Selection of an early biomarker for vascular normalization using dynamic contrast-enhanced ultrasonography to predict outcomes of metastatic patients treated with bevacizumab.

BACKGROUND: Dynamic contrast-enhanced ultrasonography (DCE-US) has been used for evaluation of tumor response to antiangiogenic treatments. The objective of this study was to assess the link between DCE-US data obtained during the first week of treatment and subsequent tumor progression. PATIENTS AND METHODS: Patients treated with antiangiogenic therapies were included in a multicentric prospective study from 2007 to 2010. DCE-US examinations were available at baseline and at day 7. For each examination, a 3 min perfusion curve was recorded just after injection of a contrast agent. Each perfusion curve was modeled with seven parameters. We analyzed the correlation between criteria measured up to day 7 on freedom from progression (FFP). The impact was assessed globally, according to tumor localization and to type of treatment. RESULTS: The median follow-up was 20 months. The mean transit time (MTT) evaluated at day 7 was the only criterion significantly associated with FFP (P = 0.002). The cut-off point maximizing the difference between FFP curves was 12 s. Patients with at least a 12 s MTT had a better FFP. The results according to tumor type were significantly heterogeneous: the impact of MTT on FFP was more marked for breast cancer (P = 0.004) and for colon cancer (P = 0.025) than for other tumor types. Similarly, the differences in FFP according to MTT at day 7 were marked (P = 0.004) in patients receiving bevacizumab. CONCLUSION: The MTT evaluated with DCE-US at day 7 is significantly correlated to FFP of patients treated with bevacizumab. This criterion might be linked to vascular normalization. AFSSAPS NO: 2007-A00399-44.

Spatial and Transient Effects during the Amplification of a Picosecond Pulse Beam by a Nanosecond Pump.

Amplification of a picosecond pulse beam by a lower intensity nanosecond pulse beam was experimentally observed in a flowing plasma. Modifications of intensity distributions in beam focal spots due to nonhomogeneous energy transfer and its transient regime were investigated. The mean transferred power reached 57% of the incident power of the nanosecond pulse beam. An imaging diagnostic allowed the intensity profile of the picosecond pulse beam to be determined, bringing to evidence the spatial nonuniformity of energy transfer in the amplified beam. This diagnostic also enabled us to observe the temporal evolution of the speckle intensity distribution because of the transfer. These results are reproduced by numerical simulations of two complementary codes. The method and the observed effects are important for the understanding of experiments with multiple crossing laser beams in plasmas.

A case of a chlorine inhalation injury in an Ebola treatment unit.

We present a 26-year-old male British military nurse, deployed to Sierra Leone to treat patients with Ebola virus disease at the military-run Kerry Town Ebola Treatment Unit. Following exposure to chlorine gas during routine maintenance procedures, the patient had an episode of respiratory distress and briefly lost consciousness after exiting the facility. Diagnoses of reactive airways disease, secondary to the chlorine exposure and a hypocapnic syncopal episode were made. The patient was resuscitated with minimal intervention and complete recovery occurred in less than 1 week. This case highlights the issues of using high-strength chlorine solution to disinfect the red zone. Although this patient had a good outcome, this was fortunate. Ensuring Ebola treatment centres are optimally designed and that appropriate management systems are formulated with extraction scenarios rehearsed are important to mitigate the chlorine-associated risk.

A case of an avoidable admission to an Ebola treatment unit with malaria and an associated heat illness.

We present a 27-year old British nurse admitted to the Kerry Town Ebola Treatment Unit, Sierra Leone, with symptoms fitting suspect-Ebola virus disease (EVD) case criteria. A diagnosis of Plasmodium falciparum malaria and heat illness was ultimately made, both of which could have been prevented through employing simple measures not utilised in this case. The dual pathology of her presentation was atypical for either disease meaning EVD could not be immediately excluded. She remained isolated in the red zone until 72 h from symptom onset. This case highlights why force protection measures are important to reduce the incidence of both malaria and heat illness in deployed military and civilian populations. These prevention measures are particularly pertinent during the current EVD epidemic where presenting with these pathologies requires clinical assessment in the 'red zone' of an Ebola treatment unit.

Microenvironment involved in FPR1 expression by human glioblastomas.

Formyl peptide receptor 1 (FPR1) activity in U87 glioblastoma (GBM) cells contributes to tumor cell motility. The present study aimed to evaluate the FPR1 expression in human GBM, the possibility to elicit agonist induced FPR1 activation of GBM cells and inhibit this activation with chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Immunohistochemistry was used to assess FPR1 expression in GBM patient samples, which was present in all 178 samples. Also FPR1 mRNA levels measured with quantitative PCR, could be detected in all 25 GBM patient samples tested. Activation of FPR1 in U87 cells, as measured by human mitochondrial-derived agonists, increased calcium mobilization, AKT and ERK1/2 phosphorylation, and ligand-induced migration. Inhibition of all responses could be achieved with CHIPS. Eight early passage human Groningen Glioma (GG) cell lines, isolated from primary GBM tissue were screened for the presence of FPR1. FPR1 mRNA and protein expression as well as receptor activation could not be detected in any of these early passage GG cell lines. However FPR1 was present in ex vivo tumors formed by the same GG cell lines after being implanted in mouse brains. FPR1 is highly expressed in human GBM specimens, it can be activated by human mitochondrial-derived agonists in U87 and inhibited with CHIPS. FPR1 cannot be detected in early passage GG cell lines in vitro, however when engrafted in the mouse brain these cells show FPR1 expression. These results suggest a role of the brain microenvironment in FPR1 expression in GBM.

Investigating the potential effect of consanguinity on type 2 diabetes susceptibility in a Saudi population.

OBJECTIVE: To examine mechanisms by which consanguinity might increase the risk of type 2 diabetes (T2D) in a Saudi population. METHODOLOGY: 362 adult male participants were recruited, 179 were T2D patients and 183 healthy siblings. T2D severity was assessed in patients by recording age at diagnosis. In healthy subjects, diabetes risk was studied by measuring the body mass index, fasting blood glucose (FBG) level, and waist circumference. Extended pedigrees were constructed to calculate inbreeding coefficients. To account for tribal relatedness degrees reported in the constructed pedigrees, assumed inbreeding coefficients for tribal relatedness were added to the calculated inbreeding coefficients. A total of 23 SNPs associated with a higher risk of T2D were genotyped. Results : A significant inverse association was detected between inbreeding coefficients and age at diagnosis (Spearman's coefficient: -0.186, p = 0.013). In 42 families, we were able to recruit 2 healthy siblings. Pearson's correlation coefficient of FBG between siblings was 0.317 (p = 0.04). The correlation between the siblings' FBG increased with an increasing degree of consanguinity. The effect of consanguinity on the FBG level was further assessed by regression line analysis and by controlling for differences in age, caloric intake, and level of physical activity (ß: -0.118, p = 0.024). No significant association between the number of T2D risk alleles and the traits was found. CONCLUSION: Our findings suggest that consanguinity might increase the risk of T2D by an earlier onset of the disease and by strengthening possible genetic effects on FBG.

The future of atrial fibrillation therapy: intervention on heat shock proteins influencing electropathology is the next in line.

Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia accounting for one-third of hospitalisations. Treatment of AF is difficult, which is rooted in the progressive nature of electrical and structural remodelling, called electropathology, which makes the atria more vulnerable for AF. Importantly, structural damage of the myocardium is already present when AF is diagnosed for the first time. Currently, no effective therapy is known that can resolve this damage.Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients. Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF. However, it is still unclear whether induction of HSPs also prolongs the arrhythmia-free interval after, for example, cardioversion of AF.In this review, we discuss the role of HSPs in the pathophysiology of AF and give an outline of the HALT&REVERSE project, initiated by the HALT&REVERSE Consortium and the AF Innovation Platform. This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF.

Validation of a turbulent Kelvin-Helmholtz shear layer model using a high-energy-density OMEGA laser experiment.

Following the successful demonstration of an OMEGA laser-driven platform for generating and studying nearly two-dimensional unstable plasma shear layers [Hurricane et al., Phys. Plasmas 16, 056305 (2009); Harding et al., Phys. Rev. Lett. 103, 045005 (2009)], this Letter reports on the first quantitative measurement of turbulent mixing in a high-energy-density plasma. As a blast wave moves parallel to an unperturbed interface between a low-density foam and a high-density plastic, baroclinic vorticity is deposited at the interface and a Kelvin-Helmholtz instability-driven turbulent mixing layer is created in the postshock flow due to surface roughness. The spatial scale and density profile of the turbulent layer are diagnosed using x-ray radiography with sufficiently small uncertainty so that the data can be used to ~0.17 µm) in the postshock plasma flow are consistent with an "inertial subrange," within which a Kolmogorov turbulent energy cascade can be active. An illustration of comparing the data set with the predictions of a two-equation turbulence model in the ares radiation hydrodynamics code is also presented.

Comparative toxicity of acaricides to honey bee (Hymenoptera: Apidae) workers and queens.

Acaricides are used to treat honey bee (Apis mellifera L.) colonies to control the varroa mite (Varroa destructor Anderson & Trueman), a worldwide threat to honey bee health. Although acaricides control a serious honey bee parasite and mitigate bee loss, they may cause harm to bees as well. We topically applied five acaricides, each with a different mode of action, to young adult queen and worker bees to generate dose-response curves and LD50. Twenty-four hours after treatment, queens were found to be three-times more tolerant of tau-fluvalinate and six-times more tolerant of thymol than workers when adjusted for body weight differences between workers (108 mg) and queens (180 mg). Queens survived the highest administered doses of fenpyroximate (1620 microg/g) and coumaphos (2700 microg/g) indicating that queens are at least 11-fold more tolerant of coumaphos and at least 54-fold more tolerant of fenpyroximate than workers. However, queens treated with as little as 54 microg/g of fenpyroximate exhibited reduced survival over 6 wk after treatment. Amitraz was the only acaricide tested for which queens were not more tolerant than workers. The striking difference in acaricide tolerance of queen and worker honey bees suggests physiological differences in how the two castes are affected by xenobiotics.

Structure of fish proteins as modified by salting procedures: A rheological and ultrastructural analysis of hake (Merluccius hubbsi) fillets.

Salting is a technique used for preserving fish meat and allows obtaining added value products. The salting process provokes several structure modifications, which in turns cause changes in the fish texture. Thus, the objective of this study was to investigate the effect of three salting procedures (dry salting [DS], mixed salting [MS] and brining [BS]) on the rheology and structure of Merluccius hubbsi (Argentine hake). Rheological properties were evaluated using dynamic oscillatory and thermorheology tests, and the structure changes by scanning electron microscopy. DS samples showed the highest values of salt concentration referred to liquid phase (zNaCl ), while BS showed the lowest ones. In all cases, elastic (G') and loss (G″) modulus increased with salting time. G' values exceeded G″ values, indicating a predominant solid behavior. DS samples presented the greatest increase in rheological parameters (G', G″ and η*). Thermomechanical spectra allowed to identify an increase in denaturation temperature (Td) of proteins (myosin and actin) for DS and MS, and to a lesser extent for BS (Td = 46.7 ± 0.4°C, Td = 50.3 ± 0.8°C, Td = 58.8 ± 0.6°C and Td = 58.2 ± 0.9°C for fresh, BS, MS and DS, respectively). Ultrastructural images evidenced conformational changes on the myofibrillar proteins and the connective tissue (collagen). BS caused the least superficial damage to hake tissue. Based on the results, BS could be the method recommended for the industrial production of salted M. hubbsi. PRACTICAL APPLICATION: During salting of hake, variations in water and salt content have a significant effect on the myofibrillar and connective tissue proteins. The study of rheological properties and microstructure allows a better understanding of the conformational changes induced by the salting process. The least surface damage exhibited by brining fillets is consistent with the mass transfer mechanism that leads to the formation of a film on the muscle surface that dilutes the salt; for this reason, compared to dry and mixed salting, brining could be the method recommended for the industrial production of salted (>15% w/w) Merluccius hubbsi.

Immunoglobulin-E-binding epitopes of wheat allergens in patients with food allergy to wheat and in mice experimentally sensitized to wheat proteins.

BACKGROUND: At present, B cell epitopes involved in food allergy to wheat are known only for a few allergens and a few categories of patients. OBJECTIVE: To characterize the epitopes of different wheat kernel allergens: α-, γ, ω2, and ω5-gliadin, a low-molecular-weight (LMW) glutenin subunit, and a lipid transfer protein (LTP1) recognized by allergic patients and by sensitized mice and provide further understanding of the role of structure in determining allergic response. METHODS: Sera were obtained from 39 patients suffering from food allergy to wheat. BALB/c mice were sensitized to gliadins or LTP1 by intraperitoneal immunizations. Continuous epitopes bound by IgE were delineated by the Pepscan technique. The response to reduced, alkylated LTP1 was compared with that of the native form to evaluate the importance of protein folding on IgE reactivity. RESULTS: Few continuous epitopes of LTP1 reacted with IgE from allergic patients and mice, but one of them was common to several patients and sensitized mice. The unfolded protein was not recognized by either patient or mouse IgE, emphasizing the major role of LTP1 folding and discontinuous epitopes in IgE-binding. In contrast, many continuous epitopes were detected by patient and mouse IgE especially for an ω5-gliadin, which is an unstructured protein, and to a lesser extent, for the other gliadins and a LMW-glutenin subunit. CONCLUSION AND CLINICAL RELEVANCE: The conformation of LTP1 appeared to have a strong impact on the type of IgE-binding epitopes elicited by this protein in both man and mouse. The responses in mice sensitized to gliadins or LTP1 were sufficiently comparable with the human response in terms of IgE-binding epitopes to provide support for the use of the mouse model in further investigations.

Sequential rupture of triceps and quadriceps tendons in a dialysis patient using hormone supplements.

Spontaneous rupture of tendons is rare, and typically occurs in large weight bearing tendons such as the quadriceps, Achilles and patellar tendon, in the context of various chronic diseases including end-stage renal disease. In general, tendon rupture in dialysis patients is associated with hyperparathyroidism, long duration of dialysis, steroid and quinolone use. We present a case of a young man on chronic dialysis who presented with sequential rupture of triceps and quadriceps tendons requiring surgical repair, several months after initiating use of multiple hormone supplements including human growth hormone and androgens. The supplements were obtained over the internet with the aim of improving his kidney function. Although this patient did have hyperparathyroidism, it is likely his PTH elevation was exacerbated by use of human growth hormone, and tendon rupture risk increased by concurrent use of an androgen supplement. This case highlights the fact that dialysis patients do utilize alternative remedies and that there may be unexpected, dialysis-specific complications associated with their use.

Co-Creation Approach with Action-Oriented Research Methods to Strengthen "Krachtvoer"; A School-Based Programme to Enhance Healthy Nutrition in Adolescents.

In recent years, the nutritional pattern of the Dutch adolescent has cautiously improved. However, progress can be gained if more Dutch adolescents adhere to the nutritional guidelines. School-based initiatives offer opportunities to deal with the unhealthy eating behaviours of adolescents via nutrition educational interventions. In designing and/or re-designing school-based interventions, it is important to enhance optimal context-oriented implementation adaptation by involving the complex adaptive school system. This paper elaborates on the way of dealing with the dynamic implementation context of the educational programme "Krachtvoer" (ENG: "Power food") for prevocational schools, how the programme can be adapted to each unique implementation context, and how the programme can be progressively kept up to date. Following a co-creation-guided approach with various intersectoral stakeholders within and outside the school setting, action-oriented mixed research methods (i.e., observations, semi-structured interviews, focus group interviews, programme usage monitoring, and questionnaires) constantly provide input to develop the programme and its implementation strategy via continuous micro-process cycles. Successful co-creation of school-based health promotion seems to be dependent on proper intersectoral cooperation between research and practice communities, a national partner network that can provide project-relevant insights and establish capacity building aimed at improving contextual fit, and a time-investment balance in and between sectors.

Markedly effective local control of hepatocellular carcinoma with a poor prognosis by combined multimodal therapy with sorafenib as a neoadjuvant approach.

Sorafenib has recently been approved as the gold standard therapy for advanced BCLC-C hepatocellular carcinomas. Although significant improvement of survival rates was shown, objective tumor response rates remained low following RECIST criteria in phases 2 and 3 studies. We report the rare case of a patient with a large hepatocellular carcinoma tumor invading suprahepatic veins in which sorafenib led to a very significant regression by about 90% of the tumor bulk, thus allowing at sterilizing the residual tumor tissue by subsequent combination of transarterial intrahepatic chemoembolization and high dose radiotherapy.

Degradation of lyophilized lipid/DNA complexes during storage: the role of lipid and reactive oxygen species.

The presence of trace amounts of metal ions in nonviral vector formulations can significantly affect the stability of lipid/DNA complexes (lipoplexes) during acute freeze-drying. The goal of the present study was to evaluate the generation of reactive oxygen species (ROS) in dried formulations of lipoplexes and in their individual components (lipid or naked DNA). The experiments were conducted in the presence or absence of a transition metal (Fe2+). Lipoplexes and their individual components were formulated in trehalose and subjected to lyophilization and stored for a period of up to 2 months at +60 degrees C. Physico-chemical characteristics and biological activity were evaluated at different time intervals. Generation of ROS during storage was determined by adding a fluorescence probe to the formulations prior to freeze-drying. We also monitored the formation of thiobarbituric reactive substances (TBARS). Our results show that ROS and TBARS form during storage in the dried state. Our findings also suggest that degradation is more rapid in the presence of lipid, even in the absence of metal. We also showed that dried naked DNA formulations are more stable without the lipid component. Effective strategies are then needed to minimize the formation and accumulation of oxidative damage of lipoplexes during storage.

The crystal structure of oxylipin-conjugated barley LTP1 highlights the unique plasticity of the hydrophobic cavity of these plant lipid-binding proteins.

The barley lipid transfer protein (LTP1) adducted by an alpha-ketol, (9-hydroxy-10-oxo-12(Z)-octadecenoic acid) exhibits an unexpected high lipid transfer activity. The crystal structure of this oxylipin-adducted LTP1, (LTP1b) was determined at 1.8A resolution. The covalently bound oxylipin was partly exposed at the surface of the protein and partly buried within the hydrophobic cavity. The structure of the oxylipidated LTP1 emphasizes the unique plasticity of the hydrophobic cavity of these plant lipid-binding proteins when compared to the other members of the family. The plasticity of the hydrophobic cavity and increase of its surface hydrophobicity induced by the oxylipin account for the improvement of the lipid transfer activity of LTP1b. These observations open new perspectives to explore the different biological functions of LTPs, including their allergenic properties.

Oxalic acid: a prospective tool for reducing Varroa mite populations in package bees.

Numerous studies have investigated using oxalic acid (OA) to control Varroa mites in honey bee colonies. In contrast, techniques for treating package bees with OA have not been investigated. The goal of this study was to develop a protocol for using OA to reduce mite infestation in package bees. We made 97 mini packages of Varroa-infested adult bees. Each package contained 1,613 +/- 18 bees and 92 +/- 3 mites, and represented an experimental unit. We prepared a 2.8% solution of OA by mixing 35 g OA with 1 l of sugar water (sugar:water = 1:1; w:w). Eight treatments were assigned to the packages based on previous laboratory bioassays that characterized the acute contact toxicity of OA to mites and bees. We administered the treatments by spraying the OA solution directly on the bees through the mesh screen cage using a pressurized air brush and quantified mite and bee mortality over a 10-day period. Our results support applying an optimum volume of 3.0 ml of a 2.8% OA solution per 1,000 bees to packages for effective mite control with minimal adult bee mortality. The outcome of our research provides beekeepers and package bee shippers guidance for using OA to reduce mite populations in package bees.

[Real-time contrast-enhanced ultrasound in the evaluation of focal liver lesions: diagnostic efficacy and economical issues from a French multicentric study]. / Echographie de contraste temps réel dans la prise en charge diagnostique des lésions nodulaires hépatiques: évaluation des performances diagnostiques et de l'impact économique sur une étude multicentrique française.

The recent introduction of high-end ultrasound equipment combined with recent contrast agents provides marked improvements in the characterization of focal liver lesions as previously reported by monocentric studies. The aim of the present study was to evaluate the diagnostic performance of Contrast-Enhanced Ultrasonography (CEUS) using SonoVue as well as its medico-economic value for characterization of focal liver lesions. These nodules were not characterized on previous CT or conventional sonography. This prospective multicentric study conducted in 15 French centres found diagnostic performances similar to those reported for CT and MRI, with a concordance rate of 84.5%, sensitivity greater than 80% and specificity greater than 90% for all types of lesions. Higher acceptance was found for CEUS compared to other imaging modalities. Economical assessment based on examination reimbursment and contrast agent cost showed a lower cost for contrast ultrasound versus CT and MRI. This French multicentric study confirmed the high diagnostic value of CEUS for focal liver lesion characterization and demonstrated a lower economical impact compared to other imaging modalities such as CT and MRI.

Fatal Aspergillus flavus rhinitis with gastrointestinal gaseous distension in a Cape porcupine.

An adult female Cape porcupine (Hystrix africaeaustralis) was presented because of marked abdominal distension, acute dyspnea, and lethargy. Physical examination and standard radiographs revealed marked and diffuse gaseous dilation of the stomach and intestines of undetermined origin. The porcupine died despite medical therapy and surgical intervention. Postmortem examination revealed chronic fungal (Aspergillus flavus) rhinitis. Given that rodents are obligate nasal breathers, the rhinitis likely resulted in substantial upper airway obstruction leading to aerophagia.

Metal contaminants promote degradation of lipid/DNA complexes during lyophilization.

Oxidation reactions represent an important degradation pathway of nucleic acid-based pharmaceuticals. To evaluate the role of metal contamination and chelating agents in the formation of reactive oxygen species (ROS) during lyophilization, ROS generation and the stability of lipid/DNA complexes were investigated. Trehalose-containing formulations were lyophilized with different levels of transition metals. ROS generation was examined by adding proxyl fluorescamine to the formulations prior to freeze-drying. Results show that ROS were generated during lyophilization, and both supercoil content and transfection rates decreased as the levels of metal-induced ROS increased. The experiments incorporating chelators demonstrated that some of these agents (e.g., DTPA, desferal) clearly suppress ROS generation, while others (e.g., EDTA) enhance ROS. Surprisingly, there was not a strong correlation of ROS generated in the presence of chelators with the maintenance of supercoil content. In this study, we demonstrated the adverse effects of the presence of metals (especially Fe(2+)) in nonviral vector formulations. While some chelators attenuate ROS generation and preserve DNA integrity, the effects of these additives on vector stability during lyophilization are difficult to predict. Further study is needed to develop potent formulation strategies that inhibit ROS generation and DNA degradation during lyophilization and storage.