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La coesistenza tra actio depositi in factum e actio depositi in ius: un problema da ridimensionare?
No full textMechanistic investigation on compounds from Amorpha fruticosa L. targeting acetylcholinesterase
No full textAcetylcholinesterase (AChE) is the enzyme targeted by drugs used for the symptomatic treatment of cognitive decline associated with Alzheimer’s disease. While in vitro data suggest the AChE inhibitory potential of A. fruticosa extracts and components such as rotenoids, in-depth mechanistic investigations are missing. A wide array of computational techniques, including ligand-based approaches, molecular docking, molecular dynamics, and machine learning-assisted toxicity prediction were enrolled in the current study, highlighting the rotenoid 6α,12α-dehydrodeguelin as a promising lead for the development of AChE inhibitors
Increased Cerebrospinal Fluid Angiotensin-Converting Enzyme 2 Fragments as a Read-Out of Brain Infection in Patients with COVID-19 Encephalopathy
No full textBackground This study assesses the cerebrospinal fluid (CSF) levels of the viral receptor angiotensin-converting enzyme 2 (ACE2) and of the serine protease TMPRSS2 fragments in patients with SARS-CoV-2 infection presenting encephalitis (CoV-Enceph). Methods The study included biobanked CSF from 18 CoV-Enceph, 4 subjects with COVID-19 without encephalitis (CoV), 21 with non-COVID-19-related encephalitis (Enceph), and 21 neurologically healthy controls. Participants underwent a standardized assessment for encephalitis. A large subset of samples underwent analysis for an extended panel of CSF neuronal, glial, and inflammatory biomarkers. ACE2 and TMPRSS2 species were determined in the CSF by western blotting. Results ACE2 was present in CSF as several species, full-length forms and 2 cleaved fragments of 80 and 85kDa. CoV-Enceph patients displayed increased CSF levels of full-length species, as well as the 80kDa fragment, but not the alternative 85kDa fragment, compared with controls and Enceph patients, characterized by increases of both fragments. Furthermore, TMPRSS2 was increased in the CSF of Enceph patients compared with controls, but not in CoV-Enceph patients. The CoV patients without encephalitis displayed unaltered CSF levels of ACE2 and TMPRSS2 species. Conclusions Patients with encephalitis displayed an overall increase in CSF ACE2, probably as a consequence of brain inflammation. The increase of the shortest ACE2 fragment only in CoV-Enceph patients may reflect the enhanced cleavage of the receptor triggered by SARS-CoV-2, thus serving to monitor brain penetrance of the virus associated with the rare encephalitis complication. TMPRSS2 changes in the CSF appeared related to inflammation, but not with SARS-CoV-2 infection
Measurement of the inclusive isolated-photon production cross section in pp collisions at TeV
No full textThe production cross section of inclusive isolated photons has been measured by the ALICE experiment at the CERN LHC in pp collisions at centre-of-momentum energy of s=13 TeV collected during the LHC Run 2 data-taking period. The measurement is performed by combining the measurements of the electromagnetic calorimeter EMCal and the central tracking detectors ITS and TPC, covering a pseudorapidity range of |ηγ|<0.67 and a transverse momentum range of 7<200GeV/c. The result extends to lower pTγ and xTγ=2pTγ/s ranges, the lowest xTγ of any isolated photon measurements to date, extending significantly those measured by the ATLAS and CMS experiments towards lower pTγ at the same collision energy with a small overlap between the measurements. The measurement is compared with next-to-leading order perturbative QCD calculations and the results from the ATLAS and CMS experiments as well as with measurements at other collision energies. The measurement and theory prediction are in agreement with each other within the experimental and theoretical uncertainties
Pathophysiology and clinical use of agents with vasodilator properties in acute heart failure. A scientific statement of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)
No full textAcute heart failure (AHF) affects millions of people each year and vasodilators have been a central part of treatment for over 25 years. The haemodynamic effects of vasodilators vary considerably among individual agents. Some vasodilators, such as nitrates, primarily act on the venous system by redistributing the circulating blood volume away from the heart towards the venous capacitance system. Other vasodilators, such as nesiritide, lead to balanced vasodilatation in the arteries and veins, decreasing left ventricular afterload and preload. Considering mechanisms of action, intravenous vasodilators are thought to be effective in patients with AHF, particularly in those with acute pulmonary oedema, where increased cardiac filling pressures and elevated systemic blood pressures occur in the absence of, or with minimal systemic fluid accumulation. However, the 2021 European heart failure guidelines have downgraded the use of vasodilators due to two recent studies and several contemporary meta-analyses failing to show benefit in terms of survival. Thus, there remains no firm recommendation suggesting the use of vasodilator treatment over usual care. In addition, despite repeated efforts to develop new vasodilatory agents, no novel therapy has outperformed traditional AHF management. In parallel with the development of novel vasodilators, changing the design of clinical trials for AHF to consider phenotype diversity of AHF patients remains an unmet need. New randomized clinical trials should particularly focus on subgroups that may mechanistically derive benefit from vasodilators, which may entail moving enrolment of patients to clinical settings close to moment of decompensation, such as the emergency department
Management of Pompe disease alongside and beyond ERT: a narrative review
No full textBackground: Pompe disease is a lysosomal storage disorder that primarily affects muscles, and its natural history has been transformed over the past 20 years by therapies designed to restore the deficient enzyme function, from the first enzyme replacement therapies (ERTs) to the gene therapy currently in development. However, despite these ground-breaking innovations, the importance of a multi-system and rehabilitative approach remains critical, as it addresses the complex systems involved in the disease and optimizes the success of pharmacological treatments. Methods: We conducted a narrative review of the current pharmacological treatments approved for Pompe disease, as well as those undergoing clinical trials. We also reviewed international recommendations for managing respiratory, musculoskeletal, and cardiac function specially focusing on the late-onset form. Results: There are no universally agreed guidelines for the multidisciplinary management and many recommendations are based on expert consensus and small interventional studies. Nevertheless, combined approaches involving ERT therapy along with specific rehabilitation and nutritional programs appear to yield beneficial effects. Conclusions: Pompe disease, one of the first neuromuscular diseases to benefit from the approval of disease-modifying therapies, is a paradigm for the importance of an integrated therapeutic-rehabilitative approach
Experimental investigation on the effect of bainite traces on wear and rolling contact fatigue in ER8 railway wheel steel.
Full text linkThe effect on wear and rolling contact fatigue of dispersed bainitic island, as a remnant of the production process of railway wheels, is still an open issue. To address this topic, an experimental campaign was carried out on an ER8 steel by means of a smallscale bi-disc machine. The specimens were extracted at different depths under the tread of a railway wheel, characterized by decreasing hardness and a bainite content. The tests were done in dry rolling-sliding condition, in some cases followed by a wet contact session. Various measurement techniques, including an innovative vision system, were employed to evaluate wear, rolling contact fatigue and surface degradation. The results showed that, in dry condition, the prevailing damage was delamination wear, whereas, in the wet phase, shelling prevailed. None of the obtained datahighlighted a detrimental effect of the bainitic content, in the concentrations considered in this study. This means that a small amount of dispersed bainite can be tolerated, reducing energy consumption, material waste and cost in the production process
Uterine Carcinosarcoma—A Retrospective Cohort Analysis from a Tertiary Centre on Epidemiology, Management Approach, Outcomes and Survival Patterns
Full text linkBackground/Objectives: Uterine carcinosarcoma (UCS) refers to a rare high-grade aggressive epithelial non-endometrioid endometrial carcinoma, with tumour cells demonstrating epithelial–mesenchymal metaplastic transition and composed of both carcinomatous epithelial and sarcomatous (homologous or heterologous) components. Methods: The aim of this study was to evaluate the epidemiology, management approach, outcomes and survival patterns of patients with UCS. Seventy-seven cases of UCS treated with primary surgery in a single tertiary centre underwent retrospective cohort analysis across a ten-year period. Observational data on clinicopathological variables and treatment pathways were reviewed and independent risk factors for relapse and mortality were analysed. Results: The 5-year disease-free and overall survival rates were 52.10% and 46.6%, respectively. Cervical stromal involvement was independently related to disease-free survival (HR = 6.26; 95%CI 1.82–21.59; p = 0.004) and overall survival (HR = 3.64; 95%CI 1.42–9.38; p = 0.007), whilst sarcomatous component type was independently related to recurrence only (HR = 3.62; 95%CI 1.38–9.51; p = 0.009) after adjusting for other pathological and treatment variables. No significant difference in recurrence or mortality was found when comparing the performance of pelvic lymph node dissection (p = 0.803 and p = 0.192 respectively) or the administration of adjuvant treatment (p = 0.546 and p = 0.627 respectively). Conclusions: Whilst our data suggests an encouraging similarity in overall survival rates compared with the literature, UCS continues to represent significant treatment challenges—with a paucity of guidelines available. Data regarding molecular analysis was not systemically available in our cohort, the more recent introduction of which (alongside the revision of endometrial cancer staging) will undoubtedly provide UCS patients with improved therapeutic options in the future
Multiplicity dependence of Υ production at forward rapidity in pp collisions at s=13 TeV
Full text linkThe measurement of Υ(1S), Υ(2S), and Υ(3S) yields as a function of the charged-particle multiplicity density, dNch/dη, using the ALICE experiment at the LHC, is reported in pp collisions at s= 13 TeV. The Υ meson yields are measured at forward rapidity (2.5<4) in the dimuon decay channel, whereas the charged-particle multiplicity is defined at central rapidity (|η|<1). Both quantities are divided by their average value in minimum bias events to compute the self-normalized quantities. The increase of the self-normalized Υ(1S), Υ(2S), and Υ(3S) yields is found to be compatible with a linear scaling with the self-normalized dNch/dη, within the uncertainties. The self-normalized yield ratios of excited-to-ground Υ states are compatible with unity within uncertainties. Similarly, the measured double ratio of the self-normalized Υ(1S) to the self-normalized J/ψ yields, both measured at forward rapidity, is compatible with unity for self-normalized charged-particle multiplicities beyond one. The measurements are compared with theoretical predictions incorporating initial or final state effects