PULMONARY FUNCTION IN RHEUMATOID ARTHRITIS TREATED WITH LOW-DOSE METHOTREXATE: A LONGITUDINAL STUDY

Lung volumes and gas exchange were investigated prospectively in 96 patients with rheumatoid arthritis selected without regard to pulmonary disorders and treated with i.m. methotrexate (MTX) injections [mean weekly dose 13.0 mg (5th-95th percentile (5-95 PC) 7.6-20.8)]. Individual changes over time during MTX treatment [mean duration 2.9 yr (5-95 PC 0.4-5.3)] were assessed by regression analyses in each individual. Forced vital capacity (FVQ remained stable in the majority of patients [mean annual change +0.8% (5-95 PC −8.1 to +14.0) of calculated normal value]. In addition, transfer factor using the indicator gas CO (TLCO) was unaltered in most patients [mean annual change − 2.1% (5-95 PC −16.2 to +11.8) of predicted value]. However, there were significant decreases in the forced expiratory volume in 1 s (FEV1) before and after inhalation of 0.2 mg salbutamol [mean annual change - 0.8% (5-;95 PC −8.4 to +3.2) and −1.3% (5-95 PC −7.8 to +3.9) of the FVC measured, respectively]. In addition, there were significant increases in alveolar-arterial Po2, gradients (P(A-a), O2) at rest and after exercise [mean annual change +1.7 mmHg (5-;95 PC −5.2 to +12.2) and +1.8 mmHg (5-95 PC −3.5 to 9.0), respectively]. Nevertheless, the amounts were small in view of the reliability of the methods applied and reflect, at least in part, the normal process of ageing. The annual change in FEV1 /FVC was negatively correlated with FEV1 /FVC at baseline (Rs = − 0.46, P < 0.001). The annual change in TL, co was also negatively correlated with TL, co at baseline (Rs = − 0.31, P = 0.028). No other risk factors for deterioration of lung volumes or gas exchange were found, including mean weekly MTX dose, age, gender, smoking, presence of rheumatoid factor and pulmonary function at baseline. We conclude that MTX has no major effect on pulmonary function in the majority of patients and that there is no evidence that patients with pre-existing pulmonary disease are at increased risk for further deterioration of lung functio

Carcinoid Tumour of the Appendix: An Analysis of 1,485 Consecutive Emergency Appendectomies

Aim: The aim of this study is to conduct a retrospective analysis of the incidence and long-term results of carcinoid tumours of the appendix in emergency appendectomies. Methods: A retrospective review of 1,485 appendectomies was performed in two centres from January 2000 until January 2006. Demographic data, clinical presentation, histopathology, operative reports and survival were scored and compared with the literature. Results: In three women and four men, carcinoid tumours were identified (0.47%). The mean age was 32.7 years (range, 20-59 years). The clinical presentation was resembling the symptoms of acute appendicitis in all cases. Laparoscopic appendectomy was the treatment of choice in five patients; in one of these patients, a conversion to laparotomy was necessary. The other two patients underwent primary open appendectomy. Five patients underwent additional surgery after the pathology report became available. Four patients underwent ileocecal resection; one other patient underwent right hemicolectomy. In none of the re-operation specimens was residual carcinoid tumour detected. After a mean follow-up of 65 months (range, 25-92), all patients were alive and disease- and symptom-free. Conclusion: Carcinoid tumours of the appendix most often present as acute appendicitis. It also emphasises the value of histopathological analysis of every removed appendix. The long-term prognosis of incidentally found carcinoids of the appendix is good

Shapes of polyhedra, mixed volumes and hyperbolic geometry

We generalize to higher dimensions the Bavard–Ghys construction of the hyperbolic metric on the space of polygons with fixed directions of edges. The space of convex d -dimensional polyhedra with fixed directions of facet normals has a decomposition into type cones that correspond to different combinatorial types of polyhedra. This decomposition is a subfan of the secondary fan of a vector configuration and can be analyzed with the help of Gale diagrams. We construct a family of quadratic forms on each of the type cones using the theory of mixed volumes. The Alexandrov–Fenchel inequalities ensure that these forms have exactly one positive eigenvalue. This introduces a piecewise hyperbolic structure on the space of similarity classes of polyhedra with fixed directions of facet normals. We show that some of the dihedral angles on the boundary of the resulting cone-manifold are equal to π/2

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

YesTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes

Mucociliary and long-term particle clearance in airways of patients with immotile cilia

Spherical monodisperse ferromagnetic iron oxide particles of 1.9 μm geometric and 4.2 μm aerodynamic diameter were inhaled by seven patients with primary ciliary dyskinesia (PCD) using the shallow bolus technique, and compared to 13 healthy non-smokers (NS) from a previous study. The bolus penetration front depth was limiting to the phase1 dead space volume. In PCD patients deposition was 58+/-8 % after 8 s breath holding time. Particle retention was measured by the magnetopneumographic method over a period of nine months. Particle clearance from the airways showed a fast and a slow phase. In PCD patients airway clearance was retarded and prolonged, 42+/-12 % followed the fast phase with a mean half time of 16.8+/-8.6 hours. The remaining fraction was cleared slowly with a half time of 121+/-25 days. In healthy NS 49+/-9 % of particles were cleared in the fast phase with a mean half time of 3.0+/-1.6 hours, characteristic of an intact mucociliary clearance. There was no difference in the slow clearance phase between PCD patients and healthy NS. Despite non-functioning cilia the effectiveness of airway clearance in PCD patients is comparable to healthy NS, with a prolonged kinetics of one week, which may primarily reflect the effectiveness of cough clearance. This prolonged airway clearance allows longer residence times of bacteria and viruses in the airways and may be one reason for increased frequency of infections in PCD patients

Motion and twisting of magnetic particles ingested by alveolar macrophages in the human lung: effect of smoking and disease

BACKGROUND: Magnetic microparticles being ingested by alveolar macrophages can be used as a monitor for intracellular phagosome motions and cytoskeletal mechanical properties. These studies can be performed in the human lung after voluntary inhalation. The influence of cigarette smoking and lung diseases on cytoskeleton dependent functions was studied. METHODS: Spherical 1.3 μm diameter ferrimagnetic iron oxide particles were inhaled by 17 healthy volunteers (40 – 65 years), 15 patients with sarcoidosis (SAR), 12 patients with idiopathic pulmonary fibrosis (IPF), and 18 patients with chronic obstructive bronchitis (COB). The retained particles were magnetized and aligned in an external 100 mT magnetic field. All magnetized particles induce a weak magnetic field of the lung, which was detected by a sensitive SQUID (superconducting quantum interference device) sensor. Cytoskeletal reorganizations within macrophages and intracellular transport cause stochastic magnetic dipole rotations, which are reflected in a decay of the magnetic lung field, called relaxation. Directed phagosome motion was induced in a weak magnetic twisting field. The resistance of the cytoplasm to particle twisting was characterized by the viscosity and the stiffness (ratio between stress to strain) of the cytoskeleton. RESULTS: One week after particle inhalation and later macrophage motility (relaxation) and cytoskeletal stiffness was not influenced by cigarette smoking, neither in healthy subjects, nor in the patients. Patients with IPF showed in tendency a faster relaxation (p = 0.06). Particle twisting revealed a non-Newtonian viscosity with a pure viscous and a viscoelastic compartment. The viscous shear was dominant, and only 27% of the shear recoiled and reflected viscoelastic properties. In patients with IPF, the stiffness was reduced by 60% (p < 0.02). An analysis of the shear rate and stress dependence of particle twisting allows correlating the rheological compartments to cytoskeletal subunits, in which microtubules mediate the pure viscous (non-recoverable) shear and microfilaments mediate the viscoelastic (recoverable) behavior. The missing correlation between relaxation and particle twisting shows that both stochastic and directed phagosome motion reflect different cytoskeletal mechanisms. CONCLUSION: Faster relaxation and a soft cytoskeleton in patients with IPF indicate alterations in cytoskeleton dependent functions of alveolar macrophages, which may cause dysfunction's in the alveolar defense, like a slower migration, a retarded phagocytosis, a disturbed phagosome lysosome fusion and an impaired clearance

Human Flt3L Generates Dendritic Cells from Canine Peripheral Blood Precursors: Implications for a Dog Glioma Clinical Trial

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads) encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK). This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs), in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF.Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-alpha and IFN-gamma. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation.These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical trials

CMS Data Processing Workflows during an Extended Cosmic Ray Run

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