No abstract

BackgroundChemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration.The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN).MethodsAfter determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration (“preventive” schedule), or once BIPN was already ensued after 4 weeks of treatment (“therapeutic” schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves.ResultsBoth schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype.ConclusionOur results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroin flammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are

Introduction: Polymethylmethacrylate (PMMA) membranes can adsorb a wide variety of uremic toxins including serum free light chains (sFLC). However, limited data are available regarding the clinical use of PMMA in multiple myeloma patients and its maximum adsorption capacity in this setting. Aim: This study aimed to measure the capacity of PMMA to adsorb sFLC and identify strategies to improve its efficiency in clinical practice. Methods: Ten patients with dialysis-dependent renal failure and high levels of sFLC were included in the study. Five patients received standard PMMA hemodialysis (HD; n = 18), while in the other 5 patients a new technique called enhanced adsorption dialysis (EAD) was used, which involves PMMA dialyzer replacement after 2 h (n = 19). In all patients, sFLC were measured at the beginning and at the end of each dialysis session to calculate the difference between start and end of treatment and the percentage removal. Results: PMMA membranes reduced sFLC in both the PMMA HD and EAD groups. PMMA HD showed similar efficiency on κ and λ percentage removal (22.3 and 21.0%, respectively, n.s.) but, in contrast, had a significantly greater effect on the delta of sFLC in κ [1,555 mg/l (-511 to +6,027)] versus λ [390 mg/l (120-650)] treatments (p = 0.007). EAD treatments only partially increased percentage removal of κ sFLC (22.3-31.0%, p = 0.38), while they had a significantly great effect on λ (21.0-53.1%, p = 0.003). A positive linear correlation was found between delta sFLC and pre-HD sFLC concentrations in PMMA HD κ treatments (r = 0.68, p < 0.02) but not for λ treatments (r = 0.54, p = 0.21), while the analysis of patients receiving EAD demonstrated a strong positive correlation for both κ and λ subtypes (r = 0.81 and r = 0.85, respectively, p < 0.008). In EAD sessions, a positive linear correlation was shown between blood flow during treatment and percentage removal of sFLC (r = 0.58, p = 0.02); however, with PMMA HD such a correlation was not observed (r = 0.28, p = 0.25). Conclusions: PMMA membranes can efficiently adsorb sFLC, but the process is limited by membrane saturation and is different between κ and λ sFLC. The new EAD technique can greatly improve λ removal but only partially act on κ sFLC. Therefore, EAD should be considered a valid economic treatment option without side effects in particular subsets of patients for the removal of sFLC.

Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelialmesenchymal transition (EMT) affects tubular cells, which under highglucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.