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Objective: This study analysed whether the persistence of both reversible airway obstruction (RAO) and elevated BE counts was associated to reduced asthma control and accelerated lung function decline in treated severe asthmatics. Methods: About 202 severe asthmatics were studied after 12–120 months of step‐5 treatment associated to anti‐IgE therapy. Following treatments, reversibility tests, after inhaling 400 mcg of Salbutamol, were performed. FEV1 > 12% or ≤12% changes differentiated RAO+ from RAO− subjects. Blood eosinophil (BE) counts after treatment were considered. Results: Pre‐/post‐treatment bronchodilator FEV1% and ACT were lower (61% [50–71], 74.4% [62.5–83.7] and 20[18–22]), whereas BE were higher (380 cells/µl [170–590]) in RAO+ compared to RAO− subjects (77% [64–88], p = 0.0001, 81.8% [66.1–94.3], p = 0.0001, 21[18–23], p = 0.045 and 230 cells/µl [80–360], p = 0.003). A negative relationship between SABA‐induced FEV1% changes and pre‐bronchodilator FEV1% (β = −0.551%; p = 0.0001) and ACT (β = −0.059; p = 0.038) was found. Conversely, post‐treatment BE levels were positively related (β = 145.565 cells/µl; p = 0.003) to FEV1 > 12% increases. A rising trend of pre‐/post‐bronchodilator FEV1% in time was observed in RAO− subjects with BE < 300 cells/µl. Conversely, we highlighted significant declining tendencies of pre/post‐bronchodilator FEV1% in RAO+ patients with BE > 300 cells/µl reaching lower values after more than 36 months of step‐5 treatment (59.6% [39.9–72.1] vs 74[66.5–89.2] of RAO+ individuals with BE < 300 cells/µl [p = 0.026] and 81.6% [66.1–91.8] of RAO‐subjects with BE > 300 cells/µl [p = 0.009]). Conclusion: Persistent SABA‐induced FEV1 > 12%, especially when associated to BE > 300 cells/ml, may be a marker of accelerated lung function decline in severe asthmatics despite maximal step‐5 treatment. The highest bronchodilation associated to the lowest BE levels should be the main goal of asthma treatment to prevent such decline. [ABSTRACT FROM AUTHOR]

Objective 3-hydroxy-3-methylglutaryl-coenzyme A ( HMG-CoA) reductase inhibitors (statins) can affect post-translational processes, thus being responsible for decreased farnesylation and geranylgeranylation of intracellular small G proteins such as Ras, Rho and Rac, essential for cell survival and proliferation. In this regard, recent in vitro and in vivo studies suggest a possible role for both statins and farnesyl transferase inhibitors in the treatment of malignancies. Within such a context, the aim of our study was to investigate effects of either simvastatin (at concentrations of 1, 15, and 30 μ m) or the farnesyl transferase inhibitor R115777 (at concentrations of 0.1, 1, and 10 μ m), on two cultures of human non-small lung cancer cells, adenocarcinoma ( GLC-82) and squamous ( CALU-1) cell lines. In particular, we evaluated actions of these two drugs on phosphorylation of the ERK1/2 group of mitogen-activated protein kinases and on apoptosis, plus on cell numbers and morphology. Materials and Methods Western blotting was used to detect ERK phosphorylation, and to assess apoptosis by evaluating caspase-3 activation; apoptosis was also further assessed by terminal deoxynucleotidyl-mediated d UTP nick end labelling ( TUNEL) assay. Cell counting was performed after trypan blue staining. Results and conclusion In both GLC-82 and CALU-1 cell lines, simvastatin and R115777 significantly reduced ERK phosphorylation; this effect, which reached the greatest intensity after 36 h treatment, was paralleled by a concomitant induction of apoptosis, documented by significant increase in both caspase-3 activation and TUNEL-positive cells, associated with a reduction in cell numbers. Our results thus suggest that simvastatin and R115777 may exert, in susceptible lung cancer cell phenotypes, a pro-apoptotic and anti-proliferative activity, which appears to be mediated by inhibition of the Ras/Raf/ MEK/ ERK signalling cascade. [ABSTRACT FROM AUTHOR]

Objectives: Both interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) are crucially involved in fibrotic events that characterize interstitial lung diseases (ILD). Therefore, the aim of this study was to investigate in primary cultures of normal and fibrotic human lung fibroblasts (HLF), exposed to either IL-6 or TGF-β1, the effects on phosphorylation of mitogen-activated protein kinases (MAPK) and cell growth of IL-6 signalling inhibition, performed by the IL-6 receptor superantagonist Sant7. Materials and methods: MAPK phosphorylation was detected by Western blotting, HLF viability and proliferation were evaluated using the trypan blue staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, respectively. Results: Sant7, at a concentration of 1 µg/mL, was capable of significantly inhibiting HLF proliferation and MAPK phosphorylation induced by cell exposure to IL-6 (100 ng/mL) or TGF-β1 (10 ng/mL), whose actions were more evident in fibrotic cells. Conclusions: These findings suggest that, in HLFs derived from patients with ILDs, the proliferative mechanisms activated by TGF-β1 are at least in part mediated by an increased release of IL-6, leading to phosphorylation-dependent MAPK activation. Such preliminary findings may thus open new therapeutic perspectives for fibrogenic ILDs, based on inhibition of signal transduction pathways stimulated by the IL-6 receptor. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the causes of congenital myasthenic syndrome (CMS), a genetic disorder affecting nuromuscular transmission, published in the previous issue.

Describes the pathophysiology of the bronchial obstruction in asthmatic patients. Relation between the ventilatory changes and gas-exchange alteration; Description of the static and dynamic properties of the respiratory system; Role of the thoracopulmonary systems in developing the thoracic system.

Peripheral neuropathy is common among patients with fragile X-associated tremor ataxia syndrome (FXTAS). Four patients with FXTAS are described with neuropathy as the presenting feature, two having received a prior diagnosis of Charcot-Marie-Tooth (CMT) disease. A fifth is described with neuropathy as the only clinical feature. A functional connection between FXTAS and neuropathy has been suggested by the presence of lamin A/C in the intranuclear, neuronal and astrocytic inclusions of FXTAS, since mutations in lamin A/C are known to give rise to an axonal form of CMT., (2007 Wiley-Liss, Inc)