A variety of environmental agents has been found to influence the development of autoimmune diseases; in particular, the studies investigating the potential association of systemic autoimmune rheumatic diseases with environmental micro and nano-particulate matter are very few and contradictory. In this study, the role of diesel exhaust particles (DEPs), one of the most important components of environment particulate matter, emitted from Euro 4 and Euro 5 engines in altering the Normal Human Bronchial Epithelial (NHBE) cell biological activity was evaluated. NHBE cells were exposed in vitro to Euro 4 and Euro 5 particle carbon core, sampled upstream of the typical emission after-treatment systems (diesel oxidation catalyst and diesel particulate filter), whose surfaces have been washed from well-assessed harmful species, as polycyclic aromatic hydrocarbons (PAHs) to: (1) investigate their specific capacity to affect cell viability (flow cytometry); (2) stimulate the production of the pro-inflammatory cytokine IL-18 (Enzyme-Linked ImmunoSorbent Assay -ELISA-); (3) verify their specific ability to induce autophagy and elicit protein citrullination and peptidyl arginine deiminase (PAD) activity (confocal laser scanning microscopy, immunoprecipitation, Sodium Dodecyl Sulphate-PolyAcrylamide Gel Electrophoresis -SDS-PAGE- and Western blot, ELISA). In this study we demonstrated, for the first time, that both Euro 4 and Euro 5 carbon particles, deprived of PAHs possibly adsorbed on the soot surface, were able to: (1) significantly affect cell viability, inducing autophagy, apoptosis and necrosis; (2) stimulate the release of the pro-inflammatory cytokine IL-18; (3) elicit protein citrullination and PAD activity in NHBE cells. In particular, Euro 5 DEPs seem to have a more marked effect with respect to Euro 4 DEPs.

In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormone–releasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic–pituitary–gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinB1, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinB1-deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinB1 with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinB1 during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons.

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BackgroundAntibodies against carbamylated proteins (anti-CarP) have been recently identified in the sera of patients with rheumatoid arthritis (RA). The objective of the study was to evaluate the prevalence, sensitivity and specificity of anti-CarP compared to anti-citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF), replicating the existing data in a large cohort of Italian patients with RA and extending the evaluation to other autoimmune rheumatic diseases (AIRDs).MethodsSerum samples (n = 607) from 309 patients with RA, 200 disease controls and 98 normal healthy subjects (NHS) were evaluated. Anti-CarP were detected using carbamylated fetal calf serum as the antigen. ACPAs were detected using second-generation ELISA and IgM RF was assessed as part of routine analysis.ResultsAnti-CarP antibodies were detected in 117 patients with RA (34.4%), ACPA in 190 patients (61.4%) and RF in 202 patients (65.3%). Two (2.04%) of the NHS were positive for anti-CarP, one NHS (1.02%) was positive for ACPA and three NHS were positive for RF (3.06%). Among disease controls, anti-CarP antibodies were detected in 33 patients (16.5%), ACPA in 29 patients (14.5%) and RF in 64 patients (32%). In particular, 16.8% of patients with systemic lupus erythematosus and 31.1% of patients with Sjögren syndrome were positive for anti-CarP. The sensitivity of anti-CarP, ACPA and RF was 46.8%, 61.8% and 64.4%, respectively and specificity was 91.95%, 89.93% and 76.51%, respectively.ConclusionsThe present study extends the knowledge of anti-CarP antibodies, confirming previous data on the diagnostic accuracy of anti-CarP in RA in a large cohort of Italian patients. Anti-CarP antibodies demonstrated relatively low sensitivity and slightly higher specificity compared to ACPA and RF. Even if predominantly present in RA, anti-CarP was detected in a variable percentage of patients with other autoimmune rheumatic diseases and their generation could be attributed to the inflammatory status; the clinical relevance of anti-CarP antibodies in these latter patients should be further determined.

The aim of this study was to analyze the effects of chronic administration of the beta(2)-agonist clenbuterol (1.5 mg x kg(-1) x day(-1) for 4 wk in the drinking water) on respiratory (diaphragm and parasternal intercostal) and hindlimb (tibialis and soleus) muscles in young rats during postnatal development (21 to 49 postnatal days). The treatment resulted in very little stimulation of muscle growth. Significant slow-to-fast transitions in the expression of myosin heavy chain isoforms and significant increases in the myofibrillar ATPase activity were found in the diaphragm and soleus, whereas tibialis anterior and intercostal muscles did not show any significant fiber-type alteration. Decrease of oxidative enzyme activities and increase of glycolytic enzyme activities were also observed. It is concluded that whereas the growth stimulation is age dependent and only detectable in adult rats, the fiber-type transformation is also present in weaning rats and particularly evident in the soleus and diaphragm. The fiber-type transformation caused by clenbuterol might lead to an enhancement of contractile performance and also to a reduced resistance to fatigue.

Edited by Wilhelm JustKeywords: Dopamine GABA Glutamate Substantia nigra Ventral tegmental area Rostromedial tegmental nucleus a b s t r a c t For regulation of voluntary movement and motivation the midbrain dopaminergic system receives input from a variety of brain regions. Often this input is mediated by local non-dopaminergic neurons within or closely associated with the dopaminergic nuclei. In addition to the dopaminergic neurons, some of these non-dopaminergic neurons also send functionally important output from the ventral midbrain to forebrain targets. The aim of this review is to introduce subtypes of GABAergic and glutamatergic neurons, which are located in the dopaminergic nuclei or the adjacent brainstem and are important for the regulation of the dopaminergic pathways. In addition, we discuss recent studies beginning to reveal mechanisms for their development, which may hold the key to understanding the diversity of these neurons.

In the present study, we performed a retrospective study on the indication, efficacy and causes of withdrawal of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE). Moreover, a review of the literature concerning the use of MMF in the real life was performed. We recorded data about indications, mean dosage, duration of treatment and reasons for drug withdrawal. The efficacy was evaluated according to changes in SLE Disease Activity Index 2000 (SLEDAI-2K), renal SLEDAI-2K and daily proteinuria, after 4 and 12 months of treatment. Six hundred and nine SLE patients were evaluated; among them, 109 patients (17.9 %) were treated with MMF (mean treatment duration 33.9 ± 31.2 months, mean dosage 28.1 ± 10.6 mg/kg). The most frequent indications for using MMF were lupus nephritis (55.9 %) and musculoskeletal manifestations (33.0 %). After 4 and 12 months, a significant reduction of mean SLEDAI-2K, renal SLEDAI and daily proteinuria, compared with baseline, was demonstrated. Thirty-one patients (28.4 %) discontinued MMF therapy (mean treatment duration at the time of discontinuation 17.5 ± 21.2 months). The incidence risks of MMF discontinuation due to inefficacy and side effects were 0.09 and 0.1, respectively. Patients with disease duration longer than 36 months (70.6 %) had a significant increased risk of MMF withdrawal (RR 0.4, P = 0.03). The results of the present study demonstrated that MMF should be considered a treatment option for SLE manifestation other than renal involvement in daily clinical practice.

HighlightsECL-based assays for measurement of adalimumab and adalimumab antibodies.Performance of ECL antibody assay not significantly improved by acid dissociation.Negative correlation between levels of antibody and free adalimumab.Negative correlation between adalimumab level and disease activity scores.