The hydroxypyridinone iron chelator CP94 increases methyl-aminolevulinate-based photodynamic cell killing by increasing the generation of reactive oxygen species.

Published onlineJOURNAL ARTICLEMethyl-aminolevulinate-based photodynamic therapy (MAL-PDT) is utilised clinically for the treatment of non-melanoma skin cancers and pre-cancers and the hydroxypyridinone iron chelator, CP94, has successfully been demonstrated to increase MAL-PDT efficacy in an initial clinical pilot study. However, the biochemical and photochemical processes leading to CP94-enhanced photodynamic cell death, beyond the well-documented increases in accumulation of the photosensitiser protoporphyrin IX (PpIX), have not yet been fully elucidated. This investigation demonstrated that MAL-based photodynamic cell killing of cultured human squamous carcinoma cells (A431) occurred in a predominantly necrotic manner following the generation of singlet oxygen and ROS. Augmenting MAL-based photodynamic cell killing with CP94 co-treatment resulted in increased PpIX accumulation, MitoSOX-detectable ROS generation (probably of mitochondrial origin) and necrotic cell death, but did not affect singlet oxygen generation. We also report (to our knowledge, for the first time) the detection of intracellular PpIX-generated singlet oxygen in whole cells via electron paramagnetic resonance spectroscopy in conjunction with a spin trap.We thank Professor Robert Hider, King's College London, for providing the iron chelating agent (CP94), and Drs Paul Eggleton and Jo Tarr (University of Exeter Medical School) for their assistance with the flow cytometry analysis. The Duchy Health Charity Ltd (DCH05-07), Peninsula Medical School and DDRC Healthcare (GD100015-122) are thanked for financial support. PGW and DCJF acknowledge financial support from the European Cooperation in Science and Technology, Belgium (COST Action BM1203/EU-ROS)

Osteochondral impaction of the posterior acetabular surface without cortical fracture of any wall or column: an undescribed pattern of acetabular injury

Surgical treatment of a unusual acetabular fracture is described. This fracture was characterized by impaction and breaking down of the posterior articular surface and comminution of lamina quadrilatera lower portion, without cortical fracture of both columns. The fracture was treated surgically through the Kocher–Langenbeck approach. A small hole was created in the acetabulum posterior wall, the impacted fragment was reduced, and the bone defect was filled with autologous bone from the greater trochanter. A plate was shaped in order to fix both bone graft and fractured fragment

Application of the speed-duration relationship to normalize the intensity of high-intensity interval training

The tolerable duration of continuous high-intensity exercise is determined by the hyperbolic Speed-tolerable duration (S-tLIM) relationship. However, application of the S-tLIM relationship to normalize the intensity of High-Intensity Interval Training (HIIT) has yet to be considered, with this the aim of present study. Subjects completed a ramp-incremental test, and series of 4 constant-speed tests to determine the S-tLIM relationship. A sub-group of subjects (n = 8) then repeated 4 min bouts of exercise at the speeds predicted to induce intolerance at 4 min (WR4), 6 min (WR6) and 8 min (WR8), interspersed with bouts of 4 min recovery, to the point of exercise intolerance (fixed WR HIIT) on different days, with the aim of establishing the work rate that could be sustained for 960 s (i.e. 4×4 min). A sub-group of subjects (n = 6) also completed 4 bouts of exercise interspersed with 4 min recovery, with each bout continued to the point of exercise intolerance (maximal HIIT) to determine the appropriate protocol for maximizing the amount of high-intensity work that can be completed during 4×4 min HIIT. For fixed WR HIIT tLIM of HIIT sessions was 399±81 s for WR4, 892±181 s for WR6 and 1517±346 s for WR8, with total exercise durations all significantly different from each other (P<0.050). For maximal HIIT, there was no difference in tLIM of each of the 4 bouts (Bout 1: 229±27 s; Bout 2: 262±37 s; Bout 3: 235±49 s; Bout 4: 235±53 s; P>0.050). However, there was significantly less high-intensity work completed during bouts 2 (153.5±40. 9 m), 3 (136.9±38.9 m), and 4 (136.7±39.3 m), compared with bout 1 (264.9±58.7 m; P>0.050). These data establish that WR6 provides the appropriate work rate to normalize the intensity of HIIT between subjects. Maximal HIIT provides a protocol which allows the relative contribution of the work rate profile to physiological adaptations to be considered during alternative intensity-matched HIIT protocols

The morphologies of massive galaxies at 1 < z < 3 in the CANDELS-UDS field : compact bulges, and the rise and fall of massive discs

We have used high-resolution, Hubble Space Telescope, near-infrared imaging to conduct a detailed analysis of the morphological properties of the most massive galaxies at high redshift, modelling the WFC3/IR H-160-band images of the similar or equal to 200 galaxies in the CANDELS-UDS field with photometric redshifts 1 10(11)M(circle dot). We have explored the results of fitting single-Sersic and bulge+disc models, and have investigated the additional errors and potential biases introduced by uncertainties in the background and the on-image point spread function. This approach has enabled us to obtain formally acceptable model fits to the WFC3/IR images of > 90 per cent of the galaxies. Our results indicate that these massive galaxies at 1 2 the compact bulges display effective radii a factor of similar or equal to 4 smaller than local ellipticals of comparable mass. These trends also appear to extend to the bulge components of disc-dominated galaxies. In addition, we find that, while such massive galaxies at low redshift are generally bulge-dominated, at redshifts 1 2 they are mostly disc-dominated. The majority of the disc-dominated galaxies are actively forming stars, although this is also true for many of the bulge-dominated systems. Interestingly, however, while most of the quiescent galaxies are bulge-dominated, we find that a significant fraction (25-40 per cent) of the most quiescent galaxies, with specific star formation rates sSFR < 10(-10) yr(-1), have disc-dominated morphologies. Thus, while our results show that the massive galaxy population is undergoing dramatic changes at this crucial epoch, they also suggest that the physical mechanisms which quench star formation activity are not simply connected to those responsible for the morphological transformation of massive galaxies into present-day giant ellipticals

Rapid detection of pandemic influenza in the presence of seasonal influenza

Background: Key to the control of pandemic influenza are surveillance systems that raise alarms rapidly and sensitively. In addition, they must minimise false alarms during a normal influenza season. We develop a method that uses historical syndromic influenza data from the existing surveillance system 'SERVIS' (Scottish Enhanced Respiratory Virus Infection Surveillance) for influenza-like illness (ILI) in Scotland. Methods: We develop an algorithm based on the weekly case ratio (WCR) of reported ILI cases to generate an alarm for pandemic influenza. From the seasonal influenza data from 13 Scottish health boards, we estimate the joint probability distribution of the country-level WCR and the number of health boards showing synchronous increases in reported influenza cases over the previous week. Pandemic cases are sampled with various case reporting rates from simulated pandemic influenza infections and overlaid with seasonal SERVIS data from 2001 to 2007. Using this combined time series we test our method for speed of detection, sensitivity and specificity. Also, the 2008-09 SERVIS ILI cases are used for testing detection performances of the three methods with a real pandemic data. Results: We compare our method, based on our simulation study, to the moving-average Cumulative Sums (Mov-Avg Cusum) and ILI rate threshold methods and find it to be more sensitive and rapid. For 1% case reporting and detection specificity of 95%, our method is 100% sensitive and has median detection time (MDT) of 4 weeks while the Mov-Avg Cusum and ILI rate threshold methods are, respectively, 97% and 100% sensitive with MDT of 5 weeks. At 99% specificity, our method remains 100% sensitive with MDT of 5 weeks. Although the threshold method maintains its sensitivity of 100% with MDT of 5 weeks, sensitivity of Mov-Avg Cusum declines to 92% with increased MDT of 6 weeks. For a two-fold decrease in the case reporting rate (0.5%) and 99% specificity, the WCR and threshold methods, respectively, have MDT of 5 and 6 weeks with both having sensitivity close to 100% while the Mov-Avg Cusum method can only manage sensitivity of 77% with MDT of 6 weeks. However, the WCR and Mov-Avg Cusum methods outperform the ILI threshold method by 1 week in retrospective detection of the 2009 pandemic in Scotland. Conclusions: While computationally and statistically simple to implement, the WCR algorithm is capable of raising alarms, rapidly and sensitively, for influenza pandemics against a background of seasonal influenza. Although the algorithm was developed using the SERVIS data, it has the capacity to be used at other geographic scales and for different disease systems where buying some early extra time is critical

Development and external validation of a dynamic prognostic nomogram for primary extremity soft tissue sarcoma survivors.

Background:Prognostic nomograms for patients with extremity soft tissue sarcoma (eSTS) typically predict survival or the occurrence of local recurrence or distant metastasis at time of surgery. Our aim was to develop and externally validate a dynamic prognostic nomogram for overall survival in eSTS survivors for use during follow-up. Methods:All primary eSTS patients operated with curative intent between 1994 and 2013 at three European and one Canadian sarcoma centers formed the development cohort. Patients with Fédération Française des Centres de Lutte Contre le Cancer (FNCLCC) grade II and grade III eSTS operated between 2000 and 2016 at seven other European reference centers formed the external validation cohort. We used a landmark analysis approach and a multivariable Cox model to create a dynamic nomogram; the prediction window was fixed at five years. A backward procedure based on the Akaike Information Criterion was adopted for variable selection. We tested the nomogram performance in terms of calibration and discrimination. Findings:The development and validation cohorts included 3740 and 893 patients, respectively. The variables selected applying the backward procedure were patient's age, tumor size and its interaction with landmark time, tumor FNCLCC grade and its interaction with landmark time, histology, and both local recurrence and distant metastasis (as first event) indicator variables. The nomogram showed good calibration and discrimination. Harrell C indexes at different landmark times were between 0.776 (0.761-0.790) and 0.845 (0.823-0.862) in the development series and between 0.675 (0.643-0.704) and 0.810 (0.775-0.844) in the validation series. Interpretation:A new dynamic nomogram is available to predict 5-year overall survival at different times during the first three years of follow-up in patients operated for primary eSTS. This nomogram allows physicians to update the individual survival prediction during follow-up on the basis of baseline variables, time elapsed from surgery and first-event history

There Is No Safe Dose of Prions

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay

Persisting right-sided chylothorax in a patient with chronic lymphocytic leukemia: a case report

Introduction Chylothorax caused by chronic lymphocytic leukemia is very rare and the best therapeutic approach, especially the role of modern immunochemotherapy, is not yet defined. Case presentation We present the case of a 65-year-old male Caucasian patient with right-sided chylothorax caused by a concomitantly diagnosed chronic lymphocytic leukemia. As first-line treatment four cycles of an immunochemotherapy, consisting of fludarabine, cyclophosphamide and rituximab were administered. In addition, our patient received total parenteral nutrition for the first two weeks of treatment. Despite the very good clinical response of the lymphoma to treatment, the chylothorax persisted and percutaneous radiotherapy of the thoracic duct was applied. However, eight weeks after the radiotherapy the chylothorax still persisted and our patient agreed to a surgical intervention. A ligation of the thoracic duct via a muscle sparing thoracotomy was performed, resulting in a complete cessation of the pleural effusion. Apart from the first two weeks our patient was treated on an out-patient basis for nearly six months. Conclusion In this case of chylothorax caused by chronic lymphocytic leukemia, immunochemotherapy in combination with conservative treatment, and even consecutive radiotherapy, were not able to stop pleural effusion, despite the very good clinical response of the chronic lymphocytic leukemia to treatment. Out-patient management using repetitive thoracocenteses can be safe as bridging until definitive surgical ligation of the thoracic duct

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Teaching appropriate interactions with pharmaceutical company representatives: The impact of an innovative workshop on student attitudes

BACKGROUND: Pharmaceutical company representatives (PCRs) influence the prescribing habits and professional behaviour of physicians. However, the skills for interacting with PCRs are not taught in the traditional medical school curriculum. We examined whether an innovative, mandatory workshop for third year medical students had immediate effects on knowledge and attitudes regarding interactions with PCRs. METHODS: Surveys issued before and after the workshop intervention solicited opinions (five point Likert scales) from third year students (n = 75) about the degree of bias in PCR information, the influence of PCRs on prescribing habits, the acceptability of specific gifts, and the educational value of PCR information for both practicing physicians and students. Two faculty members and one PCR led the workshop, which highlighted typical physician-PCR interactions, the use of samples and gifts, the validity and legal boundaries of PCR information, and associated ethical issues. Role plays with the PCR demonstrated appropriate and inappropriate strategies for interacting with PCRs. RESULTS: The majority of third year students (56%, 42/75) had experienced more than three personal conversations with a PCR about a drug product since starting medical school. Five percent (4/75) claimed no previous personal experience with PCRs. Most students (57.3%, 43/75) were not aware of available guidelines regarding PCR interactions. Twenty-eight percent of students (21/75) thought that none of the named activities/gifts (lunch access, free stethoscope, textbooks, educational CD-ROMS, sporting events) should be restricted, while 24.0% (8/75) thought that students should be restricted only from sporting events. The perceived educational value of PCR information to both practicing physicians and students increased after the workshop intervention from 17.7% to 43.2% (chi square, p = .0001), and 22.1% to 40.5% (p = .0007), respectively. Student perceptions of the degree of bias of PCR information decreased from 84.1% to 72.9% (p = .065), but the perceived degree of influence on prescribing increased (44.2% to 62.1% (p = .02)). CONCLUSIONS: Students have exposure to PCRs early in their medical training. A single workshop intervention may influence student attitudes toward interactions with PCRs. Students were more likely to acknowledge the educational value of PCR interactions and their impact on prescribing after the workshop intervention