5-(carbamoylmethylene)-oxazolidin-2-ones as a promising class of heterocycles inducing apoptosis triggered by increased ROS levels and mitochondrial dysfunction in breast and cervical cancer

Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 and HeLa cells. The tested compounds displayed a wide range of cytotoxicity on these cancer cell lines, measured by MTT assay, exhibiting no cytotoxicity on non-tumorigenic MCF-10A cells. Among the nine tested derivatives, four displayed a good anticancer potential. Remarkably, OI compound showed IC50 values of 17.66 and 31.10 µM for MCF-7 and HeLa cancer cells, respectively. Furthermore, we assessed OI effect on the cell cycle by FACS analysis, highlighting a G1 phase arrest after 72 h, supported by a low expression level of Cyclin D1 protein. Moreover, mitochondrial membrane potential was reduced after OI treatment driven by high levels of ROS. These findings demonstrate that OI treatment can inhibit MCF-7 and HeLa cell proliferation and induce apoptosis by caspase-9 activation and cytochrome c release in the cytosol. Hence, 5-(carbamoylmethylene)-oxazolidin-2-ones have a promising anticancer activity, in particular, OI derivative could represent a good candidate for in vivo further studies and potential clinical use

Association between serum Mg2+ concentrations and cardiovascular organ damage in a cohort of adult subjects

Magnesium (Mg2+) levels are associated with insulin resistance, hypertension, atherosclerosis, and type 2 diabetes (T2DM). We evaluated the clinical utility of physiological Mg2+ in assessing subclinical cardiovascular organ damage including increased carotid artery intima-media thickness (c-IMT) and left ventricular mass index (LVMI) in a cohort of well-characterized adult non-diabetic individuals. Age-and gender-adjusted correlations between Mg2+ and metabolic parameters showed that Mg2+ circulating levels were correlated negatively with body mass index (BMI), fasting glucose, and 2h-oral glucose tolerance test (OGTT) glucose. Similarly, Mg2+ levels were significantly and negatively related to c-IMT and LVMI. A multivariate regression analysis revealed that age (β = 0.440; p < 0.0001), BMI (β = 0.225; p < 0.0001), and Mg2+ concentration (β = −0.122; p < 0.01) were independently associated with c-IMT. Age (β = 0.244; p = 0.012), Mg2+ (β = −0.177; p = 0.019), and diastolic blood pressure (β = 0.184; p = 0.038) were significantly associated with LVMI in women, while age (β = 0.211; p = 0.019), Mg2+ (β = −0.171; p = 0.038) and the homeostasis model assessment index of insulin resistance (HOMA-IR) (β = −0.211; p = 0.041) were the sole variables associated with LVMI in men. In conclusion, our data support the hypothesis that the assessment of Mg2+ as part of the initial work-up might help unravel the presence of subclinical organ damage in subjects at increased risk of cardiovascular complications

Expanding Glucocerebrosidase Involvement in Neurodegeneration: D419H Mutation Causing Dementia with Lewy Bodies

Mutations in the glucocerebrosidase gene (GBA) are a common genetic risk factor for Dementia with Lewy Bodies (DLB). Hereby, we describe an Italian family with three DLB relatives harboring the D419H GBA variant. The pedigree analysis indicates a dominant inheritance pattern, suggesting that heterozygous GBA mutations may differently affect the risk of Parkinson-dementia syndromes. This should be taken into account for genetic counseling in relatives of patients with GBA associated Parkinson’s Disease/DLB

Behavior of four main dairy pathogenic bacteria during manufacturing and ripening of pecorino siciliano cheese

Background: Consumption of raw cheese may be associated with different diseases. This study aimed to evaluate behavior of four pathogenic bacteria during manufacture and ripening of Protected Designation of Origin (PDO) Pecorino Siciliano cheese. Methods: The experimental cheese groups were inoculated with pathogenic bacteria, including Escherichia coli O157, Listeria monocytogenes, Salmonella Enteritidis, and Staphylococcus aureus. The cheese making processes were monitored from milk curdling until 3 months ripened cheeses and the levels of Lactic Acid Bacteria (LAB) and the four dairy pathogens were evaluated by plate counts. Randomly Amplified Polymorphic DNA (RAPD)-Polymerase Chain Reaction (PCR) analysis was applied to confirm that the colonies isolated during the several steps of production were the same strains added in milk. Statistical analysis was done using XLStat software. Results: The levels of mesophilic and thermophilic coccus and rod LAB in curd were comparable in both trials and reached values between 8-9 log10 Colony Forming Unit (CFU)/g in cheeses at 90 days of ripening. The four pathogenic bacteria were found in experimental curd at levels higher than those inoculated in milk and completely disappeared after 60 days of ripening. The RAPD analysis clearly demonstrated the presence of the added strain during production and confirmed the results of plate counts. Conclusion: This work showed that the production conditions of PDO Pecorino Siciliano cheese decreased growth of E. coli O157, L. monocytogenes, S. Enteritidis, and S. aureus

Pd-Catalysed oxidative carbonylation of α-amino amides to hydantoins under mild conditions

The first example of palladium-catalysed oxidative carbonylation of unprotected α-amino amides to hydantoins is described here. The selective synthesis of the target compounds was achieved under mild conditions (1 atm of CO), without ligands and bases. The catalytic system overrode the common reaction pathway that usually leads instead to the formation of symmetrical ureas

POS1240 HYDROXYCHLOROQUINE CARDIOTOXICITY: A CASE-CONTROL STUDY COMPARING PATIENTS WITH COVID19 AND PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Antimalarials have been associated with QT prolongation in COVID19 patients but are generally safe in patients with rheumatologic disease.Objectives:Aim of the study was to compare the prevalence of QTc prolongation between COVID19 and Systemic Lupus Erythematosus (SLE) patients treated with hydroxychloroquine (HCQ).Methods:We included consecutive patients with SARS-CoV-2 infection confirmed by nasopharyngeal swab and patients taking HCQ for SLE. A prolonged QTc was defined as an increase in QTc intervals >60 ms (compared with baseline) or as a QTc of ≥500 ms.Results:We enrolled 58 COVID19 patients (median age 70.5 years, IQR 25). HCQ, without or with azithromycin, was given to 26 (44.8%) and 15 patients (25.9%), respectively; 17 (29.3%) had not received either drug. The median baseline QTc was 432 (IQR 36) and prolonged QTc was observed in 15 (26%) patients (12 QTc≥500 ms and 3 patients ΔQTc>60 ms). We didn't find significant differences in QTc prolongation among the three treatment groups. Baseline QTc (OR 111.5) and D-dimer (OR 78.3) were independently associated to QTc prolongation.Compared to the 50 SLE patients (median age of 38.5 years, IQR 22), chronically treated with HCQ, patients with COVID19 showed significantly longer QTc (p < 0.001) (Table 1).Conclusion:This is the first study demonstrating that, differently from COVID19 patients, patients with SLE are not susceptible to HCQ-induced long QT syndrome and arrhythmia. The combined arrhythmogenic effect of SARS-CoV-2 infection and HCQ could account for the excess of QTc prolongation and fatal arrhythmias described in patients with COVID19.Table 1.Difference in clinical and demographic features between Systemic Lupus Erythematosus and COVID19 patients.Demographic FeaturesSLE patientsCovid-19 patientsp-ValueN°5058Female4323< 0.001Age (years)45 (17)70.5 (25)< 0.001Comorbidities N %Hypertension15 (30)24 (48)0.2Cardiovascular diseses8 (16)13 (22.4)0.4COPD1 (2)9 (15.5)0.016Thyroid disease8 (16)8 (13.8)0.75Chronic kidney disease4 (8)5 (8.6)0.91Population characteristics Median (IQR)HCQ (mg/die)400 (125)400< 0.001HCQ Time (days)3255 (5790)7< 0.001QTc (ms)SLEDAI-2KSDI432 (36.25)0 (4)0395 (80)--< 0.001--Disclosure of Interests:None declare

Tocilizumab or glucocorticoids treatment for patients with SARS-CoV-2 pneumonia: An observational study

Objective: To estimate the effect of tocilizumab or glucocorticoids in preventing death and intubation in patients hospitalized with SARS-CoV-2 pneumonia.Methods: This was a retrospective cohort study enrolling all consecutive patients hospitalized at Reggio Emilia AUSL between February the 11th and April 14th 2020 for severe COVID19 and treated with tocilizumab or glucocorticoids (at least 80 mg/day of methylprednisolone or equivalent for at least 3 days).The primary outcome was death within 30 days from the start of the considered therapies. The secondary outcome was a composite outcome of death and/or intubation. All patients have been followed-up until May 19th 2020, with a follow-up of at least 30 days for every patient. To reduce confounding due to potential non-comparability of the two groups, those receiving tocilizumab and those receiving glucocorticoids, a propensity score was calculated as the inverse probability weighting of receiving treatment conditional on the baseline covariates.Results and conclusion: Therapy with tocilizumab alone was associated with a reduction of deaths (OR 0.49, 95% CI 0.21-1.17) and of the composite outcome death/intubation (OR 0.35, 95% CI 0.13-0.90) compared to glucocorticoids alone. Nevertheless, this result should be cautiously interpreted due to a potential prescription bias.(c) 2021 Sociedade Brasileira de Infectologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Consensus-based statements for the management of mitochondrial stroke-like episodes [version 1; peer review: 2 approved]

BACKGROUND: Focal-onset seizures and encephalopathy are prominent features of a stroke-like episode, which is a severe neurological manifestation associated with subtypes of mitochondrial disease. Despite more than 30 years of research, the acute treatment of stroke-like episodes remains controversial. METHODS: We used the modified Delphi process to harness the clinical expertise of a group of mitochondrial disease specialists from five European countries to produce consensus guidance for the acute management of stroke-like episodes and commonly associated complications. RESULTS: Consensus on a new definition of mitochondrial stroke-like episodes was achieved and enabled the group to develop diagnostic criteria based on clinical features, neuroimaging and/or electroencephalogram findings. Guidelines for the management of strokelike episodes were agreed with aggressive seizure management strongly recommended at the outset of stroke-like episodes. CONCLUSIONS: Our consensus statement defines stroke-like episodes in terms of an epileptic encephalopathy and we have used this to revise both diagnostic criteria and guidelines for management. A prospective, multi-centre, randomised controlled trial is required for evaluating the efficacy of any compound on modifying the trajectory of stroke-like episodes

Analysis of transient seepage through a river embankment by means of centrifuge modelling

Earthen river embankments are typically in unsaturated conditions during their lifetime and the degree of saturation within their bodies may vary significantly throughout the year, due to seasonalfluctuations of the river stage, as well as infiltrations of meteoric precipitation and evapotranspiration phenomena. Given the significant effects of partial saturation on the hydro-mechanical behaviour of soils, realistic assumptions on the actual water content distribution inside the embankments are essential forproperly modelling their response to hydraulic loadings. In this framework, centrifuge modelling is a useful tool to get insights into the evolution of saturation conditions of a water retaining structure during flood events. It allows for the direct observation of the groundwater flow process, which is hardly detectable at the prototype scale, enabling, at the same time, the validation and calibration of predictive numerical tools.In this paper, the results of a centrifuge test carried out on small-scale physical model of a compacted silty clayey sand embankment subjected to a simulated high-water event, at the enhanced gravity of 50-g, are presented and discussed. The physical model was carefully instrumented with potentiometers, miniaturized pore pressure transducers and tensiometers. Pore pressures and suctions measured during the experiment showed that the stationary flow conditions were reached only after an unrealistic hydrometric peak persistence. It therefore emerges that, for the design and/or the assessment of the safety conditions of a river embankment similar to the one tested, the simplified hypothesis of a steady-state seepage, in equilibrium with the maximum river stage expected could result, in many cases, an excessively conservative assumption

Independent validation of sepsis index for sepsis screening in the emergency department

(1) Background: The early detection of sepsis is still challenging, and there is an urgent need for biomarkers that could identify patients at a high risk of developing it. We recently developed an index, namely the Sepsis Index (SI), based on the combination of two CBC parameters: monocyte distribution width (MDW) and mean monocyte volume (MMV). In this study, we sought to independently validate the performance of SI as a tool for the early detection of patients at a high risk of sepsis in the Emergency Department (ED). (2) Methods: We enrolled all consecutive patients attending the ED with a request of the CBC. MDW and MMV were measured on samples collected in K3-EDTA tubes on the UniCel DxH 900 haematology analyser. SI was calculated based on the MDW and MMV. (3) Results: We enrolled a total of 703 patients stratified into four subgroups according to the Sepsis-2 criteria: control (498), infection (105), SIRS (52) and sepsis (48). The sepsis subgroup displayed the highest MDW (median 27.5, IQR 24.6–32.9) and SI (median 1.15, IQR 1.05–1.29) values. The ROC curve analysis for the prediction of sepsis showed a good and comparable diagnostic accuracy of the MDW and SI. However, the SI displayed an increased specificity, positive predictive value and positive likelihood ratio in comparison to MDW alone. (4) Conclusions: SI improves the diagnostic accuracy of MDW for sepsis screening