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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.

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.

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.

Contains fulltext : 204292.pdf (Publisher’s version ) (Open Access) Background: Accurate diagnosis of melanocytic lesions is challenging, even for expert pathologists. Nowadays, whole-slide imaging (WSI) is used for routine clinical pathology diagnosis in several laboratories. One of the limitations of WSI, as it is most often used, is the lack of a multiplanar focusing option. In this study, we aim to establish the diagnostic accuracy of WSI for melanocytic lesions and investigate the potential accuracy increase of z-stack scanning. Z-stack enables pathologists to use a software focus adjustment, comparable to the fine-focus knob of a conventional light microscope. Materials and Methods: Melanocytic lesions (n = 102) were selected from our pathology archives: 35 nevi, 5 spitzoid tumors of unknown malignant potential, and 62 malignant melanomas, including 10 nevoid melanomas. All slides were scanned at a magnification comparable to use of a x40 objective, in z-stack mode. A ground truth diagnosis was established on the glass slides by four academic dermatopathologists with a special interest in the diagnosis of melanoma. Six nonacademic surgical pathologists subspecialized in dermatopathology examined the cases by WSI. Results: An expert consensus diagnosis was achieved in 99 (97%) of cases. Concordance rates between surgical pathologists and the ground truth varied between 75% and 90%, excluding nevoid melanoma cases. Concordance rates of nevoid melanoma varied between 10% and 80%. Pathologists used the software focusing option in 7%-28% of cases, which in 1 case of nevoid melanoma resulted in correcting a misdiagnosis after finding a dermal mitosis. Conclusion: Diagnostic accuracy of melanocytic lesions based on glass slides and WSI is comparable with previous publications. A large variability in diagnostic accuracy of nevoid melanoma does exist. Our results show that z-stack scanning, in general, does not increase the diagnostic accuracy of melanocytic.

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.

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.

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 …

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)

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.

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. "

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.

This study deals with the influence of bubbles on a vertical air–water pipe flow, for gas-lift applications. The effect of changing the bubble size is of particular interest as it has been shown to affect the pressure drop over the pipe. Local measurements on the bubbles characteristics in the wall region were performed, using standard techniques, such as high-speed video recording and optical fibre probe, and more specific techniques, such as two-phase hot film anemometry for the wall shear stress and conductivity measurement for the thickness of the liquid film at the wall. The injection of macroscopic air bubbles in a pipe flow was shown to increase the wall shear stress. Bubbles travelling close to the wall create a periodic perturbation. The injection of small bubbles amplifies this effect, because they tend to move in the wall region; hence, more bubbles are travelling close to the wall. A simple analysis based on a two-fluid set of equations emphasised the importance of the local gas fraction fluctuations on the wall shear stress.

A theoretical investigation has been made of the flow of a rigid core surrounded by an annular liquid layer through a horizontal tube. Special emphasis is placed on the question how the gravity force on the core, caused by a possible density difference between the core and the annular layer, is counterbalanced.

A new method is developed to calculate the frequencies, amplitudes, and energy losses of the modes of an open resonator consisting of two plane circular mirrors.

Chronic intestinal pseudo-obstruction (CIPO) represents a rare and severe condition characterized by failure of the intestinal tract to propel its contents normally [1, 2]. The condition presents with clinical features such as abdominal pain, vomiting, distended abdomen, constipation, and diarrhea [1, 2]. These symptoms resemble an intestinal mechanical obstruction in the absence of a demonstrable lesion occluding the gut. It is thought that this can result from disturbance of the intestinal motor function, supplied by the enteric nervous system (ENS). The neurons of the ENS are contained in two groups of ganglia: the myenteric (Auerbach's) and the submucosal (Meissner's) plexuses. The ENS has the unique ability to control most gut functions, such as regulating vascular tone, secretion/absorption, and gut motility [3, 4]. Given these important functions of the ENS, it is not surprising that damage to the ENS results in digestive disorders and reduced quality of life. Human and experimental evidence indicates that inflammation can occur in the ENS, resulting in severe intestinal motor impairment. Inflammation of the ENS has indeed been observed in some cases of CIPO [3, 5, 6]. Many efforts have been made to classify CIPO. Based on histological examination, CIPO may be categorized as primary, secondary, or idiopathic in nature [1]. Primary CIPO can be classified into three major categories of gastrointestinal neuromuscular disorders (GINMD): mesenchymopathies, myopathies, and neuropathies, depending on the predominant involvement of interstitial cells, smooth muscle cells, or enteric neurons, respectively [1, 7]. The enteric neuropathies underlying CIPO can be subdivided into two major entities: (a) degenerative neuropathies, without any evident inflammatory response and (b) inflammatory neuropathies, referred to as myenteric ganglionitis [3, 8]. Inflammation within the myenteric ganglia is a recognized primary cause of CIPO, but the mechanisms through which the dysfunction occurs and the mechanisms leading to enteric neuropathies remain poorly understood [3, 4]. In this case report, we present the first male neonate with eosinophilic myenteric ganglionitis underlying CIPO and report his successful recovery following steroid treatment.