Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy

Long term variability of Cygnus X-1: VII. Orbital variability of the focussed wind in Cyg X-1 / HDE 226868 system

Binary systems with an accreting compact object are a unique chance to investigate the strong, clumpy, line-driven winds of early type supergiants by using the compact object's X-rays to probe the wind structure. We analyze the two-component wind of HDE 226868, the O9.7Iab giant companion of the black hole Cyg X-1 using 4.77 Ms of RXTE observations of the system taken over the course of 16 years. Absorption changes strongly over the 5.6 d binary orbit, but also shows a large scatter at a given orbital phase, especially at superior conjunction. The orbital variability is most prominent when the black hole is in the hard X-ray state. Our data are poorer for the intermediate and soft state, but show signs for orbital variability of the absorption column in the intermediate state. We quantitatively compare the data in the hard state to a toy model of a focussed Castor-Abbott-Klein-wind: as it does not incorporate clumping, the model does not describe the observations well. A qualitative comparison to a simplified simulation of clumpy winds with spherical clumps shows good agreement in the distribution of the equivalent hydrogen column density for models with a porosity length on the order of the stellar radius at inferior conjunction; we conjecture that the deviations between data and model at superior conjunction could be either due to lack of a focussed wind component in the model or a more complicated clump structure.Comment: proposed for acceptance in A&A, 11 pages, 11 figures (two in appendix

X-ray and Radio Monitoring of GX 339-4 and Cyg X-1

Previous work by Motch et al. (1985) suggested that in the low/hard state of GX339-4, the soft X-ray power-law extrapolated backward in energy agrees with the IR flux level. Corbel and Fender (2002) later showed that the typical hard state radio power-law extrapolated forward in energy meets the backward extrapolated X-ray power-law at an IR spectral break, which was explicitly observed twice in GX339-4. This has been cited as further evidence that jet synchrotron radiation might make a significant contribution to the observed X-rays in the hard state. We explore this hypothesis with a series of simultaneous radio/X-ray hard state observations of GX339-4. We fit these spectra with a simple, but remarkably successful, doubly broken power-law model that indeed requires a spectral break in the IR. For most of these observations, the break position as a function of X-ray flux agrees with the jet model predictions. We then examine the radio flux/X-ray flux correlation in Cyg X-1 through the use of 15 GHz radio data, obtained with the Ryle radio telescope, and Rossi X-ray Timing Explorer data, from the All Sky Monitor and pointed observations. We find evidence of `parallel tracks' in the radio/X-ray correlation which are associated with `failed transitions' to, or the beginning of a transition to, the soft state. We also find that for Cyg X-1 the radio flux is more fundamentally correlated with the hard, rather than the soft, X-ray flux.Comment: To Appear in the Proceedings of "From X-ray Binaries to Quasars: Black Hole Accretion on All Mass Scales" (Amsterdam, July 2004). Eds. T Maccarone, R. Fender, L. H

Multifrequency Observations of the Virgo Blazars 3C 273 and 3C 279 in CGRO Cycle 8

We report first observational results of multifrequency campaigns on the prominent Virgo blazars 3C 273 and 3C 279 which were carried out in January and February 1999. Both blazars are detected from radio to gamma-ray energies. We present the measured X- to gamma-ray spectra of both sources, and for 3C 279 we compare the 1999 broad-band (radio to gamma-ray) spectrum to measured previous ones.Comment: 5 pages including 3 figures, latex2e, to appear in: 'Proc. of the 5th Compton Symposium', AIP, in pres

The value of reasons for encounter in early detection of colorectal cancer

BACKGROUND: Symptoms with a high predictive power for colorectal cancer (CRC) do not exist. OBJECTIVE: To explore the predictive value of patients' reason for encounter (RFE) in the two years prior to the diagnosis of CRC. METHODS: A retrospective nested case-control study using prospectively collected data from electronic records in general practice over 20 years. Matching was done based on age (within two years), gender and practice. The positive likelihood ratios (LR+) and odds ratios (OR) were calculated for RFE between cases and controls in the two years before the index date. RESULTS: We identified 184 CRC cases and matched 366 controls. Six RFEs had significant LR + and ORs for CRC, which may have high predictive power. These RFEs are part of four chapters in the International Classification of Primary Care (ICPC) that include tiredness (significant at 3-6 months prior to the diagnosis; LR+ 2.6 and OR 3.07; and from 0 to 3 months prior to the diagnosis; LR+ 2.0 and OR 2.36), anaemia (significant at three months before diagnosis; LR+ 9.8 and OR 16.54), abdominal pain, rectal bleeding and constipation (significant at 3-6 months before diagnosis; LR+ 3.0 and OR 3.33; 3 months prior to the diagnosis LR+ 8.0 and OR 18.10) and weight loss (significant at three months before diagnosis; LR+ 14.9 and OR 14.53). CONCLUSION: Data capture and organization in ICPC permits study of the predictive value of RFE for CRC in primary care

On the Absorption of X-rays in the Interstellar Medium

We present an improved model for the absorption of X-rays in the ISM intended for use with data from future X-ray missions with larger effective areas and increased energy resolution such as Chandra and XMM, in the energy range above 100eV. Compared to previous work, our formalism includes recent updates to the photoionization cross section and revised abundances of the interstellar medium, as well as a treatment of interstellar grains and the H2molecule. We review the theoretical and observational motivations behind these updates and provide a subroutine for the X-ray spectral analysis program XSPEC that incorporates our model.Comment: ApJ, in press, for associated software see http://astro.uni-tuebingen.de/nh

Going with the flow: can the base of jets subsume the role of compact accretion disk coronae?

The hard state of X-ray binaries (XRBs) is characterized by a power law spectrum in the X-ray band, and a flat/inverted radio/IR spectrum associated with occasionally imaged compact jets. It has generally been thought that the hard X-rays result from Compton upscattering of thermal accretion disk photons by a hot, coronal plasma whose properties are inferred via spectral fitting. Interestingly, these properties-especially those from certain magnetized corona models-are very similar to the derived plasma conditions at the jet footpoints. Here we explore the question of whether the `corona' and `jet base' are in fact related, starting by testing the strongest premise that they are synonymous. In such models, the radio through the soft X-rays are dominated by synchrotron emission, while the hard X-rays are dominated by inverse Compton at the jet base - with both disk and synchrotron photons acting as seed photons. The conditions at the jet base fix the conditions along the rest of the jet, thus creating a direct link between the X-ray and radio emission. We also add to this model a simple iron line and convolve the spectrum with neutral reflection. After forward-folding the predicted spectra through the detector response functions, we compare the results to simultaneous radio/X-ray data obtained from the hard states of the Galactic XRBs GX339-4 and Cygnus X-1. Results from simple Compton corona model fits are also presented for comparison. We demonstrate that the jet model fits are statistically as good as the single-component corona model X-ray fits, yet are also able to address the simultaneous radio data.Comment: Accepted to the Astrophysical Journal. 14 pages, emulateapj.st

DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents?

DT-diaphorase (DTD) is an important enzyme for the bioreductive activation of the new alkylating indoloquinone EO9. In preclinical studies, EO9 has shown selective anti-tumour activity against solid tumours and under hypoxic conditions. The levels of three reductive enzymes have been determined in three types of human solid tumours, together with corresponding normal tissues and normal liver. DTD enzyme activities were measured in tumour extracts using 2,6-dichlorophenolindophenol (DCPIP) and NADH as substrates; cytochrome P450 reductase or cytochrome b5 reductase activities were assessed with cytochrome c and NADPH or NADH respectively. DTD activity was highest in non-small-cell lung (NSCLC)-tumours (mean 123 nmol DCPIP min-1 mg-1), followed by colon carcinoma (mean 75 nmol min-1 mg-1) and squamous cell carcinoma of the head and neck (6-fold lower than NSCLC). DTD activity was very low in normal liver and normal lung (4-6 nmol min-1 mg-1), while the levels in normal colon mucosa or normal mucosa of the head and neck region were in the same range as the corresponding tumours. The levels of the two other reductive enzymes, cytochrome P450 reductase (CP450R) and cytochrome b5 reductase (Cb5R), were 5 to 25-fold lower than those of DTD in all the tissues, except for normal liver, in which DTD was 2 to 4-fold lower. The degree of variation found for DTD (range 4-250 nmol min-1 mg-1), was not observed for these enzymes (CP450R, 0.8-7.8 nmol cytochrome c min-1 mg-1; Cb5R, 3.5-27.6 nmol min-1 mg-1).(ABSTRACT TRUNCATED AT 250 WORDS