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The external genitalia of the female spotted hyena are male in character, consistent with virilization by androgens during embryogenesis that results in the fusion of the vaginal labia to form a pseudo scrotum and enlargement of the clitoris to form a phallus. Explanations advanced to account for these anatomic differences have centered on the production or metabolism of androgens in utero or on abnormalities of the androgen receptor (such as a constitutively active AR). The structure of the spotted hyena AR was examined at the level of genomic DNA and cDNA. Southern analysis detected two Eco RI endonuclease cleavage fragments (4.4 and 4.7 kb) that encode the bulk of the AR hormone-binding domain. Isolation of the smaller fragment from a size fractionated genomic library revealed that it contained exons 6, 7 and 8. The remaining portions of the coding sequence were cloned by RT-PCR and RACE analyses. The spotted hyena cDNA sequence predicts protein 912 amino acids in length, which is most closely related to the sequence of the dog AR. Although a number of differences in the predicted amino acid sequence are identified, particularly within the amino terminus, only single amino acid substitutions are present in the DNA- and ligand-binding domains compared to the human AR. In transfection assays, the spotted hyena AR does not exhibit constitutive activity and responds normally to a range of androgenic and non-androgenic ligands. These findings suggest that the structural changes in the AR do not account for the abnormal virilization in the female spotted hyena. These results serve to focus attention on processes proximal (an abnormality of hormone formation in situ) or distal (activation by other mechanisms of processes normally regulated by androgen) to the AR as the cause of the virilization. [Copyright &y& Elsevier]

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]

Although platinum-based two-drug combinations represent the elective therapeutic approach for advanced/metastatic NSCLC, there is still interest in exploring the efficacy and tolerability of platinum-free combinations including third generation agents in selected NSCLC population. Based on the satisfying activity of gemcitabine (G), ifosfamide (I) and paclitaxel (T) as single agents in NSCLC, we have designed a phase II study to explore an alternative approach to platinum-containing regimens using a combination of these three drugs. To investigate the activity/toxicity of T 175 mg/m2 on day 1, I 3 g/m2 on day 1 (with Mesna uroprotection) and G 1,000 mg/m2 on day 1–8, every 3 weeks in the treatment of advanced/metastatic NSCLC, 46 patients (38 male, 8 female) with NSCLC were enrolled: mean age 58 (range 33–70); Stage IIIB/IV = 15/31; ECOG PS 0-1/2 = 31/15; Histology: adenocarcinoma = 20, squamous = 14, large cell = 3, NSCLC = 8, adenosquamous = 1. A total of 221 cycles have been administered (median number 4.8 for patients). In intent-to-treat analysis, partial response was achieved in 17 patients (36.95%), stable disease and progressive disease was detected in 16 (34.78%) and 10 (21.73%) patients, respectively. Time to progression was 30.9 weeks; median survival time was 42.7 weeks; the survival rates at 12 and 18 months were 34.79 and 15.21%, respectively. No toxic deaths occurred. No patients experienced grade 4 neutropenia and thrombocytopenia. Neutropenia grade 3 occurred in 10 patients (21.7%); Anemia grade 3 in 1 (2.1%); Thrombocytopenia grade 2 in two patients (4.3%) and grade 3 in one (2.1%). Peripheral neuropathy grade 1 occurred in ten (21.7%) and grade 2 in two patients (4.3%). Additional non-haematological toxicities were mild nausea, emesis and fatigue. GIT is well tolerated and active regimen in both advanced and metastatic NSCLC. These data suggest future investigations for GIT schedule as a possible alternative to platinum-based regimens in selected advanced/metastatic NSCLC patients where survival, tolerability and quality of life are the primary goals. [ABSTRACT FROM AUTHOR]

A new compact, multiband, single-feed planar inverted-F antenna (PIFA) for laptop computers is presented. The proposed large-bandwidth radiating system is designed to operate in the IEEE 802.11a (5.725–5.825 GHz), IEEE 802.11b (2.4–2.48 GHz), and HIPERLAN2 (5.470–5.725 GHz) frequency bands. The overall size of the antenna and its dimensions are suitable for its installation in any position along the border of the display of a laptop computer. The design procedure is illustrated and discussed. The antenna behavior has been analyzed by resorting to both a conformal finite-difference time-domain (CFDTD) simulation procedure and a finite-element method (FEM) based technique. The simulation results are shown for the antenna in free space as well as when it is mounted in the border of a notebook display. A prototype is realized and the measurement results show good agreement with the simulation data. © 2005 Wiley Periodicals, Inc. Microwave Opt Technol Lett 46: 454–458, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.21015 [ABSTRACT FROM AUTHOR]

Short-acting β2-agonists are currently recommended for symptom relief in asthma and the treatment of mild, acute exacerbations in COPD. However, formoterol has as fast an onset of action as salbutamol with the additional benefit of longer-lasting bronchodilation (approximately 12 h). Furthermore, systemic side effects observed with formoterol are of a similar duration but less pronounced than with short-acting β2-agonists. In this double-blind, randomized, cross-over study, 20 adult patients with reversible chronic airway obstruction (intrinsic asthma or COPD) inhaled single doses of formoterol 9 μg or salbutamol 100 μg (group A) or formoterol 18 μg or salbutamol 200 μg (group B). FEV1 was measured prior to and 5, 10, 15, 20, 25 and 30 min following inhalation of study drug. No significant differences in FEV1 values were observed between group A (P=0.704) or group B (P=0.270) at baseline, or at 5 (Group A: P=0.340; Group B: P=0.559) and 15 min (Group A: P=0.526; Group B: P=0.818) post dose. No adverse events were reported during the study. Formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at the recommended doses. [Copyright &y& Elsevier]