Dose, dose-rate and field size effects on cell survival following exposure to non-uniform radiation fields

For the delivery of intensity-modulated radiation therapy (IMRT), highly modulated fields are used to achieve dose conformity across a target tumour volume. Recent in vitro evidence has demonstrated significant alterations in cell survival occurring out-of-field which cannot be accounted for on the basis of scattered dose. The radiobiological effect of area, dose and dose-rate on out-of-field cell survival responses following exposure to intensity-modulated radiation fields is presented in this study. Cell survival was determined by clonogenic assay in human prostate cancer (DU-145) and primary fibroblast (AG0-1522) cells following exposure to different modulated field configurations delivered using a X-Rad 225 kVp x-ray source. Uniform survival responses were compared to in- and out-of-field responses in which 25-99% of the cell population was shielded. Dose delivered to the out-of-field region was varied from 1.6-37.2% of that delivered to the in-field region using different levels of brass shielding. Dose rate effects were determined for 0.2-4 Gy min⁻¹ for uniform and modulated exposures with no effect seen in- or out-of-field. Survival responses showed little dependence on dose rate and area in- and out-of-field with a trend towards increased survival with decreased in-field area. Out-of-field survival responses were shown to scale in proportion to dose delivered to the in-field region and also local dose delivered out-of-field. Mathematical modelling of these findings has shown survival response to be highly dependent on dose delivered in- and out-of-field but not on area or dose rate. These data provide further insight into the radiobiological parameters impacting on cell survival following exposure to modulated irradiation fields highlighting the need for refinement of existing radiobiological models to incorporate non-targeted effects and modulated dose distributions.

Obesity and kidney disease in type 1 and 2 diabetes: an analysis of the National Diabetes Audit

Background: Obesity is increasingly prevalent in many countries. Obesity is a major risk factor for the development of type 2 diabetes but its relationship with diabetic kidney disease (DKD) remains unclear. Some studies have suggested that the metabolic syndrome (including obesity) may be associated with DKD in type 1 diabetes. Aim: To investigate the association between obesity and DKD. Design: Retrospective cross-sectional study. Methods: National Diabetes Audit data were available for the 2007–08 cycle. Type 1 and 2 diabetes patients with both a valid serum creatinine and urinary albumin:creatinine ratio were included. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, albuminuria or both. Logistic regression was used to analyse associations of obesity (body mass index ≥30 kg/m2) and other variables including year of birth, year of diagnosis, ethnicity and stage of kidney disease. Results: A total of 58 791 type 1 and 733 769 type 2 diabetes patients were included in the analysis. After adjustment, when compared with type 1 diabetes patients with normal renal function those with DKD were up to twice as likely to be obese. Type 2 DKD patients were also more likely to be obese. For example, type 2 diabetes patients with an eGFR <15 ml/min/1.73 m2 and normoalbuminuria, microalbuminuria or macroalbuminuria were all more likely to be obese; odds ratios (95% CI) 1.65 (1.3–2.1), 1.56 (1.28–1.92) and 1.27 (1.05–1.54), respectively. Conclusions: This study has highlighted a strong association between obesity and kidney disease in type 1 diabetes and confirmed their association in type 2 diabetes.

A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

A simple disc wind model for broad absorption line quasars

Approximately 20 per cent of quasi-stellar objects (QSOs) exhibit broad, blue-shifted absorption lines in their ultraviolet spectra. Such features provide clear evidence for significant outflows from these systems, most likely in the form of accretion disc winds. These winds may represent the ‘quasar’ mode of feedback that is often invoked in galaxy formation/evolution models, and they are also key to unification scenarios for active galactic nuclei (AGN) and QSOs. To test these ideas, we construct a simple benchmark model of an equatorial, biconical accretion disc wind in a QSO and use a Monte Carlo ionization/radiative transfer code to calculate the ultraviolet spectra as a function of viewing angle. We find that for plausible outflow parameters, sightlines looking directly into the wind cone do produce broad, blue-shifted absorption features in the transitions typically seen in broad absorption line (BAL) QSOs. However, our benchmark model is intrinsically X-ray weak in order to prevent overionization of the outflow, and the wind does not yet produce collisionally excited line emission at the level observed in non-BAL QSOs. As a first step towards addressing these shortcomings, we discuss the sensitivity of our results to changes in the assumed X-ray luminosity and mass-loss rate, Ṁwind. In the context of our adopted geometry, Ṁwind ∼ Ṁacc is required in order to produce significant BAL features. The kinetic luminosity and momentum carried by such outflows would be sufficient to provide significant feedback.

The incidence and rate of rhegmatogenous retinal detachment seven years after cataract surgery in patients with high myopia

Background: Cataract extraction is the most commonly performed surgery in the National Health Service. Myopia increases the risk of postoperative rhegmatogenous retinal detachment (RRD). The aim of this study was to determine the incidence and rate of RRD seven years after cataract extraction in highly myopic eyes. Methods: Retrospective review was performed of notes of all high myopes (axial length 26.0 mm or more) who underwent cataract extraction during the study period in one centre. Results: 84 eyes met the study criteria. Follow-up time from surgery was 93 to 147 months (median 127 months). The average axial length was 28.72 mm (sd 1.37). Two eyes developed post-operative RRD; the incidence was 2.4% and the rate one RRD per 441.6 person-years. The results of 15 other studies on the incidence of RRD after cataract extraction in high myopia were pooled and combined with our estimate. Conclusion: Both patients in our study who developed RRD had risk factors for this complication as well as high myopia. Risk factors are discussed in the light of our results and the pooled estimate. Our follow-up time is longer than most. Future case series should calculate rates to allow meaningful comparison of case series. © The Ulster Medical Society, 2009.

Tailoring ionic liquid catalysts: structure, acidity and catalytic activity of protonic ionic liquids based on anionic clusters, [(HSO4)(H2SO4)x]− (x = 0, 1, or 2)

Aiming at inexpensive Brønsted-acidic ionic liquids, suitable for industrial-scale catalysis, a family of protonic ionic liquids based on nitrogen bases and sulfuric acid has been developed. Variation of the molar ratio of sulfuric acid, χH2SO4, was used to tune acidity. The liquid structure was studied using 1H NMR and IR spectroscopies, revealing the existence of hydrogen-bonded clusters, [(HSO4)(H2SO4)]−, for χH2SO4 > 0.50. Acidity, quantified by Gutmann Acceptor Number (AN), was found to be closely related to the liquid structure. The ionic liquids were employed as acid catalysts in a model reaction; Fischer esterification of acetic acid with 1-butanol. The reaction rate depended on two factors; for χH2SO4 > 0.50, the key parameter was acidity (expressed as AN value), while for χH2SO4 > 0.50 it was the mass transport (solubility of starting materials in the ionic liquid phase). Building on this insight, the ionic liquid catalyst and reaction conditions have been chosen. Conversion values of over 95% were achieved under exceptionally mild conditions, and using an inexpensive ionic liquid, which could be recycled up to eight times without diminution in conversion or selectivity. It has been demonstrated how structural studies can underpin rational design and development of an ionic liquid catalyst, and in turn lead to a both greener and economically viable process.

Propagation modelling and measurements in a populated indoor environment at 5.2 GHz

Human occupants within indoor environments are not always stationary and their movement will lead to temporal channel variations that strongly affect the quality of indoor wireless communication systems. This paper describes a statistical channel characterization, based on experimental measurements, of human body effects on line-of-sight indoor narrowband propagation at 5.2 GHz. The analysis shows that, as the number of pedestrians within the measurement location increases, the Ricean K-factor that best fits the empirical data tends to decrease proportionally, ranging from K=7 with 1 pedestrian to K=0 with 4 pedestrians. Level crossing rate results were Rice distributed, while average fade duration results were significantly higher than theoretically computed Rice and Rayleigh, due to the fades caused by pedestrians. A novel CDF that accurately characterizes the 5.2 GHz channel in the considered indoor environment is proposed. For the first time, the received envelope CDF is explicitly described in terms of a quantitative measurement of pedestrian traffic within the indoor environment.

Increase in the pharmacological management of Type 2 diabetes with pay-for-performance in primary care in the UK

Aims To determine whether the financial incentives for tight glycaemic control, introduced in the UK as part of a pay-for-performance scheme in 2004, increased the rate at which people with newly diagnosed Type 2 diabetes were started on anti-diabetic medication.

Methods A secondary analysis of data from the General Practice Research Database for the years 1999-2008 was performed using an interrupted time series analysis of the treatment patterns for people newly diagnosed with Type 2 diabetes (n=21 197).

Results Overall, the proportion of people with newly diagnosed diabetes managed without medication 12months after diagnosis was 47% and after 24months it was 40%. The annual rate of initiation of pharmacological treatment within 12months of diagnosis was decreasing before the introduction of the pay-for-performance scheme by 1.2% per year (95% CI -2.0, -0.5%) and increased after the introduction of the scheme by 1.9% per year (95% CI 1.1, 2.7%). The equivalent figures for treatment within 24months of diagnosis were -1.4% (95% CI -2.1, -0.8%) before the scheme was introduced and 1.6% (95% CI 0.8, 2.3%) after the scheme was introduced.

Conclusion The present study suggests that the introduction of financial incentives in 2004 has effected a change in the management of people newly diagnosed with diabetes. We conclude that a greater proportion of people with newly diagnosed diabetes are being initiated on medication within 1 and 2years of diagnosis as a result of the introduction of financial incentives for tight glycaemic control.

The reaction path of CO and Fe2O3 in a chemical-looping combustion system

The reaction mechanism of CO and Fe₂O₃ in a chemical-looping combustion (CLC) was studied based on density functional theory (DFT) at B3LYP level in this paper. The structures of all reactants, intermediate, transition structures and products of this reaction had been optimized and characterized. The reaction path was validated by means of the intrinsic reaction coordinate (IRC) approach. The result showed that the reaction was divided into two steps, the adsorbed CO molecule on Fe ₂O₃ surface formed a medium state with one broken Fe-O bond in step1, and in step2, O atom broken here oxidized a subsequent CO molecule in the fuel reactor. Thus, Fe₂O₃ molecule transport O from air to oxide CO continually in the CLC process. The activation energy and rate coefficients of the two steps were also obtained.

Estimated Glomerular Filtration Rate Decline as a Predictor of Dialysis in Kidney Transplant Recipients

BACKGROUND: It is now common for individuals to require dialysis following the failure of a kidney transplant. Management of complications and preparation for dialysis are suboptimal in this group. To aid planning, it is desirable to estimate the time to dialysis requirement. The rate of decline in the estimated glomerular filtration rate (eGFR) may be used to this end.

METHODS: This study compared the rate of eGFR decline prior to dialysis commencement between individuals with failing transplants and transplant-naïve patients. The rate of eGFR decline was also compared between transplant recipients with and without graft failure. eGFR was calculated using the four-variable MDRD equation with rate of decline calculated by least squares linear regression.

RESULTS: The annual rate of eGFR decline in incident dialysis patients with graft failure exceeded that of the transplant-naïve incident dialysis patients. In the transplant cohort, the mean annual rate of eGFR decline prior to graft failure was 7.3 ml/min/1.73 m(2) compared to 4.8 ml/min/1.73 m(2) in the transplant-naïve group (p < 0.001) and 0.35 ml/min/1.73 m(2) in recipients without graft failure (p < 0.001). Factors associated with eGFR decline were recipient age, decade of transplantation, HLA mismatch and histological evidence of chronic immunological injury.

CONCLUSIONS: Individuals with graft failure have a rapid decline in eGFR prior to dialysis commencement. To improve outcomes, dialysis planning and management of chronic kidney disease complications should be initiated earlier than in the transplant-naïve population.

Mitotic Arrest Deficiency Protein 2 (MAD2) and Histone Deacetylase 6 (HDAC6) Present a Complex Relationship in Their Regulation and Expression and Subsequent Impact on Chemoresponsiveness

Introduction:
Ovarian cancer patients presenting with advanced stage (III/IV)
canceraretreatedwithcarboplatinumincombinationwithpaclitaxel.Despitea
significant initial response rate, fewer than 20% of patients become long-term
survivors. We have published that low MAD2 expression levels associate with
reduced progression free survival (PFS) in patients with high-grade serous
epithelial ovarian cancer (EOC). Moreover, we have demonstrated that MAD2
expressionisdown-regulatedbythemicroRNAmiR-433(
Furlong et al., 2011
).
Interestingly, miR-433 also down-regulates HDAC6 (
Simon et al., 2010
), which
uniquely deacetylates
a
-tubulin prior to HDAC6s binding to
b
-tubulin.
In vitro
studies have shown that HDAC6 inhibition in combination with paclitaxel
treatment enhances chemoresistant cancer cell death. To date, an interaction
between MAD2 and HDAC6 has not been reported.
Experimental design:
MAD2 and HDAC6 immunohistochemistry (IHC) and
Western blot analyses were performed to investigate the role of HDAC6 and
MAD2 in chemoresistance to paclitaxel in high-grade serous EOC.
Results and Discussion:
In vitro
experiments demonstrated that overex-
pression of pre-miR-433, which targets MAD2, resulted in down-regulation
of HDAC6 in EOC cell lines. High levels of HDAC6 are co-expressed with
MAD2 in the paclitaxel resistant UPN251 and OVCAR7 cell lines. While, all
4 paclitaxel resistant EOC cell lines express higher levels of miR-433 than
the paclitaxel sensitive A2780 cells, only ovca432 and ovca433 demonstrated
down-regulation of both HDAC6 and MAD2. Paclitaxel binds to
b
-tubulin and
causesmicrotubulepolymerizationinpaclitaxelsensitivecellsasdemonstrated
by tubulin acetylation in A2780 cells. However, paclitaxel failed to cause a
significant acetylation of
a
-tubulin and microtubule stabilisation in the resistant
UPN251 cells. Therefore resistance in this cell line may be mediated by
aberrantly high HDAC6 activity. We have previously shown that MAD2 knock-
down cells are resistant to paclitaxel (
Furlong F., et al., 2011; Prencipe M.,
et al., 2009
). We measured HDAC6 protein expression in MAD2 knockdown
cells and showed that MAD2 knockdown is associated with concomitant
up-regulation of HDAC6. We hypothesise that the up-regulation of HDAC6
by MAD2 knockdown renders cancer cells more resistant to paclitaxel and
increases the invasive potential of these cells. On-going experiments will test
this hypothesis. Lastly we have observed differential MAD2 and HDAC6 IHC
staining intensity in formalin fixed paraffin embedded EOC samples.
In conclusion
, we have reported on a novel interaction between MAD2 and
HDAC6 which may have important consequences for paclitaxel resistant EOC.
Moreover, understanding chemo-responsiveness in ovarian tumours will lead
to improved patient management and treatment options for women diagnosed
with this disease

Generation of 10μW relativistic surface high-harmonic radiation at a repetition rate of 10 Hz

Experimental results on relativistic surface HHG at a repetition rate of 10 Hz are presented. Average powers in the 10?W range are generated in the spectral range of 51 to 26 nm (24-48 eV). The surface harmonic radiation is produced by focusing the second-harmonic of a high-power laser onto a rotating glass surface to moderately relativistic intensities of 3×10 ¹⁹Wcm ^?2. The harmonic emission exhibits a divergence of 26 mrad. Together with absolute photon numbers recorded by a calibrated spectrometer, this allows for the determination of the extreme ultraviolet (XUV) yield. The pulse energies of individual harmonics are reaching up to the μJ level, equivalent to an efficiency of 10 ^?5. The capability of producing stable and intense high-harmonic radiation from relativistic surface plasmas may facilitate experiments on nonlinear ionization or the seeding of free-electron lasers. © IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.

A study of the kinetic solvent isotope effect on the destruction of microcystin-LR and geosmin using TiO2 photocatalysis

We have previously reported the effectiveness of TiO₂ photocatalysis in the destruction of species generated by cyanobacteria, specifically geosmin and microcystin-LR. In this paper we report an investigation of factors which influence the rate of the toxin destruction at the catalyst surface. A primary kinetic solvent isotope effect of approximately 1.5 was observed when the destruction was performed in a heavy water solvent. This is in contrast to previous reports of a solvent isotope effect of approximately 3, however, these studies were undertaken with a different photocatalyst material. The solvent isotope effect therefore appears to be dependent on the photocatalyst material used. The results of the study support the theory that the photocatalytic decomposition occurs on the catalyst surface rather than in the bulk of the solution. Furthermore it appears that the rate determining step is not oxygen reduction as previously reported. 

Processes influencing the destruction of microcystin-LR by TiO2 photocatalysis

We have previously reported the effectiveness of TiO₂ photocatalysis in the destruction of the cyanotoxin microcystin-LR [P.K.J. Robertson, L.A. Lawton, B. Münch, J. Rouzade, J. Chem. Soc., Chem. Commun., 4 (1997) 393; P.K.J. Robertson, L.A. Lawton, B. Münch, B.J.P.A. Cornish, J. Adv. Oxid. Technol., in press]. In this paper we report an investigation of factors which influence the rate of the toxin destruction at the catalyst surface. A primary kinetic isotope effect of approximately 3 was observed when the destruction was performed in a heavy water solvent. Hydroxylated compounds were observed as products of the destruction process. No destruction was observed when the process was investigated under a nitrogen atmosphere.

A combined transient and computational study of the dissociation of N(2)O on platinum catalysts

The energetics of the low-temperature adsorption and decomposition of nitrous oxide, N(2)O, on flat and stepped platinum surfaces were calculated using density-functional theory (DFT). The results show that the preferred adsorption site for N(2)O is an atop site, bound upright via the terminal nitrogen. The molecule is only weakly chemisorbed to the platinum surface. The decomposition barriers on flat (I 11) surfaces and stepped (211) surfaces are similar. While the barrier for N(2)O dissociation is relatively small, the surface rapidly becomes poisoned by adsorbed oxygen. These findings are supported by experimental results of pulsed N(2)O decomposition with 5% Pt/SiO(2) and bismuth-modified Pt/C catalysts. At low temperature, decomposition occurs but self-poisoning by O((ads)) prevents further decomposition. At higher temperatures some desorption Of O(2) is observed, allowing continued catalytic activity. The study with bismuth-modified Pt/C catalysts showed that, although the activation barriers calculated for both terraces and steps were similar, the actual rate was different for the two surfaces. Steps were found experimentally to be more active than terraces and this is attributed to differences in the preexponential term. (C) 2004 Elsevier Inc. All rights reserved.