Studies on the persistence of estradiol benzoate and nortestosterone decanoate in hair of cattle following treatment with growth promoters, determined by ultra-high-performance liquid chromatography-tandem mass spectrometry

Measurement of steroid esters in bovine hair samples, using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS), provides a powerful tool for identifying animals treated illicitly with growth promoters. The successful application of such testing requires appropriate sampling of hair from treated animals. This paper describes the results of hair analysis by LC-MS/MS for two animal studies in which animals were treated with estradiol-3-benzoate and nortestosterone decanoate. The results from the first animal study indicate that animals treated with these anabolic steroids may not always be identified from analysis of hair samples; positive test results occur sporadically and only for some of the treated animals. The results from the second animal study identify conditions attaching to positive hair samples, such as, that concentrations of steroid esters in hair are related to distance of sampling from point of injection and to time post-treatment, that concentrations of steroid esters in hair are related to dose given to the animal but that this relationship may vary over time post-treatment, and that steroid esters may be measured in regrowth hair taken some weeks after treatment. Steroid esters are determined along the length of the hair, confirming that accumulation of steroid esters into hair occurs from various sources, including blood, sweat and sebum. The reported research provides some useful insights into the mechanisms governing the persistence of steroid esters in bovine hair following illicit treatment with growth promoters. (C) 2009 Elsevier B.V. All rights reserved.

Fabrication and characterisation of high resistivity SOI substrates for monolithic high energy physics detectors

Silicon on Insulator (SOI) substrates offer a promising platform for monolithic high energy physics detectors with integrated read-out electronics and pixel diodes. This paper describes the fabrication and characterisation of specially-configured SOI substrates using improved bonded wafer ion split and grind/polish technologies. The crucial interface between the high resistivity handle silicon and the SOI buried oxide has been characterised using both pixel diodes and circular geometry MOS transistors. Pixel diode breakdown voltages were typically greater than 100V and average leakage current densities at 70 V were only 55 nA/ sq cm. MOS transistors subjected to 24 GeV proton irradiation showed an increased SOI buried oxide trapped charge of only 3.45x1011cn-2 for a dose of 2.7Mrad

High-performance liquid chromatographic determination of 17 beta-estradiol and 17 beta-estradiol-3-acetate solubilities and diffusion coefficients in silicone elastomeric intravaginal rings

A rapid, sensitive reversed-phase high-performance liquid chromatographic method has been developed for the determination of in vitro release of 17 beta-estradiol and its ester prodrug, 17 beta-estradiol-3-acetate, from silicone intravaginal rings. Partial hydrolysis of the acetate under the aqueous conditions provided by the 1% benzalkonium chloride release medium necessitates its conversion to 17 beta-estradiol prior to HPLC analysis. Both steroid peaks have been fully resolved from the benzalkonium chloride peaks by the reported chromatographic method,which employs a C-18 bonded reversed-phase column, an acetonitrile-water (50:50, v/v) mobile phase and a UV detection wavelength of 281 nm. The peak area versus 17 beta-estradiol concentration was found to be linear over the range of 0.0137-1347 mu g ml(-1) The HPLC method has also been used to determine the silicone solubilities and diffusion coefficients of the two related steroids. The almost 100-fold increase in 17 beta-estradiol-3-acetate release from the silicone core-type intravaginal rings compared to 17 beta-estradiol is shown to be due to a 60-fold increase in silicone solubility and a one and a half-fold increase in diffusitivity. The results demonstrate that an effective estrogen replacement therapy dose of 17 beta-estradiol may be administered from a silicone intravaginal reservoir device containing the labile 17 beta-estradiol-3-acetate prodrug. (C) 2000 Elsevier Science B.V. All rights reserved.

Low-dose hypersensitivity in Chinese hamster V79 cells targeted with counted protons using a charged-particle microbeam

The Gray Laboratory charged-particle microbeam has been used to assess the clonogenic ability of Chinese hamster V79 cells after irradiation of their nuclei with a precisely defined number of protons with energies of 1.0 and 3.2 MeV. The microbeam uses a 1-mum. silica capillary collimator to deliver protons to subcellular targets with high accuracy. The detection system is based on a miniature photomultiplier tube positioned above the cell dish, which detects the photons generated by the passage of the charged particles through an 18-mum-thick scintillator placed below the cells. With this system, a detection efficiency of greater than 99% is achieved. The cells are plated on specially designed dishes (3-mum-thick Mylar base), and the nuclei are identified by fluorescence microscopy. After an incubation period of 3 days, the cells are revisited individually to assess the formation of colonies from the surviving cells. For each energy investigated, the survival curve obtained for the microbeam shows a significant deviation below I Gy from a response extrapolated using the LQ model for the survival data above 1 Gy. The data are well fitted by a model that supports the hypothesis that radioresistance is induced by low-dose hypersensitivity. These studies demonstrate the potential of the microbeam for performing studies of the effects of single charged particles on cells in vitro. The hypersensitive responses observed are comparable with those reported by others using different radiations and techniques. (C) 2001 by Radiation Research Society.

Low dose effects of ionizing radiation on normal tissue stem cells

In recent years, there has been growing evidence for the involvement of stem cells in cancer initiation. As a result of their long life span, stem cells may have an increased propensity to accumulate genetic damage relative to differentiated cells. Therefore, stem cells of normal tissues may be important targets for radiation-induced carcinogenesis.

Knowledge of the effects of ionizing radiation (IR) on normal stem cells and on the processes involved in carcinogenesis is very limited. The influence of high doses of IR (>5 Gy) on proliferation, cell cycle and induction of senescence has been demonstrated in stem cells. There have been limited studies of the effects of moderate (0.5–5 Gy) and low doses (<0.5 Gy) of IR on stem cells however, the effect of low dose IR (LD-IR) on normal stem cells as possible targets for radiation-induced carcinogenesis has not been studied in any depth. There may also be important parallels between stem cell responses and those of cancer stem cells, which may highlight potential key common mechanisms of their response and radiosensitivity.

This review will provide an overview of the current knowledge of radiation-induced effects on normal stem cells, with particular focus on low and moderate doses of IR.

Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.

METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.

RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.

CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Cellular signalling effects in high precision radiotherapy

Radiotherapy is commonly planned on the basis of physical dose received by the tumour and surrounding normal tissue, with margins added to address the possibility of geometric miss. However, recent experimental evidence suggests that intercellular signalling results in a given cell's survival also depending on the dose received by neighbouring cells. A model of radiation-induced cell killing and signalling was used to analyse how this effect depends on dose and margin choices. Effective Uniform Doses were calculated for model tumours in both idealised cases with no delivery uncertainty and more realistic cases incorporating geometric uncertainty. In highly conformal irradiation, a lack of signalling from outside the target leads to reduced target cell killing, equivalent to under-dosing by up to 10% compared to large uniform fields. This effect is significantly reduced when higher doses per fraction are considered, both increasing the level of cell killing and reducing margin sensitivity. These effects may limit the achievable biological precision of techniques such as stereotactic radiotherapy even in the absence of geometric uncertainties, although it is predicted that larger fraction sizes reduce the relative contribution of cell signalling driven effects. These observations may contribute to understanding the efficacy of hypo-fractionated radiotherapy.

Increasing fruit and vegetable intake has no effect on retinal vessel caliber in adults at high risk of developing cardiovascular disease

BACKGROUND AND AIM: Retinal vessel abnormalities are associated with cardiovascular disease (CVD) risk. To date, there are no trials investigating the effect of dietary factors on the retinal microvasculature. This study examined the dose response effect of fruit and vegetable (FV) intake on retinal vessel caliber in overweight adults at high CVD risk.

METHODS AND RESULTS: Following a 4 week washout period, participants were randomized to consume either 2 or 4 or 7 portions of FV daily for 12 weeks. Retinal vessel caliber was measured at baseline and post-intervention. A total of 62 participants completed the study. Self-reported FV intake indicated good compliance with the intervention, with serum concentrations of zeaxanthin and lutein increasing significantly across the groups in a dose-dependent manner (P for trend < 0.05). There were no significant changes in body composition, 24-h ambulatory blood pressure or fasting blood lipid profiles in response to the FV intervention. Increasing age was a significant determinant of wider retinal venules (P = 0.004) whereas baseline systolic blood pressure was a significant determinant of narrower retinal arterioles (P = 0.03). Overall, there was no evidence of any short-term dose-response effect of FV intake on retinal vessel caliber (CRAE (P = 0.92) or CRVE (P = 0.42)).

CONCLUSIONS: This study demonstrated no effect of increasing FV intake on retinal vessel caliber in overweight adults at high risk of developing primary CVD.

Time-resolved dosimetric verification of respiratory-gated radiotherapy exposures using a high-resolution 2D ionisation chamber array

The aim of this work was to track and verify the delivery of respiratory-gated irradiations, performed with three versions of TrueBeam linac, using a novel phantom arrangement that combined the OCTAVIUS® SRS 1000 array with a moving platform. The platform was programmed to generate sinusoidal motion of the array. This motion was tracked using the real-time position management (RPM) system and four amplitude gating options were employed to interrupt MV beam delivery when the platform was not located within set limits. Time-resolved spatial information extracted from analysis of x-ray fluences measured by the array was compared to the programmed motion of the platform and to the trace recorded by the RPM system during the delivery of the x-ray field. Temporal data recorded by the phantom and the RPM system were validated against trajectory log files, recorded by the linac during the irradiation, as well as oscilloscope waveforms recorded from the linac target signal. Gamma analysis was employed to compare time-integrated 2D x-ray dose fluences with theoretical fluences derived from the probability density function for each of the gating settings applied, where gamma criteria of 2%/2 mm, 1%/1 mm and 0.5%/0.5 mm were used to evaluate the limitations of the RPM system. Excellent agreement was observed in the analysis of spatial information extracted from the SRS 1000 array measurements. Comparisons of the average platform position with the expected position indicated absolute deviations of  <0.5 mm for all four gating settings. Differences were observed when comparing time-resolved beam-on data stored in the RPM files and trajectory logs to the true target signal waveforms. Trajectory log files underestimated the cycle time between consecutive beam-on windows by 10.0  ±  0.8 ms. All measured fluences achieved 100% pass-rates using gamma criteria of 2%/2 mm and 50% of the fluences achieved pass-rates  >90% when criteria of 0.5%/0.5 mm were used. Results using this novel phantom arrangement indicate that the RPM system is capable of accurately gating x-ray exposure during the delivery of a fixed-field treatment beam.