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Simple Summary Barrett's esophagus (BE) is the only known precursor lesion of esophageal adenocarcinoma (EAC). Endoscopic surveillance plays an important role in the timely detection of neoplastic progression. However, the cost-effectiveness of current surveillance strategies is debatable. Previous studies have shown that male Barrett's patients have lower neoplastic progression risk than females. However, these studies do not provide a more practical translation of these sex disparities into different surveillance intervals. The current multicenter prospective cohort study aimed to evaluate sex differences in 868 BE patients; not only with respect to neoplastic progression risk, but also concerning the difference in time to detection of high-grade dysplasia (HGD)/EAC: time to neoplastic progression was estimated to be almost twice as low in males than in females. In contrast, the stage of neoplasia appeared to be higher in females. Our results can guide future discussions for sex-specific guidelines, supporting the implementation of neoplastic risk stratification per individual patient in BE surveillance. Recommendations in Barrett's esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11-4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33-10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29-0.95) and HGD (AR 0.40, 95% CI 0.19-0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.

Interfacial waves in core-annular pipe flow are studied through two-phase numerical simulations. Here the water annulus is turbulent, whereas the oil core stays laminar. The low-Reynolds number Launder & Sharma k−ε model is applied. By extracting the moving wave shape from the two-phase results and imposing this as a solid boundary in a single-phase simulation for the water annulus gives single-phase results (for the pressure drop and holdup ratio) that are in close agreement with values obtained from the two-phase approach. The influence of wave amplitude and wave length on the pressure drop and hold up ratio is then studied by using the single-phase flow model. This gives insight in the appearance of core-annular flow, where the water-based Fanning wall-friction factor and the hold-up ratio are selected as the most important quantities. The effect of watercut and eccentricity on these quantities is also investigated.

Paediatric kidney tumours comprise many different subtypes, each being heterogeneous in their cellular as well as genetic composition. Advances in the past decade in 3D culture models create new opportunities for the generation of preclinical models capturing this phenotypic and genetic heterogeneity, potentially enabling the generation of patient-tailored therapies.

Background In patients with Crohn’s disease (CD), postoperative prophylactic medication based on clinical risk stratification is recommended in international guidelines to prevent recurrence after ileocolonic resection (ICR). This study aimed to evaluate the risk of endoscopic recurrence after implementation of a predefined management algorithm after ICR incorporating clinical risk stratification. Methods In this multicenter, prospective clinical cohort study, CD patients (≥16 years) were included who were scheduled for ICR and gave informed consent. Endoscopy-guided treatment (no prophylactic medication directly after ICR) was recommended in patients at low risk (LR) of postoperative recurrence, and prophylactic medication (immunosuppressant/biological) in high risk (HR). HR was defined as ≥1 risk factor: smoking, penetrating disease, re-resection. Clinical and histologic risk factors for endoscopic recurrence (Rutgeerts’ score ≥i2) were assessed using logistic regression models and ROC curves based on predicted probabilities. Results In total 213 CD patients were included (median age 34.5 years, 65.3% women): 93 (43.7%) at LR and 120 (56.3%) at HR (smoking 45 (21.3%); penetrating disease 51 (23.9%); re-resection 51 (23.9%)). Adherence to the proposed management algorithm was 65%; 76/93 (81.7%) in the LR (no prophylaxis) and 61/120 (50.8%) in the HR population (prophylaxis). Endoscopic recurrence in LR patients was 69% without prophylaxis versus 48% with prophylaxis (p=0.070); in HR 78% without prophylaxis versus 55% with prophylaxis (p=0.019). Clinical risk stratification corresponded with an area under the curve (AUC) of 0.64 (95%CI 0.55–0.73) (Figure 1). Clinical factors combined with histology (active inflammation, granulomas, plexitis in resection margins) increased the AUC to 0.69 (95% CI 0.61–0.88) (Figure 1). Conclusion This prophylactic medication algorithm in CD patients based on clinical risk stratification after ICR, results in an absolute risk reduction of endoscopic recurrence of 23% in HR versus 21% increase in LR patients in whom medication is omitted. For this latter population, further refinement of risk stratification is required, and may include histologic assessment.

1D, 2D and 3D numerical simulations were carried out with the Reynolds-Averaged Navier-Stokes equations (RANS) for horizontal oil-water core-annular flow in which the oil core stays laminar while the water layer is turbulent. The turbulence is described with the Launder-Sharma low-Reynolds number k−ϵ model. The simulation results are compared with experiments carried out in our lab in a 21 mm diameter pipe using oil and water with a viscosity ratio of 1150 and a density ratio of 0.91. The 1D results represent perfect turbulent CAF (i.e. no gravity, no interfacial waves), the 2D results represent axi-symmetric CAF (i.e. no gravity, with interfacial waves), and the 3D results represent eccentric CAF (i.e. with gravity, with interfacial waves). The simulation results typically show a turbulent water annulus in which the structure of the (high-Reynolds number) inertial sublayer can be recognized. The pressure drop reduction factor (which is the ratio between the pressure drop for CAF and the pressure drop for single phase viscous oil flow) for the 2D and 3D results is about the same, but its value is about 35% higher than in the experiment. The hold-up ratio in the 3D model is close to the experimental value, but the 2D prediction is slightly lower. The eccentricity predicted by the 3D simulations is much higher than in the experiment. Most likely, the observed differences between the simulations and the experiments are due to limitations of using a low-Reynolds number k−ϵ model. In particular the water layer at the top in the 3D results shows a relaminarization, which might be absent in the experiment.

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel., In this Consensus Statement, the pathology panel of the International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RSTG) present the pathology and molecular biology protocol for Wilms tumours in the UMBRELLA SIOP-RTSG 2016 protocol.

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

International audience; Renal tumors comprise approximately 7% of all malignant pediatric tumors. This is a highly heterogeneous group of tumors, each with its own therapeutic management, outcome, and association with germline predispositions. Histopathology is the key in establishing the correct diagnosis, and therefore pathologists with expertise in pediatric oncology are needed for dealing with these rare tumors. While each tumor shows different histologic features, they do have considerable overlap in cell type and histologic pattern, making the diagnosis difficult to establish, if based on routine histology alone. To this end, ancillary techniques, such as immunohistochemistry and molecular analysis, can be of great importance for the correct diagnosis, resulting in appropriate treatment. To use ancillary techniques cost-effectively, we propose a pattern-based approach and provide recommendations to aid in deciding which panel of antibodies, supplemented by molecular characterization of a subset of genes, are required.

Stratified gas–liquid flow is a flow regime typically encountered in multiphase pipelines. The understanding and modeling of this regime is of engineering importance especially for the oil and gas industry. In this work, simulations have been conducted for stratified air–water flow in pipes. We solved the Reynolds-averaged Navier–Stokes (RANS) equations with the volume of fluid (VOF) method. The aim of this work was to evaluate the performance of the k–ω shear stress transport (SST) turbulence model with and without damping of the turbulence at the gas–liquid interface. Simulation results were compared with some of the latest experimental results found in the literature. A comparison between the simulated velocity and kinetic energy profiles and the experimental results obtained with the particle image velocimetry (PIV) technique was conducted. The characteristics of the interfacial waves were also extracted and compared with the experiments. It is shown that a proper damping of the turbulence close to the interface is needed to obtain agreement with the experimental pressure drop and liquid hold-up. In its current form, however, RANS with the k–ω turbulence model is still not able to give an accurate prediction of the velocity profiles and of the interface waves.

Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100 ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80 mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40–100% in < 1 hr and BChE (40% in 8 h). These findings will be used to develop a macaque model with RS194 B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule.

It has been identified that one of the dosages listed within the above article was incorrectly abbreviated during the production process. This is now presented correctly in this article.

In the version of this article initially published online it was not open access, this has now been corrected.

Feline leukemia virus (FeLV) is a naturally transmitted gammaretrovirus that infects domestic cats. FeLV-945, the predominant isolate associated with non-T-cell disease in a natural cohort, is a member of FeLV subgroup A but differs in sequence from the FeLV-A prototype, FeLV-A/61E, in the surface glycoprotein (SU) and long terminal repeat (LTR). Substitution of the FeLV-945 LTR into FeLV-A/61E resulted in pathogenesis indistinguishable from that of FeLV-A/61E, namely, thymic lymphoma of T-cell origin. In contrast, substitution of both FeLV-945 LTR and SU into FeLV-A/61E resulted in multicentric lymphoma of non-T-cell origin. These results implicated the FeLV-945 SU as a determinant of pathogenic spectrum. The present study was undertaken to test the hypothesis that FeLV-945 SU can act in the absence of other unique sequence elements of FeLV-945 to determine the disease spectrum. Substitution of FeLV-A/61E SU with that of FeLV-945 altered the clinical presentation and resulted in tumors that demonstrated expression of CD45R in the presence or absence of CD3. Despite the evident expression of CD45R, a typical B-cell marker, T-cell receptor beta (TCRβ) gene rearrangement indicated a T-cell origin. Tumor cells were detectable in bone marrow and blood at earlier times during the disease process, and the predominant SU genes from proviruses integrated in tumor DNA carried markers of genetic recombination. The findings demonstrate that FeLV-945 SU alters pathogenesis, although incompletely, in the absence of FeLV-945 LTR. Evidence demonstrates that FeLV-945 SU and LTR are required together to fully recapitulate the distinctive non-T-cell disease outcome seen in the natural cohort.

Sustained antiviral responses of chronic hepatitis C virus (HCV) infection have improved recently by the use of direct-acting antiviral agents along with interferon (IFN)-α and ribavirin. However, the emergence of drug-resistant variants is expected to be a major problem. We describe here a novel combinatorial small interfering RNA (siRNA) nanosome-based antiviral approach to clear HCV infection. Multiple siRNAs targeted to the highly conserved 5′-untranslated region (UTR) of the HCV genome were synthesized and encapsulated into lipid nanoparticles called nanosomes. We show that siRNA can be repeatedly delivered to 100% of cells in culture using nanosomes without toxicity. Six siRNAs dramatically reduced HCV replication in both the replicon and infectious cell culture model. Repeated treatments with two siRNAs were better than a single siRNA treatment in minimizing the development of an escape mutant, resulting in rapid inhibition of viral replication. Systemic administration of combinatorial siRNA-nanosomes is well tolerated in BALB/c mice without liver injury or histological toxicity. As a proof-of-principle, we showed that systemic injections of siRNA nanosomes significantly reduced HCV replication in a liver tumor-xenotransplant mouse model of HCV. Our results indicate that systemic delivery of combinatorial siRNA nanosomes can be used to minimize the development of escape mutants and inhibition of HCV infection.

Phase inversion experiments have been performed with a water–oil flow through a pipe to study the effect of the addition of a surfactant or of salt on the critical dispersed phase volume fraction (at the point of phase inversion). The addition of a surfactant caused a small change in the critical volume fraction, but the general form of the ambivalence region in the inversion map remained the same. The influence of salt was negligible.

Infectivity and persistence by Borrelia burgdorferi , the etiologic agent of Lyme disease, rely stringently on regulatory events. Among these is the downregulation of lipoprotein antigen expression, exemplified by outer surface protein C (OspC), at the advent of specific immunity in the mammalian host. B. burgdorferi spirochetes that lack the linear plasmid 28-1 (lp28-1) succumb to the host's immune response. We thus explored the notion that these two phenomena were related—that lp28-1 − organisms fail to downregulate ospC and thus are cleared following the appearance of anti-OspC antibody in the murine host. The lp-28-1 − isolate and a wild-type (wt) isolate bearing the complete set of plasmids were grown in dialysis membrane chambers that were implanted into rat peritoneal cavities. Analysis of mRNA and protein from these cultures showed that OspC expression levels by lp28-1 − organisms are abnormally high in vivo. A time course analysis of ospC expression in tissues following infection indicates also that temporal diminution of the dominant antigen OspC is impaired in lp28-1 − spirochetes. Finally, passive transfer of monoclonal OspC-specific antibody into SCID mice 8 days postinfection cleared lp28-1 − spirochetes, yet the wt organisms persisted in a majority of animals. These findings indicate that incomplete repression of OspC by lp28-1 − organisms renders them susceptible to immune-mediated clearance. The lp28-1 plasmid must harbor one or more genes involved in OspC downregulation.

An experimental study of the phase inversion process in an oil–water flow through a pipe was carried out. Special attention was paid to the critical concentration of the dispersed phase at which phase inversion occurs and to the change in morphological structures during inversion. To that purpose two different types of experiments were performed: (1) continuous experiments during which the dispersed phase fraction was gradually increased and (2) direct experiments whereby oil and water were injected simultaneously into the pipe at a certain concentration. During the experiments detailed pictures were taken of the phase inversion process and simultaneously the electrical conductivity of the mixture was measured to determine which liquid formed the continuous phase and which the dispersed phase. Also the pressure gradient over several parts of the pipe was measured. For continuous experiments the critical concentration was found to depend on the injection phase volume fraction. The critical concentration was significantly higher for continuous experiments than for direct experiments. The change in morphological structures during phase inversion was the same for the two types of experiments. During inversion the concentration of drops of the (originally) dispersed phase becomes so high, that they coalesce at certain places in the flow field and form relatively large, rather complex, morphological structures. With a further increase in concentration of the (originally) dispersed phase these morphological structures grow in size and start to form the new continuous phase in which again complex structures are present, but this time consisting of the (originally) continuous phase.

Laboratory experiments have been performed on the flow of oil, water and air through a vertical pipe in order to study the gas-lift technique for oil–water flows. Special attention was paid to the phase inversion phenomenon, by which the continuous phase switches to the dispersed phase and vice versa. By using different types of gas injectors the influence of the bubble size of the injected air on the efficiency of the gas-lift technique (in particular at the point of phase inversion) was studied. Also the gas and liquid mixture velocities were varied. The air bubbles were detected by means of optical fibre probes. Local measurements of the time-averaged gas volume fraction, bubble size and bubble velocity were carried out, as well as pressure measurements. Phase inversion is associated with a sharp increase of the pressure gradient. With air injection the pressure gradient (for the oil–water–air flow) is always significantly smaller than for the case of oil–water flow, except at the point of phase inversion where the pressure drop can be even be higher than for oil–water flow. It was also found that air injection does not significantly change the critical concentration of oil and water where phase inversion occurs. An important phenomenon to explain these results is, that the presence of the dispersed (oil or water) phase has a significant influence on the bubble size. Also the influence of the gas flow rate on the distribution of the oil and water phases in a cross-section of the pipe plays a significant role.

Objective: To determine the ability of the Trunk Impairment Scale (TIS) to discriminate between PD and healthy controls and to investigate which clinical characteristics would predict the outcome on the TIS.Background: The TIS is an instrument originally developed to evaluate trunk function in stroke patients. As patients with Parkinson’s disease (PD) classically have axial symptoms, this study wanted to determine whether the TIS can be suitably applied to this population. Methods: The design involved a cross-sectional study on 26 subjects with PD. Participants were evaluated with the TIS to assess their static and dynamic sitting balance and trunk movement coordination. A spinal mouse was used to determine postural deformity in sitting and standing. Twentysix control subjects were selected from an existing database, matched for age and sex. Results: Patients consisted of 17 males and 9 females with a mean age of 65 years (SD9), a median Hoehn and Yahr stage of 2.5 (range 2-4) and median UPDRS III score of 25 (range 8-36). Controls had a mean age of 65 (SD12). Patients with PD scored significantly lower on the TIS (p.0001) compared to the healthy individuals. When analysing 14 patients from HY stage 2 separately, TIS-scores were also significantly different from controls (p0.0003) and from the 15 patients in HY stage 3 and 4 (p0.04). Overall patients scored a median of 18 between 11-23 of the total range of 0-23 on the TIS. Controls had a median of 22 (range 17-23). Multivariate linear regression analysis showed that disease severity (UPDRS III) (R20.54, p.0001) and age (added R20.09, p.03) were significant variables in predicting trunk impairment in PD. Spinal mouse results revealed that 38% of patients had thoracic kyphosis in stance and 12% in sitting. Patients with more pronounced thoracic kyphosis in sitting also had decreased TIS scores (Rs-0.56, p0.0027). Conclusion: Disease severity, age and degree of thoracic kyphosis in sitting are important determinants of trunk impairment in PD. The TIS is able to discriminate between trunk motor performance in persons with early PD and age-matched controls. Patients did not use the full range of the scale. Further reliability study is indicated to validate an adapted version of the TIS.

The gas-lift technique comprises the injection of gas bubbles in vertical oil wells to increase production. It is based on a reduction of the tubing gravitational pressure gradient. Several fluid-flow phenomena influencing such vertical gas-liquid flows are discussed. These effects include the radial distribution of void fraction and of gas and liquid velocity, flow regime changes, and system stability problems. Associated consequences for gas-lift performance and related optimization approaches are also discussed.

() An experimental in®estigation has been made of the influence of the initial bubble size and bubble concentration distribution on the gaslift efficiency for a ®ertical air water flow through a pipe of 72-mm dia. and 18-m height. Three significantly different bubble injectors were used. It was found that with decreasing bubble size, the liquid production increases at constant gas flow rate and, hence, the gaslift efficiency increases. Also, the initial concentration distribution can be significant, as this distribution can influence the coalescence of bubbles close to the injector. With decreasing bubble size, the transition from bubbly flow to slug flow can be postponed. This is one of the main reasons for the beneficial effect of the bubble size on gaslift efficiency. A theoretical model has been de®eloped to predict the influence of the bubble size on the gaslift efficiency. The agreement is reasonable.

A theoretical model for gas–liquid annular/dispersed flow through a venturi meter is reported. It is based on an earlier model developed for venturi scrubbers. Changes implemented are based on new research and on the different physics between the two cases. The predictions of the model have been tested using information from recent experiments on venturi meters employed for measuring wet-gas flows with a liquid volume fraction up to 10%. The model gives good predictions with appropriate values of a small set of input variables.

SummaryWe report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.

Background Electronic nicotine delivery systems (ENDS) are a new class of tobacco products that is rapidly gaining interest from producers, consumers and researchers alike. Yet, there is no cross-national evidence about their use and perceived harm and associated socio-demographics characteristics. This study aims to assess the prevalence of ENDS use, harm perception and use as a cessation tool in the European Union and …

The first decade of the new millennium saw an upsurge in global financing for health. When the world took stock of progress on the Millennium Development Goals in mid-2010 the one addressing maternal health showed the least progress. Did maternal health miss the boat? In mid-2010 the Secretary-General of the United Nations launched a “Global Strategy for Women’s and Children’s Health”, also known as the “Every Woman Every Child” initiative. Has the tide now turned in favour of maternal health? The authors try to answer this question by first examining whether maternal health really missed out with respect to increased global funding and why this may have occurred. They then assess whether the new initiative will make a difference by comparing several elements of the approach taken by HIV/AIDS activist to that of maternal health activists. They suggest that real progress requires international financing, thus pledges must become robust and reliable commitments. They conclude that the absence of an organisational structure in the current initiative means the global maternal health financing revolution will probably not happen.

Objective—To describe the clinical signs following ingestion of an herbal supplement containing guarana and ma huang in dogs, estimate minimum dose at which clinical signs of toxicosis and death were reported, and evaluate treatment options.Design—Retrospective study.Animals—47 dogs with evidence of ingestion of an herbal supplement containing primarily guarana and ma huang.Procedure—Records of dogs that had ingested an herbal supplement containing ma huang and guarana between July 1997 and October 1999 were retrieved from the National Animal Poison Control Center database. Data were retrieved and reviewed regarding signalment, dose ingested, clinical signs, laboratory test results, treatment, and final outcome. Cases were assessed by staff veterinarians as toxicosis or suspected toxicosis on the basis of strength of evidence supporting a diagnosis.Results—Most dogs (80%) developed clinical signs of toxicosis within 8 hours of ingestion, and clinical signs persisted for up to 48 hours. Hyperactivity, tremors, seizures, and behavior changes were reported in 83% of dogs; other signs included vomiting (47%), tachycardia (30%), and hyperthermia (28%). Seventeen percent of the dogs died or were euthanatized. Estimated doses of guarana and ma huang ranged from 4.4 to 296.2 mg/kg (1.98 to 133.2 mg/lb) and 1.3 to 88.9 mg/kg (0.58 to 40.0 mg/ lb) of body weight, respectively; minimum dose at which death was reported was 19.1 mg of guarana/kg (8.7 mg/lb) and 5.8 mg of ma huang/kg (2.6 mg/lb).Conclusions and Clinical Relevance—Accidental ingestion of herbal supplements containing primarily guarana and ma huang in dogs can lead to a potentially lethal condition that may require prompt detoxification and supportive treatment for several days. Most dogs recovered with supportive treatment. (J Am Vet Med Assoc2001;218:225–229)

Summary Field measurements have revealed that the pressure drop over a borehole during drilling of a slim oil well or a well with a long reach can depend significantly on the rotation speed of the drillpipe. In this paper we discuss analytical, numerical and experimental studies to explain this effect for the case of a Newtonian liquid in the borehole. Special attention is paid to the inertial forces in the liquid (in the annulus), caused by the rotation and eccentricity of the drillpipe. It is concluded that for large values of these inertial forces the axial pressure drop depends significantly on the rotation speed of the drillpipe. A pressure drop simulator (also valid for the case of a non-Newtonian liquid in the borehole) has been developed, that includes this effect and is in good agreement with field test data.

A physical model for the dynamics of a dispersion of solid spherical particles in an incompressible viscous fluid is outlined and used to calculate the turbulence modulation in a stationary, homogeneous and isotropic turbulent flow with particles. Starting from a postulated fluid turbulence spectrum in the absence of particles, the physical model predicts the corresponding fluid turbulence spectrum in the presence of particles and the particles turbulence spectrum as function of frequency and wavenumber. There are two versions of the model. The first one uses a point-force approximation for the particles and takes into account the hydrodynamic interaction between the particles. The second version accounts for the detailed flow around the (finite-diameter) particles, but does not consider their hydrodynamic interaction. The spectra, calculated with the two versions, are used to determine the turbulence intensity of the fluid and particles as function of three relevant dimensionless groups. It is found that in general the differences between the results of the point-particle model and the finite-diameter-particle model are significant. So one has to be careful with point-particle models. The effect of the hydrodynamic interaction between the particles is up to a volume fraction of 0.1 still mostly negligible.

In a randomized, cross-over study, we prospectively compared the efficacy and quality of two methods to achieve conscious sedation with propofol in 11 unpremedicated, anxious dental patients. Each patient underwent two dental procedures, one that was conducted under target-controlled infusion (TCI) by the anesthesiologist (ACS), and the other that used patient-controlled sedation (PCS). The initial target concentration in the ACS mode was 2.5 microg/mL, which was manipulated in both directions until the desired clinical end point was achieved. In the PCS mode, a 4-mg bolus of propofol (10 mg/mL) was delivered at each activation of the machine, infused over 7 s without a lockout interval. The anxious dental patients could induce and maintain conscious sedation with the PCS settings. The mean (range) venous blood propofol concentrations were not significantly different with either mode: ACS 1.8 (0.8-2.7) microg/mL and PCS 1.2 (0.2-2.5) microg/mL. The level of patient satisfaction, quality of sedation, and treatability were not different for either mode of sedation. The intensity of amnesia for intraoperative events was related to the blood concentrations achieved. In the ACS mode, one patient became unresponsive (sedation level 4) immediately after the start of sedation. No adverse cardiorespiratory effects resulted from either mode of propofol sedation. Five patients expressed a strong preference for PCS, and three would prefer ACS in the future. The results of the present study suggest that with these PCS settings, a satisfactory level of conscious sedation and a high level of patient satisfaction was achieved.In a randomized, cross-over study, the blood propofol concentrations necessary to achieve conscious sedation in anxious dental patients using a target-controlled infusion conducted by the anesthesiologist versus patient-controlled sedation were not different. With the patient-controlled sedation settings, a satisfactory level of conscious sedation and a high level of patient satisfaction were achieved.

Infusion of propofol by a target-controlled infusion (TCI) system is effective in achieving conscious sedation for anxious patients presenting for dental surgery. It is a common clinical observation that anxious patients require more anaesthetic drugs than non-anxious individuals. In study 1 we have defined blood propofol concentrations necessary for conscious sedation in both anxious (n = 23) and non-anxious (n = 18) patients. The pump performance of the TCI system, using Gepts' pharmacokinetic model, was evaluated in these two patient groups. Subsequently, clearance of propofol was compared in the two groups. Mean measured venous serum propofol concentrations obtained between 20 and 35 min after the optimal sedation level was reached were 1.6 (SD 0.2) micrograms ml-1 in the anxious patients compared with 1.7 (0.3) micrograms ml-1 in the control group (study 1) and 1.4 (0.27) micrograms ml-1 in study 2. The pump systematically overpredicted measured propofol concentrations in both groups (study 1). There was no significant difference in propofol clearance between the two groups. In study 2, an optimized set of microconstants was derived which should more accurately predict the pharmacokinetic profile of the anxious population and this set was tested prospectively in another group of 12 anxious dental patients. Bias and precision with the optimized kinetic set were significantly less than the values obtained in study 1. We conclude that there was no significant pharmacokinetic differences between anxious and non-anxious subjects receiving subanaesthetic doses of propofol for conscious sedation.

The influence of ultrasonic radiation on the flow of a liquid through a porous medium is analyzed. The analysis is based on a mechanism proposed by Ganiev et al. according to which ultrasonic radiation deforms the walls of the pores in the shape of travelling transversal waves. Like in peristaltic pumping, the travelling transversal wave induces a net flow of the liquid inside the pore. In this article, the wave amplitude is related to the power output of an acoustic source, while the wave speed is expressed in terms of the shear modulus of the porous medium. The viscosity as well as the compressibility of the liquid are taken into account. The Navier–Stokes equations for an axisymmetric cylindrical pore are solved by means of a perturbation analysis, in which the ratio of the wave amplitude to the radius of the pore is the small parameter. In the second-order approximation a net flow induced by the travelling wave is found. For various values of the compressibility of the liquid, the Reynolds number and the frequency of the wave, the net flow rate is calculated. The calculations disclose that the compressibility of the liquid has a strong influence on the net flow induced. Furthermore, by a comparison with the flow induced by the pressure gradient in an oil reservoir, the net flow induced by a travelling wave can not be neglected, although it is a second-order effect.

The suprachiasmatic nucleus is synchronized by the light:dark cycle and is the master biologic clock that serves as a pacemaker to regulate circadian rhythms. We explored the hypothesis that spectral transmittance (tint) of light through caging alters circadian rhythms of endocrine and metabolic plasma constituents in nonpigmented Sprague-Dawley rats. Rats (Crl:SD; n = 12 per group) were housed in a 12:12-h light:dark environment (300 lx; 123.0 μ W/cm(2); lights on, 0600) in either clear-, amber-, blue-, or red-tinted rodent cages. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and measured for melatonin, total fatty acids, pH, glucose, lactic acid, corticosterone, insulin, and leptin. As expected, plasma melatonin levels were low during the light phase but higher during the dark phase in all groups; however, when compared with the clear-cage group, rats in amber-, blue-, and red-tinted cages had 29%, 74%, and 48%, respectively, greater total daily melatonin levels due to an increased duration and, in some cases, amplitude of the nocturnal melatonin signal. No differences were found in dietary and water intake, body growth rates, total fatty acids, pH, or glucose among groups. Disruptions in circadian rhythms, manifesting as alterations in phase timing, amplitude, or duration, occurred in the melatonin, lactic acid, corticosterone, insulin, and leptin levels of rats in tinted compared with clear cages. Therefore, the use of variously tinted animal cages significantly alters circadian rhythms in plasma measures of metabolism and physiology in laboratory rats, thus potentially altering the outcomes of scientific investigations.

Unclassified sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as sudden infant death syndrome (SIDS). USID and SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five DNA variants from 11 genes previously implicated in the serotonin household or in the congenital central hypoventilation syndrome, of which some have been associated with SIDS before, were tested. Of all DNA variants considered, only the length variation of the polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3 polyalanine repeat that we found in six of 160 SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene.

To assess a drug delivery system that can rapidly achieve and maintain a constant blood concentration of Propofol (2,6 di-isopropyl phenol) which, in subanaesthetic doses, is an effective intravenous sedative for treating anxious or handicapped patients in dentistry:Design The clinical use of a computer controlled infusion system to induce and maintain conscious sedation with propofol was prospectively studied. Based on a 3-compartment pharmacokinetic model, the system calculates the initial bolus dose and infusion rates to achieve a user-selected target blood concentration.Setting Amsterdam Center for Special Dental Care.Subjects 89 patients attending for dental treatment.Results Treatment could be performed within 2 minutes after the onset of the infusion. The median therapeutic target blood propofol concentration was 2.5 mu g/ml and the median recovery time was 9 minutes. Transient oversedation (38 procedures) could easily be treated by decreasing the target concentration. No adverse cardiorespiratory effects resulted from propofol sedation. Venous blood propofol concentrations were measured in 25 anxious patients. The kinetic data set used in this study underestimated the distribution and elimination of propofol in our patients.Conclusions Computer controlled infusion of propofol can provide satisfactory and safe conscious sedation in dental patients. "

Light entrains normal circadian rhythms of physiology and metabolism in all mammals. Previous studies from our laboratory demonstrated that spectral transmittance (color) of light passing through cages affects these responses in rats. Here, we addressed the hypothesis that red tint alters the circadian nocturnal melatonin signal and circadian oscillation of other metabolic and physiologic functions. Female nude rats (Hsd:RH-Foxn1(rnu); n = 12 per group) were maintained on a 12:12-h light (300 lx; 123.0 μW/cm(2); lights on 0600):dark regimen in standard polycarbonate translucent clear or red-tinted cages. After 1 wk, rats underwent 6 low-volume blood draws via cardiocentesis over a 4-wk period. Plasma melatonin levels were low during the light phase (1.0 ± 0.2 pg/mL) in rats in both types of cages but were significantly lower in red-tinted (105.0 ± 2.4 pg/mL) compared with clear (154.8 ± 3.8 pg/mL) cages during the dark. Normal circadian rhythm of plasma total fatty acid was identical between groups. Although phase relationships of circadian rhythms in glucose, lactic acid, pO2, and pCO2 were identical between groups, the levels of these analytes were lower in rats in red-tinted compared with clear cages. Circadian rhythms of plasma corticosterone, insulin, and leptin were altered in terms of phasing, amplitude, and duration in rats in red-tinted compared with clear cages. These findings indicate that spectral transmittance through red-colored cages significantly affects circadian regulation of neuroendocrine, metabolic, and physiologic parameters, potentially influencing both laboratory animal health and wellbeing and scientific outcomes.

Stable cointegrates between incRh-1 octopine (Ach5) and nopaline (C58) Ti-plasmids, present in ten independently isolated Agrobacterium tumefaciens strains, showed identical restriction endonuclease patterns. Each cointegration event had taken place in the common sequence between the T-regions of both Ti-plasmids. This illustrates a high preference for this region when used in the formation of cointegrates. Four crown gall tissues, obtained after transformation of Nicotiana tabacum cells by one of the mutants, were analysed by using Southern blot analysis for their T-DNA structure. The borders of T-DNA frequently appeared to differ from T-DNA borders previously detected in tumour tissues that had been induced by Agrobacterium strain C58 or Ach5. Therefore, it was concluded that possibly a less stringent mechanism exists for the integration into plant DNA of T-DNA, derived from a composite (octopine/nopaline) T-region than for integration of T-DNA from a normal (octopine or nopaline) T-region.

Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582–91. ©2016 AACR.

Introduction: The National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative seeks to characterize the genomes of high-risk pediatric tumors to identify therapeutic targets. The High-Risk Renal Tumor TARGET initiative includes the analysis of pre-therapy favorable histology Wilms Tumors (FHWT) that relapsed and tumors with diffuse anaplasia (unfavorable histology; DAWT). These two tumor subsets have survival rates of approximately 50% and 60%, respectively. Experimental procedures: Genomic sequencing (whole genome [WGS] or exome [WXS]), global copy number analysis, and global gene expression analysis were performed on a discovery set of 117 (78 FHWT, 39 DAWT) pre-therapy high-risk WTs treated on National Wilms Tumor Study-5 (NWTS-5). To determine the frequency of recurrent variants, targeted sequencing (Illumina HiSeq2500) was performed on a validation set of pre-therapy tumor DNA from a case-cohort of all FHWT treated on NWTS-5 (531 FHWT) and all available 118 DAWT treated on NWTS-5 (these groups include tumors from the discovery set). Results: WGS and WXS revealed an average of 21.74 ± 22.6 high-quality variants per DAWT (range, 3-131) and 13.8 ± 10.9 per FHWT (range 2-58). Genes previously reported to be recurrently mutated in WT were mutated at the following frequencies in the validation set: WTX (6%), CTNNB1 (15%), WT1 (7.5%), DROSHA (11%), DGCR8 (4.5%), XPO5 (2%), SIX1/2 (7%), and MLLT1 (3%). In addition, mutations were identified in three genes that impact the NMYC pathway, which is known to be involved in renal development. These include MYCN P44L/H (4%), MAX R60Q (2%), and novel mutations in NONO (2%); these mutations were mutually exclusive. Novel mutations in BCOR, a transcriptional corepressor that regulates both gene expression during development and chromatin modification, were found in 3% of validation set tumors. Analysis of global gene expression revealed significant up-regulation of genes associated with kidney development, extracellular matrix organization, and epithelial tube development in BCOR-mutant tumors compared with precursor lesions (5 hyperplastic perilobar nephrogenic rests). TP53 mutations were identified in 48% of DAWTs and 1% of FHWTs. The above data do not include copy number changes, which were recurrently detected in WT1, WTX, NMYC, and TP53. Conclusions: Through the TARGET initiative, we have identified several novel, potential driver mutations that occur in WT and have not been reported in other pediatric tumors. The majority of these genes are known to function in processes critical to early development and/or specifically in renal development. Many of these mutations are accompanied by Wnt activating mutations or 11p15 biallelic expression. However, approximately 50% of WTs lack clear driver mutations. Future studies will need to focus on elucidating epigenetic alterations in these tumors as well as genetic changes outside of protein-coding regions. Citation Format: Samantha L. Gadd, Amy L. Walz, Ariadne HAG Ooms, Vicki Huff, Daniela S. Gerhard, Malcolm A. Smith, Jaime M. Guidry Auvil, Leandro Hermida, Tanja Davidsen, Patee Gesuwan, Daoud Meerzaman, Yussanne Ma, Marco A. Marra, Jeffrey S. Dome, Charles G. Mullighan, David A. Wheeler, Oliver A. Hampton, Julie M. Gastier-Foster, Nicole Ross, Elizabeth J. Perlman. The genetic landscape of Wilms tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-180.

A numerical study (taking into account inertial -, viscous - and pressure forces) has been made of eccentric core-annular flow through a horizontal pipe, special attention being paid to the vertical force on the core. The viscosity of the core is assumed to be so large that it behaves as a rigid solid. A wave is present at its surface. The shape of the wave is based on experimental results published earlier in the open literature. Due to the eccentricity the centre line of the core is shifted in the upward vertical direction with respect to the centre line of the tube. The vertical force on the core was found to be dependent on the Reynolds number: at small values of the Reynolds number the force is in the upward vertical direction, at large values the force is downward. This means that at large values of the Reynolds number an upward buoyancy force on the core due to a density difference between core and annulus can be counterbalanced. So a stationary core-annular flow is then possible.

AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment. METHODS: We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient JFH1 virus. S3-GFP replicon cell line was injected subcutaneously into γ-irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-α (IFN-α). RESULTS: A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-α cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. CONCLUSION: A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-α supports use of this model to test other anti-HCV drugs.

As is well known Fermi, Pasta and Ulam [1] studied the energy redistribution between the linear modes of a one-dimensional chain of particles connected via weakly nonlinear springs. To their surprise no apparent tendency to equipartition of energy was observed in their numerical experiments. Much more knowledge is now available about this problem (see, for instance, the recent book by Gallavotti [2] or the review by Cambell et al. [3] in the focus issue on the FPU-problem in the journal Chaos).

Summary The aim of this paper is to investigate experimentally the fouling of a porous material by external particles and the optimal way to clean the porous material with high-frequency acoustic waves. In particular, we are interested in the fouling by mud particles of the near-wellbore region of an oil reservoir. In the experiments, therefore, we used natural sandstone as porous material and mud particles as fouling particles. To generate fouling, mud particles were flushed through a sandstone core. Next, the core was treated with very short bursts of ultrasound, and the change in permeability was measured after each burst. (Earlier papers report only the end result after applying the total amount of acoustic energy.) Experiments were carried out under different acoustic-cleaning conditions to investigate the influence of the relevant parameters on the cleaning process. For instance, the amplitude of the acoustic waves, the duration of the bursts, and the time between the bursts were varied. During the ultrasonic-cleaning process, brine flowed through the core. The effect of this flow was studied by changing the flow rate. Also, the effect of the temperature, pressure, and initial core permeability on the cleaning process was investigated. The experimental results show that short bursts of acoustic energy are more efficient for cleaning than long bursts or continuous application of ultrasound (for the same total amount of acoustic energy). The overall conclusion is that the optimal method of ultrasonic cleaning is to apply many very short bursts of low-amplitude acoustic energy, with a short rest time between the bursts while keeping the liquid (brine) flow at a very low velocity. More acoustic energy is needed to clean a core with a high initial permeability than a core with a low initial permeability. At low pressure, cavitation occurs and prevents the generation of ultrasonic bursts. Cavitation can even have a negative effect on the cleaning process.

A novel and versatile in vitro assay system is presented which has considerable scope for accurate description of environmentally and/or genetically induced changes in the architecture of intact plant root systems. Use of the assay system is exemplified by the analysis of potato plants with visibly distinct root systems. These were obtained by growth of normal and transgenic potato plants, transformed with Agrobacterium Tcyt and rol genes on standard culture medium and on media supplemented with NAA and zeatin. Consequences for parameters such as root weight, root length, percentage secondary roots and root density distribution with depth were quantified. The logarithmic regression: log10(ϱ)=A+Bd, in which ϱ is the root density (root weight per media volume) at depth d, proved useful in quantifying the decline of root density with depth by the single slope parameter B. From the calculated relations for the various root systems, and their root weights, profiles of their comparable root weight distributions were drawn. A number of features and drawbacks, and possible uses of the assay system are discussed.

From over forty independently isolated potato lines transformed with wild-type and promoter-mutated T-cyt genes [12], a number of lines were selected for examination of phenotypic changes in growth and development for plants grown in soil in a controlled environment. The three lines chosen for most detailed examination showed a wide spectrum of phenotypic changes. In comparisons with control potato cv. Desiree, the plants of one line had a two- to three-fold increase in biomass production during early vegetative growth, advanced senescence and a shortened plant life-span. Another line showed abnormal cellulytic senescence. In two lines there were increases in tuber numbers and more skewed tuber size distributions which correlated with reduced shoot apical dominance and shortened dormancy of the stored tubers. None of the lines showed altered timing of onset of tuberization or flowering, although tuberization was consistently delayed when expressed as a function of increasing total plant weight. A hypothesis is proposed to explain the diverse phenotypes which postulates that (1) T-cyt transformation causes enhanced sensitivity to cytokinins in specific types of shoot cells which are already targets for regulation by normal root-derived cytokinins; (2) two distinct types of shoot target cells are present, one in shoot meristems and one in leaves; (3) the two types can acquire enhanced sensitivity, either separately or in combination depending on the particular T-cyt transformation event. The scope for using the transformed plants in subsequent physiological, biochemical and molecular studies, aimed at examining the molecular basis of the model or selected consequences of T-cyt transformation in altering regulation of potato plant growth and development, is discussed. The attention is drawn to the possible involvement at the subcellular level of sucrose phosphate synthase in mediating the phenotypic effects caused by T-cyt transformation.