Search

PRISMA is a hyperspectral satellite mission launched by the Italian Space Agency (ASI) in April 2019. The mission is designed to collect data at global scale for a variety of applications, including those related to the cryosphere. This study presents an evaluation of PRISMA Level 1 (L1) and Level 2 (L2D) products for different snow conditions. To the aim, PRISMA data were collected at three sites: two in the Western European Alps (Torgnon and Plateau Rosa) and one in East Antarctica (Nansen Ice Shelf). PRISMA data were acquired contemporary to both field measurements and Sentinel‐2 data. Simulated Top of the Atmosphere (TOA) radiance data were then compared to L1 PRISMA and Sentinel‐2 TOA radiance. Bottom Of Atmosphere (BOA) reflectance from PRISMA L2D and Sentinel‐2 L2A data were then evaluated by direct comparison with field data. Both TOA radiance and BOA reflectance PRISMA products were generally in good agreement with field data, showing a Mean Absolute Difference (MAD) lower than 5%. L1 PRISMA TOA radiance products resulted in higher MAD for the site of Torgnon, which features the highest topographic complexity within the investigated areas. In Plateau Rosa we obtained the best comparison between PRISMA L2D reflectance data and in situ measurements, with MAD values lower than 5% for the 400–900 nm range. The Nansen Ice Shelf instead resulted in MAD values <10% between PRISMA L2D and field data, while Sentinel‐2 BOA reflectance showed higher values than other data sources. Plain Language Summary: Satellite imaging spectroscopy data provide valuable information on Earth surface processes. In this study we evaluated data acquired from the PRISMA satellite mission in the Alps and Antarctica. Those studies are important to validate satellite observations with contemporary field measurements since they open the possibility of quantitatively use PRISMA data for cryosphere monitoring. Key Points: We present an evaluation of PRISMA Level 1 and Level 2 products for different snow conditionsContemporary to PRISMA acquisition, field spectroscopy data were collected on snow in the Alps and in AntarcticaBoth radiance and reflectance PRISMA products were generally in good agreement with field data [ABSTRACT FROM AUTHOR]

Background: Since the first observations of patients with COVID‐19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. Objective: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial–endothelial barrier. Methods: One hundred seventy‐four COVID‐19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. Results: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL‐8) and interleukin 10 (IL‐10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID‐19 and compared with postmortem findings in a control group (bacterial pneumonia‐ARDS and H1N1‐ARDS). ICU patients had lower serum albumin than IMW patients [20 (18–23) vs 28 (24–33) g L−1, P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2‐to‐FiO2 ratio and worst chest X‐ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL‐8 and IL‐10 levels in BALF. Electron microscopy examinations of eight out of ten COVID‐19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. Conclusion: Hypoalbuminaemia may serve as severity marker of epithelial–endothelial damage in patients with COVID‐19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID‐19 and might be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Indium phosphide (InP)‐based high electron mobility transistors (HEMTs) with an offset gate enable higher maximum oscillation frequency (fMAX) values because of the resulting reduction in gate‐to‐source resistance. Following this approach, improved direct current (DC) characteristics and cutoff frequencies (fT/fMAX > 410/710 GHz with LG = 50 nm) are shown with respect to centered gate devices. However, HEMTs with an offset gate show degraded noise performances compared with centered gate devices because of a higher gate leakage current. The results show that offsetting the gate closer to the source is not desirable for ultra‐low‐noise performance. [ABSTRACT FROM AUTHOR]

Thermal inertia has been successfully used in remote sensing applications that span from geology, geomorphology to hydrology. In this paper, we propose the use of thermal inertia for describing snow dynamics. Two different formulations of thermal inertia were tested using experimental and simulated data related to snowpack dynamics. Experimental data were acquired between 2012 and 2017 from an automatic weather station located in the western Italian Alps at 2,160 m. Simulations were obtained using the one‐dimensional multilayer Crocus model. Results provided evidences that snowmelt phases can be recognized, and average snowpack density can be estimated reasonably well from thermal inertia observations (R2 = 0.71; RMSE = 65 kg/m3). The empirical model was also validated with manual snow density measurements (R2 = 0.80; RMSE = 54 kg/m3). This study is the first attempt at the exploitation of thermal inertia for snow monitoring, combining optical and thermal remote sensing data. Plain Language Summary: Alpine snow represents a fundamental reservoir of fresh water at midlatitude. Remote sensing offers the opportunity to estimate snow properties in different spectral domains. In particular, the knowledge of the spatial and temporal variability of snow density could allow modeling of the snow water equivalent, which knowledge is crucial for managing water resources in the face of current climate change. In this study we show for the first time that snow thermal inertia can contribute to monitoring of snowmelt processes and snow density, opening new perspectives for remote sensing of the cryosphere. Key Points: Snow thermal inertia resembles the different phases of snowmelt processesAn empirical model is proposed for estimating snow density from apparent thermal inertiaThis study may open new perspectives in remote sensing of snowmelt processes [ABSTRACT FROM AUTHOR]

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES. [ABSTRACT FROM AUTHOR]

The natural flow regime of many rivers in the USA has been impacted by anthropogenic structures. This loss of connectivity plays a role in shaping river ecosystems by altering physical habitat characteristics and shaping fish assemblages. Although the impacts of large dams on river systems are well documented, studies on the effects of low-head dams using a functional guild approach have been fewer. We assessed river habitat quality and fish community structure at 12 sites on two rivers; the study sites included two sites below each dam, two sites in the pool above each dam and two sites upstream of the pool extent. Fish communities were sampled from 2012 to 2015 using a multi-gear approach in spring and fall seasons. We aggregated fishes into habitat and reproductive guilds in order to ascertain dams' effects on groups of fishes that respond similarly to environmental variation. We found that habitat quality was significantly poorer in the artificial pools created above the dams than all other sampling sites. Fast riffle specialist taxa were most abundant in high-quality riffle habitats farthest from the dams, while fast generalists and pelagophils were largely restricted to areas below the downstream-most impoundment. Overall, these dams play a substantial role in shaping habitat, which impacts fish community composition on a functional level. Utilizing this functional approach enables us to mechanistically link the effects of impoundments to the structure of fish communities and form generalizations that can be applied to other systems. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Keywords: albumin; COVID-19; hypoalbuminemia; pulmonary leakage EN albumin COVID-19 hypoalbuminemia pulmonary leakage 390 391 2 02/22/22 20220301 NES 220301 Dear Editor, We thank Dr. Domenico Lapenna for his interesting comment [1], which gives us the opportunity to further underline the complexity of the topic of hypoalbuminemia in COVID-19, both from the pathophysiologic point of view and from the treatment perspective. According to these premises, COVID-19 patients have been excluded from an ongoing large prospective randomized controlled trial on HAS in critically ill patients in Italy (ALBIOSS-BALANCED, NCT03654001). Further evidence from large studies with well-defined inclusion criteria and endpoints is needed to assess the effects of HAS administration in severe COVID-19 patients. [Extracted from the article]

Variations in photosynthesis still cause substantial uncertainties in predicting photosynthetic CO2 uptake rates and monitoring plant stress. Changes in actual photosynthesis that are not related to greenness of vegetation are difficult to measure by reflectance based optical remote sensing techniques. Several activities are underway to evaluate the sun-induced fluorescence signal on the ground and on a coarse spatial scale using space-borne imaging spectrometers. Intermediate-scale observations using airborne-based imaging spectroscopy, which are critical to bridge the existing gap between small-scale field studies and global observations, are still insufficient. Here we present the first validated maps of sun-induced fluorescence in that critical, intermediate spatial resolution, employing the novel airborne imaging spectrometer HyPlant. HyPlant has an unprecedented spectral resolution, which allows for the first time quantifying sun-induced fluorescence fluxes in physical units according to the Fraunhofer Line Depth Principle that exploits solar and atmospheric absorption bands. Maps of sun-induced fluorescence show a large spatial variability between different vegetation types, which complement classical remote sensing approaches. Different crop types largely differ in emitting fluorescence that additionally changes within the seasonal cycle and thus may be related to the seasonal activation and deactivation of the photosynthetic machinery. We argue that sun-induced fluorescence emission is related to two processes: (i) the total absorbed radiation by photosynthetically active chlorophyll; and (ii) the functional status of actual photosynthesis and vegetation stress. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a disease that increases the pulmonary vascular resistance, causing hypertrophy and subsequent right heart failure. Oxidative stress is involved in the pathogenesis of PAH, and estrogen is considered an antioxidant. Thus, the aim of this study was to test the hypothesis that estrogen could attenuate PAH by modulating oxidative stress. Female Wistar rats were ovariectomized or suffered the surgery simulation (sham). After 7 days, subcutaneous pellets with 17 β-estradiol or sunflower oil were implanted. At this time, PAH was induced by means of a single dose of monocrotaline (MCT) (60 mg·kg-1 i.p.). The experimental groups were as follows: (1) sham, (2) sham + MCT, (3) ovariectomy (O), (4) ovariectomy + MCT (OM), (5) ovariectomy + estrogen replacement + MCT (ORM). Hemodynamic measurements were performed 21 days after MCT or saline. Nonovariectomized animals were assessed in the stage of diestrus. Afterwards, the rats were killed to collect the heart, the lung and the liver to evaluate morphometry. Samples of the right ventricle were used to analyse the reduced glutathione : oxidized glutathione ratio. Lung congestion in the OM group, which was decreased in the ORM group, was observed. Right ventricle end-diastolic pressure was increased in the OM and the ORM groups. The glutathione ratio decreased in the groups O, OM and ORM. The data suggest that estrogen can exert great influence on the cellular redox balance. The maintenance of physiological estrogen levels may help to avoid the appearance of pulmonary oedema, characteristic of this model of PAH, and right ventricular failure. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This research aims at developing a remote sensing technique for monitoring the interannual variability of the European larch phenological cycle in the Alpine region of Aosta Valley (Northern Italy) and to evaluate its relationships with climatic factors. Phenological field observations were conducted in eight test sites from 2005 to 2007 to determine the dates of completion of different phenological phases. MODerate Resolution Imaging Spectrometer (MODIS) 250 m 16-days normalized difference vegetation index (NDVI) time series were fitted with double logistic curves and the dates corresponding to different features of the curves were determined. Comparison with field data showed that the features of the fitted NDVI curve that allowed the best estimate of the start and end of the growing season were the zeroes of its third derivative (MAE of 6 and 4 days, respectively). The start and end of season were also estimated with the spring warming (SW) and growing season index (GSI) phenological models. MODIS start and end of season dates generally agreed with those obtained by the SW and GSI climate-driven phenological models. However, phenological models provided erroneous results when applied in years with anomalous meteorological conditions. The relationships between interannual variability of the larch phenological cycle and climate were investigated by comparing the mean start and end of season yearly anomalies with air temperature anomalies. A strong linear relationship ( R2=0.91) was found between mean spring temperatures and mean start of season dates, with an increase of 1 °C in mean spring temperature leading to a 7-day anticipation of mean larch bud-burst date. Leaf coloring dates were found to be best related with mean September temperature ( R2=0.77), but with higher spring temperatures appearing to lead to earlier leaf coloring. [ABSTRACT FROM AUTHOR]

Background: Many studies have been conducted to assess the effects of fentanyl on the autonomic nervous system (ANS) by heart rate variability (HRV) analysis, but disagreement on the results is still present due to confounding influences introduced by concomitant administration of other drugs or opioid-related transitory respiratory depression. We performed a single-drug controlled-breathing study on healthy volunteers to assess the impact of fentanyl on ANS. Methods: HRV as a measure of sympathovagal balance was prospectively analyzed with an autoregressive model in 11 subjects during spontaneous and paced breathing (PB) at 20 breaths/min both before and after fentanyl 1 mcg/kg administration. HRV total power, sympathovagal balance (low-frequency/high-frequency ratio) and normalized spectral powers were considered (LFnu, HFnu). Results: Fentanyl led to a reduction of LFnu (from 55.2±23.3 to 43.2±24.1, P<0.05) without HFnu increase during PB. A decrease in R– R interval variance (from 3345.6±3333.4 to 1806.9±1328.6 ms2, P<0.05) was shown after fentanyl administration during spontaneous but not PB. PB alone decreased the HRV total power and R– R interval variance. Conclusions: Low-dose fentanyl administration in healthy volunteers leads to sympathetic and overall ANS modulation decrease, with a trend toward vagal activation. [ABSTRACT FROM AUTHOR]

Background Scabies is a very common skin infection in convicts. The SIMSPE Society (Società Italiana di Medicina e Sanità Penitenziaria) has organized and conducted a multicentre, randomized, comparative, parallel group, investigator-blinded trial to evaluate the efficacy and tolerability of synergized pyrethrins foam (PF) in comparison with benzyl benzoate (BB) lotion. Methods A total of 240 convicted patients, enrolled in eight National Jail Institutions, with a clinical diagnosis of scabies, were treated with PF ( n = 120) for three consecutive days or BB ( n = 120) for five consecutive days. Primary study endpoints were the clinical cure rate and the local tolerability. Secondary endpoints were clinical evolution of scabietic lesions and itching intensity. Study outcomes were assessed using appropriate semiquantitative scores at baseline and after 2 and 4 weeks. A second treatment cycle was applied if after 2 weeks the patient was not judged clinically cured. Results At week 2, a total of 75% (95% CI: 66–82%) and 71% (95% CI: 62–78%) of patients showed a complete clinical cure rate in the PF and BB groups, respectively. At week 4, the percentage of totally cured patients increased up to 95% (95% CI: 89–97%) and 91% (95% CI: 83–94%) in the PF and BB groups, respectively ( P = NS between groups). At week 4, 5% in the PF group and 9% in the BB group complained of itching. Burning and irritation after treatment applications were more common in the BB group in comparison with the PF group. The tolerability score was better in the PF group in comparison with to BB group (2.9 vs. 2.2; P = 0.0001). A total of 95% of patients in the PV group had a good tolerability score (i.e. = 3) in comparison with 41% in the BB group. Conclusion Our results show that a 3-day treatment with pyrethrins thermofobic foam is at least as effective as a 5-day treatment with benzyl benzoate lotion in convicted subjects with scabies. The foam formulation is better tolerated than the benzyl benzoate lotion. [ABSTRACT FROM AUTHOR]

The effect of fusicoccin (FC) on the K+ -stimulated Na+ efflux in root cells of Na+ loaded barley roots was studied. FC (0.02mM) stimulated Na+ efflux in the presence of K+ and its effect was synergistic with that of K+, in a similar way as its effect on proton extrusion. Decreasing the pH of the elution medium promoted Na+ efflux and partially replaced the effect of FC. As FC is known to increase the electrochemical proton gradient at the plasmalemma level, these results are consistent with the hypothesis that Na+ is extruded in exchange for H+. A further support to this view came from the finding that Na+ efflux was also promoted by a lipophilic cation, tributylbenzylammonium (TBBA+), which stimulates H+ extrusion and is generally accepted not to enter the cells by means of the same carrier as K+. [ABSTRACT FROM AUTHOR]

Dissociation of active H+ extrusion (-ΔH+) from K+ uptake in pea and maize root segments was attempted by substituting K+ in the incubation medium with lipophilic cations assumed to enter the cell by passive, non-specific, permeation through the lipid component of the plasmalemma. Among the compounds tested, tributylbenzylammonium significantly stimulated -ΔH+ in the absence of other monovalent cations in the medium. This effect was much more evident when the experiment was carried out in the presence of fusicoccin, which strongly stimulates proton extrusion and monovalent cation uptake, and hyperpolarizes the transmembrane electric potential in these materials. Also the lipophilic cations tetraphenylphosphonium, dimethyldibenzylammonium and hexylguanidine markedly stimulated FC-promoted -ΔH+. Octylguanidine at a low concentration induced an early stimulation followed by a strong inhibition of -ΔH+. A complete lack of additivity was observed between the effects of lipophilic cations and that of K+ on H+ extrusion. Lipophilic cations severely inhibited K+ uptake. These data are interpreted as supporting the view of an electric, rather than a chemical, (namely, involving the same carrier system) nature of the coupling of active H+ extrusion with K+ influx. [ABSTRACT FROM AUTHOR]

To evaluate the effect of a hydrophilic and a lipophilic beta-blocker on the autonomic nervous system, 20 normal subjects were studied under baseline conditions and 7 days after being randomly assigned to metoprolol (200 mg/day), nadolol (80 mg/day), and placebo. Under each condition, the time-domain parameters were analyzed by means of 24-hour ECG monitoring and the frequency-domain parameters by means of the autoregressive method using 10-minute ECGs during rest, controlled respiration, and after a head-up tilt test. The alpha index (the gain in the relationship between the RR period and systolic arterial pressure variability) was also calculated. Both nadolol and metoprolol significantly increased all of the time-domain parameters except the standard deviation of the RH intervals; they also modified the frequency-domain parameters. Both blunted the significant reduction in the high frequency (HF) component and alpha index during tilt. In normal subjects, hydrophilic and lipophilic beta-blockers similarly modify the time- and frequency-domain parameters that are particularly evident when high sympathetic tone is present (during daytime and tilt). The value of the alpha index was increased by both beta-blockers in the HF, but not in the low frequency band; this difference might be due to the fact that the former is a measure of the vagal component of the baroreflex control and the latter a measure of the sympathetic component. The effects of hydrophilic and lipophilic beta-blockers on the time- and frequency-domain parameters of heart rate variability are similar. [ABSTRACT FROM AUTHOR]

Background: Rabbits are sensitive to dietary cholesterol and rapidly develop hypercholesterolemia, leading to prominent subfertility. Sterol regulatory element-binding protein isoform 2 drives the intracellular cholesterol pathway in many tissues, including the testicles. Its abnormal regulation could be the mainly responsible for the failure of suppressing cholesterol synthesis in a cholesterol-enriched environment, ultimately leading to testicular and seminal alterations. However, extra-virgin olive oil consumption has beneficial properties that promote lowering of cholesterol levels, including the recovery of seminal parameters altered under a high-fat diet., Objectives: Our goal was to investigate the effects of high-fat diet supplementation with extra-virgin olive oil at the molecular level on rabbit testes, by analyzing sterol regulatory element-binding protein isoform 2 protein and its corresponding downstream effectors., Materials and Methods: During 12 months, male rabbits were fed a control diet, high-fat diet, or 6-month high-fat diet followed by 6-month high-fat diet plus extra-virgin olive oil. Serum lipids, testosterone levels, bodyweight, and seminal parameters were tested. The mRNA and protein levels of sterol regulatory element-binding protein isoform 2, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and low-density lipoprotein receptor were determined by semi-quantitative polymerase chain reaction and Western blotting techniques. The expression pattern of sterol regulatory element-binding protein isoform 2 protein in the rabbit testicles was studied by indirect immunofluorescence. In addition, testicular cholesterol was detected and quantified by filipin staining and gas chromatography., Results: The data showed that the addition of extra-virgin olive oil to high-fat diet reduced testicular cholesterol levels and recovered the expression of sterol regulatory element-binding protein isoform 2, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and low-density lipoprotein receptor initially altered by the high-fat diet., Discussion and Conclusions: The combination of high-fat diet with extra-virgin olive oil encourages testicular recovery by modifying the expression of the enzymes related to intracellular cholesterol management., (© 2023 American Society of Andrology and European Academy of Andrology.)

Introduction: In this study, we sought to evaluate the prevalence and association of pre-transplant atrial fibrillation (AF) on 30-day postoperative outcomes in patients undergoing orthotopic liver transplant (OLT)., Method: The National Inpatient Sample Database was queried from 2011 to 2017 for relevant ICD-9 and ICD-10 procedural and diagnostic codes. Baseline characteristics and in-hospital outcomes were compared in patients who underwent OLT with AF and those without., Results: Among 45,357 patients who underwent OLT, women made up 35.8% of the overall population. The prevalence of AF before transplant was 2932 (6.5%) with a trend toward increasing prevalence, with an average annual change rate of 4.19%. Applying propensity score matching to control for potential confounding factors, there was no association between pre-transplant AF and in-hospital mortality in patients undergoing OLT, however there was a higher incidence of perioperative complications including: acute kidney injury, ventricular tachycardia, major bleeding, blood product transfusion, and septic shock., Conclusion: In patients undergoing OLT, pre-transplant AF is increasing in prevalence and appears to be associated with similar in-hospital mortality but worse perioperative outcomes. Greater emphasis should be placed on AF in the preoperative cardiovascular risk stratification of patients undergoing OLT., (© 2022 Wiley Periodicals LLC.)

Background: Chronic obstructive pulmonary disease (COPD) is a cause of ventricular dysfunction. However, in the setting of patients with heart failure undergoing left ventricular assist device (LVAD) implantation, there is a paucity of data on the association between COPD and in-hospital outcomes., Methods and Results: Retrospective cohort study based on the NIS including patients ≥18 years who underwent LVAD implantation from 2011 to 2017. Multivariate regression was used to evaluate the impact of COPD on in-hospital outcomes. A total of 25,503 patients underwent LVAD implantation, of which 13.8% also had COPD. COPD group was older (median 62 vs. 58 years), and more males (82% vs. 76.4%, p < .001 for both). COPD group had more hypertension, diabetes, atrial tachyarrhythmias, dyslipidemia, prior stroke, coronary artery diseases, pulmonary hypertension, and chronic kidney disease (p < .001 for all). No differences in strokes, infections, mechanical circulatory support, and LVAD thrombosis. There was a higher incident of inpatient acute kidney injury, major bleeding, cardiac complications, thromboembolism, and cardiac arrest in patients without COPD (p < .05 for all). Compared with no-COPD group, COPD group had a lower mortality (6.2% vs. 12.4%; odds ratio, 0.59; confidence interval, 0.512-0.685; p < .05)., Conclusion: Patients with COPD undergoing LVAD implantation have more comorbidities, without an associated increase mortality., (© 2020 Wiley Periodicals LLC.)

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDE R ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management., (© 2019 Wiley Periodicals, Inc.)

Aims: We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level., Methods: We determined the inhibitory potency of 2a-c on Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts)., Results: Our prototypical pluripotent analogue 2a interferes with Aβ oligomerization process thus reducing Aβ oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a., Conclusion: Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues., (© 2014 John Wiley & Sons Ltd.)

Carbonylation of proteins is an irreversible oxidative damage, often leading to a loss of protein function, which is considered a widespread indicator of severe oxidative damage and disease-derived protein dysfunction. Whereas moderately carbonylated proteins are degraded by the proteasomal system, heavily carbonylated proteins tend to form high-molecular-weight aggregates that are resistant to degradation and accumulate as damaged or unfolded proteins. Such aggregates of carbonylated proteins can inhibit proteasome activity. Alarge number of neurodegenerative diseases are directly associated with the accumulation of proteolysis-resistant aggregates of carbonylated proteins in tissues. Identification of specific carbonylated protein(s) functionally impaired and development of selective carbonyl blockers should lead to the definitive assessment of the causative, correlative or consequential role of protein carbonylation in disease onset and/or progression, possibly providing new therapeutic approaches.

Background: ¹³C breath test analysis requires accurate ¹³CO₂measurements., Aim: To perform a multicentre study to evaluate the repeatability and reproducibility of breath ¹³CO₂analysis., Methods: Two series of 25 paired randomly coded tubes (each consisting of 23 ¹³CO₂-enriched breath samples and two samples of standard reference pure CO₂with certified δ ¹³C(PDB)) were sent to participating centres for ¹³CO₂measurement. Each series of tubes was analysed 10 days apart. The repeatability and reproducibility of ¹³C measurements was assessed by Mandel's k and h statistics., Results: Twenty-two centres participated in the study: 18 showed good inter- and intra-laboratory variability, whilst four showed abnormally high inter- or intra-laboratory variability. Breath test results were also significantly affected by the accuracy of the ¹³C analytical procedures., Conclusions: A low accuracy of ¹³C measurements may significantly affect the results of breath tests, leading to inappropriate clinical decisions. Standardization of ¹³C analysis is required to guarantee optimal ¹³C measurements and accurate ¹³C breath test results.

Aims: To assess the effect of local hyperthermia on the systemic absorption of mitomycin C (MMC) during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma of the bladder, and to establish the likely safety of this procedure., Methods: Group 1 (n = 12) received 20 mg intravesical MMC plus local hyperthermia, group 2 (n = 13) 20 mg MMC alone, group 3 (n = 16) 40 mg MMC plus local hyperthermia and group 4 (n = 10) 40 mg MMC alone. Patients in groups 1, 2, and 4 underwent post-tumour resection adjuvant treatment, whereas those in group 3 still had tumour present and were treated to eradicate it. Intravesical instillation lasted 60 min, with the solution (50 ml) being replaced after the first 30 min. Blood samples were taken before, and every 15 min during instillation. MMC concentrations in plasma and in urine were determined by h.p.l.c., Results: The highest MMC plasma concentration (67.9 ng ml(-1)) occurred in a patient in group 3. This value was well below the threshold concentration (400 ng ml-1) for myelosuppression. Local hyperthermia associated with the intravesical chemotherapy enhanced plasma MMC concentrations at 30, 45 and 60 min compared with chemotherapy alone (Group 1 vs 2, P < or = 0.008). Systemic exposure to MMC was not significantly increased by doubling the intravesical dose when intravesical chemotherapy alone was administered. Patients in group 3 displayed the highest degree of MMC absorption and the greatest variability in pharmacokinetics between patients., Conclusions: Local hyperthermia enhances the systemic absorption of MMC during intravesical chemotherapy for bladder cancer. In the doses used, plasma MMC concentrations were always more than six times lower than those shown to cause toxicity.

In this study, 6 chronic anuric uremic patients underwent lactate hemofiltration (HF) with a substitution fluid, prepared in bags, for 3 months and bicarbonate HF, with continuous on-line preparation of the substitution fluid, for 3 months. We determined Na+, Cl-, K+, total calcium (Ca), ionized calcium (Ca2+), phosphate, intact parathormone (I-PTH), pH, PCO2, PO2, and HCO3- in plasma before, during, and after the treatment, as well as Ca, Ca2+, phosphate, and I-PTH in the ultrafiltrate. Moreover, heart rate (HR) and mean arterial pressure (MAP) were continually recorded during the procedure. Furthermore, the patients underwent echocardiographic study before and after the session. In comparison with lactate, bicarbonate HF caused a significant increase in HCO3- and a decrease in K+ plasma concentrations. This was detectable, with lower significance, even 44 h after the end of the treatment. At the end of the long interdialytic period (68 h after the end of the treatment), no significant difference was detectable. pH and PCO2 showed a significant but transient increase during HF. The other parameters investigated did not differ significantly between the two methods.

With the aim of treating with short sessions even chronic uremic patients with cardiovascular instability, we have developed our previous findings about paired filtration dialysis (hemofiltration-hemodialysis in series) by a method we call high-efficiency paired filtration dialysis (HEPFD). We have treated with this method for 6 months 6 chronic anuric uremic patients previously treated for 6 months with hemofiltration (HF) because of their cardiovascular instability. By comparison with HF, HEPFD shows much higher clearances of small molecules with consequent significant decrease of their predialytic values, improvement of Kt/V value, lower beta 2-microglobulin clearance (its predialytic value remains unchanged), and the same tolerability. HEPFD allows short, efficient, and well-tolerated treatments even in patients with cardiovascular instability.

Levels of plasma lipids and the fatty acid composition of major plasma lipid classes have been determined in chronically uremic patients before and after treatments with hemofiltration, high efficiency paired filtration dialysis, or acetate-free biofiltration. The major findings are a decrease of triglycerides and an increase of total free fatty acids (FFAs) at the end of the dialytic session--already reported in the literature--that do not appear to be strictly dependent on heparin administration. The changes in the plasma concentrations of selected saturated and polyunsaturated fatty acids, which may contribute to alteration of functional parameters in the cardiovascular system in dialyzed patients, are different in the various types of techniques.