Inflammatory myopathy associated with statins: report of three cases.

Statins are well-established lipid-lowering drugs that reduce morbidity and mortality due to cardiovascular disease and cause adverse effects relatively rarely. It is still unclear whether statins are capable of inducing an immune-mediated response directed against skeletal muscle. Here, we present the cases of three patients who developed inflammatory myopathy in the course of statin treatment. Moreover, multiple mitochondrial DNA deletions were found in two of them. The ability of statins to induce an immune-mediated response and their interactions with mitochondrial metabolism pathways are discussed.

Resistin in idiopathic inflammatory myopathies.

INTRODUCTION: The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity. METHODS: Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association among resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed. RESULTS: In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53 ± 6.84 vs. 4.54 ± 1.08 ng/ml, P < 0.0001) and correlated with C-reactive protein (CRP) levels (r = 0.328, P = 0.044) and myositis disease activity assessment visual analogue scales (MYOACT) (r = 0.382, P = 0.026). Stronger association was observed between the levels of serum resistin and CRP levels (r = 0.717, P = 0.037) as well as MYOACT (r = 0.798, P = 0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r = 0.650, P = 0.067) in anti-Jo-1 positive patients. Furthermore, in patients with dermatomyositis, serum resistin levels significantly correlated with MYOACT (r = 0.667, P = 0.001), creatine kinase (r = 0.739, P = 0.001) and myoglobin levels (r = 0.791, P = 0.0003) and showed a trend towards correlation with CRP levels (r = 0.447, P = 0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1ß and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes. CONCLUSIONS: The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.

The extracellular matrix and diffusion barriers in focal cortical dysplasias.

Focal cortical dysplasias (FCDs) of the brain are recognized as a frequent cause of intractable epilepsy. To contribute to the current understanding of the mechanisms of epileptogenesis in FCD, our study provides evidence that not only cellular alterations and synaptic transmission, but also changed diffusion properties of the extracellular space (ECS), induced by modified extracellular matrix (ECM) composition and astrogliosis, might be involved in the generation or spread of seizures in FCD. The composition of the ECM in FCD and non-malformed cortex (in 163 samples from 62 patients) was analyzed immunohistochemically and correlated with the corresponding ECS diffusion parameter values determined with the real-time iontophoretic method in freshly resected cortex (i.e. the ECS volume fraction and the geometrical factor tortuosity, describing the hindrances to diffusion in the ECS). The ECS in FCD was shown to differ from that in non-malformed cortex, mainly by the increased accumulation of certain ECM molecules (tenascin R, tenascin C, and versican) or by their reduced expression (brevican), and by the presence of an increased number of astrocytic processes. The consequent increase of ECS diffusion barriers observed in both FCD type I and II (and, at the same time, the enlargement of the ECS volume in FCD type II) may alter the diffusion of neuroactive substances through the ECS, which mediates one of the important modes of intercellular communication in the brain - extrasynaptic volume transmission. Thus, the changed ECM composition and altered ECS diffusion properties might represent additional factors contributing to epileptogenicity in FCD.

The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies.

OBJECTIVES: The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies. METHODS: S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6). IF staining was used to co-localize S100A4 with selected cells. Cytokine expression and protein synthesis in S100A4-treated cells were analysed by RT-PCR and ELISA. RESULTS: S100A4 protein was significantly up-regulated in muscle tissue of patients with inflammatory myopathies compared with control individuals and was associated particularly with the presence of mononuclear infiltrates. Only few regenerating muscle fibres in PM/DM expressed S100A4. Then we analysed the effect of S100A4 on human myocytes and peripheral blood mononuclear cells (PBMCs). Although S100A4 did not affect myocytes, stimulation of PBMCs with S100A4 significantly induced the expression and synthesis of TNF-α, IL-1ß and IL-6, but not of IFN-α. We showed that S100A4 is not directly involved in perforin/granzyme B-induced apoptosis and that it does not modulate the expression of Bax and Bcl2 mRNA in myocytes and PBMCs. CONCLUSION: Increased expression of S100A4 in inflamed muscle tissue highlights its potential role in the pathogenesis of inflammatory myopathies. S100A4 may act as a cytokine-like factor indirectly promoting muscle fibre damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines.

Immunohistochemical prognostic markers in intracranial ependymomas: systematic review and meta-analysis.

Distinction between grade II ependymomas and anaplastic ependymomas based on histopathological examination solely is problematic and, therefore, the management of intracranial ependymomas remains controversial. The aim of this study was to conduct a systematic review (SR) and meta-analysis (MA) of data published on immunohistochemical prognostic markers (IPM) in intracranial ependymomas (IE), and to establish an evidence-based perspective on their clinical value. Following the extensive search based on a strictly defined group of key words, 30 studies reporting results on IPM in IE were identified. Due to a pronounced inter-study heterogeneity, only 14 publications fulfilled the criteria for inclusion into SR. From the total of 67 immunohistochemical markers, 18 were found to correlate with prognosis. However, owing to inadequate data publishing, MA could be performed only with data on proliferation marker MIB-1 (Ki-67) from 5 publications, including 337 patients: The pooled hazard ratio for overall survival was 3.16 (95% confidence interval = 1.96-5.09; p < 0.001) implicating that patients suffering from tumors with higher immunohistochemical expression of MIB-1 had a significantly worse outcome. Marked inter-study heterogeneity and incomplete data publishing in primary studies significantly limited extent of the SR, and the possibility of performing MA. Although the prognostic impact of MIB-1 immunoexpression in IE could be confirmed, there remains lack of further reliable IPM that could be used in routine diagnosis. We encourage to search for new, useful markers, as well as to standardize lab-techniques and data interpretation algorithms across laboratories in order to increase data compatibility.