The ballasted track superstructure is characterized by a relative quick deterioration of track geometry due to ballast settlements and the accumulation of sleeper voids. The track zones with the sleeper voids differ from the geometrical irregularities with increased dynamic loading, high vibration, and unfavorable ballast-bed and sleeper contact conditions. This causes the accelerated growth of the inhomogeneous settlements, resulting in maintenance-expensive local instabilities that influence transportation reliability and availability. The recent identification and evaluation of the sleeper support conditions using track-side and on-board monitoring methods can help planning prevention activities to avoid or delay the development of local instabilities such as ballast breakdown, white spots, subgrade defects, etc. The paper presents theoretical and experimental studies that are directed at the development of the methods for sleeper support identification. The distinctive features of the dynamic behavior in the void zone compared to the equivalent geometrical irregularity are identified by numeric simulation using a three-beam dynamic model, taking into account superstructure and rolling stock dynamic interaction. The spectral features in time domain in scalograms and scattergrams are analyzed. Additionally, the theoretical research enabled to determine the similarities and differences of the dynamic interaction from the viewpoint of track-side and on-board measurements. The method of experimental investigation is presented by multipoint track-side measurements of rail-dynamic displacements using high-speed video records and digital imaging correlation (DIC) methods. The method is used to collect the statistical information from different-extent voided zones and the corresponding reference zones without voids. The applied machine learning methods enable the exact recent void identification using the wavelet scattering feature extraction from track-side measurements. A case study of the method application for an on-board measurement shows the moderate results of the recent void identification as well as the potential ways of its improvement. The ballasted track superstructure is the most-used superstructure worldwide due to its low construction costs, flexibility of application, automated maintenance, etc. However, it has significant disadvantages due to the relatively quick deterioration of its geometric quality. The ballast layer has the highest influence on track geometry quality, which causes high maintenance costs. The costs consist of track inspection and corrective maintenance costs that, despite the high automation, still reach up to 30% of the overall maintenance costs ,2. The fNowadays, subgrade and sleeper support condition monitoring and estimation is presented by different on-board and track-side methods. The existing on-board monitoring methods , left arThe present track-side methods for void identification on, more generally, stiffness measurement , center Another concept of track sleeper support monitoring is on-board measurement from regular trains , right. -Mechanical modelling of track and vehicle interaction for cases of void and the equivalent geometrical irregularities;-Exploration of differences in time and frequency domain between both cases of the irregularity;-Wavelet scattering feature extraction and selection of the significant features from modelled recordings of axle-box acceleration;-Development of the method for vertical rail deflection extraction from high-speed video recordings;-Signal processing of the collected track-side measurements to extract the vibration features of wheel and rail oscillations in the void and reference zone;-Statistical processing and void severity classification using machine learning methods;-A case study of void identification on a common crossing from on-board measurements on regular trains.The present paper demonstrates an approach for the identification of the sleeper support condition. The aim of the study is the development of the methods that allow to differentiate between the void and geometrical irregularity based on track-side and on-board measurements. Different to other reviewed studies, the present research includes both mechanical modelling and a data-driven approach based on the developed method for efficient data acquisition from many void defect zones. The study is produced in the following steps:The objective of the section is the exploration of the dynamic behavior of the railway track with sleeper voids, its influence on track-side and on-board measurements using mathematical modelling and its principal differences to the behavior in a geometrical irregularity. There have been many papers published over the last decades devoted to modelling of track dynamic behavior in the void zone.A theoretical study of the sleeper contact impact due to unsupported sleepers is presented in the study  using FEThe presented literature review shows many studies on modelling the dynamic track behavior considering the sleeper support conditions. Most of the studies are based on more or less detailed FEM models with or without coupled MBS vehicle models. However, many studies over the last years show an increase of interest in robust models based on 2D beam models and even on analytical approaches. Such models can be better fitted to the description of complex short-time nonlinear and long-term interaction processes in track rather than the redundant geometrical dimension of the FEM models. Nevertheless, all models suffer from the lack of good experimental validation of the effects of the dynamic behavior in the voided zone.The modeling in the present study is based on a three-beam model, whicht is coupled with a two-mass discrete model. The model is similar to that in the previous studies of the authors . Howeverη2(x) depend on the void parameters. The interaction force between the beams is presented in The voids under the sleeper with length xn elements of a beam over the length L corresponds to the system of ordinary differential equations that in matrix form is written as follows:M] is the matrix of element masses; [C] is the matrix of damping in connecting layers; [K] is the matrix of stiffness taking into account the bending rigidity of the beam; The numeric model of M] has a diagonal form with a non-zero main diagonal. It consists of two scalars MU and MB corresponding to unsprung and sprung masses and three square blocks [M1], [M2] and [M3] with dimensions N × N corresponding to the number of elements into which each beam is divided (3). The matrix of damping [C] (4) takes into account the interaction between the neighbor beams and the system of two vehicle masses. The contact interaction is introduced by the matrix The finite difference method was used for the differential equation solution. The mass matrix [The stiffness matrix The vector column of external loading The model parameters presented in Experimental measurements  show thaThe simulated geometrical irregularity is chosen considering the research aim of the void identification from the other irregularities. Therefore, the case of the equivalent to void geometrical irregularity is determined using the quasistatic passing of the model for the void case. The equivalent to void geometrical irregularity corresponds to the wheel trajectory line and is shown in The simulation results are presented as the track deflection and accelerations corresponding to on-board and track-side measurements. The wheel trajectory has a similar process as the rail deflection one for the track section in the middle side of the void. The similarities of wheel and rail dynamic behavior in the voided zone are clearly presented on the acceleration diagrams, explained by the mutual oscillation of wheel and rail while passing the void zone. Thus, the dynamic behavior due to the voided zone is present in both track-side and on-board measurements, which can be used for void monitoring and identification.The simulation results for the equivalent to void geometric irregularity are presented in To provide a consistent analysis of the dynamic behavior, a comparison of the wheel trajectory and accelerations for different depths of void and the equivalent geometrical irregularities is presented in The wheel dynamic behavior in the equivalent geometric irregularities for the different void depth is different to the void case. The wheel oscillations are formed by the wave of the irregularity and some similarity to the impact interaction is caused by the applied equivalent irregularity derived from the void irregularity.The presented analysis of the dynamic behavior in the void zone shows the differences to the similar geometric irregularity both from the viewpoint of the track-side and on-board measurements. Different to the track-side measurements, the on-board measurements do not allow to determine the deflection of the rail elastic wave. However, the wheel trajectory variation due to the rail deflection within the void depth can be theoretically identified using the features of the dynamic interaction in the void zone. The similarities of the track-side and on-board measurements enable to use the track-side measurements for the identification of the voids from on-board ones after filtering the low frequency part of rail elastic wave deflection.To explore the time-frequency differences of the simulated accelerations, wavelet scattering analysis is used. The research approaches in mechanical and railway engineering over the recent decades are characterized by a growing interest in applying wavelet frameworks to signal processing. The continuous wavelet transform method and global wavelet power spectra were used for evaluating degradation at railway crossings using axle-box acceleration measurements in . A data-The wavelet analysis has the benefit of multilevel and flexible time frequency resolution that results in the advantage of time localization and stability over Fourier transforms. However, it has more computational complexity and discrete wavelet transform or wavelet packet decomposition do not separate the carrier and modulated frequency on amplitude modulation . The ensThe wavelet scattering transform (WST), applied in the present study, forms translation and time-invariant, stable, and informative signal representations. It is stable to deformations and preserves class discriminability, which makes it particularly effective for classification. The WST has wavelet advantages with the application of a scaling window and a complex wavelet operator cascaded by averaging convolution to extract information. Moreover, it requires less computation, signal energy can be concentrated at a low bandwidth, features can be extracted at any layer.The overall process of WST consists of three main operations: convolution, nonlinearity and averaging, as described in s to the , top: thThe Matlab wavelet scattering tools  were useBefore extracting the features from the modelled signals, the signals are oversampled to correspond to the experimentally determined signal length. The features of wavelet scattering coefficients are extracted for the number of resolutions across all orders of the scattering transform and the resolution of the scattering coefficients. The wavelet time scattering decomposition is constructed with the two filter banks: eight wavelets per octave in the first filter bank and one wavelet per octave in the second filter bank. The overall number of extracted features is 1232 for the signal length 2100, which corresponds to the measured signal sets. The diagrams of extracted features for the cases of void irregularities and the geometrical one as well as their significance are presented in The region of interest for the void detection are features 10 to 25 and 122 to 128, where the difference between the 2-, 3-, 4-mm lines are the lowest, which can be used as a common void indicator. The aim of the section is the development of an efficient method for in situ measurements and the collection of the statistical information to use for the development of the method for void identification and classification using track-side and on-board measurements. The in situ information collection from many different void zones is based on high efficiency multipoint photogrammetric measurements with low-cost, high-speed cameras. Additionally, control measurements with conventional methods were applied for the photogrammetric method validation.Image and video processing methods in the photogrammetric measurements are often used for railway and civil engineering applications. The application of a system of synchronized high-speed cameras to measure absolute longitudinal and vertical rail displacements using DIC is presented in . The DICThe application of the photogrammetric method for the diagnostic of transition zones is presented in ,69. The Another trend in the application of image and video-processing methods is related to deep-learning computer vision algorithms such as YOLO3 and others ,73,74,75Most of the presented photogrammetric measurements studies are usually directed on a deflection measurement of a single point at one object with one camera. However, analysis of multiple points of relative motion could provide promising results, such as those presented in the studies ,77. The One of the most significant limitations of the reviewed studies is the low time-resolution of the used cameras that does not allow to acquire information about the dynamic impact of the sleepers on the ballast in the void zones. Additionally, most of the studies were used for a limited number of measurements due to the method complexity, which did not allow to collect the statistical information. The limitations are taken into account in the present study. The proposed method for the sleeper void identification is based on experimental information collected in track-side measurements of multipoint rail deflection. The high-speed video recording measurements were carried out in 15 different problem zones of Swiss railways (SBB) by infrastructure managers. The measurement evaluations were produced by ETH Zürich  and TU DThe measurement of rail deflection using high-speed video recordings is a cost-effective alternative to the LVDT  measurement, which enabled the collection of statistical information. The application of the DIC method increases the accuracy of marker tracking from 0.61 mm/pixels to about ±0.05 mm, which makes the accuracy of the video method sufficient for low rail-deflections in the reference zones , top. AdThe typical measurement cases for different void damage from low to high are shown in A data-driven approach is used to recover the relation of the measured rail accelerations and sleeper support conditions. The relation is used for the development of the method for sleeper void detection and quantification using track-side and on-board measurements.Various data-driven approaches were proposed in numerous studies on railway infrastructure diagnostics over the last years. A one-dimensional convolutional neural network was proposed in the study  for damaThe study  exploresMost of the presented studies are based on data-driven deep-learning approaches, spectral signal processing for feature extraction and either experimental or simulation-based sources of statistical information. However, only a few studies present both data-driven and model-based approaches together. The application of mathematical modelling and numerical simulation could potentially improve the data-driven approach. On the other side, some studies replace real measurements with the simulated ones without comparison to experimental measurements.The present statistical investigation is based on experimental data collected from 15 damage zones using the developed high-speed photogrammetrical tool for rail deflection measurements. Thereby, the simulation results of the track–train dynamic interaction in voided and reference zones as well as their time-frequency analysis are used to improve the data-driven approach. The improvement consists of the additional model-based feature selection. The flowchart of the statistical processing is presented in The acceleration time series dataset is in the second step processes to extract time-frequency domain features using the previously constructed wavelet scattering network. After the feature extraction, the dimension is reduced from 2000 time-series variables for the input data to 154 wavelet scattering features. After the following model-based feature selection, the number of features is reduced to 88. In the next step, two supervised machine learning approaches were used: support vector machine (SVM) and k-nearest neighbor classifier (KNN). The main reason why the machine learning methods were preferred to the popular deep learning ones is the relatively small dataset of the experimental measurements. Additionally, the machine learning models are simpler in interpretation.The rail deflection dataset consists of two groups: the first for the measurements in the various ballast damage zones and the second for the simultaneous measurement in the reference zone, 10 outside the void zone. Each measurement zone is equipped by three markers for rail deflection measurements. The measurements were carried out in each measurement zone for about 12 train passages of different train types with velocities in range the of 100 to 160 km/h. The overall dataset of successful measurements is 652 time series. The comparison of the time-series datasets for the void and reference zone is presented in The histograms of maximal rail deflection distribution in the voided and reference zone are depicted in The acceleration datasets derived from deflections are presented in he paper , where tIn order to carry out on-board monitoring of voided sleepers, the decision rules should be obtained that enable, based on the acceleration measurement as input, to decide the severity degree of the void damage as the output. Here, we present a way to establish a decision rule. Three levels of severity are considered: void-free zone, void with depth less 3 mm, and void with more than 3 mm depth. The data are labelled in the corresponding classes: REF, HL1 and HL2. The data are randomly split in 70/30 training and test datasets and a fivefold cross-validation scheme was used.The cubic SVM and fine KNN classifiers were used to obtain the optimal decision boundaries between classes of sleeper support state. The KNN algorithm is a robust and simple classifier . It is bThe SVM classifier finds the optimal decision boundary with regard to the bias variance trade-off. It stays accurate to the training points and makes an accurate prediction with new points. The SVM presents the advantages, compared to other machine learning techniques, that it can make both linear and non-linear classifications and can better deal with outliers than KNN. The classification results for cubic SVM is presented in To prove the applicability of the developed method of void identification, the trained statistical models were applied for a real on-board measurement. The sleeper support conditions on a common crossing were estimated using on-board inertial measurements on a regular train , left 1. TherebyThe classification results for the SVM and KNN classifiers are presented in The research review presents many approaches on track-side and on-board track conditions identification. However, only on-board inertial measurements could be a cost-effective and frequent method for the sleeper support condition estimation. Many studies demonstrate that the on-board measurements from regular trains can provide the comparable condition estimation as the exact but expensive measurement trains. Thereby, the main difficulty is the correct interpretation of the inertial measurements. Other studies present a successful application of artificial intelligence methods for railway engineering applications.The mechanical modeling shows that the track dynamic behavior in the void zone was different to the equivalent geometrical irregularity specific pattern. The pattern is related to one or more dynamic impacts of the rail-sleepers grid to the ballast bed during void closure. The impacts appear in the zone before the wheel reaches it. The applied wavelet scattering to modelled on-board accelerations allowed to create the framework for the automatic extraction of significant features of the voided zone. Additionally, modelling shows that the dynamic behavior due to the voided zone is present in both track-side and on-board measurements.The statistical data about the dynamic behavior of railway track in many voided zones were collected using high-speed video cameras. The developed computer vision software allowed to extract exact and free-from-interference multipoint information about the rail vibrations. The method is simpler and more efficient than the conventional LVDT method, which allowed quick and cost-effective information collection from many problem zones.The collected statistical information was used to train the machine learning classifier models. The time series is separated in two independent variables: the vector of maximal sleeper void and the corresponding rail acceleration series dataset. Thereby, the Winkler-line rail deflections process is removed from rail deflections to avoid the bias to the predictor variable. An additional reason for the high-pass filtering is the intention to investigate the vibration information that is the same both for the track-side and on-board measurements. The model testing using a fully independent dataset demonstrated good enough classification results.However, the classification with the real on-board measurements of an axle-box acceleration on a common crossing was not so optimistic. There are many explanations for the insufficient good classification results of the on-board axle-box measurements on the common crossing. The mechanical explanation is that the measurements on the common crossing have the influence of the complicated geometrical irregularities that influence the wheel trajectory. The wheel accelerations depend on the long-wave structural irregularity, short-wave wear irregularity under the influence of lateral wheel position and the wheel profile irregularities itself ,53,96. TThe statistical reason of insufficient classification results is that only three measurements were used for the void estimation. Many experimental studies on wheel and rail common crossing interaction show that the axle-box acceleration measurements are subjected to high random variation due to many influencing factors. Thus, sleeper condition estimation with many different on-board measurements would bring more certainty to the classification results. The bad differentiation between the HL1 and HL2 for both classes can also be explained with unknown true state of the sleeper support condition for 4.7 Mt and 26.8 Mt since the tamping works produced are not known. The good support condition with the low void can be assumed for the measurement 0.07 Mt. However, even in this case, an insignificant void cannot be excluded due to impact interaction in the crossing zone that causes quick differential settlements.(1)One or more dynamic impacts of the rail-sleepers grid to the ballast bed occurs while void closure happens.(2)The track dynamic behavior in the void zone is different to the geometrical irregularity-specific pattern.(3)The similar dynamic behavior due to the voided zone is present in both track-side and on-board measurements.(4)The developed framework for the wavelet scattering feature extraction together with mechanical modeling allow to select the significant features for the void zone.(5)The application of machine learning methods allows good enough automatic recognition of the void zones.(6)The pre-trained model testing for on-board measurements from a common crossing zone shows a moderate result of the void identification.The presented research shows the possibility to identify the void irregularity and classify its severity using both track-side and on-board measurements. The research is based on the data-driven approach supported by a mechanical model feature selection. The classification using simple machine learning methods shows good enough results for isolated void irregularities. However, the identification results at switch locations are less convincing due to the multiple other interactions taking place. The classification results could be further improved by using more advanced deep-learning methods. On the other hand, the application of the mechanical model for multiple irregularities could improve the data-driven classification. The following partial conclusions of the research can be proposed:


Multiple myeloma is characterized by malignant proliferation of clonal plasma cells. Usually, appears as a generalized disease but it can present as solitary bone plasmacytoma or a solitary soft tissue mass or extramedullary plasmacytoma. In the case of extramedullary involvement, it could present as soft tissue plasmacytomas and the prognosis is poor. The 18F-FDG PET/CT could be a valuable tool for characterization of the medullary and extramedullary involvement. We present a case of F18-FDG PET/CT with extramedullary involvement with soft tissue plasmacytomas in the setting of MM. This showed multiple soft tissue masses in extremities, abdomen, and thorax wall with high FDG uptake and hypermetabolic lytic bone lesions  is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment (Palumbo and Anderson The role of imaging in the work-up of patients with MM is aimed at allowing the recognition of both the effects of myeloma cells on the skeletal system and the presence of extramedullary disease (Nanni and Zamagni F18-FDG PET/CT can help to identify areas of metabolic activity in whole body that represent clonal plasma cell proliferation while MRI is particularly well suited for the imaging of bone marrow (Ferraro et al. This case represents an unusual presentation of multiple myeloma in 18F-FDG PET/CT and emphasizes on the value of whole-body images for characterization of the medullary and extramedullary involvement.


The positions of the transmission spectra maxima in a one-component film are different for different film thicknesses. The best correlation of the maxima positions of the dye transmission spectra in solid and liquid solutions was observed for thicknesses of films close to a few (up to 10) monolayers. On the other hand, the absorption spectra maxima positions of one-component dye films (upper 10 nm) and composite films with high concentration, did not match the corresponding positions of absorption spectra maxima recorded in solutions. Comparison of the absorption spectra in one-component dye films and in solutions indicates the presence of both monomers and their aggregates in one-component films . Simultaneously with aggregation manifestation in the absorption spectra, the intensity of fluorescence of one-component dye films dramatically decreases. A quantum chemical simulation of the possible relative arrangement of two dye molecules indicates that the most possible of the simplest types of aggregates are physical dimers. Films of practical importance  possess a high quantum yield of fluorescence when reaching an impurity concentration of a few percent (aggregation does not take place yet).The spectral properties of new boron-containing dyes were studied. One-component (pure dyes) and composite “Alq This similarity indicates that, mainly, the dye molecules are involved in the film formation and there is no spectral manifestation of their fragments . The recorded absorption spectra of one-component films of all dye samples were compared with the absorption spectra of dyes in solution and in the solid matrix Alqifferent . Moreove3 matrix, which is not observed in composite films at low concentrations of dye. Therefore, in our opinion, the most probable explanation for the difference in the absorption spectra of dyes in solutions and one-component films is the presence of both monomers and dimers in the films.As can be seen from 3) molecules can be neglected). The parameters of the four lowest electron transitions in possible dimers of the dyes studied were calculated using the TD/DFT/ WB97XD method  for different configurations are shown in Scheme A corresponds to dimers of H-type (H-type dimer is the first stage of H-aggregate formation). In the case of The calculated dimer parameters (data of the first and higher excited states) were compared with data of the experimentally obtained absorption spectra see , Table 23 films. It was found that the dimers of such a type form involving guest dye molecules in the Alq3 matrix, starting at their concentration near 1–3%. The following increase in impurity concentration leads to a dramatically decreasing in a film’s fluorescence intensity. This effect should be taken into account in the process of luminescent materials development based on the studied dyes.In summary, we can conclude that it is most likely that the structure of one-component films of the abovementioned dyes is formed due to both monomers and dimers that do not take place in liquid solutions. The absorption, fluorescence spectra, and quantum chemical calculations indicate that these dimers are dimers of H-type. These dimers form in one-component thin films of dyes as well as in their solid solutions in Alq


The Editorial Office has been unable to confirm such findings directly with authorities at the institution in accordance with standard practice. Given the nature of the concerns raised, the Editor-in-Chief wishes to alert the readers to interpret the results presented here with caution.Corresponding authors Insug Kang and Eui-Ju Yeo stated on behalf of all co-authors that they agree to this Expression of Concern.


The objectives of this study were to investigate burnout in a sample of Irish Hospital Consultants and its association with psychopathology (symptoms of depression and anxiety). We examined the effect of personality factors on the development of psychopathology in response to burnout and in relation to work-related stress among the participants.This is a cross-sectional survey, utilising validated psychometric measures. Self-reported online questionnaires were distributed to all hospital consultants registered with the Irish Hospital Consultants Association distribution list and were completed between September to December 2016. Questionnaires sought to determine demographic information; work-related characteristics; burnout related phenomena: emotional exhaustion, depersonalization, and a reduced sense of personal effectiveness (Maslach Burnout Inventory [MBI-GS]); symptoms of depression and anxiety .A total of 477 hospital consultants  from hospitals in Ireland took part in the study. Of those studied, 42% reported high levels of burnout. The Depression and Anxiety Stress Scale revealed that Consultants were experiencing high levels of stress symptoms but comparatively low levels of anxiety symptoms. The study population scored highest on the conscientiousness and agreeableness subscales and lowest on the neuroticism subscale. Those who scored higher in the neuroticism subtype appeared to be at an increased risk of burnout.The prevalence of work-related burnout in consultants is of concern. The psychological burden of burnout is reflected in reported symptoms of stress and depression. Personality, particularly conscientiousness and agreeableness appears to impact the development of physician burnout. Strategies that modulate the relationship between personality and burnout may be beneficial for optimal health care delivery. Further research is needed to identify appropriate short and long-term strategies to ensure physician wellbeing and optimal delivery of patient care.


This study indicated the effect of the latent classes of stress on the physical and psychological health outcomes in Korea. Using the 2010 Korea Health Panel Study, 1,689 middle-aged adults  were analyzed to identify the latent classes of stress by gender using Latent Profile Analysis (LPA). After the determination of the number of latent classes, health outcomes  were also regressed on the latent classes including covariates . The perceived stresses  are classified as the 2-class model for women and the 3-class model for men. The classes of women are named 'high stress and 'low stress; however, the classes of men are named 'family-related stress', 'disease stress', and 'low stress.' The different combinations of stress are associated with anxiety/depression and health status respectively. This study will discuss the difference of latent stress classes by gender and extend the understanding of stress groups and health outcomes.


Following publication, concerns were raised regarding image manipulation. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers' guidelines.This retraction was approved by the Chief Editors of Frontiers in Cellular and Development and the Editor-in-Chief of Frontiers. The authors [did] agree to this retraction.


A multimodality approach is often used in the management of high-grade soft tissue sarcoma of the extremity (eSTS). Limb-sparing surgery is the keystone of eSTS management, often accompanied with radiotherapy (RTX) and/or chemotherapy (CTX). The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guideline recommend RTX and CTX in selected groups of high-risk patients.Our cross-sectional study aimed to acquire insight into the variation of eSTS management across the world and to assess the importance of several clinicopathologic risk factors for the indication of multimodality therapy.The optimal management of patients with eSTS remains an important field of research. Recent developments of prediction tools and advances in genomics and proteomics may allow for better patient selection for multimodality therapy. Because in recent years some retrospective studies have been performed to assess the use of these tools for the indication of multimodality therapy, further studies are needed to improve patient selection for the indication of multimodality therapy, with a special focus on perioperative CTX and new perioperative modalities. Also, the cost-effectiveness of chest CT scan versus chest X-ray and the use of prognostic tools for patient-tailored follow-up regimen should be explored. Given the rarity and heterogeneity of eSTS, large collaborative efforts of international sarcoma centers are crucial to further improve patient-tailored management of eSTS.


Flavone acetic acid (FAA) is a novel antitumour agent that has a profound effect on the vasculature in murine tumour models. Previously we have shown that FAA induces a coagulopathy and thrombocytopaenia in tumour-bearing mice, and the purpose of the present study was to determine the significance of the FAA-induced intravascular coagulation in the antitumour action of FAA. Several anticoagulant agents were tested for their effectiveness in altering ex vivo coagulation of murine plasma; heparin and ancrod were found to be most effective. These agents were administered to tumour-bearing mice prior to FAA and TNF treatment with little effect on the induced regrowth delay. However: the FAA-induced consumption of platelets in tumour-bearing mice was not blocked by anticoagulant treatment. These data suggest that platelet consumption occurs independently of the normal coagulation pathway, and further that fibrin deposition may not be a major factor in the antitumour action of FAA.


We have analysed 174 gastric carcinomas from the United Kingdom and from Japan for the presence of Epstein-Barr virus (EBV) using in situ hybridisation for the small EBV-encoded nuclear RNAs (EBERs). EBV was detected in the tumour cells in all of six undifferentiated gastric carcinomas with prominent lymphoid stroma  but only in three of the remaining 168 typical gastric adenocarcinomas (1.8%). No differences were observed between the British and the Japanese cases. One case with an EBV-positive UCNT showed adjacent areas of EBV-negative typical adenocarcinoma. It is uncertain whether these patterns represent two independent carcinomas or whether they are the result of heterogeneous EBV infection in a single tumour. In the remaining EBV-positive carcinomas, viral transcripts were detected in virtually all tumour cells, indicating that EBV infection must have taken place early in the neoplastic process and suggesting that the virus is likely to be of pathogenetic significance for the virus-associated tumours. Immunohistology demonstrated absence of detectable levels of the EBV-encoded latent membrane protein, LMP1, and nuclear antigen, EBNA2. The BZLF1 protein which induces the switch from latent to lytic infection was demonstrated in a small proportion of the tumour cells in three cases. The close association of EBV with undifferentiated gastric carcinomas compared to the variable association with gastric adenocarcinomas suggests fundamentally different roles for the virus in the aetiology of these two malignancies.


Using the breast carcinoma cell line MDA-MB 468 as immunogen, we have produced six new rat monoclonal antibodies (mAbs) against the human EGF receptor (EGFR) and are investigating their use for diagnostic and therapeutic applications in cancer patients whose tumours overexpress these receptors. The mAbs  were selected on the basis that they bound to the extracellular domain of the EGFR and blocked growth factor-receptor interaction. Competitive assays showed that, with the exception of antibody ICR65, the mAbs bound to one of two distinct epitopes on the external domain of the EGFR. ICR65, however, cross-reacted with mAbs binding to both epitopes. All of the mAbs immunoprecipitated the 170 kDa glycoprotein from cells expressing the EGFR but not the 185 kDa product of the related c-erbB-2 proto-oncogene. Unlike EGF and TGF alpha none of the mAbs stimulated the growth of quiescent human foreskin fibroblasts but they inhibited the EGF and TGF alpha induced growth stimulation of these cells in vitro. When tested for their effect on tumour cells the mAbs were found to inhibit the growth in vitro of a number of human tumours that overexpressed the EGFR  but they were without effect on tumour cell lines expressing low or undetectable amounts of the receptor. Our initial results indicate that this new generation of antibodies which bind with high affinity to the EGFR, block growth factor-receptor interaction and inhibit the growth of human squamous carcinoma cell lines overexpressing the receptor have potential for clinical application.


A retrospective population-based case-control interview study has been conducted in three distinct areas in the north of England where local excesses of children with leukaemia have been reported. A total of 109 cases of childhood (0-14 years at diagnosis) leukaemia and non-Hodgkin's lymphoma who were born in one of the study areas and diagnosed there between 1974 and 1988 were included in the study. One control per case was matched on sex, date-of-birth and health district of birth. The objective was to compare residential histories of cases and controls and in particular to determine whether case children had lived in the same place at the same time more often than controls. The residential distance between two children was taken to be the smallest geographical distance between homes they had 'occupied' simultaneously for a period of at least 6 months between conception and diagnosis. Case children were more likely than expected to have other cases as their nearest neighbours by residential distance . A detailed examination of the nearest neighbour pattern permits the generation of further specific hypotheses. These suggest that persistent infection established in utero or early infancy may be involved in the development of some cases of childhood leukaemia. Horizontal transmission of the agent(s) within small communities may occur but there is no evidence of direct contact between cases.


Small-cell neuroendocrine carcinoma of the lung is known to express products related to the vasopressin gene, although these products have been reported to sometimes differ from those generated by neurones of the hypothalamo-neurohypophyseal system. To further investigate vasopressin gene expression in neuroendocrine carcinomas, we performed immunohistochemistry on 24 histologically classified small-cell carcinomas using antibodies directed against different regions of the vasopressin precursor. All of the tumours examined contained at least two parts of the vasopressin precursor, suggesting that vasopressin might have a biological role in these tumours and indicating a role for these products in tumour diagnosis and treatment. Sixty-seven per cent of the tumours contained immunoreactivity for all major regions of the precursor: vasopressin, vasopressin-associated human neurophysin, the bridging region between the hormone and the neurophysin, and vasopressin-associated human glycopeptide. However, 33% of the tumours examined appeared to express only part of the vasopressin precursor, as evidenced by the absence of immunoreactivity for the neurophysin and/or the glycopeptide. These results support the proposition that both normal and abnormal vasopressin gene expression occurs in small-cell carcinoma of the lung.


The provision of education, training and pedagogy, its associated science is being radically impacted by technological developments and changing methodologies in the imparting and acquisition of knowledge. This is resulting in the thrust and focus of higher education moving from a traditional university centred process to a more student-orientated one. The Internet's propensity for real-time interaction makes computer-based training, or distance learning, viable for accommodating medical education needs. In medicine many concepts are visual or structural and in many cases clinical reasoning is based on spatial abstraction of structures. Incorporating these principles, the Institute developed the concept of the Virtual Study Centre (VSC), utilising methodologies which take advantage of the developments in web based computing and communication infrastructures to specifically address the difficulties associated with existing methods of distance learning.The VSC is a 'hypermedia' learning environment, which offers a more flexible approach to learning for both producers and users of educational material. It is achieved through distributed student access to networked learning resources. A project team was established to define the specific models of learning scenarios where synchronous interaction played an important role. Utilising an assessment matrix based on the requirement outcomes of the learning scenarios, it evaluated products available in the web-based training area for quality, extent and complexity in respect to multimedia design, interactivity and overall ease of use. Each product had to comply with their criteria under the following headings: technical composition, infra-structural design, regional and cultural constraints. A compromise in the quality and speed of audio and video was not an option. To provide the best we expected the best from the products so that we could provide a well-crafted teaching system, which could be used throughout the medical profession.We have identified the optimal model based standards required in software tool-sets to develop and support multimedia web-based training.A fundamental element in the provision of distance education is interaction. This paper illustrates the considerable deficit in the availability of quality media-rich tool-sets on the market, which enables optimum interaction. It details the research undertaken in the provision of the levels of interaction necessary to provide a fully integrated web-based education facility and the difficulties of tailoring a traditionally taught course for the web. It develops and explores the issues surrounding the monitoring, examination and identification of students and defines an approach to underpin optimum tool-set assessment and utilisation.


S. cerevisiae and point out the value of this relatively untapped source of information.The recently emerged protein interaction network paradigm can provide novel and important insights into the innerworkings of a cell. Yet, the heavy burden of both false positive and false negative protein-protein interaction data casts doubt on the broader usefulness of these interaction sets. Approaches focusing on one-protein-at-a-time have been powerfully employed to demonstrate the high degree of conservation of proteins participating in numerous interactions; here, we expand his 'node' focused paradigm to investigate the relative persistence of 'link' based evolutionary signals in a protein interaction network of P. falciparum /Yeast orthologs, as proof-of-principle that high-order network topology can be used comparatively to deduce local network structure in non-model organisms.The trend for highly connected proteins to be preferably conserved in evolution is stable, even in the context of tremendous noise in the underlying protein interactions as well as in the assignment of orthology among five higher eukaryotes. We find that local clustering around interactions correlates with preferred evolutionary conservation of the participating proteins; furthermore the correlation between high local clustering and evolutionary conservation is accompanied by a stable elevated degree of coexpression of the interacting proteins. We use this conserved interaction data, combined with High local clustering is a criterion for the reliability of an interaction and coincides with preferred evolutionary conservation and significant coexpression. These strong and stable correlations indicate that evolutionary units go beyond a single protein to include the interactions among them. In particular, the stability of these signals in the face of extreme noise suggests that empirical protein interaction data can be integrated with orthologous clustering around these protein interactions to reliably infer local network structures in non-model organisms. H. pylori  reflects the number of the bin we assign a data point with a xi coordinate. Representing the nith bin on the x-axis, we place On a logarithmic scale, we define the bin size The advantage of logarithmic binning is an elevated degree of noise reduction which is dependent on the bin size ,43. Althcontains detailed statistical measurements of presented correlations. Furthermore, we show results of the perturbation analysis of coexpression coefficients as briefly addressed in the main paper.Click here for file


Using in vitro techniques, bone marrow (BM) function has been studied in 25 patients in complete remission and at least one year after the completion of MVPP chemotherapy for Hodgkin's disease. The numbers of granulocyte/macrophage (GM-CFC) and fibroblastoid (CFU-F) progenitors were significantly lower than controls and there was no evidence of any improvement with time (median months off treatment was 30 for GM-CFC and 34 for CFU-F). In long-term BM culture production of haemopoietic cells were strikingly lower in the post-MVPP group and the development of adherent stromal cell populations was also significantly less. In addition, the yield of GM-CFC in adherent layers after four weeks of culture was significantly lower than in controls. We conclude that following MVPP chemotherapy and in apparently disease free and haematologically normal individuals there is evidence of impaired BM function up to nine years after the completion of treatment. These abnormalities may be relevant to the known increased risk of acute non-lymphocytic leukaemias in this group of patients and are likely to render the BM less able to withstand subsequent insults such as further chemotherapy or infection. The eventual development of BM failure is also a possibility and long-term follow-up of these patients is essential.


The clinical use of anti-oestrogens in breast cancer therapy has traditionally been restricted to tumours that contain measurable oestrogen receptor protein. However, it is now widely recognised that the clinical response to adjuvant anti-oestrogen therapy appears to be independent of the oestrogen receptor content of the primary tumour. The study reported here was designed to investigate the possibility that human stromal cells can respond to anti-oestrogens by an increased synthesis of the inhibitory growth factor, transforming growth factor beta (TGF-beta). Two established human fetal fibroblast strains were used as models for the breast cancer stromal fibroblasts. These cells were found to respond to the addition of anti-oestrogens by a large increase in their synthesis of biologically active TGF-beta. Despite the application of ligand binding, immunoassay and Northern analysis, no oestrogen receptor or oestrogen receptor mRNA was detected in either of the human fetal fibroblasts strains. These observations may provide a mechanism of action of anti-oestrogens that is independent of the presence of oestrogen receptor in the tumour epithelial cells, and thus provide an explantation for the counter-intuitive results of adjuvant anti-oestrogen action.


The Hospital Anxiety and Depression Scale (HADS) is a widely used screening tool designed as a case detector for clinically relevant anxiety and depression. Recent studies of the HADS in coronary heart disease (CHD) patients in European countries suggest it comprises three, rather than two, underlying sub-scale dimensions. The factor structure of the Chinese version of the HADS was evaluated in patients with CHD in mainland China.Confirmatory factor analysis (CFA) was conducted on self-report HADS forms from 154 Chinese CHD patients.Little difference was observed in model fit between best performing three-factor and two-factor models.The current observations are inconsistent with recent studies highlighting a dominant underlying tri-dimensional structure to the HADS in CHD patients. The Chinese version of the HADS may perform differently to European language versions of the instrument in patients with CHD. In China, economic transition, urbanization, industrialization and an aging population have quickly increased the incidence and prevalence of coronary heart disease (CHD) in the past decades . CHD hasThe Hospital Anxiety and Depression Scale (HADS)  is a widThe original English version has been translated into and validated in many languages, including Chinese -12. The A recent review  of the HIn Europe, the HADS has been applied extensively in the studies of patients with CHD as an index of both outcome and the effect of therapeutic intervention -23. TherThe study used a cross-sectional design. To address the research question confirmatory factor analysis methods were used on a pooled HADS data set from mainland Mandarin-speaking patients admitted to hospital with CHD.The factor structure of the HADS was determined using confirmatory factor analysis using Mplus version 3 . The weiThe first author administered the Chinese version of HADS to patients for self-completion. Demographic data and medical history were also obtained from patients and medical charts.One hundred and sixty patients with CHD were initially enrolled into the study of which 154 completed the questionnaires. The patients ranged in age from 38 to 86 years with a mean age of 60 years (SD = 10.37). One hundred and twenty (77.9%) patients were males. In terms of the clinical data, over two thirds of subjects were angina patients. The study was conducted in the general cardiovascular wards of two large university-based teaching hospitals in Xi'an City of China. Inclusion criteria were diagnoses of angina pectoris or myocardial infarction, no known psychiatric problems, and could understand Chinese. The study was conducted over a four-month period. The clinical ethical committee of the two university affiliated hospitals in Xi'an approved the study. Informed consent was obtained from all patients prior to commencement of the study.The mean HADS anxiety (HADS-A) sub-scale score was 6.16 (SD 3.86) and the mean HADS depression (HADS-D) sub-scale score was 6.43 SD 4.12). Based on Snaith and Zigmond's  interpre. Based oThe finding of high proportions of Chinese CHD patients screening positive with anxiety and depression using the HADS is consistent with previous studies conducted in China or in western countries ,5,34,35The CFA findings are in many respects, rather surprising. It has been suggested that the bi-dimensional underlying factor structure of the HADS observed in many early psychometric evaluations of this instrument is an artifact of the factor extraction method  and that the instrument is indeed tri-dimensional, a perspective supportive by more recent studies using CFA . In studGiven the observation that tri-dimensional models offered a similar fit to the data as bi-dimensional models, the issue of scoring the instrument as a tri-dimensional instrument is worthy of discussion. It has been previously suggested that the HADS could be scored as a three sub-scale instrument . HoweverThe finding of virtually identical fit characteristics of the best performing two and three-factor models also raises the issue of conclusively defining the underlying factor structure of the HADS. The HADS clearly cannot be both bi-dimensional and tri-dimensional within the same data set and further clarification of the structure of the instrument is desirable since this may provide additional evidence not only on the limitations of the HADS, but also the development, enhancement and possible future revision of this widely used measure. The current study was limited by sample size and this may be an important factor in clarifying the relative performance of the competing models tested. It is worthy of note that a number of studies that have utilised factor analysis with large sample sizes have found a clear advantage in model fit of tri-dimensional models over the traditional anxiety/depression bi-dimensional model of the HADS ,18,26. LPrevious findings of the factor structure of the Chinese version of the HADS in Cantonese-speaking Chinese CHD patients in Hong Kong indicates clear and consistent superiority of three-factor models in fits to data . One posThe original validation of the Chinese version of the HADS  identifiIt should be acknowledged that the current study had a number of limitations, in particular, the modest sample size and the absence of a comparison to a 'gold standard' such as a structured clinical interview to assess for anxiety and depressive disorder. Further research addressing these limitations is recommended.WW participated in the design of the study and assisted in the drafting of the manuscript. VL participated in the design of the study and assisted in the drafting of the manuscript. CM participated in the design of the study, performed the statistical analysis and assisted in the drafting of the manuscript.


Multiple primary tumours occurring in a three-year population-based series of patients with histopathologically peer-reviewed sarcomas from North West England were ascertained in order to look at the patterns of neoplasms seen. A total of 30 out of the 310 patients entered in the study had additional primary tumours. Very few patients were aged under 60 years at diagnosis of both their malignancies. The youngest was a known case of neurofibromatosis and, although seven patients were diagnosed with a sarcoma and carcinoma of the breast--a combination of cancers characteristic of the Li-Fraumeni cancer family syndrome--no other patients could directly be identified as suffering from any other cancer predisposition syndrome.


We quantified and examined the kinetics of DNA interstrand cross links (DNA-ISC) caused by Cis dichlorodiammine platinum (DDP) using the method of alkaline elution in 58 highly purified human ovarian tumours growing in primary culture. A large heterogeneity in both the quantity and kinetics of DDP induced DNA-ISC was observed in cultures derived from neoplasms of different patients and from different lesions of the same patient. In the majority of cases. DNA-ISC lasted for prolonged time intervals after 1 h drug exposure, being significantly repaired only 48 or 72 h following drug washout. The persistence of DNA-ISC is probably due to a prolonged formation of these lesions for up to 24 h as assessed by the change in the repair kinetics that occurred after preventing new DNA-ISC formation by quenching of monoadducts with thiourea. The inefficient repair of DDP monoadducts appears therefore to be a possible reason for the permanence of DNA-ISC. These studies suggest that the long permanence of DNA-ISC in human ovarian cancer could be the basis for the high selectivity of DDP for this human malignancy.


The prevalence of nausea and emesis among a series of out-patients (n = 95) receiving mainly mild-to moderately-emetic cytotoxics, was assessed, along with levels of psychological morbidity. Particular focus was given to the rates of psychologically-based (anticipatory) nausea and emesis. Results indicated that 23% of patients experienced anticipatory nausea and the majority reported that this occurred before at least half of the previous treatment cycles. Both emetic challenge of chemotherapy regimen and younger age were linked to this anticipatory effect. The data clearly indicated that nausea and emesis, both post-treatment and in anticipation of treatment, carried a psychological cost with anxiety being highest in those experiencing anticipatory nausea and/or emesis. The role of anxiety in the aetiology of psychologically-based nausea and emesis was not evaluated and it is considered that a prospective study is needed to clarify the exact contribution of psychological factors in the incidence of both post-treatment and anticipatory side-effects.


Samples of colorectal carcinoma, adenoma and normal colorectal mucosa were examined for the expression of TGF-beta by immunohistochemistry. Immunoreactivity for TGF-beta was present in 52 out of a total of 58 samples of normal mucosa examined. In adenomas and carcinomas TGF-beta expression was observed in eight out of ten and 46 out of 48 samples respectively and was largely restricted to epithelial cells. In normal mucosa differential expression of TGF-beta was present within epithelial cells, those in the upper parts of the crypts showing enhanced immunoreactivity compared to cells in the proliferative compartment. This pattern of differential staining is consistent with TGF-beta having an important role in the control of growth and differentiation in colonic mucosa.


Initial classifications of 1009 testicular tumours were reviewed as part of a population based survey of all testicular neoplasms in Victoria, Australia, between 1950 and 1978. All reviews were made by one of two pathologists at the Peter MacCallum Cancer Institute, using the system of the British Testicular Tumour Panel. Accuracy of diagnosis varied markedly over the time period and with pathological category. Seven cases were initially designated malignancies but were determined to be non-malignant conditions upon review. In each decade, review reduced the proportion of seminomas and increased the proportion of non-seminoma germ cell tumours (NSGCT) and non germ cell tumours. Reclassification resulted in changed age specific incidences of seminoma and NSGCT, most noticeably in 1950-59. Trends in age standardised incidence of seminoma and NSGCT were not affected by reclassification although the values were. The trend in age standardised incidence of non germ cell tumours was affected by reclassification. The implications of the changes in classification for epidemiological studies and clinical management are discussed.


The mutagenic and cytotoxic activity of two newly synthesized doxorubicin derivatives and of one daunorubicin derivative were studied in V79 Chinese hamster cells and bacteria . The results showed that all the compounds tested were cytotoxic and mutagenic for both prokaryotic and eukaryotic cells. However, in both systems, the two 4-desmethoxy- and the 4'-desoxy-derivatives were more active than the parent compounds, indicating that modifications in the aglycone or in the sugar moiety can produce appreciable changes in the biological properties of the anthracycline antibiotics. The in vitro activities observed in this study correlated with the in vivo antitumour potency.


Multiple sclerosis is a chronic disease of uncertain aetiology. Variations in its disease course make it difficult to impossible to accurately determine the prognosis of individual patients. The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) developed an "online analytical processing (OLAP)" tool that takes advantage of extant clinical trials data and allows one to model the near term future course of this chronic disease for an individual patient.For a given patient the most similar patients of the SLCMSR database are intelligently selected by a model-based matching algorithm integrated into an OLAP-tool to enable real time, web-based statistical analyses. The underlying database (last update April 2005) contains 1,059 patients derived from 30 placebo arms of controlled clinical trials. Demographic information on the entire database and the portion selected for comparison are displayed. The result of the statistical comparison is provided as a display of the course of Expanded Disability Status Scale (EDSS) for individuals in the database with regions of probable progression over time, along with their mean relapse rate. Kaplan-Meier curves for time to sustained progression in the EDSS and time to requirement of constant assistance to walk (EDSS 6) are also displayed. The software-application OLAP anticipates the input MS patient's course on the basis of baseline values and the known course of disease for similar patients who have been followed in clinical trials.This simulation could be useful for physicians, researchers and other professionals who counsel patients on therapeutic options. The application can be modified for studying the natural history of other chronic diseases, if and when similar datasets on which the OLAP operates exist. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. Currently there is no cure for MS, but there are treatments for its relapsing forms that reduce the short and mid-range impact of the disease. It remains impossible to accurately predict the prognosis of individual patients, which could be important for patient counselling and in weighing therapeutic options. The Sylvia Lawry Centre for MS Research in Munich (SLCMSR) uses data from clinical trials and natural history studies to develop mathematical models for the course of the disease which might assist in the efforts to accurately determine short, mid and long-range prognosis. The "individual risk profile" project makes the Centre's large database available to health care professionals via access to a representative part of the database.The SLCMSR database consist of data from most natural history studies and the placebo arms of nearly all randomised controlled clinical trials in MS patients from the last decade. The data are anonymised, homogenized and pooled from the academic and corporate sources. As of April 2005, 45 separate data sets and 81,000 patient-years of data from 20,000 patients were included. The database is divided into so-called "open" and "closed" parts. The "open" database is accessible by researchers  at their discretion. The "closed" database is accessible only to authorized staff on behalf of the Validation Committee of the Centre as part of the validation policy of the SLCMSR [An interdisciplinary team of neurologists, information technology specialists, and biostatisticians developed a Java-based OLAP tool using the statistical software package R 2.0.1 . The souRegistered OLAP users access the database via their internet browser, select values for patient characteristics of their interest and get displays of the observed disease course for placebo patients from the database with matching characteristics.The essential component of the OLAP is a matching algorithm. A given patient of interest is "identified" by a set of covariates which are widely accepted to be potential prognostic factors -7: the nThis descriptive report is based on 1,059 patients from placebo arms of controlled clinical trials available from release 1.0 of the SLCMSR database (April 2005).The patient baseline characteristics of the database are summarized in table The advantages of OLAP-tools based on a unified database ("data warehousing") are widely applied in business and increasingly used in medical research and medical decision-making. In this report we describe a tool for investigating the course of MS based on specific clinical data and using that information to project disease course in patients of interest.The predictive power of this tool is limited by restrictions of the composition of patients and duration of observations in the current release of the database. The clinical data are restricted to data from the placebo groups of randomized clinical trials, which may not reflect disease outcomes in patients not involved in clinical trials and certainly do not reflect the impact of daily disease management of patients in non-research clinical settings. Additionally, the observation period of the included patients is limited to a maximum of 3 years (median follow-up 2.2 years) of observation, thus limiting the ability to accurately project longer term outcomes for patients with what is a life-long disease.A comparison of the tool with population based prevalence cohorts -7 is theIn addition, the utility of the OLAP tool as a predictor of disease course is limited by the patient characteristics in the parent dataset. For instance, there are only a small number of patients with a primary progressive course of MS in the SLCMSR dataset, and this subtype cannot be sufficiently analysed yet. The advantage of the OLAP tool (compared with a purely model based prediction), however, is that this limitation is transparent to the user figure .The "individual risk profile" project is based on a comprehensive database and the programming of an OLAP-tool. Our initial intention is to pilot the use of the database amongst neurologists and other researchers experienced in MS with an interest in clinical trials. This phase should provide informed feedback on the utility of the tool for clinical or research use. Updated versions are planned with expanded databases in particular inclusion of long-term natural history data and a broader spectrum of predictors.Most developmental steps of this project as well as principles of the creation of the underlying database are not disease-specific. It will be of interest to apply the methods and software developed at the SLCMSR for studying MS to other chronic diseases like heart failure, chronic obstructive pulmonary disease, or diabetes mellitus.Project name: OLAP Individual Risk ProfileProject home page: Operating systems: Web based applicationProgramming language: R, JavaOther requirements: CSS1/UTF-8 compliant browser is required License: Free, anyone may use the service for non-commercial purposes.Any restrictions to use by non-academics: No.The author(s) declare that they have no competing interest.Martin Daumer and Michael Scholz developed together the idea, Michael Scholz implemented the first version of the tool, and Christian Lederer planned and devised the refined method. Christian Lederer and Anneke Neuhaus programmed the current version of the OLAP-tool. Jerry Wolinsky is chair of the SLC's scientific advisory committee and has tested and evaluated several versions of the tool. All co-authors contributed in critically discussing the overall concept, testing the tool in various stages of its development in on site and during joint conference calls, writing and critical reviewing the manuscript. All coauthors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:IRPolap.R. The R source code underlying the IRP web application.Click here for file


To determine the cause of the increased content of carbohydrate-bound phosphate in tumour lysosomal hydrolases, the activity and kinetics in human hepatocellular carcinoma of two enzymes involved in the formation of mannose-6-phosphate in lysosomal hydrolases UDP-GlcNAc: lysosomal enzyme GlcNAc alpha l-phosphotransferase (GlcNAc-phosphotransferase) and phosphodiester glycosidase were studied. The activity level of the phosphotransferase with artificial and natural substrates was elevated  in hepatoma compared to that in uninvolved tissue, while the phosphodiester glycosidase of hepatoma was at a level similar to that of the uninvolved tissue. To verify a previous observation that cathepsin D of human hepatoma contained increased GlcNAc-phosphomannose, the protease was examined for carbohydrate phosphorylation by the GlcNAc-phosphotransferase. The protease from normal human liver was much more phosphorylated than hepatoma protease, confirming the previous observation. The predominant phosphorylation of the protease occurred in one of two major heavy subunits, with some phosphorylation in one of two minor light subunits.


A cytogenetic follow-up study of patients treated with chemotherapy for gestational trophoblastic tumours was undertaken. In some cases, high levels of chromosome damage were found to persist in lymphocytes for several years after completion of therapy. These results are compared with those found in similar studies of non-malignant and other malignant diseases. The relevance of these findings to the risk of subsequent chemotherapy-induced malignancy is discussed.


This is a short comment on the editorial on Electromagnetic Interference in Implantable Rhythm Devices - The Indian Scenario in the July-September issue of the journal . Regardi


An analysis of cytology reporting within Victorian Cytology Service demonstrates that the proportion of Papanicolaou smears which were reported as including an endocervical component increased from approximately one half during 1987-89 to more than three quarters during 1990-91. The improvement coincided with the routine provision of special sampling instruments to all practitioners supplemented by an education program. Despite the increase in endocervical sampling, no increase in the rate of reporting of high-grade intraepithelial lesions of the cervix has occurred. An increase between the two time periods in the cytological reporting of adenocarcinoma, adenocarcinoma in situ and endocervical dyskaryosis has occurred, but does not reach statistical significance.


To evaluate the natural history of a disease and the effects of therapeutic interventions, it is important to determine which are the causes of treatment failure and to assess the extent to which each cause contributes to the total failure rate. The paper presents a new biostatistical technique to decompose the total event-free survival of a diseased population into cause-specific failure rates. The technique was based on a competing risk approach thereby avoiding biases related to assumptions of independence between different types of event. Such assumptions are inherent in the conventional Kaplan-Meier or actuarial methods. The competing risk method was used to analyse the pattern of failure among 2,850 pre- and postmenopausal patients with early-stage breast cancer and the results were compared to those obtained using conventional methods. The following events were analysed: loco-regional recurrence, distant metastasis, contralateral breast cancer, other new primary malignancies, and intercurrent deaths. The rate of new primary malignancies was found to be significantly higher in post- than in premenopausal patients (6% vs 3% at 10 years). In low-risk, node-negative postmenopausal patients the incidence of recurrences from breast cancer were found to be no greater than other types of events. This observation highlights the significance of the effect of different adjuvant therapies not only on the disease itself but also on the risk of second primary malignancies and other intercurrent diseases. In general, it was found that the conventional statistical methods tended to overestimate the event-specific rates. In conclusion, the method based on competing risks permits an unbiased analysis of all types of events determining the total event-free survival. It is thus useful for the description of the natural history of breast cancer as well as other diseases.


The binding and biological activity of human TNF alpha on endothelial and tumour cells has been studied in the presence of monoclonal antibodies (MAbs). In particular, one monoclonal antibody to TNF alpha (MAb 32) has been identified which failed to inhibit binding and cytotoxicity of TNF alpha on WEHI-164 tumour cells but which was a potent inhibitor of TNF alpha-induced endothelial cell procoagulant activity on bovine aortic endothelial cells. The ability of MAb 32 to inhibit selectively the actions of TNF alpha on endothelial cells but not on tumour cells suggests a mechanism for enhancement of the anti-tumour action of TNF alpha in vivo when in complex with this antibody. Treatment of tumour bearing mice (WEHI-164 and Meth A fibrosarcoma) with TNF alpha-MAb 32 complex resulted in a 5- to 10-fold enhancement in the potency of the cytokine in comparison to free TNF alpha. Complexes between this cytokine and other MAbs generally resulted in either no effect or inhibition of TNF alpha activity in vivo and in vitro. Neither intact MAb 32 nor FAb' fragments of MAb 32 showed any tumour regressive activity in the absence of TNF alpha. The FAb' fragments were equipotent to the bivalent form of the antibody in enhancing TNF alpha activity. These data provide evidence that it is possible to segregate the individual biological activities of TNF alpha with concomitant enhancement of the tumour regressive activity of the cytokine in vivo.


Cytokinetic parameters of various types of lung cancer were determined in bronchoscopy specimens after in vivo labelling with the thymidine analogue bromodeoxyuridine (BrdU). The S-phase fraction and BrdU labelling index were measured flow cytometrically, allowing calculation of the S-phase transit time and potential tumour doubling time. The methodology used was found to be feasible for obtaining cytokinetic data from 76% of the bronchial biopsy samples. Despite the difference in clinical behaviour and growth pattern between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), no significant differences were observed between the mean values of the cytokinetic parameters of SCLC and NSCLC. The estimated cell loss factor was higher in NSCLC than in SCLC. It appears that the growth of a tumour, as clinically observed, is to a considerable extent influenced by cell loss. In accord with this assumption is the fact that we have observed non-BrdU labelled S-phase cells, both in tumour biopsies and in apparently normal tissue. The presence of these so-called unlabelled S-phase cells in relation to cell loss is discussed.


Burkitt's lymphoma, an Epstein-Barr virus (EBV)-associated non-Hodgkin's malignant lymphoma is endemic in an area of Africa known as the Lymphoma Belt. This zone is demarcated by climatic requirements of temperature and rainfall. EBV-activating plant factors are among several co-factors which have been proposed for the development of epidemic Burkitt's Lymphoma (eBL). The distribution of Euphorbia tirucalli, a plant which possesses EBV-activating substances and can induce the characteristic 8:14 translocation of eBL in EBV-infected lymphoblastic cell lines in vitro, conforms closely to the climatic requirements of the Lymphoma. This plant, other EBV-activating plants and plants of unknown EBV-activating status with medicinal uses, are found significantly more often at the homes of eBL patients in Malawi than in those of controls. The possible role of these plant factors in the pathogenesis of eBL and their routes of bodily access are discussed. It is postulated that the associations described in this paper provide support for the theory that EBV-activating plants are co-factors involved in the pathogenesis of some cases of eBL.


It has been suggested that the size of the nuclei of epithelial basal cells can be used in predicting the likelihood of malignant transformation of epithelium. This proposition was assessed in rat palatal epithelium after the carcinogen 4-nitroquinoline-1-oxide had been applied to the epithelium for varying periods of time. No consistent alterations in basal cell nuclear size, including area, perimeter, diameter and regularity of form were found with routine light microscopy as the epithelium passed through various stages of dysplasia to carcinoma. This finding casts doubt on the value of using a variation of basal cell nuclear size as a predictor of malignant transformation.


The mechanism of bowel obstruction in colorectal cancer is likely to involve interactions between tumour cells, host fibroblasts and the extracellular matrix. The role of fibroblast-mediated matrix reorganisation in malignant structures of the large bowel was examined in an in vitro collagen matrix model in which tumour cells and fibroblasts were cultured under serum-free conditions. Colon cancer cells secreted a factor(s) which enhanced the ability of colon fibroblasts to contrast a collagen matrix without an associated mitogenic response by the fibroblasts. Within uncontracted collagen gels marked elongation of fibroblast cell processes was observed in the presence of the tumour-derived factor(s). We propose that matrix reorganisation by host fibroblasts in the wall of the human colon is responsible, at least in part, for malignant large bowel obstruction.


To compare the relative heat sensitivities of human normal and neoplastic cells of the same tissue type, a study was carried out of the relative sensitivities to heat of granulocyte/macrophage progenitor cells (CFU-GM) derived from the peripheral blood and bone marrow of normal subjects and patients with chronic granulocytic leukaemia (CGL). Nucleated haemopoietic cells were incubated at temperatures in the range 41.5 degrees C to 44.0 degrees C for various periods before culture in agar. The results of these experiments showed that CFU-GM from normal blood were consistently less sensitive to damage by heat than normal marrow CFU-GM. There was no comparable difference in the relative heat sensitivities of CFU-GM from blood and marrow of patients with CGL and no significant difference between the heat sensitivities of CFU-GM derived from marrow from normal individuals and patients with CGL. The observed difference in heat sensitivity of CFU-GM from normal blood and marrow accords with other data suggesting that the two progenitor cell compartments are distinct: the blood CFU-GM may represent a more primitive population of committed progenitor cells. In CGL, CFU-GM in the blood may much more closely resemble those in the marrow. The data provide no support for the hypothesis that malignant cells differ intrinsically from their normal counterparts in respect of sensitivity to damage by hyperthermia.


Postmenopausal patients with primary breast cancer were treated with tamoxifen, ethynyloestradiol or prednisolone for up to 12 days before mastectomy and the effects of pretreatments with these drugs on the activities of phosphofructokinase (PFK), 6-phosphogluconate dehydrogenase (6PGDH) and alpha-glycerolphosphate dehydrogenase  in the carcinomas were compared with age, stage and menopausal status matched untreated controls. The administration of tamoxifen or prednisolone resulted in a significant increase in the activity of alpha-GPDH and the alpha-GPDH/6PGDH ratio, whereas ethynyl-oestradiol treatment produced a significant decrease in the activity of the enzyme and the ratio. When tamoxifen and ethynyl-oestradiol were administered together, it was found that tamoxifen failed to reverse the oestrogen-induced reduction in the activity of alpha-GPDH. Since increased activity of the enzyme or a higher alpha-GPDH/6PGDH ratio are associated with a lower risk of recurrence , it is postulated that the beneficial effects of tamoxifen or prednisolone in terms of prolongation of the relapse free interval might be mediated via alterations in the activity of alpha-GPDH in micrometastases. The activities of PFK and 6PGDH remained unaffected by these treatments.


The growth inhibitory effects of all-trans and 13-cis retinoic acid (RA) and of the synthetic retinoids TTNPB, TTNPB-ethylester and TTNN were studied on seven human epithelial ovarian cancer cell lines and one ovarian teratocarcinoma cell line. Six of seven ovarian adenocarcinoma cell lines were inhibited in their growth by RA and by synthetic retinoids in a dose dependent manner. No response to these substances was observed for the ovarian teratocarcinoma cell line. The knowledge that RA and retinoids exert their action on the cells via nuclear receptors led us to examine the expression of RAR-alpha, -beta and -gamma mRNA by these cell lines by polymerase chain reaction following reverse transcription. All cell lines expressed RAR-alpha and -gamma mRNA and six of the eight cell lines were found to express additionally RAR-beta mRNA, among them the ovarian teratocarcinoma cell line. Our data indicate that there was no direct association between the presence of RAR subtype transcripts and the response to retinoids in ovarian cancer cell lines.


Modern strategies for the diagnosis and treatment of cardiac arhythmias include besides non-invasive methods an increasing variety of invasive and curative therapeutic strategies. In order to define proper rhythmologic diagnosis and to develop an optimal treatment strategy for individual patients, a high degree of rhythmologic expertise is necessary. Adequate platforms for information exchange, where physicians can meet rhythmologic experts to allow proper handling of individual rhythmologic problems are desirable. Thus, the Heart Center Leipzig develops the Web- and Fax-based consultancy and information service "EcgConsult".The service utilizes the network capabilities of the Internet and of the common telecommunication network. This way information input can be achieved either by using a browser/email-client or by using a fax machine. All input from both networks is collected on a centralised mail-server (SSL-POP3 protocol). User interaction on the Web site is achieved with dynamic HTML and a moderated List-Server. The List-Server and an additional discussion area on the Web site are moderated by the Consultants at the Heart Center Leipzig, adequate processing of the site-content and technical management of the site have been outsourced to the university Internet workgroup Elchsoft/Medkonsult.A prototype of the site and the communication architecture for fax/email have been established and successfully beta-tested. Any consulting physician can easily send ECGs and additional material to the server with any fax-machine, where they are automatically TIFF-file converted. A password-protected site is already in use with selected clinicians (http://www.ecgconsult.de). For mobile site management, a web-based Control-Center has been designed. Outlines of contract models for members, guidelines for security purposes of the web-based communication, a business/cost plan and models for the logistic request management as well as for member/patient identification have been developed.The platform "EcgConsult" provides a network with fast and easy access to a specific target group and thus allows easy information exchange between the Heart Center Leipzig and rhythmologic experts and non-experts. This exchange may generate synergy effects by offering both groups a variety of data and information. Due to the use of web- and fax-based technology, the access to the service is easy and does not require PC-equipment or a scanner. The requests can be answered by the Heart Center consultants from any remote location world-wide. For the future open-ended architecture allows the participation of further consultants from clinics all over the world. The knowledge gathered from this project may help setting up guidelines for the development of other web-based medical competence centers / information services.


Spinal cord injury (SCI) causes the death of neurons and glial cells due to the initial mechanical forces  and through a cascade of secondary molecular events  that exacerbate cell death. The loss of neurons and glial cells that are not replaced after the injury is one of the main causes of disability after SCI. Evidence accumulated in last decades has shown that the activation of apoptotic mechanisms is one of the factors causing the death of intrinsic spinal cord (SC) cells following SCI. Although this is not as clear for brain descending neurons, some studies have also shown that apoptosis can be activated in the brain following SCI. There are two main apoptotic pathways, the extrinsic and the intrinsic pathways. Activation of caspase-8 is an important step in the initiation of the extrinsic pathway. Studies in rodents have shown that caspase-8 is activated in SC glial cells and neurons and that the Fas receptor plays a key role in its activation following a traumatic SCI. Recent work in the lamprey model of SCI has also shown the retrograde activation of caspase-8 in brain descending neurons following SCI. Here, we review our current knowledge on the role of caspase-8 and the Fas pathway in cell death following SCI. We also provide a perspective for future work on this process, like the importance of studying the possible contribution of Fas/caspase-8 signaling in the degeneration of brain neurons after SCI in mammals. Spinal cord injury (SCI) can cause permanent disability due to the dysfunction of motor, autonomic and sensory systems. There are also high economical costs associated with the care of SCI patients. In the USA, the lifetime cost of a SCI patient is between 1.1 and 4.6 million US dollars  barrier and trigger the release of cytokines and reactive oxygen species  increases neuronal survival, decreases retraction of corticospinal tract fibers and improves functional recovery after a transection SCI at T9 in mice (Sung et al., The studies in rodent models have important implications for human SCI, because the Fas pathway is also activated in primates, including humans, after SCI (Jia et al., As shown in the previous section, most studies focused on the role of caspase-8 and Fas in apoptosis of intrinsic SC cells. But, some of these studies also showed that the manipulation of FasL/Fas signaling leads to a significant increase in the regeneration/preservation of descending axons (Demjen et al., In contrast to mammals, lampreys show an amazing capacity for functional recovery following SCI. The regeneration of descending neurons is a key event in the recovery of swimming after SCI in lampreys (see Shifman et al., Glued (Carson et al., The work in lampreys suggests that activated caspase-8 could also play a role in the death of descending neurons of mammals after SCI. Interestingly, in olfactory neurons of mice, appearance of activated caspase-8 in the cell body after olfactory bulbectomy depends on microtubule-based retrograde transport of activated caspase-8 by its association with dynactin p150Several reports have confirmed that the activation of caspase-8 and the extrinsic apoptotic pathway is one of the mechanisms causing cell death after SCI and that the FasL/Fas signaling pathway plays a key role in this process. Surprisingly, no study has yet attempted to directly inhibit caspase-8 after SCI. This experimental approach could be of interest, especially because caspase-8 activation is not only caused by Fas receptor activation, which could lead to further improvements in recovery from SCI. Also, another aim for future work, and based on the lamprey results, should be to investigate the possible activation of caspase-8 in descending neurons of mammals after SCI and the implication of Fas signaling and microtubule retrograde transport in this process. Finally, translation of all this knowledge to pre-clinical studies or even clinical trials is of obvious and crucial importance.AB-I wrote the manuscript with help from DS-C. DS-C prepared the figure and the table. All the work was supervised by AB-I.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Current antidepressant pharmacotherapy remains unsatisfactory because of its limited adherence and partial therapeutic efficacy. Accordingly, there is a crucial need of validated animal models that fully reflect the nature of the disease and do not only separate facets of the disorder.We read with great interest the recent publication of As these data clearly contrast with those from previous published studies , an obviDaily variations in anxiety-like behavior are also observed in rodents. The importance of time-of-day (circadian) effects on the etiology of mood disorders and the timing of drug treatments (chronotherapy) as well as of the significant role of clock genes  has been


A 23-year-old female patient with a family history of pulmonary tuberculosis and tuberculous spondylodiscitis was hospitalized for swelling of the left anterior-external surface of the left thigh, (A) with altered general status. Biology has shown a biological inflammatory syndrome. The ultrasound showed a collection opposite the great trochanter fusing towards the lodge of the gluteus muscle and forward towards the terminal part of the common chief ischio-psoas. MRI of the hips revealed an intra-muscular collection of the antero-lateral side of the thigh root, taking contrast in the periphery, involving the quadriceps muscle and tensor of facia lata, (B and C). The biopsy of the collection under ultrasound guidance brought back 30 cc of casein. The diagnosis of tuberculosis of the quadriceps muscle and tensor of the facia lata was based on the positivity of the tuberculin skin test, (D), the positivity of the PCR for Mycobacterium tuberculosis in the puncture fluid and histology showing multiple epithelioid granulomas centered by caseous necrosis. There were no other tuberculous sites. The patient was treated with antituberculosis drugs for 12 months with good progress. Muscular tuberculosis (MT) is a rare localization of the disease (0.01 to 2%). Its occurrence without associated bone involvement is exceptional. MT often simulates a muscular tumor. MRI contributes to the improvement of the sensitivity of the diagnosis of MT because it allows to specify the extent of the muscular lesions and to orient the site of the muscular biopsy. The diagnosis is essentially based on histology.


The type of bearing material that should be used in revision surgery after the failure of ceramic-on-ceramic total hip arthroplasty (THA) remains controversial. In the case of ceramic fracture, the residual ceramic particles can cause consequent metallosis when metal implants are used for revision THA. On the other hand, in the case of THA failure without ceramic fracture, revision THA with a metal femoral head provides satisfactory results. We report an unusual case of progressive osteolysis due to metallosis that developed after revision THA for ceramic liner dissociation without a liner fracture performed using a metal femoral head and polyethylene liner. The residual metal debris and abnormal pumping motion of the polyethylene liner due to the breakage of the locking system or the aspherical metal shell being abraded by the ceramic head seemed to be the cause of the progressive osteolysis. Alumina ceramic components have been used in total hip arthroplasty (THA) for over 30 years. These implants were introduced to reduce wear and to increase long-term survivorship. A modular layered acetabular component, consisting of an alumina ceramic liner housed in an ultra-high-molecular-weight polyethylene shell (ABS liner) that is held in a titanium alloy metal shell (AMS HA shell), was developed in Japan  for use in alumina ceramic-on-ceramic THA. The main limitations of this component are the risk of ceramic liner fracture and failure of the ceramic liner fixation system –3. MoreoA 64-year-old man underwent primary THA with alumina-on-alumina bearings on the right side for the treatment of secondary osteoarthritis due to developmental dysplasia of the hip by posterolateral approach . The impThe type of bearing that should be used after a fracture in ceramic-on-ceramic THA remains controversial, and there are no prospective studies since few patients suffer this complication. Revision THA with metal-on-polyethylene pairing is not feasible. Despite performing radical synovectomy and thorough washout of the hip joint, it may not be possible to remove all of the minute ceramic fragments following such ceramic fracture. While ceramic is a material with higher rigidity than metal, severe damage to the metal head and the polyethylene liner may occur due to wear from residual ceramic particles, resulting in early failure as metallosis , 9. On tIn the case of acetabular component failure without ceramic fracture, revision THA with a metal femoral head can be a reasonable treatment option because of the absence of residual ceramic particles in the joint . In the At the rerevision surgery, we considered that removal of the cup and radical debridement of the osteolytic lesion and pseudotumor were necessary. We performed rerevision THA using a reinforcement plate with bulk structural allograft. This technique is also useful for recovering bone stock and restoring the leg length and an adequate hip center .We have presented a unique case of progressive osteolysis after revision surgery comprising exchange of the femoral head and liner due to ceramic acetabular liner dissociation in THA with a modular layered acetabular component. It is important to consider the possibilities of damage to the metal shell as well as the polyethylene liner locking mechanism in the case of ceramic articulation failure treated by such exchange of the liner and femoral head. In such cases, the removal of the entire implant and complete debridement of the metal debris may be required for reconstruction surgery.


The Susan Britton Wills Unit at the Bristol General Hospital is a small and busy multidisciplinary psychiatric unit, providing a wide range of in-patient, out-patient and day-patient services for the residents of Bristol Health District.


Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to a disruption of the sense of first-person perspective and self-presence that is associated with a variety of anomalous subjective experiences. Recent cross-sectional and prospective pilot studies provided preliminary support for the notion that SD may provide a means of further “closing in” on individuals truly at high-risk for psychosis, particularly of schizophrenia spectrum disorders (SSD). The goal of this study was to replicate and extend these pilot findings by examining the long-term persistence of SD and the degree to which their level in adolescence predicts SSD seven years later in young adulthood.The 7-year stability of SD and their association with later in life SSD were explored in a sample of 40 young adults. SD was assessed with the Examination of Anomalous Self-Experience (EASE), prodromal symptoms and syndromes were assessed with the Structured Interview for Prodromal Syndromes (SIPS), present and lifetime diagnoses of schizophrenia-spectrum and other co-morbid disorders were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) in adolescence and the Operational Criteria (OPCRIT) checklist for psychotic and affective illness in young adulthood, level of distress with the Mood and Anxiety States Questionnaire (MASQ), and psychosocial functioning with the Strength and Difficulties Questionnaire (SDQ).Forty young adults  out of the 82 who had participated seven years earlier in a study on the association between SD and attenuated psychosis symptoms (APS) were available and agreed to participate in the 1-year follow-up . There were no significant differences between those who were available and those who lost for the follow-up assessment on any of the major socio-demographic or clinical variables at baseline. Eight (20%) of the 40 participants in the present study met diagnostic criteria for an SSD . The total EASE score was slightly higher in young adulthood compared to seven years earlier. However, this can reflect a difference in the administration method of the EASE between the two occasions. Consistent with our first hypothesis, the correlation between the total EASE score at baseline and 7-year follow-up was moderate and significant . Similarly, consistent with our second hypothesis, SD at baseline was a significant predictor of an SSD diagnosis in young adulthood.These results provide further support for the temporal stability of SD over time. Also, they provide further support for the notion that SD is a phenotypic indicator of risk for SSD.