroseismic field with the intensities of historical earthquakes. The small village of Onna is settled on quaternary alluvium and suffered during the L’Aquila event an extremely heavy damage in the masonry structures with intensity IX–X on the Mercalli-Cancani-Sieberg (MCS) scale. The village of Monticchio, far less than 1.3 km from Onna, is mostly situated on Meso- zoic limestone and suffered a smaller level of damaging (VI MCS). In the present paper, we analyze the aftershock recordings at seismic stations deployed in a small area of the middle-Aterno valley including Onna and Monticchio. The aim is to investigate local ampli-fication effects caused by the near-surface geology. Because the seismological stations are close together, vulnerability and near-source effects are assumed to be constant. The wave- form analysis shows that the ground motion at Onna is systematically characterized by large high-frequency content. The frequency resonance is varying from 2 to 3 Hz and it is related to alluvial sediments with a thickness of about 40 m that overlay a stiffer Pleistocene substrate. The ground motion recordings of Onna are well reproduced by the predictive equation for the Italian territory.Published783-8072T. Sorgente SismicaJCR Journalreserve

11.Hypoxic ventilatory depressionと思われる一症例について(第551回千葉医学会例会・第9回麻酔科例会・第18回千葉麻酔懇話会)

FISH analysis on metaphase nuclei (top panel) of cultured cells derived from peripheral blood leukocytes of the proband of family 2 by using BAC probes for 11p15.5-15.4 (RP11-11A9, 3,236,552-3,356,012, green) and 11q22.3 (RP11-179B7, 104,298,339-104,459,797, red). The green signal on both homologues is visible only at chr11p, demonstrating the presence of an in cis duplication and excluding an unbalanced translocation. FISH analysis on interphase nuclei (bottom panel) using the BACs RP11-699D10 (2.9–3.0 Mb, red) and RP11-11A9 (green), hybridizing within the duplication. Note that single and duplicated signals can be seen on the two homologues, respectively. The red-green-green-red order of the duplicated signals indicates that the duplication is inverted. (PDF 52 kb

Site effect studies following the 2016 Mw 6.0 Amatrice Earthquake (Italy): the Emersito Task Force activities

On August 24, 2016, at 01:36 UTC a MW 6.0 earthquake struck an extensive area of the Central Apennines (Italy) be-tween the towns of Norcia and Amatrice. Due to the mainshock magnitude and the widespread damaging level of build-ings in the epicentral area, the Emersito task force has been mobilized by the Istituto Nazionale di Geofisica e Vulcanologia (INGV). The aim of Emersito is to carry out and coordinate the monitoring of local site effects, caused by geological and geomorphological settings. During the first days of the seismic emergency, Emersito installed a tempo-rary seismic network for site effect studies at 4 municipalities close to the epicentral area (Amandola, Civitella del Tronto, Montereale and Capitignano), using 22 stations equipped with both velocimetric and accelerometric sensors. The selection of the sites where stations have been installed was mainly driven by the proximity to the epicentral area (without interfere with the rescue operations) and by peculiar geologic and geomorphologic settings (topographic irregu-larities, fault zones, alluvial plains). Preliminary analyses performed on ambient noise and aftershocks signals show that directional amplification effects may have occurred at stations installed on the top of topographic irregularities. We also observed the lengthening and amplification of the seismograms and a variability of the peaked frequency across the sedi-mentary basin between Montereale and Capitignano, probably related to a different thickness of the deposits. Further analyses are necessary to assess the correlation with surface geology.Published4T. Sismologia, geofisica e geologia per l'ingegneria sismica1SR. TERREMOTI - Servizi e ricerca per la Società1IT. Reti di monitoraggioJCR Journa

CLASH-VLT: Abell S1063: Cluster assembly history and spectroscopic catalogue

Context. The processes responsible for galaxy evolution in different environments as a function of galaxy mass remain heavily debated. Rich galaxy clusters are ideal laboratories in which to distinguish the role of environmental versus mass quenching because they consist of a full range of galaxies and environments. Aims. Using the CLASH-VLT survey, we assembled an unprecedentedly large sample of 1234 spectroscopically confirmed members in Abell S1063. We found a dynamically complex structure at «zcl»= 0.3457 with a velocity dispersion σv = 1380-32+26 km s-1. We investigated cluster environmental and dynamical effects by analysing the projected phase-space diagram and the orbits as a function of galaxy spectral properties. Methods. We classified cluster galaxies according to the presence and strength of the [OII] emission line, the strength of the Hδ absorption line, and colours. We investigated the relation between the spectral classes of galaxies and their position in the projected phase-space diagram. We separately analysed red and blue galaxy orbits. By correlating the observed positions and velocities with the projected phase-space constructed from simulations, we constrained the accretion redshift of galaxies with different spectral types. Results. Passive galaxies are mainly located in the virialised region, while emission-line galaxies lie beyond r200 and are accreted into the cluster at a later time. Emission-line and post-starburst galaxies show an asymmetric distribution in projected phase-space within r200; emission-line galaxies are prominent at Δv/σ ≲ -1.5 and post-starburst galaxies at Δv/σ ≲ 1.5, suggesting that backsplash galaxies lie at high positive velocities. We find that low-mass passive galaxies are accreted into the cluster before high-mass galaxies. This suggests that we observe as passives only the low-mass galaxies that are accreted early into the cluster as blue galaxies. They had the time to quench their star formation. We also find that red galaxies move on more radial orbits than blue galaxies. This can be explained if infalling galaxies can remain blue by moving on tangential orbits