Flat bundles, von Neumann algebras and KK-theory with R/Z\R/\Z-coefficients

Let $M$ be a closed manifold and $\alpha : \pi_1(M)\to U_n$ a representation. We give a purely $K$-theoretic description of the associated element $[\alpha]$ in the $K$-theory of $M$ with $\R/\Z$-coefficients. To that end, it is convenient to describe the $\R/\Z$-$K$-theory as a relative $K$-theory with respect to the inclusion of \C in a finite von Neumann algebra $B$. We use the following fact: there is, associated with $\alpha$, a finite von Neumann algebra $B$ together with a flat bundle \cE\to M with fibers $B$, such that E_\a\otimes \cE is canonically isomorphic with \C^n\otimes \cE, where $E_\alpha$ denotes the flat bundle with fiber \C^n associated with $\alpha$. We also discuss the spectral flow and rho type description of the pairing of the class $[\alpha]$ with the $K$-homology class of an elliptic selfadjoint (pseudo)-differential operator $D$ of order 1

Glycaemic control with Mesenchymal Stem Cells and Endothelial Progenitor Cells in an experimental model of pancreatic islet transplantation

Insulin-Dependent Diabetes Mellitus (IDDM or type 1) is an autoimmune, chronic disease characterised by hyperglycaemia, resulting from an inflammatory infiltration of the islets of Langerhans. The selective destruction of β-cells leads to a lower insulin secretion from the endocrine pancreas. The mainstay treatment for IDDM patients is chronic insulin injection. Although insulin therapy has dramatically reduced mortality from diabetes, patients often incur in complications such as nephropathy, neuropathy, angiopathy and retinopathy. Moreover, patients are risk severe and sometimes fatal hypoglycaemic events. Pancreas transplantation is currently the only therapeutic approach to restore normoglycaemia and maintain long-term glucose homeostasis; moreover, this procedure improves patients’ quality of life. An alternative to the replacement of the whole pancreas is the transplantation of islet of Langherans cells, isolated from donor pancreata and infused into the recipient’s liver via the portal vein. Compared to solid organ transplantation, the advantages of islet transplantation consist in a relatively simple surgical procedure with low incidence of peri-operative risks. Nevertheless, the particular structure of pancreatic islets resulted in being injured after the isolation procedure. However, the recurrence of immune response after transplantation and the diabetogenic and growth-stunting side effects of immunosuppressants are major challenges to the application of islet transplantation. In the last decade many studies have demonstrated the efficacy of cell therapy either with Mesenchymal Stem Cells (MSCs) or Endothelial Progenitor Cells (EPCs) treatment when co-transplanted with pancreatic islets. The first type of cells were reported to modulate the immune response in an allogeneic transplant, preventing the graft-versus-host disease (GVHD) and also improving graft function in the long-term by maintaining glucose homeostasis. The EPCs showed to have strong revascularization properties in several diseases, such as cardiovascular disorders, atherosclerosis and diabetes. This thesis aims to investigate the role of MSCs and EPCs in prolonging graft survival of pancreatic islet transplantation in a chemically induced rat model of type 1 diabetes in order to prolong the graft function and reach normoglycaemic levels in the long-term. We used a rat model to investigate the effect of MSCs and EPCs in combination with islets of Langerhans (700 IE + 500,000 EPCs and 700 IE + 500,000 MSCs) in a syngeneic and an allogeneic diabetic-induced rat model which underwent pancreatic islet transplantation via the portal vein. These types of transplants were compared with islet alone treatment (700 IE), either syngeneic or allogeneic. We obtained the reversal of the diabetic status in animals up to 6 months after the transplant when they had received islets and EPCs, and up to 75 days post transplant when they had received islets and MSC therapy. The glycaemic values were also confirmed by intraperitoneal glucose tolerance test measures for animals transplanted with IE and EPCs either in syngeneic or allogeneic models. From data obtained from molecular biology assays on ex vivo liver tissues deriving from transplanted animals, we observed that a regulation in the revascularization and angiogenesis genes (VEGF-A, ANG-1, PECAM-1, SDF-1) occurred. Thus, EPCs could act through a regulatory mechanism as shown by their angiogenic gene expression. These data suggested that both MSCs and EPCs were able to revascularize pancreatic islets and improve the syngeneic graft survival up to a complete healing in our diabetic animal model

The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal an-ti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibi-otics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. Methods: The Food and Drug Administra-tion (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, ‘unmasking’, dataset analyses were carried out as well. Results: Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications ,which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed signif-icant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7–20.3), 14.3 (9.1–22.4) and 58.7 (36.3–95.9). Conclusions: A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.Peer reviewe

Upgrade of the HIVIPP Deposition Apparatus for Nuclear Physics Thin Targets Manufacturing

The High Energy Vibrational Powder Plating (HIVIPP) technique allows for the preparation of targets starting from refractory metal powders with negligible material losses during the process, thus preserving the expensive isotope-enriched materials. An upgraded HIVIPP apparatus was developed at the Legnaro National Laboratory of the National Institute of Nuclear Physics (INFN-LNL), and it is reported in this work. Particular attention was paid to the design of the sample holder, the automation of the power supply, and the control of the process, all with the aim of obtaining a versatile and reliable apparatus. Several tests have been carried out and the related results are reported proving the flexibility of the apparatus and the process reproducibility. The main result is a 'ready to use' technology at INFN-LNL for the preparation of isotopically enriched refractory metal targets that cannot be manufactured using standard techniques

SiO2/Ladder-Like Polysilsesquioxanes Nanocomposite Coatings: Playing with the Hybrid Interface for Tuning Thermal Properties and Wettability

The present study explores the exploitation of ladder-like polysilsesquioxanes (PSQs) bearing reactive functional groups in conjunction with SiO2 nanoparticles (NPs) to produce UV-curable nanocomposite coatings with increased hydrophobicity and good thermal resistance. In detail, a medium degree regular ladder-like structured poly (methacryloxypropyl) silsesquioxane (LPMASQ) and silica NPs, either naked or functionalized with a methacrylsilane (SiO2@TMMS), were blended and then irradiated in the form of a film. Material characterization evidenced significant modifications of the structural organization of the LPMASQ backbone and, in particular, a rearrangement of the silsesquioxane chains at the interface upon introduction of the functionalized silica NPs. This leads to remarkable thermal resistance and enhanced hydrophobic features in the final nanocomposite. The results suggest that the adopted strategy, in comparison with mostly difficult and expensive surface modification and structuring protocols, may provide tailored functional properties without modifying the surface roughness or the functionalities of silsesquioxanes, but simply tuning their interactions at the hybrid interface with silica fillers

Co-Transplantation of endothelial progenitor cells and pancreatic islets to induce long-lasting normoglycemia in streptozotocin-treated diabetic rats

Graft vascularization is a crucial step to obtain stable normoglycemia in pancreatic islet transplantation. Endothelial progenitor cells (EPCs) contribute to neoangiogenesis and to the revascularization process during ischaemic events and play a key role in the response to pancreatic islet injury. In this work we co-transplanted EPCs and islets in the portal vein of chemically-induced diabetic rats to restore islet vascularization and to improve graft survival. Syngenic islets were transplanted, either alone or with EPCs derived from green fluorescent protein (GFP) transgenic rats, into the portal vein of streptozotocin-induced diabetic rats. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests were performed. Real time-PCR was carried out to evaluate the gene expression of angiogenic factors. Diabetic-induced rats showed long-lasting (6 months) normoglycemia upon co-transplantation of syngenic islets and EPCs. After 3–5 days from transplantation, hyperglycaemic levels dropped to normal values and lasted unmodified as long as they were checked. Further, glucose tolerance tests revealed the animals' ability to produce insulin on-demand as indexed by a prompt response in blood glucose clearance. Graft neovascularization was evaluated by immunohistochemistry: for the first time the measure of endothelial thickness revealed a donor-EPC-related neovascularization supporting viable islets up to six months after transplant. Our results highlight the importance of a newly formed viable vascular network together with pancreatic islets to provide de novo adequate supply in order to obtain enduring normoglycemia and prevent diabetes-related long-term health hazards

Action Selection and Motor Decision Making: Insights from Transcranial Magnetic Stimulation

In everyday life, goal-oriented motor behaviour relies on the estimation of the rewards/costs associated with alternative actions and on the appropriate selection of movements. Motor decision making is defined as the process by which a motor plan is chosen among a set of competing actions based on the expected value. In the present literature review we discuss evidence from transcranial magnetic stimulation (TMS) studies of motor control. We focus primarily on studies of action selection for instructed movements and motor decision making. In the first section, we delve into the usefulness of various TMS paradigms to characterise the contribution of motor areas and distributed brain networks to cued action selection. Then, we address the influence of motivational information (e.g., reward and biomechanical cost) in guiding action choices based on TMS findings. Finally, we conclude that TMS represents a powerful tool for elucidating the neurophysiological mechanisms underlying action choices in humans

Nanotopography Induced Human Bone Marrow Mesangiogenic Progenitor Cells (MPCs) to Mesenchymal Stromal Cells (MSCs) Transition

Mesangiogenic progenitor cells (MPCs) are a very peculiar population of cells present in the human adult bone marrow, only recently discovered and characterized. Owing to their differentiation potential, MPCs can be considered progenitors for mesenchymal stromal cells (MSCs), and for this reason they potentially represent a promising cell population to apply for skeletal tissue regeneration applications. Here, we evaluate the effects of surface nanotopography on MPCs, considering the possibility that this specific physical stimulus alone can trigger MPC differentiation toward the mesenchymal lineage. In particular, we exploit nanogratings to deliver a mechanical, directional stimulus by contact interaction to promote cell morphological polarization and stretching. Following this interaction, we study the MPC-MSC transition by i. analyzing the change in cell morphotype by immunostaining of the key cell-adhesion structures and confocal fluorescence microscopy, and ii. quantifying the expression of cell-phenotype characterizing markers by flow cytometry. We demonstrate that the MPC mesengenic differentiation can be induced by the solely interaction with the NGs, in absence of any other external, chemical stimulus. This aspect is of particular interest in the case of multipotent progenitors as MPCs that, retaining both mesengenic and angiogenic potential, possess a high clinical appeal

Cohort study of prevalence and phenomenology of tremor in dementia with Lewy bodies

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p \u3c 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p \u3c 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors. Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-6853-y) contains supplementary material, which is available to authorized users

Quantum dots labelling allows detection of the homing of mesenchymal stem cells administered as immunomodulatory therapy in an experimental model of pancreatic islets transplantation

Cell transplantation is considered a promising therapeutic approach in several pathologies but still needs innovative and non-invasive imaging technologies to be validated. The use of mesenchymal stem cells (MSCs) attracts major interest in clinical transplantation thanks to their regenerative properties, low immunogenicity and ability to regulate immune responses. In several animal models, MSCs are used in co-transplantation with pancreatic islets (PIs) for the treatment of type I diabetes, supporting graft survival and prolonging normal glycaemia levels. In this study we investigated the homing of systemically administered MSCs in a rat model of pancreatic portal vein transplantation. MSCs labelled with quantum dots (Qdots) were systemically injected by tail vein and monitored by optical fluorescence imaging. The fluorescence signal of the liver in animals co-transplanted with MSCs and PIs was significantly higher than in control animals in which MSCs alone were transplanted. By using magnetic labelling of PIs, the homing of PIs into liver was independently confirmed. These results demonstrate that MSCs injected in peripheral blood vessels preferentially accumulate into liver when PIs are transplanted in the same organ. Moreover, we prove that bimodal MRI-fluorescence imaging allows specific monitoring of the fate of two types of cells