Finite Element Quadrature of Regularized Discontinuous and Singular Level Set Functions in 3D Problems

Regularized Heaviside and Dirac delta function are used in several fields of computational physics and mechanics. Hence the issue of the quadrature of integrals of discontinuous and singular functions arises. In order to avoid ad-hoc quadrature procedures, regularization of the discontinuous and the singular fields is often carried out. In particular, weight functions of the signed distance with respect to the discontinuity interface are exploited. Tornberg and Engquist (Journal of Scientific Computing, 2003,19: 527-552) proved that the use of compact support weight function is not suitable because it leads to errors that do not vanish for decreasing mesh size. They proposed the adoption of non-compact support weight functions. In the present contribution, the relationship between the Fourier transform of the weight functions and the accuracy of the regularization procedure is exploited. The proposed regularized approach was implemented in the eXtended Finite Element Method. As a three-dimensional example, we study a slender solid characterized by an inclined interface across which the displacement is discontinuous. The accuracy is evaluated for varying position of the discontinuity interfaces with respect to the underlying mesh. A procedure for the choice of the regularization parameters is propose

Water services in Italy: implementation of the reform and efficiency of providers

The paper investigates the organization of the Italian water sector in the light of the reforms of public utilities. The aim is to examine the degree of implementation of the water sector reform (the so-called Galli Law of 1994) and assess the performance of operators through a study of their financial indicators and a non-parametric efficiency analysis. The information sources include two Bank of Italy surveys carried out in 2007 on local public water authorities and local water service providers. Financial indicators point to a low return on equity: for more than half of the firms it is lower than the risk-free interest rate. The non-parametric efficiency analysis does not reveal significant economies of scope and highlights a certain degree of variability of technical efficiency scores. This suggests that there is room for efficiency gains through the introduction of comparative competitive mechanisms such as the yardstick competition.water supply, data envelopment analysis, public utilities, natural monopoly, regulation

Platelet abnormalities and platelet-to-lymphocyte ratios in canine immunosuppressant-responsive and non-responsive enteropathy: A retrospective study in 41 dogs

Few studies have examined platelet alterations in dogs with chronic enteropathy. Our aim was to investigate platelet count (PLT), mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) in dogs diagnosed with immunosuppressant-responsive enteropathy (IRE). In this retrospective study of 41 dogs, data regarding signalment, canine chronic enteropathy clinical activity index (CCECAI), endoscopic and histopathological scores, PLT, MPV, PLR, total serum protein concentrations, albumin, and iron were collected. Clinical response and relapse were assessed with the evaluation of CCECAI over time. One month after starting therapy, dogs with >25% CCECAI reduction were considered responders. During a three-month CCECAI evaluation as part of a twelve-month follow-up, a CCECAI >3 together with a ≥2 unit increase in responder dogs was considered a relapse. PLT and PLR displayed significant negative correlation with MPV. MPV was positively correlated with total protein and albumin levels and negatively correlated with CCECAI. Three dogs were classified as non-responders, and 14 relapsed within 12 months. No differences were observed in PLT, MPV, or PLR between responding/non-responding and relapsing/non-relapsing groups. PLT, MPV, and PLR correlated with total protein, albumin, and CCECAI, confirming PLT as a potential marker, and suggesting MPV as a new marker of clinical efficacy against canine IRE

Immunosuppressant-Responsive Enteropathy and Non-Responsive Enteropathy in Dogs: Prognostic Factors, Short- and Long-Term Follow Up

A multicentre prospective study was performed to assess whether clinical, hematobiochemical, endoscopic and histopathological parameters were associated with mortality, clinical response and relapse of disease in short- and long-term follow-up of a total of 165 dogs with chronic inflammatory enteropathy, of which 150 had immunosuppressant responsive enteropathy (IRE), and 15 had non-responsive enteropathy (NRE) dogs. Clinical severity (CCECAI) was evaluated from presentation (T0) to 18 months (T18) from diagnosis. T0 body condition score (BCS), selected haematological parameters and endoscopic and histopathological scores were evaluated. Presence/absence of histopathological duodenal lesions was recorded. Responders were evaluated using CCECAI at T1. Relapse was evaluated from T3 to T18. Long-term responders included dogs who responded at T1 and showed no relapse. Dogs were divided into responders/non-responders, survivors/non-survivors and relapsed/non-relapsed. At T1, 15/165 dogs (9%) were considered NRE. Sixteen dogs (11%) were considered relapsed at T3, 8% at T6 and 10% at T12, and none of 96 dogs relapsed at T18. NREs showed significantly lower BCS than IREs. Non-survivors showed a significantly lower serum albumin concentration and BCS than survivors. Non-responders, relapsed or non-survivors had higher presence of lacteal dilatation compared to long-term responders. Dogs with IRE showed a good clinical course with a low relapse rate, with only a few dogs in the NRE group. Reduction of BCS, albumin and lacteal dilatation at diagnosis may be considered negative prognostic factors for response, mortality and long-term disease remission

Extended virtual element method for two-dimensional fracture modeling in linear elasticity

The virtual element method (VEM), is a stabilized Galerkin scheme deriving from mimetic finite differences, which allows for very general polygonal meshes, and does not require the explicit knowledge of the shape functions within the problem domain. In the VEM, the discrete counterpart of the continuum formulation of the problem is defined by means of a suitable projection of the virtual shape functions onto a polynomial space, which allows the decomposition of the bilinear form into a consistent part, reproducing the polynomial space, and a correction term ensuring stability. In the present contribution, we outline an extended virtual element method (X-VEM) for two-dimensional elastic fracture problems where, drawing inspiration from the extended finite element method (X-FEM), we extend the standard virtual element space with the product of vector-valued virtual nodal shape functions and suitable enrichment fields, which reproduce the singularities of the exact solution. We define an extended projection operator that maps functions in the extended virtual element space onto a set spanned by the space of linear polynomials augmented with the enrichment fields. Numerical examples in 2D elastic fracture are worked out to assess convergence and accuracy of the proposed method for both quadrilateral and general polygonal meshes

Protective effects of the combination Bifidobacterium longum plus lactoferrin against NSAID-induced enteropathy

Objectives Non-steroidal anti-inflammatory drugs can exert detrimental effects in the lower digestive tract. This study examined the protective effects of a combination of the probiotic Bifidobacterium longum BB536 (Bifidobacterium) with the prebiotic lactoferrin in a rat model of diclofenac-induced enteropathy. Methods Enteropathy was induced in 40-week-old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Lactoferrin (100 mg/kg BID), Bifidobacterium (2.5\u2022106 CFU/rat BID) or their combination were administered 1 hour before diclofenac. At the end of treatments, the ileum was processed for the evaluation of histological damage, myeloperoxidase (MPO) and malondialdehyde (MDA) levels, as well as the expression of toll-like receptors 2 and 4 (TLR-2/-4) and the activation of downstream signaling molecules (MyD88 and NF-kB p65). Blood hemoglobin and fecal calprotectin were also assessed. Results Diclofenac induced intestinal damage, along with increments of MPO and MDA, overexpression of TLR-2, TLR-4, MyD88 and NF-kB p65, increase in fecal calprotectin and decrease in blood hemoglobin levels. Lactoferrin or Bifidobacterium alone prevented diclofenac-induced enteric damage, and the changes in blood hemoglobin, MPO, MDA, fecal calprotectin and NF-kB p65. Bifidobacterium, but not lactoferrin, decreased TLR-4 expression, while none of them affected MyD88 overexpression. TLR-2 expression was slightly enhanced by all treatments. The combined administration of lactoferrin and Bifidobacterium reduced further the intestinal damage, and restored MPO and blood hemoglobin levels. Conclusions Diclofenac induced ileal mucosal lesions by activation of inflammatory and pro-oxidant mechanisms. These detrimental actions were prevented by the combination of lactoferrin with Bifidobacterium likely through the modulation of TLR-2/-4/NF-kB pro-inflammatory pathways

Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays

open12Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride's mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules (9b, 9g, and 9j), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.openParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, EnricoParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, Enric