Comparing treatment options for chronic inflammatory neuropathies and choosing the right treatment plan

Introduction: Chronic inflammatory neuropathies are disorders caused by an immune response to peripheral nerve. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and neuropathy associated with anti-MAG IgM monoclonal gammopathy and other less frequent neuropathies. Several immune therapies have been proven to be effective in these neuropathies even if the best therapeutic option is still unsettled. Areas covered: The authors reviewed the literature to compare the efficacy and safety of currently used immune therapies in these neuropathies. The authors also analyzed the effect of other immune suppressive agents and of biological agents including rituximab, eculizumab, natalizumab, alemtuzumab and fingolimod that were found effective in other autoimmune diseases. Expert commentary: Despite the reported efficacy of a number of new immune therapies in some patients with immune mediated neuropathies, their efficacy has not been so far confirmed in randomized controlled studies. High-dose intravenous immunoglobulin (IVIg) (and subcutaneous immunoglobulin [SCIg] for maintenance treatment), steroids and plasma exchange remain the only therapy of proven efficacy in CIDP, IVIg in MMN and, with certain limits, rituximab and, occasionally plasma exchange in neuropathy associated with anti-MAG antibodies. New biological agents are also on the horizon but their efficacy needs to be proved in controlled studies

Functionalised peptide hydrogel for the delivery of cardiac progenitor cells.

Heart failure (HF) remains one of the leading causes of death worldwide; most commonly developing after myocardial infarction (MI). Since adult cardiomyocytes characteristically do not proliferate, cells lost during MI are not replaced. As a result, the heart has a limited regenerative capacity. There is, therefore, a need to develop novel cell-based therapies to promote the regeneration of the heart after MI. The delivery and retention of cells at the injury site remains a significant challenge. In this context, we explored the potential of using an injectable, RGDSP-functionalised self-assembling peptide - FEFEFKFK - hydrogel as scaffold for the delivery and retention of rat cardiac progenitor cells (CPCs) into the heart. Our results show that culturing CPCs in vitro within the hydrogel for one-week promoted their spontaneous differentiation towards adult cardiac phenotypes. Injection of the hydrogel on its own, or loaded with CPCs, into the rat after injury resulted in a significant reduction in myocardial damage and left ventricular dilation

Corticosteroids in chronic inflammatory demyelinating polyneuropathy : a retrospective, multicentre study, comparing efficacy and safety of daily prednisolone, pulsed dexamethasone, and pulsed intravenous methylprednisolone

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) can be treated with corticosteroids or intravenous immunoglobulins. Various corticosteroid regimens are currently used in CIDP, but it is unknown whether they are equally efficacious. In this retrospective study, we compared efficacy and safety of three corticosteroid regimens in CIDP patients. Methods: We included treatment na\uefve patients that fulfilled the EFNS/PNS criteria for CIDP. Patients were treated with corticosteroids according to the local protocol of three CIDP expertise centres. Corticosteroid regimens consisted of daily oral prednisolone, pulsed oral dexamethasone, or pulsed intravenous methylprednisolone. Outcomes were number of responders to treatment, remission rate of treatment responders, overall probability of 5-year remission, and the occurrence of adverse events. Results: A total of 125 patients were included. Sixty-seven (54%) patients received daily prednisone or prednisolone, 37 (30%) pulsed dexamethasone, and 21 (17%) pulsed intravenous methylprednisolone. Overall, 60% (95% CI 51\u201369%) responded to corticosteroids, with no significant difference between the three treatment regimens (p = 0.56). From the 75 responders, 61% (95% CI 50\u201373%) remained in remission, during a median follow-up of 55\ua0months (range 1\u2013197\ua0months). The probability of responders reaching 5-year remission was 55% (95% Cl 44\u201370%), with no difference between the three groups. Adverse events leading to a change in treatment occurred in ten patients (8%). Two patients had a serious adverse event. Conclusion: Corticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders. There were no differences between treatment modalities in terms of efficacy and safety

Frequency and time to relapse after discontinuing 6-month therapy with IVIg or pulsed methylprednisolone in CIDP

Background: We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening. Methods: By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1-60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up. Results: Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1-57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7-60). Worsening occurred 1-24 months (median 4.5) after IVIg discontinuation and 1-31 months (median 14) after IVMP discontinuation (p=0.0126). Conclusions: A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP

Unraveling gene expression profiles in peripheral motor nerve from Amyotrophic Lateral Sclerosis patients : insights into pathogenesis

The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68 1710-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies

Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation

The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p < 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p < 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p < 0.05) and 2.1-fold (p < 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality

The expression of HSP27 is associated with poor clinical outcome in intrahepatic cholangiocarcinoma

<p>Abstract</p> <p>Background</p> <p>The heat shock proteins (HSPs) 27-kDa (HSP27) and 72-kDa (HSP72), are ubiquitous chaperone molecules inducible in cells exposed to different stress conditions. Increased level of HSPs are reported in several human cancers, and found to be associated with the resistance to some anticancer treatments and poor prognosis. However, there is no study of the relationship between HSPs expression and patient's prognosis in intrahepatic cholangiocarcinoma (IHCCA). In this exploratory retrospective study, we investigated the expressions of HSP27 and HSP72 as potential prognostic factors in IHCCA.</p> <p>Methods</p> <p>Thirty-one paraffin-embedded samples were analyzed by immunohistochemical methods using HSP27 and HSP72 monoclonal antibodies. Proliferation rate was assessed in the same specimens by using monoclonal antibody against phosphorylated histone H3 (pHH3). Fisher's exact test was used to assess the hypothesis of independence between categorical variables in 2 × 2 tables. The ANOVA procedure was used to evaluate the association between ordinal and categorical variables. Estimates of the survival probability were calculated using the Kaplan-Meier method, and the log rank test was employed to test the null hypothesis of equality in overall survival among groups. The hazard ratio associated with HSP27 and HSP72 expression was estimated by Cox hazard-proportional regression.</p> <p>Results</p> <p>The expression of HSP27 was related to mitotic index, tumor greatest dimension, capsular and vascular invasion while the expression of HSP72 was only related to the presence of necrosis and the lymphoid infiltration. Kaplan-Maier analysis suggested that the expression of HSP27 significantly worsened the patients' median overall survival (11 ± 3.18 vs 55 ± 4.1 months, P-value = 0.0003). Moreover HSP27-positive patients exhibited the worst mean survival (7.0 ± 3.2 months) in the absence of concomitant HSP72 expression.</p> <p>Conclusion</p> <p>The expression of HSP27, likely increasing cell proliferation, tumor mass, vascular and capsular invasion, might promote aggressive tumor behaviour in IHCCA and decrease patients' survival. Immunohistochemical detection of HSP27 on routine sections may provide a reliable prognostic marker for IHCCA able to influence the therapeutic strategies for this cancer.</p