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In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.

Background: Recent literature suggests viscoelastic test (VET)-guided transfusion management could be associated with reduced blood product administration in patients undergoing liver transplantation. Objectives: To assess the effectiveness of coagulation management guided by VETs compared with conventional coagulation tests (CCTs) in reducing blood product transfusion in patients undergoing liver transplantation. Design: Systematic review and meta-analysis of randomised (RCTs) and nonrandomised clinical trials performed according to PRISMA guidelines. The protocol was previously published (PROSPERO: CRD42021230213). Data sources: The Cochrane Central Library, PubMed/MEDLINE, Embase and the Transfusion Evidence Library were searched up to 30 th January 2022. Eligibility criteria: Setting: operating room. Patients: liver transplantation recipients. Intervention: use of VETs versus CCTs. Main outcome measures: the primary outcome was the mean number of transfused units for each blood product including red blood cells (RBCs), fresh frozen plasma (FFP), platelets (PLTs) and cryoprecipitate. Secondary outcomes included mortality rate, intensive care unit (ICU) and hospital length of stay (LOS). Results: Seventeen studies ( n = 5345 patients), 15 observational and two RCTs, were included in this review. There was a mean difference reduction in RBCs [mean difference: -1.40, 95% confidence interval (95% CI), -1.87 to -0.92; P < 0.001, I2 = 61%) and FFP units (mean difference: -2.98, 95% CI, -4.61 to -1.35; P = < 0.001; I2 = 98%) transfused in the VETs group compared with the CCTs one. A greater amount of cryoprecipitate was administered in the VETs group (mean difference: 2.71, 95% CI, 0.84 to 4.58; P = 0.005; I2 = 91%). There was no significant difference in the mean number of PLT units, mortality, hospital and ICU-LOS. Conclusion: Our meta-analysis demonstrated that VETs implementation was associated with reduced RBC and FFP consumption in liver transplantation pati

The administration of analgesic drugs in elderly patients should take into account age-related physiological changes, loss of efficiency of homeostatic mechanisms, and pharmacological interactions with chronic therapies. Underestimation of pain in patients with impaired cognition is often linked to difficulties in pain assessment. In the preoperative phase, it is essential to assess the physical status, cognitive reserve, and previous chronic pain conditions to plan effective analgesia. Furthermore, an accurate pharmacological history of the patient must be collected to establish any possible interaction with the whole perioperative analgesic plan. The use of analgesic drugs with different mechanisms of action for pain relief in the intraoperative phase is a crucial step to achieve adequate postoperative pain control in older adults. The combined multimodal and opioid-sparing strategy is strongly recommended to reduce side effects. The use of various adjuvants is also preferable. Moreover, the implementation of non-pharmacological approaches may lead to faster recovery. High-quality postoperative analgesia in older patients can be achieved only with a collaborative interdisciplinary team. The aim of this review is to highlight the perioperative pain management strategies in the elderly with a special focus on intraoperative pharmacological interventions.

Luigi Ferrajoli, in his work La logica del diritto. Dieci aporie nell’opera di Hans Kelsen (2016), pointed out ten aporias in Hans Kelsen’s pure theory of law. This paper deals with the fifth aporia, that is the of Kelsen’s concept of a “norm”. The paper firstly distinguishes two different questions on the concept of a norm underlying the pure theory of law: the question “What is a norm?”, and the question “What has the meaning of a norm within a legal system?”; it secondly distinguishes three different levels of interpretation of a norm: (i) interpretation of the semantic meaning of norm sentences, (ii) interpretation of the subjective intrinsic pragmatic meaning of the norm creating act; (iii) interpretation of the extrinsic objective normative meaning of the norm creating act; it thirdly suggests that the existence of a norm is the ideal (ideel) existence of a meaning, not the empirical existence of an act.

Per il positivismo giuridico tradizionale, l’idea che alcune norme create dal legislatore attraverso atti di normazione formalmente validi possano costituire “diritto illegittimo” sembra essere una contraddizione in termini. Questa tesi viene tuttavia messa esplicitamente in discussione nella teoria assiomatizzata del diritto di Luigi Ferrajoli, che pur si propone come uno sviluppo della teoria pura del diritto di Hans Kelsen. Il dissenso da Kelsen si incentra sul problema dell’applicazione dei principi logici di contraddizione e di implicazione al diritto, applicazione impossibile per Kelsen, necessaria invece per Ferrajoli per l’identificazione del diritto illegittimo. Gli autori della prefazione ricostruiscono i nodi teorici fondamentali della critica di Ferrajoli a Kelsen, e mostrano come Ferrajoli proponga di superare i limiti della teoria pura kelseninana attraverso l'elaborazione di un costituzionalismo logico., For traditional legal positivism, the idea that certain legal norms created through valid enactments can be "unlawful law" seems to be self-contradictory. This view is explicitly disputed by Luigi Ferrajoli's axiomatized theory of law, which is nonetheless presented as a development of Hans Kelsen's pure theory of law. The dispute focus on the problem of the application of the logical principles of contradiction and implication to legal systems: an impossible application for Kelsen, a necessary one for Ferrajoli, since the theory of law should identify "unlawful norms" within the legal system. The authors of this preface reconstruct the main theoretical claims of Ferrajoli's critique to Kelsen, and show how he suggests to overcome the theoretical limits of the pure theory of law through the delieation of a logical constitutionalism.

Pleurectomy Combined With Hyperthermic Intrathoracic Chemotherapy: Hemodynamic Optimization in a Challenging Case

Mononeuropathy after surgery may occur and hereditary neuropathy with liability to pressure palsies is a possible pathological condition related to paresis after hip surgery. We present a case of 66-year-old man presenting severe weakness at inferior limb muscles after hip prosthesis revision. Clinic and electrophysiology showed severe right fibular nerve damage and ultrasound found a marked enlargement of the same nerve, associated with focal enlargements in other nerves. A diagnosis of hereditary neuropathy with liability to pressure palsies was suspected and confirmed by genetic test. The patient gradually recovered returning to a normal daily active life. Ultrasound was crucial for diagnosis. The suspicion and diagnosis of latent neuropathy, which can occur after surgical intervention, may lead to a better understand of the risks of the surgery, specific for the patient, and avoid the wrong attribution to surgical malpractice.

Mononeuropathy after surgery may occur and hereditary neuropathy with liability to pressure palsies is a possible pathological condition related to paresis after hip surgery. We present a case of 66-year-old man presenting severe weakness at inferior limb muscles after hip prosthesis revision. Clinic and electrophysiology showed severe right fibular nerve damage and ultrasound found a marked enlargement of the same nerve, associated with focal enlargements in other nerves. A diagnosis of hereditary neuropathy with liability to pressure palsies was suspected and confirmed by genetic test. The patient gradually recovered returning to a normal daily active life. Ultrasound was crucial for diagnosis. The suspicion and diagnosis of latent neuropathy, which can occur after surgical intervention, may lead to a better understand of the risks of the surgery, specific for the patient, and avoid the wrong attribution to surgical malpractice.

Fetal cytotrophoblasts colonize the decidual spiral arteries during pregnancy and partially replace the endothelium by an as yet unknown mechanism. To clarify this issue, we cocultured trophoblast cells (TCs) and decidual endothelial cells (DECs) isolated from first trimester placentae and found by electron microscopic analysis that TCs adhered to DECs and migrated through the interendothelial junctions within 24 h. Since extravillous TCs were shown by FACS analysis to express vascular-endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM)-1, we investigated the role of these junctional molecules in TC adhesion to DECs and transendothelial migration of cytotrophoblasts. Both VE-cadherin and PECAM-1 were present at the contact sites between TCs and DECs in decidual sections. TC adhesion and migration were markedly inhibited by mAbs to VE-cadherin and marginally by mAb to PECAM-1. Increased expression of VE-cadherin was observed at the contact areas between TCs and DECs, whereas PECAM-1 was found to be redistributed from intercellular junctions. The induction of apoptosis of DECs by TCs, as the mechanism responsible for their replacement, was ruled out by the negative staining with TUNEL of DECs cocultured with TCs and the absence of DNA fragmentation. In conclusion, VE-cadherin is involved in transendothelial migration of TCs, and replacement of DECs by TCs is not the result of apoptosis.

Antiphospholipid-mediated endothelium perturbation plays a role in antiphospholipid syndrome (APS)-associated vasculopathy. Antiphospholipid antibodies activate endothelium both in vitro and in vivo experimental models by inducing a pro-inflammatory/-coagulant phenotype; the antibodies recognize Î22 glycoprotein I (Î22GPI) on human endothelial cells (EC) from different parts of the vasculature. In spite of such large in vitro evidence, few studies have addressed the issue whether or not a comparable endothelial perturbation might be detectable in vivo. We investigated several indirect ex vivo parameters of endothelial dysfunction: plasma levels of soluble adhesion molecules (sADM), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays. The study included: patients with primary antiphospholipid syndrome (n=32), with the syndrome secondary to non-active systemic lupus erythematosus (SLE, n=10), six patients with persistent antiphospholipid positivity at medium/high titre without any clinical manifestation of the syndrome. Fifty-two age and sex matched healthy subjects have been enrolled as controls. In addition, circulating endothelial cells identified by flow cytometry and the brachial artery flow-mediated vasodilation (FMV) were evaluated in 26 patients (20 primary and 6 lupus syndromes) and 30 healthy controls. Plasma levels of soluble adhesion molecules did not differ from controls, while a significant increase in von Willebrand factor titres (P<0.05) was found. No significant difference was found regarding the number of circulating endothelial cells and flow-mediated vasodilation. As a whole, these findings do suggest that antiphospholipid antibodies per se are not able to support a full-blown endothelial perturbation in vivo. As shown in antiphospholipid syndrome experimental animal models, a two-hit hypothesis is suggested. © 2004 Elsevier Ltd. All rights reserved

The abortion-prone mating combination CBA/J × DBA/2 has been recognized as a model of preeclampsia, and complement activation has been implicated in the high rate of pregnancy loss observed in CBA/J mice.We have analyzed the implantation sites collected from DBA/2-mated CBA/J mice for the deposition of the complement recognition molecules using CBA/J mated with BALB/c mice as a control group. MBL-A was observed in the implantation sites of CBA/J × DBA/2 combination in the absence of MBL-C and was undetectable in BALB/c-mated CBA/J mice. Conversely, C1q was present in both mating combinations. Searching for other complement components localized at the implantation sites of CBA/J × DBA/2, we found C4 and C3, but we failed to reveal C1r. These data suggest that complement is activated through the lectin pathway and proceeds to completion of the activation sequence as revealed by C9 deposition. MBL-A was detected as early as 3.5 d of pregnancy, and MBL-A deficiency prevented pregnancy loss in the abortion-prone mating combination. The contribution of the terminal complex to miscarriage was supported by the finding that pregnancy failure was largely inhibited by the administration of neutralizing Ab to C5. Treatment of DBA/2-mated CBA/J mice with Polyman2 that binds to MBL-A with high affinity proved to be highly effective in controlling the activation of the lectin pathway and in preventing fetal loss.