Costimulatory blockade: A novel approach to the treatment of glomerular disease?

Costimulatory pathways (Cluster of differentiation 28, tumor necrosis factor-related, adhesion and T Cell Ig- and mucin-domain molecules) regulating the interactions between receptors on the T cells and their ligands expressed on several cell types, have a key role in controlling many immunological and non immunological processes. Indeed, accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions, such as allograft rejection, atherosclerosis, rheumatoid arthritis, psoriasis and renal diseases, including glomerulonephritis. Primary or secondary (i.e., associated with infections, drugs or systemic diseases, such as systemic lupus erythematosus, diabetes, etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms. Since costimulatory molecules, in particular CD80 and CD40, have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis, costimulation has been thought as a new therapeutic target for patients with glomerular diseases. However, although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases, clinical trials reported contrasting results. So, at this moment, there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis. Here, we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach

Design of a Highly Portable Data Logging Embedded System for Naturalistic Motorcycle Study

According to Motorcycle Industrial Council (MIC), in USA the number of owned motorcycle increased during last few years and most likely will keep increasing. However, the number of the deadly crash accidents associated with motorcycles is on the rise. Although MIC doesn\u27t explain why the accident rate has increased, the unprotected motorcyclist gear can be one of the reasons. The most recent National Highway Traffic Safety Administration (NHTSA) annual report stated that its data analyses are based on their experiences and the best judgment is not based on solid scientific experiment [3]. Thus, building a framework for the data acquisition about the motorcyclist environment is a first step towards decreasing motorcyclist crashes. There are a few naturalistic motorcycle studies reported in the literature. The naturalistic motorcycle study also identifies the behaviors and environmental crash hazards. The primary objective of this thesis work is to design a highly portable data logging embedded system for naturalistic motorcycle study with capability of collecting many types of data such as images, speed, acceleration, time, location, distance approximation, etc. This thesis work is the first phase (of three phases) of a naturalistic motorcycle study project. The second phase is to optimize system area, form factor, and power consumption. The third phase will be concerned with aggressive low power design and energy harvesting. The proposed embedded system design is based on an Arduino microcontroller. A whole suite of Arduino based prototype boards, sensor boards, support software, and user forum is available. The system is high portable with capability to store up to eight (8) hours of text/image data during a one month study period. We have successfully designed and implemented the system and performed three trial runs. The data acquired has been validated and found to be accurate

Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging

Background Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation. Methods We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period. Results Hemodialysis kynurenine and kynurenine/L - tryptophan blood ratio levels were significantly higher, when compared to the control group, indicating an increased indoleamine 2,3-dioxygenase-1 activity in hemodialysis patients. At the end of the low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers period, L - tryptophan serum levels remained unchanged vs both low-flux bicarbonate hemodialysis and hemodialfitration. Kynurenine levels instead decreased, resulting in a significant reduction of kynurenine/L - tryptophan blood ratio and indoleamine 2,3-dioxygenase-1 activity, when matched to both low-flux bicarbonate hemodialysis and HDF respectively. Serum nitric oxide control group levels, were significantly lower when compared to all hemodialysis patient groups. Interestingly, low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers nitric oxide serum levels from venous line blood samples taken 60 min after starting the hemodialysis session were significantly lower vs serum taken simultaneously from the arterial blood line. Conclusions The treatment with more biocompatible hemodialysis procedure as low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, reduced indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation when compared to both low-flux bicarbonate hemodialysis and hemodialfitration. These data suggest that low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers lowering hemodialysis inflammaging, could be associated to changes of proinflammatory signalling a regulated molecular level

Determinants of surgeon choice in cases of suspected implant rupture following mastectomy or aesthetic breast surgery: Clinical implications

Implant ruptures may be diagnosed by physical examination, ultrasound (US), and magnetic resonance imaging (MRI). The absence of standard guidelines to approach to implant ruptures may cause unnecessary surgical revisions in the absence of radiological confirmation of prosthetic damages.The purpose of this study was to analyze the diagnostic procedures applied to patients with suspected prosthetic rupture and surgeon choices to perform a revision or to plan a clinical and radiological follow-up.We conducted a retrospective study on 62 women submitted to revision surgery due to radiological diagnosis of suspected implant rupture, following mastectomy or aesthetic reconstruction, and admitted to a Plastic Surgery Department between 2008 and 2018.Seventy-three implants, believed to be ruptured, were explanted. One-third of these were intact and unnecessarily explanted. US associated with MRI evaluation resulted in the most helpful diagnostical method.A standardized clinical and radiological approach is essential to manage breast implant ruptures successfully. An innovative protocol is proposed in order to: ensure the appropriate management of implant ruptures and prevent unnecessary surgical revisions; reduce the risk of claims for medical malpractice in cases of unsatisfactory final aesthetic results or worse than before

Renal involvement in mushroom poisoning: The case of Orellanus syndrome

none8Although mushroom poisoning is a rare cause of acute renal injury, in some cases it may lead to the development of a severe and irreversible renal failure. Orellanus syndrome is the most important example of organic renal damage related to mushroom consumption. It is caused by the ingestion of orellanine, the main toxin of different types of Cortinarius mushrooms (Cortinarius speciosissimus, C. orellanus, C. orellanoides, etc.), and it is characterized by progressive clinical phases with a predominant kidney involvement, finally requiring renal replacement therapy in about 10% of cases. Renal damage is often late and associated with a histological picture of interstitial nephritis. Diagnosis is essentially clinical and no specific therapy has been shown to be effective in preventing and treating renal damage. Here, we describe the case of a patient with mixed wild mushroom poisoning, presenting the typical clinical signs and course of the Orellanus syndrome. This case offers us the opportunity to review the main clinical features of this severe and little-known intoxication.openEsposito, P; La Porta, E; Calatroni, M; Bianzina, S; Libetta, C; Gregorini, M; Rampino, T; Dal Canton, AEsposito, P; La Porta, E; Calatroni, M; Bianzina, S; Libetta, Carmelo; Gregorini, Marilena; Rampino, Teresa; DAL CANTON, Antoni

Management of mineral metabolism in hemodialysis patients: discrepancy between interventions and perceived causes of failure

none8BACKGROUND: Mineral and bone disorders (MBD) in patients undergoing hemodialysis (HD) are a major clinical complication. Current therapeutic strategies do not attain the expected results. The Italian audit on mineral metabolism was implemented to investigate MBD management through a "patient-oriented" approach. METHODS: Clinical and laboratory data pertinent to MBD from 509 prevalent adult patients on chronic HD were recorded and examined (audit), after which individual strategies were elaborated to improve MBD control. Their effectiveness was evaluated 6 months after the audit (Post-6). RESULTS: The audit disclosed poor MBD control in a high percentage of patients (56 %). Low compliance to treatment was the major determinant of failure (in 43.5 % of cases). Logistic regression showed a direct correlation between high degree of compliance and the achievement of therapeutic targets, e.g. parathyroid hormone: odds ratio (OR) 2.48, p = 0.015. In contrast, a minority of the proposed interventions (14.7 %) included strategies to improve patient compliance. At Post-6, despite a significant increase in drug prescription (p < 0.05 vs. audit), the rate of successful MBD control was unchanged. CONCLUSIONS: Low compliance with treatment is a major, but still neglected, cause of failure in the achievement of MBD control in HD patients.Esposito, P; Rampino, T; Gregorini, M; Tinelli, C; De Silvestri, A; Malberti, F; Coppo, R; Dal Canton, A.Esposito, P; Rampino, Teresa; Gregorini, Marilena; Tinelli, C; De Silvestri, A; Malberti, F; Coppo, R; DAL CANTON, Antoni

Costimulatory Pathways in Kidney Transplantation: Pathogenetic Role, Clinical Significance and New Therapeutic Opportunities.

Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways