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Image-guided small animal irradiation platforms deliver small radiation fields in the medium energy x-ray range. Commissioning of such platforms, followed by dosimetric verification of treatment planning, are mostly performed with radiochromic film. There is a need for independent measurement methods, traceable to primary standards, with the added advantage of immediacy in obtaining results. This investigation characterizes a small volume ionization chamber in medium energy x-rays for reference dosimetry in preclinical irradiation research platforms. The detector was exposed to a set of reference x-ray beams (0.5–4 mm Cu HVL). Leakage, reproducibility, linearity, response to detector’s orientation, dose rate, and energy dependence were determined for a 3D PinPoint ionization chamber (PTW 31022). Polarity and ion recombination were also studied. Absorbed doses at 2 cm depth were compared, derived either by applying the experimentally determined cross-calibration coefficient at a typical small animal radiation platform ‘user’s’ quality (0.84 mm Cu HVL) or by interpolation from air kerma calibration coefficients in a set of reference beam qualities. In the range of reference x-ray beams, correction for ion recombination was less than 0.1%. The largest polarity correction was 1.4% (for 4 mm Cu HVL). Calibration and correction factors were experimentally determined. Measurements of absorbed dose with the PTW 31022, in conditions different from reference were successfully compared to measurements with a secondary standard ionization chamber. The implementation of an End-to-End test for delivery of image-targeted small field plans resulted in differences smaller than 3% between measured and treatment planning calculated doses. The investigation of the properties and response of a PTW 31022 small volume ionization chamber in medium energy x-rays and small fields can contribute to improve measurement uncertainties evaluation for reference and relative dosimetry of small fields delivered by preclinical irradiators while maintaining the traceability chain to primary standards.

Introduction Orbital cellulitis accounts for approximately 2,500 pediatric hospitalizations annually. Although suspicion for orbital cellulitis is high with presenting symptoms of proptosis, conjunctival swelling, diplopia, fever, and leukocytosis, a broad differential diagnosis should be considered. Case Description A previously healthy 8-year-old female presented to the emergency department after her teacher noticed one week of progressive right eye swelling. She endorsed photophobia, painful blurry vision, diplopia, as well as recent rhinorrhea, sore throat, and subjective fevers. She denied eye trauma, headache, dizziness, weakness, or rash. Social history was notable for emigration from Guatemala three years prior and lack of health insurance, though …

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

The safe administration of oil-based depot, and other long-acting intramuscular antipsychotic injections, is an integral and distinct aspect of the role of registered nurse practitioners within mental health nursing. This article provides an evaluation of education and training workshops for inpatient and community nurses at West London Mental Health NHS Trust. There was a significant (p > 0.05) difference in pre- and post-training self-ratings for knowledge, confidence and attitude observed.

Triceps tendon ruptures are rare injuries and are frequently missed on initial presentation to the emergency department. In cases of complete rupture, surgical repair is recommended but no guidelines exist on the optimum reconstructive technique or rehabilitation. We present a surgical technique and rehabilitation programme for the management of these injuries. A midline posterior incision is performed, the ruptured triceps tendon is identified and mobilized, and the tendon footprint is prepared. The tendon is then repaired using bone suture anchors, with a parachute technique, and held in 40° of flexion. The rehabilitation programme is divided into five phases, over a period of 12 weeks. Range of movement is gradually increased in a brace for the first 6 weeks. Rehabilitation is gradually increase in intensity, progressing from isometric extension exercises to weight-resisted exercises, and finally plyometrics and throwing exercises. Our surgical technique provides a solid tendon repair without the need for further metalwork removal. The graduated rehabilitation programme also helps to protect the integrity of the repair at the same time as enabling patients to gradually increase the strength of the triceps tendon and ultimately return to sport activities.

While migration has been shown to be a risk factor for HIV, variation in HIV prevalence by subgroups of migrants needs further exploration. This paper documents the HIV prevalence and key characteristics among male foreign migrants in Cape Town, South Africa and the effectiveness of respondent-driven sampling (RDS) to recruit this population. Participants in this cross-sectional study completed a behavioral risk-factor questionnaire and provided a dried blood sample for HIV analysis. Overall HIV prevalence was estimated to be 8.7 % (CI 5.4–11.8) but varied dramatically by country of origin. After adjusting for country of origin, HIV sero-positivity was positively associated with older age (p = 0.001), completing high school (p = 0.025), not having enough money for food (p = 0.036), alcohol use (p = 0.049), and engaging in transactional sex (p = 0.022). RDS was successful in recruiting foreign migrant men. A better understanding of the timing of HIV acquisition is needed to design targeted interventions for migrant men.

Children who experience the imprisonment of a parent or close relative are more likely to have poorer outcomes including lower school attainment and an increased risk of truancy, school exclusion and socio-emotional difficulties. This paper reports on a research project, undertaken in 2011, into support provision in schools for children who experience parental imprisonment. Through the analysis of data collected by interviewing a range of representatives of schools including head-teachers, stakeholders, parents and children in one local authority in the South West of England we explore the different realities of experiencing the imprisonment of a parent or close relative. Consequently, we offer a critique of the support provision currently available and make a number of suggestions as to how schools might support this group of potentially ‘vulnerable’ children. This includes raising awareness of this group of children through the use of resources, posters and training; a focus on the individual needs of t...

Some of the largest improvements in clinical outcomes for patients with solid cancers observed over the past 3 decades have been from concurrent treatment with chemotherapy and radiotherapy (RT). The lethal effects of RT on cancer cells arise primarily from damage to DNA. Ruthenium (Ru) is a transition metal of the platinum group, with potentially less toxicity than platinum drugs. We postulated that ruthenium-arene complexes are radiosensitisers when used in combination with RT. We screened 14 ruthenium-arene complexes and identified AH54 and AH63 as supra-additive radiosensitisers by clonogenic survival assays and isobologram analyses. Both complexes displayed facial chirality. At clinically relevant doses of RT, radiosensitisation of cancer cells by AH54 and AH63 was p53-dependent. Radiation enhancement ratios for 5–10 micromolar drug concentrations ranged from 1.19 to 1.82. In p53-wildtype cells, both drugs induced significant G2 cell cycle arrest and apoptosis. Colorectal cancer cells deficient in DNA damage repair proteins, EME1 and MUS81, were significantly more sensitive to both agents. Both drugs were active in cancer cell lines displaying acquired resistance to oxaliplatin or cisplatin. Our findings broaden the potential scope for these drugs for use in cancer therapy, including combination with radiotherapy to treat colorectal cancer.

This study compares first-generation and continuing-generation female college students in terms of: (a) level of parents' emotional and informational support; (b) level of students' stress; and (c) the relationship between both types of parent support and students' stress during the transition to college. We collected survey data from an ethnically diverse sample of 339 young women about to enter college. Results indicate first-generation students perceive less emotional and informational parent support than do continuing-generation students. First-generation students who perceive higher levels of parent emotional support have less stress than those who do not. However, neither type of parent support significantly predicted stress levels for continuing-generation students.

Summary Reasons for performing study: Abnormal epidermal stem cell regulation may contribute to the pathogenesis of equine chronic laminitis. Objective: To analyse the involvement of p63, a regulator of epidermal stem cell proliferative potential, in chronic laminitis. Methods: Epidermal tissues from skin, coronet and lamellae of the dorsal foot were harvested from 5 horses with chronic laminitis and 5 control horses. Tissues were analysed using histopathology, immunofluorescence microscopy and quantitative immunoblotting Results: Hoof lamellae of laminitic horses had a lower frequency of p63 positive cells than control lamellae, particularly in the distal region. Quantitative immunoblotting confirmed reduced p63 expression in the laminitic distal lamellar region. The decreased p63 expression in laminitic epidermal lamellae was most apparent in the abaxial region adjacent to the hoof wall and highly associated with the formation of terminally differentiated, dysplastic and hyperkeratotic epidermis in this region, whereas lamellae from control horses maintained high p63 expression throughout the axial-abaxial axis. Conclusions: Expression of p63 in equine skin resembles that reported in other species, including man and rodents, suggesting that p63 can serve as a marker for the proliferative potential of equine epidermal stem cells. p63 expression was significantly lower in the chronic laminitic hoof than in that of control horses, suggesting laminitic hoof epithelium has more limited proliferative potential with a shift towards differentiation. This may reflect reduced activity of epidermal stem cells in laminitic hoof. It is proposed that p63 contributes to the maintenance of hoof lamellae and that misregulation of p63 expression may lead to epidermal dysplasia during lamellar wedge formation. Potential relevance: This study suggests that loss of epidermal stem cells contributes to the pathogenesis of equine laminitis. Autologous transplantation of p63-positive epidermal stem cells from unaffected regions may have regenerative therapeutic potential for laminitic horses.

The dermo-epidermal interface that connects the equine distal phalanx to the cornified hoof wall withstands great biomechanical demands, but is also a region where structural failure often ensues as a result of laminitis. The cytoskeleton in this region maintains cell structure and facilitates intercellular adhesion, making it likely to be involved in laminitis pathogenesis, although it is poorly characterized in the equine hoof lamellae. The objective of the present study was to identify and quantify the cytoskeletal proteins present in the epidermal and dermal lamellae of the equine hoof by proteomic techniques. Protein was extracted from the mid-dorsal epidermal and dermal lamellae from the front feet of 5 Standardbred geldings and 1 Thoroughbred stallion. Mass spectrometry-based spectral counting techniques, PAGE, and immunoblotting were used to identify and quantify cytoskeletal proteins, and indirect immunofluorescence was used for cellular localization of K14 and K124 (where K refers to keratin). Proteins identified by spectral counting analysis included 3 actin microfilament proteins; 30 keratin proteins along with vimentin, desmin, peripherin, internexin, and 2 lamin intermediate filament proteins; and 6 tubulin microtubule proteins. Two novel keratins, K42 and K124, were identified as the most abundant cytoskeletal proteins (22.0 ± 3.2% and 23.3 ± 4.2% of cytoskeletal proteins, respectively) in equine hoof lamellae. Immunoreactivity to K14 was localized to the basal cell layer, and that to K124 was localized to basal and suprabasal cells in the secondary epidermal lamellae. Abundant proteins K124, K42, K14, K5, and a1-actin were identified on 1- and 2-dimensional polyacrylamide gels and aligned with the results of previous studies. Results of the present study provide the first comprehensive analysis of cytoskeletal proteins present in the equine lamellae by using mass spectrometry-based techniques for protein quantification and identification.

On October 22-23, 2008, an ACSM Roundtable was convened at the Uniformed Services University (Bethesda, MD) to discuss return-to-play or return-to-duty for people who have experienced exertional heat illness (EHI) and to develop consensus-based recommendations. The conference assembled experts from the civilian sports medicine community and the Department of Defense to discuss relevant EHI issues, such as potential long-term consequences, the concept of thermotolerance, and the role of thermal tolerance testing in return-to-play decisions. Although the group was unable to move forward with new consensus recommendations, they clearly documented critical clinical concerns and scientific questions, including the following: 1) no uniform core definitions of EHI; 2) limited validated criteria to assess recovery from exertional heat stroke (EHS); and 3) inadequate ability to predict who may be predisposed to a subsequent heat injury after EHS. Areas of potential future research are identified.

Objective—To determine effects of exercise training without dietary restriction on adiposity, basal hormone and lipid concentrations and glucose and insulin dynamics in overweight or obese, insulin-resistant horses. Animals—12 overweight or obese (body condition score ≥ 7), insulin-resistant (insulin sensitivity ≤ 1.2 × 10−4 L/min/mU) geldings. Procedures—4 horses remained sedentary, and 8 horses were exercised for 4 weeks at low intensity and 4 weeks at higher intensity, followed by 2 weeks of detraining. Prior to and after each training period, frequently sampled IV glucose tolerance tests with minimal model analysis were performed and baseline plasma insulin, glucose, triglycerides, non-esterified fatty acids, and leptin concentrations were analyzed. Adiposity was assessed by use of morphometrics, ultrasonic subcutaneous fat thickness, and estimation of fat mass from total body water (deuterium dilution method). Results—Body weight and fat mass decreased by 4% (mean ± SD, 20 ± 8 kg) and 34% (32 ± 9 kg), respectively, compared with pre-exercise values, with similar losses during low- and higher-intensity training. There was no effect of exercise training on subcutaneous fat thickness, plasma hormone and lipid concentrations, or minimal model parameters of glucose and insulin dynamics. Conclusions and Clinical Relevance—Results suggested that moderate exercise training without concurrent dietary restriction does not mitigate insulin resistance in overweight or obese horses. A more pronounced reduction in adiposity or higher volume or intensity of exercise may be necessary for improvement in insulin sensitivity in such horses.

Objective—To determine the effects of diet-induced weight gain on glucose and insulin dynamics and plasma hormone and lipid concentrations in horses. Animals—13 adult geldings. Procedures—Horses were fed 200% of their digestible energy requirements for maintenance for 16 weeks to induce weight gain. Frequently sampled IV glucose tolerance tests were performed before and after weight gain to evaluate glucose and insulin dynamics. Adiposity (assessed via condition scoring, morphometric measurements, and subcutaneous fat depth) and plasma concentrations of insulin, glucose, nonesterified fatty acids, triglycerides, and leptin were measured on a weekly or biweekly basis. Results—Mean ± SD body weight increased by 20% from 440 ± 44 kg to 526 ± 53 kg, and body condition score (scale, 1 to 9) increased from 6 ± 1to8 ± 1. Plasma glucose, triglyceride, and nonesterified fatty acid concentrations were similar before and after weight gain. Leptin and insulin concentrations increased with weight gain. Mean ± SD insulin sensitivity decreased by 71 ± 28%, accompanied by a 408 ± 201% increase in acute insulin response to glucose, which resulted in similar disposition index before and after weight gain. Conclusions and Clinical Relevance—Diet-induced weight gain in horses occurred concurrently with decreased insulin sensitivity that was effectively compensated for by an increase in insulin secretory response. Obesity resulted in hyperinsulinemia and hyperleptinemia, compared with baseline values, but no changes in lipid concentrations were apparent. Preventing obesity is a potential strategy to help avoid insulin resistance, hyperinsulinemia, and hyperleptinemia in horses.

Due to global climate change, the world will, on average, experience a higher number of heat waves, and the intensity and length of these heat waves is projected to increase. Knowledge about the implications of heat exposure to human health is growing, with excess mortality and illness occurring during hot weather in diverse regions. Certain groups, including the elderly, the urban poor, and those with chronic health conditions, are at higher risk. Preventive actions include: establishing heat wave warning systems; making cool environments available (through air conditioning or other means); public education; planting trees and other vegetation; and modifying the built environment to provide proper ventilation and use materials and colors that reduce heat build-up and optimize thermal comfort. However, to inspire local prevention activities, easily understood information about the strategies' benefits needs to be incorporated into decision tools. Integrating heat health information into a comprehensive adaptation planning process can alert local decision-makers to extreme heat risks and provide information necessary to choose strategies that yield the largest health improvements and cost savings. Tools to enable this include web-based programs that illustrate effective methods for including heat health in comprehensive local-level adaptation planning; calculate costs and benefits of several activities; maps showing zones of high potential heat exposure and vulnerable populations in a local area; and public awareness materials and training for implementing preventive activities. A new computer-based decision tool will enable local estimates of heat-related health effects and potential savings from implementing a range of prevention strategies.

Inflammatory and redox signals could render lamellar tissue susceptible to damage and contribute to higher risk for laminitis in obese or insulin resistant ponies just as these factors contribute to health risks in humans with metabolic syndrome. This study evaluated circulating markers of inflammatory and redox status in ponies that had a history of recurrent bouts of pasture-associated laminitis (PL, n = 42) or had never developed clinical laminitis (NL, n = 34) under the current management conditions. There were no differences (P0.05) between PL and NL ponies for markers of antioxidant function (glutathione, glutathione peroxidase, superoxide dismutase) or increased oxidative pressure (malondialdehyde, apoptosis, 3-nitrotyrosine). Inflammatory status, as indicated by fibrinogen concentration, was also not different between pony groups (P = 0.84). However, PL ponies had higher (P0.001) plasma concentrations of the pro-inflammatory cytokine TNF-alpha than NL ponies. This suggests that a predisposition to laminitis is associated with increased circulating inflammatory cytokines. TNF-alpha could also represent a contributing factor to increased insulin resistance observed in laminitis prone ponies. These results provide new insight into potential mechanisms and risk factors underlying laminitis.

Summary Reasons for performing study: The ability to predict ponies at increased risk of laminitic episodes, when exposed to nutrient dense pasture, would facilitate management to avoid disease. Objectives: To identify variables and clinically useful cut-off values with reproducible diagnostic accuracy for the prediction of ponies that subsequently developed laminitis when exposed to nutrient dense pasture. Methods: A cohort of predominantly Welsh and Dartmoor ponies from a closed herd was evaluated in March 2006 (n = 74) and March 2007 (n = 57). Ponies were categorised as never laminitic or previously laminitic according to reported laminitic history and as clinically laminitic (CL) if laminitis was observed within 3 months following evaluation. Body condition score (BCS), cresty neck score (CNS), girth and neck circumferences (NC), withers height, blood pressure and hoof surface temperature, and plasma insulin, glucose, triglyceride, leptin, cortisol, ACTH, uric acid and TNF-α concentrations were measured. Analysis of sensitivity, specificity and receiver operating characteristic curves was used to evaluate the diagnostic accuracy for a variable to predict CL ponies. Results: Variables with diagnostic accuracy for the prediction of CL ponies included insulin, leptin, BCS, CNS, and NC:height ratio. Specific cut-off values of insulin (>32 mu/l), leptin (>7.3 ng/ml), BCS (≥7), CNS (≥4) and NC:height ratio (>0.71) had reproducible diagnostic accuracy for the prediction of laminitis. Combining tests did not result in higher diagnostic accuracy than individual tests of insulin or leptin during either evaluation. Conclusions: Tests of insulin and leptin concentrations and measures of generalised (BCS) and localised (CNS or NC:height ratio) obesity were beneficial in the prediction of laminitic episodes. Potential relevance: These results highlight the importance of monitoring and reducing insulin concentration, and generalised and regional obesity in ponies to reduce risk of laminitis.

This paper reviews regional climate knowledge and vulnerability in the northern Mexico San Pedro River Basin, with a focus on water quality, quantity, and management issues on the Mexican side of the border. A discussion based on the available literature is supplemented by a survey assessing concerns about water and the quality and usability of climate and hydrologic information available to water managers and communities. The surveys indicate that the central concern for urban residents is the lack of reliable potable water due to frequent service breakdowns–with climate change and variability, specifically drought and high temperatures, as contributing factors. Water managers desire appropriate meteorological and hydrologic information to improve planning strategies, but access to this information remains limited. Considerable disagreement exists about who should pay for previously free or low-cost water and wastewater treatment. Urban users have little incentive to conserve because of the present flat, low rate and frustration with service. In rural areas, while a majority of ranchers recognize that variable climate and water loss could increasingly jeopardize their lifestyle, they seldom use meteorological information in planning or modify their water consumption. Climate vulnerability also includes potential for serious environmental health issues due to the presence of heavy metals and organic contaminants in the San Pedro.

This paper derives sharp estimates of the error arising from explicit and implicit approximations of the constant-coefficient 1D convection-diffusion equation with Dirac initial data. The error analysis is based on Fourier analysis and asymptotic approximation of the integrals resulting from the inverse Fourier transform. This research is motivated by applications in computational finance and the desire to prove convergence of approximations to adjoint partial differential equations.

This paper presents a convergence analysis of Crank-Nicolson and Rannacher time-marching methods which are often used in finite difference discretisations of the Black-Scholes equations. Particular attention is paid to the important role of Rannacher's startup procedure, in which one or more initial timesteps use Backward Euler timestepping, to achieve second order convergence for approximations of the first and second derivatives. Numerical results confirm the sharpness of the error analysis which is based on asymptotic analysis of the behaviour of the Fourier transform. The relevance to Black-Scholes applications is discussed in detail, with numerical results supporting recommendations on how to maximise the accuracy for a given computational cost.

646 Background: Tumour heterogeneity is a key determinants of cancer resistance. Serial sampling of cell free (cf)DNA may detect evolving somatic mutations. Monitoring cancers after therapies e.g. selective internal radiation therapy (SIRT) require new biomarkers as RECIST imaging was developed to assess response to chemotherapy and may not reflect tumour changes due to new therapeutic strategies. The utility of cfDNA to detect recurrence and predict response is emerging. The objective of this study was to sequence serial cfDNA samples from patients with liver predominant metastatic disease receiving SIRT, and explore the feasibility of using this method to detect evolution of somatic mutations after high dose radiation. Methods: A prospective imaging biomarker study was performed in patients with colorectal liver metastases (CRLM) receiving SIRT. Plasma was extracted and frozen within 4 hours at 3 time points: baseline, 4 and 10 weeks after SIRT. Ion Torrent Amplicon sequencing was performed using cancer hotspot panel v.2. Sequencing of primary tumours was obtained by pyrosequencing. Results: Twenty-four patients with CRLM were recruited from March – Dec 2015, and 18 had cfDNA extracted for sequencing at a minimum of two time points. Ion Torrent amplicon sequencing of baseline cfDNA showed high concordance with formalin-fixed paraffin-embedded (FFPE) tumour samples. Serial cfDNA sequencing in a patient with partial response by imaging, detected 22% KRAS G12C mutation at baseline, which decreased to 1.5% by 4 weeks, then was undetectable 10 weeks after SIRT. Sequencing of another patient’s cfDNA revealed persistence of KRAS G13D and a truncating APCmutation at both 4 and 10 weeks after SIRT, consistent with the patient’s progressive disease. Conclusions: Cell-free DNA is emerging as a biomarker in colorectal cancer. Our measurements of mutational status in baseline cfDNA and FFPE samples show high concordance. This study reports that serial cfDNA sequencing detects changes in mutational status and specific mutations following high dose radiation to the liver. This adds to the evidence of cfDNA as a tool to detect evolution of somatic mutations following therapy.

As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin-resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure-specific endonuclease XPF-ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S-phase arrest and persistence of double-strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF-ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial. What's new? With options for systemic treatment of malignant melanoma (MM) on the rise, there is an increasing need to develop biomarkers for patient selection. To that end, this study explored the possibility of a biomarker to improve objective response rates to the drug oxaliplatin. The study reveals a mechanism by which mammalian cells are rendered hypersensitive to oxaliplatin that centers around the loss of endonuclease XPF-ERCC1. Sensitivity to oxaliplatin was directly related to XPF and ERCC1 protein levels. The findings indicate that XPF may be a suitable biomarker for MM patient selection for oxaliplatin therapy. © 2013 UICC.

Population size distributions were examined for 12 species of trees co-occurring at Chamela Biological Station in Jalisco, Mexico. Species had been selected as congeneric pairs and trios similar in gross morphology and ecology in order better to identify correlates of relative abundance. Rarer species were found unanimously to have more irregular distributions of individuals among size classes than more common species when distributions were compared to a smooth, descending curve constructed from population mean stem diameters (an exponential distribution). Examination among species of patterns of deviation from these corresponding smooth distributions indicates that the most reasonably inferred cause for the observed pattern is consistent differences in degree of fluctuation in recruitment into adult size classes. These results thereby suggest a demographic difference between locally rarer and more common species that may be generally associated with observed differences in relative abundance and indicate a focus for management of rarity in forest trees.

The role of nurses in primary care is understudied. The purpose of this study was to describe the current registered nurse (RN) role in three Primary Care Networks (PCNs) in western Canada and to identify opportunities for optimal utilization of RNs in these settings. Case study methodology included interviews and document review. Although the RN role evolved during the study, most RNs focused on chronic disease management. Role ambiguity was evident between nurses and with interprofessional team members. Relationships of RNs to other providers, particularly physicians, impacted the enactment of the nursing role. Other barriers to role enactment included physician fee-for-service remuneration, management structures and processes, lack of access to electronic medical records and lack of previous opportunities to apply primary health-care education in the practice setting. Further work is needed to optimize the RN role in primary care to ensure maximum impact for patients, providers and the health system overall.

Schools have been identified as playing a key role in supporting the children of prisoners. This paper reports on a study, which explored the support provision offered in schools to children who experience parental imprisonment. By interviewing school representatives, stakeholders, parents and children, we illustrate the support available in schools, the issues that arise and ways in which support provision can be strengthened. Our findings indicate that children of prisoners often constitute a 'forgotten' group in schools, and we suggest that an awareness of these children and the challenges they face needs to be raised amongst education practitioners and policy-makers. Language: en

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.

Paper focusing on the impacts of harmonic distortion from charging electric vehicles on low voltage networks.

Ponies suffering from recurrent episodes of laminitis when grazed at pasture (pasture-associated laminitis) exhibit phenotypes similar to those associated with human metabolic syndrome. In humans, evidence suggests that the obesity-related morbidities associated with metabolic syndrome, including diabetes and cardiovascular disease, are caused by an increase in the production of advanced glycoxidation end-products (AGEs). These end-products have been recognised as putative pro-inflammatory mediators and are considered a 'risk factor' for human health. However, the evaluation of AGEs in laminitic ponies has not been explored. The aim of this study was to compare plasma concentrations of the AGE pentosidine (PENT) in ponies presenting with clinical features of equine metabolic syndrome (EMS) with a history of recent laminitis and/or showing signs of laminitis at the time of sampling (LP) with those with no prior history of clinical laminitis (NL). Age, body condition score (BCS) and bodyweight were recorded and blood samples collected for the measurement of plasma concentrations of PENT, glucose, insulin, triglycerides (TG), non-esterified fatty acids (NEFA) and cortisol. Insulin sensitivity was assessed by the reciprocal of the square root of insulin (RISQI) and the insulin:glucose ratio. Plasma PENT concentrations were twofold higher (P0.005) in LP than in NL ponies. Significant (P0.05) correlations were also evident between PENT and insulin, RISQI, TG and age. These preliminary findings are consistent with the hypothesis that glycoxidation in laminitis is associated with EMS.

Excess alcohol consumption and associated harms in terms of health, crime and disorder have been highlighted by the government and media, causing considerable public concern. This study quantified the number of patient attendances at an urban adult and children's emergency department (ED) directly attributable to alcohol intoxication, and investigated ways in which the inter-agency sharing of anonymised information could be used to design, implement and monitor interventions to reduce these harms.Intoxicated patients attending either the adult or children's ED were prospectively identified by qualified nursing staff and anonymised data collected by a dedicated researcher. Collaboration and data sharing between health, police, social services, university experts and local authorities was achieved through the establishment of steering and operational groups with agreed objectives and the formation of a shared anonymised database.The proportion of patients attending the ED as a result of alcohol intoxication was 4% in adults and1% in children. 70% of patients were male, with a mean age of 30 years, and 72% attended between 20.00 and 08.00 h. The most common reason for ED attendance was accident (34%), followed closely by assault (30%). 27% of patients had done most of their drinking at home, 36% in a pub and 16% in a nightclub. Inter-agency collaboration proved highly successful: pooling of anonymised data created a much clearer picture of the extent of the problem and immediately suggested strategies for intervention.The initiative to achieve inter-agency collaboration and data sharing was highly successful, with clear potential for the development and implementation of interventions that will reduce ED attendance due to excess alcohol consumption.

This study described a scoring system for the assessment of apparent neck adiposity and evaluated morphometric measurements for assessment of neck and overall adiposity. Twenty-one barren Thoroughbred mares, 13 Arabian geldings and 75 Welsh, Dartmoor, or crossbred pony mares, were clinically examined and blood samples analysed for insulin, glucose, leptin, and triglycerides. Bodyweight (BW), height, length, girth and abdominal circumferences, neck length, neck crest height and neck circumference were measured, and body condition scores (BCS) and cresty neck scores (CNS) were rated. Girth:height ratio had the strongest associations with BCS (r(s)=0.64, P0.001 in horses; r(s)=0.83, P0.001 in ponies) and blood variables, such as leptin (r(s)=0.39, P=0.024 in horses; r(s)=0.68, P0.001 in ponies). Crest height and neck circumference:height ratio had the strongest association with CNS (r(s)0.50, P0.01) and blood variables, such as insulin (r(s)0.40, P0.05). Cresty neck score was useful in the assessment of neck crest adiposity and had physiological relevance, as demonstrated by associations with blood variables. Girth:height was the most suitable morphometric for assessment of overall adiposity, and either crest height or neck circumference:height was a suitable morphometric for assessment of apparent neck adiposity.

Objectives:We report our observations on one soldier with abnormal hyperthermia during exercise in the heat compared with prior exercise and following acute local (non-febrile) infection. Also, we report on 994 heat stroke hospitalizations in the U.S. Army. It is known that prior infection is a risk factor for heat illness and some of the 37 heat stroke deaths cited infections (eg, pneumonia, influenza) in the medical records.Results:This case report illustrates complete recovery from abnormal hyperthermia, which occurred in a laboratory setting during mild, low intensity exercise. In a field setting, this case may have resulted in serious heat illness. As with most of the heat stroke cases, rapid medical attention (ie, cooling and rehydration) and the age group (19 to 26) that represents majority of the heatstroke cases in U.S. Army are likely factors that contribute successful treatment of heatstroke in the field environment.Conclusions:We conclude that acute inflammatory response can augment the hyperthermia of exercise and possibly increase heat illness susceptibility. Furthermore, it is important for health care providers of soldiers and athletes to monitor acute local infections due to the potential thermoregulatory consequences during exercise in the heat.

Equine pasture-associated laminitis is a devastating disease manifested in the hoof and associated with obesity, dietary carbohydrate and insulin resistance, risk-factors which parallel human metab...

Background Globally and nationally large numbers of people are injured each year, yet there is little information on the impact of these injuries on people's lives, on society and on health and social care services. Measurement of the burden of injuries is needed at a global, national and regional level to be able to inform injured people of the likely duration of impairment; to guide policy makers in investing in preventative measures; to facilitate the evaluation and cost effectiveness of interventions and to contribute to international efforts to more accurately assess the global burden of injuries. Methods/Design A prospective, longitudinal multi-centre study of 1333 injured individuals, atttending Emergency Departments or admitted to hospital in four UK areas: Swansea, Surrey, Bristol and Nottingham. Specified quotas of patients with defined injuries covering the whole spectrum will be recruited. Participants (or a proxy) will complete a baseline questionnaire regarding their injury and pre-injury quality of life. Follow up occurs at 1, 4, and 12 months post injury or until return to normal function within 12 months, with measures of health service utilisation, impairment, disability, and health related quality of life. National estimates of the burden of injuries will be calculated by extrapolation from the sample population to national and regional computerised hospital in-patient, emergency department and mortality data. Discussion This study will provide more detailed data on the national burden of injuries than has previously been available in any country and will contribute to international collaborative efforts to more accurately assess the global burden of injuries. The results will be used to advise policy makers on prioritisation of preventive measures, support the evaluation of interventions, and provide guidance on the likely impact and degree of impairment and disability following specific injuries.

Inflammatory monocytes (Ly6Chi CCR2hi) play a critical role in steering the course of responses against microbial infections of the lung. Lung monocytes can take up live fungi or bacteria and transport them to draining mediastinal lymph nodes (mLN). How microbes are taken up and trafficked by monocytes from the pulmonary site of infection is poorly understood. To study monocyte-mediated microbial trafficking, we developed a system to trace monocytes that carry particles from the lung to mLNs. Herein, we used mice expressing GFP or the diphtheria toxin receptor under the control of the CCR2 promoter to determine the impact of intratracheally instilled toll-like receptor (TLR) agonists on trafficking of with fluorescent, polystyrene microspheres from the lung to mLNs. This system recapitulates monocyte recruitment and trafficking seen during in vivo infections. Monocytes infiltrated the interstitial space in response to TLR2 agonists. And while neutrophils were the primary cell population associated with instilled microspheres in the lung, they did not deliver them independently to mLNs. Conversely, adoptively transferred monocytes successfully delivered microspheres to mLNs of CCR2+-cell-depleted mice. Our current system and findings empower us to further dissect the process of monocyte uptake of inhaled particles and antigen delivery to lymphocytes of mLNs, which may in turn inform novel vaccine strategies in an age of increasing emergence of antibiotic-resistant pathogens.

Molecules derived from gut-colonizing microbes contribute to intestinal homeostasis by stimulating innate immune receptors and maintaining a basal level of activation of host antimicrobial defenses. Depletion of intestinal microbes by treatment with antibiotics severely dampens these responses, increasing the risk for colonization and infection with pathogenic bacteria. A major consequence of antibiotic treatment is downregulation of the antimicrobial protein RegIII-γ. RegIII-γ expression is markedly decreased during antibiotic treatment but can be induced by administration of Toll-like receptor (TLR) ligands derived from Gram-negative bacteria. This observation suggests a role for Gram-negative organisms in stimulating RegIII-γ intestinal levels. In this study, we investigated the ability of several E. coli and K. pneumoniae strains to induce RegIII-γ in the mouse intestine during antibiotic stress. We find that although both bacterial species colonize the gastrointestinal tract of antibiotic-treated mice, only E. coli restores RegIII-γ expression in the ileum. E. coli, but not K. pneumoniae, induces IL-22 expression, a requisite step for RegIII-γ, induction, in the small intestinal lamina propria. Flagellin and TLR5 signaling are not required for E.coli-mediated RegIII-γ induction. Our findings suggest that Gram-negative bacteria colonizing the intestine differ in their ability to mediate IL-22-dependent RegIII-γ.