Feasibility randomised controlled trial examining the effects of the Anti-Doping Values in Coach Education (ADVICE) mobile application on doping knowledge and attitudes towards doping among grassroots coaches.

OBJECTIVES: Sports coaches are influential in whether athletes dope, but receive very little antidoping education, particularly within entry-level coaching qualifications. We tested the feasibility of an antidoping intervention, delivered via a mobile application, which was designed to increase coaches' knowledge of doping and to reduce favourable doping attitudes. METHODS: A two-arm randomised controlled trial, with grassroots coaches who coach young amateur athletes aged between 14 and 18 years of age, was conducted. The Anti-Doping Values in Coach Education (ADVICE) mobile application included modules on fair play, substances, nutritional supplements, rules and leadership. The primary outcome was the change in doping knowledge, 6 weeks after receiving the mobile application. The secondary outcome was changes in doping attitudes. RESULTS: Grassroots coaches (n=200; aged between 18 and 71 years, with between 1 and 42 years of coaching experience) from 29 different countries completed baseline assessments, and 85 completed follow-up assessments, and were included in mixed analysis of variance analyses. The intervention increased coaches' knowledge about doping and also reduced favourable doping attitudes in the experimental arm. CONCLUSION: The ADVICE mobile application is a feasible method for delivering and increasing grassroots coaches' knowledge of banned substances and the potential side effects of doping. Mobile application-based resources could facilitate a much wider dissemination of antidoping education.

Children's First Experience of Taking Anabolic-Androgenic Steroids can Occur before Their 10th Birthday: A Systematic Review Identifying 9 Factors That Predicted Doping among Young People.

Taking performance-enhancing drugs (PEDs) can cause serious and irreversible health consequences, which can ultimately lead to premature death. Some young people may take PEDs without fully understanding the ramifications of their actions or based on the advice from others. The purpose of this systematic review was to identify the main factors that predicted doping among young people. The literature was systematically reviewed using search engines, manually searching specialist journals, and pearl growing. Fifty-two studies, which included 187,288 young people aged between 10 and 21 years of age, 883 parents of adolescent athletes, and 11 adult coaches, who were interviewed regarding young athletes, were included in this review. Nine factors predicted doping among young people: gender; age; sports participation; sport type; psychological variables; entourage; ethnicity; nutritional supplements; and health harming behaviors. In regards to psychological variables, 22 different constructs were associated with doping among young people. Some psychological constructs were negatively associated with doping (e.g., self-esteem, resisting social pressure, and perfectionist strivings), whereas other were positively associated with doping (e.g., suicide risk, anticipated regret, and aggression). Policy makers and National Anti-Doping Organizations could use these findings to help identify athletes who are more at risk of doping and then expose these individuals to anti-doping education. Based on the current findings, it also appears that education programs should commence at the onset of adolescence or even late childhood, due to the young age in which some individuals start doping.

Altered expression of the poly(ADP-ribosyl)ation enzymes in uveal melanoma and regulation of PARG gene expression by the transcription factor ERM.

PURPOSE: Poly(ADP-ribosyl)ation is a reversible post-translational modification that requires the contribution of the enzymes poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG). Our study explores expression and activity of PARP-1 and PARG in uveal melanoma cell lines with varying tumorigenic properties. METHODS: Gene profiling on microarrays was conducted using RNA prepared from the uveal melanoma cell lines T97, T98, T108, and T115. The activity of PARP-1 and PARG was monitored by enzymatic assays, whereas their expression was measured by Western blot and PCR. The PARG promoter was analyzed using promoter deletions and site-specific mutagenesis in transfection analyses. The transcription factors binding the PARG promoter were studied by electrophoretic mobility shift assay (EMSA) analyses. Suppression of PARP-1 and PARG expression was performed in T97 and T115 cells by RNAi, and their tumorigenic properties monitored by injections into athymic mice. RESULTS: Expression of PARP-1 was found to vary considerably between uveal melanoma cell lines with distinctive tumorigenic properties in vivo. Sp1 and the ETS protein ERM were shown to bind to the PARG gene promoter to ensure basal transcription in uveal melanoma. Importantly, suppression of PARG gene expression in T97 and T115 cells increased their capacity to form tumors in athymic mice, whereas suppression of PARP-1 significantly reduced or almost entirely abolished tumor formation. CONCLUSIONS: Our results suggest that while overexpression of PARP-1 may confer a proliferative advantage to aggressive uveal melanoma tumors, PARG may, on the other hand, support a tumor suppressor function in vivo.

Roogle: an information retrieval engine for clinical data warehouse.

High amount of relevant information is contained in reports stored in the electronic patient records and associated metadata. R-oogle is a project aiming at developing information retrieval engines adapted to these reports and designed for clinicians. The system consists in a data warehouse (full-text reports and structured data) imported from two different hospital information systems. Information retrieval is performed using metadata-based semantic and full-text search methods (as Google). Applications may be biomarkers identification in a translational approach, search of specific cases, and constitution of cohorts, professional practice evaluation, and quality control assessment.

Poly(ADP-ribose) metabolism analysis in the nematode Caenorhabditis elegans.

Poly(ADP-ribose) polymerases (PARPs) are a well-conserved family of enzymes found in many species. These enzymes catalyze poly(ADP-ribosyl)ation, a modification of proteins implicated in a variety of nuclear processes, such as DNA damage signaling and repair, cell death and survival, and transcription. Poly(ADP-ribose) glycohydrolase (PARG) is responsible for the specific hydrolysis of poly(ADP-ribose) (PAR), the product of poly(ADP-ribosyl)ation, and its action is required for the modified proteins to regain their original function in the cell. The metabolism of PAR can be studied in the nematode Caenorhabditis elegans as genes encoding PARP and PARG enzymes have been identified and characterized in its genome. We have shown the capacity of these PARPs to produce PAR as well as the capacity of the nematode to catabolize PAR into ADP-ribose units through the enzymatic activity of its PARGs. Therefore, C. elegans is a novel model to study PAR metabolism in eukaryotes that offers new avenues to investigate the role(s) of poly(ADP-ribosyl)ation in development as well as DNA repair, programmed cell death, and aging.

Photoactivated multivitamin preparation induces poly(ADP-ribosyl)ation, a DNA damage response in mammalian cells.

Multivitamin preparation (MVP) is part of total parenteral nutrition given to premature infants. Photoactivated MVP carries an important load in peroxides, but their cellular effects have not yet been determined. We hypothesized that these peroxides may elicit a DNA-damage response. We found that photoactivation of MVP and the resulting peroxide production were time-dependent and required the simultaneous presence of ascorbic acid and riboflavin. Cells treated with photoactivated MVP showed strongly stimulated poly(ADP-ribosyl)ation, an early DNA-damage response in mammals. Poly(ADP-ribosyl)ation stimulation was dependent on the presence of ascorbic acid and riboflavin in the photoactivated MVP. It did not occur in the presence of a specific PARP inhibitor nor in mouse fibroblasts deficient in PARP-1. Photoactivated MVP was able to induce single- and double-strand breaks in DNA, with a predominance of single-stand breaks. The presence of double-strand breaks was further confirmed using a 53PB1 focus analysis. Finally, photoactivated MVP was shown to be toxic to human cells and induced caspase-independent cell death. These results suggest that photoactivated MVP carries an important toxic load able to damage DNA and induce cell death. This study also emphasizes the importance of protecting MVP solution from light before use in preterm infants.

Prognosis for isolated skin recurrence after breast cancer treated by mastectomy.

UNLABELLED: Isolated skin recurrence after mastectomy (ISRAM) for breast cancer is a rare event for which treatment is difficult and subject to debate. PATIENTS AND METHODS: The records of 75 patients presenting with ISRAM were reviewed retrospectively. The factors liable to affect recurrence prognosis were analyzed, and included both factors related to the primary tumor and its treatment and those related to the recurrence itself. RESULTS: The size of the primary tumor is correlated with the inflammatory nature of the recurrence as well as overall survival. Metastatic lymph node involvement also affects the risk of inflammatory recurrence and is correlated with overall survival. Salvage mastectomy for local recurrence after primary breast-conserving surgery followed by ISRAM has a poor prognosis in terms of recurrence-free survival, and chest wall radiotherapy after primary mastectomy reduces the risk of metastatic development after ISRAM. When confronted with ISRAM, 2 factors affect prognosis: the inflammatory nature of the recurrence impairs overall survival and chest wall radiotherapy reduces the risk of secondary systemic disease. CONCLUSION: these results underline the importance of good local control when treating the primary tumor (to reduce the risk of ISRAM occurrence, and improve its prognosis if it occurs) and the advantage of locoregional and systemic treatment in the presence of ISRAM and in particular its inflammatory presentation.

The DNA damage-inducible C. elegans tankyrase is a nuclear protein closely linked to chromosomes.

Tankyrases are protein members of the poly(ADP-ribose) polymerase family bearing several ankyrin domain and a WGR domain. They have functional role in telomere maintenance, are found at centrosome, and are associated with vesicular secretion. This diversity in localization and function makes it difficult to identify a unified role for tankyrases. We have shown that the C. elegans orthologue PME-5 is among the most transcriptionally up-regulated genes following ionizing radiations, linking a tankyrase with DNA damage response. Our analysis showed that the up-regulation of PME-5 is translated at the protein level, suggesting an effective role in DNA damage response or DNA repair. In order to gain more information on the potential role of PME-5 in DNA damage response, we analyzed its sub-cellular localization. Using immunostaining as well as gfp reporter assay, we have shown a nuclear localization for PME-5. Moreover, we showed that PME-5 is a ubiquitous nuclear protein expressed throughout the development of the worm and is closely linked to chromatin and condensed chromosomes. Taken together, our data suggest that C. elegans can be used to study the nuclear roles of tankyrase.

Caenorhabditis elegans LET-767 is able to metabolize androgens and estrogens and likely shares common ancestor with human types 3 and 12 17beta-hydroxysteroid dehydrogenases.

Mutations that inactivate LET-767 are shown to affect growth, reproduction, and development in Caenorhabditis elegans. Sequence analysis indicates that LET-767 shares the highest homology with human types 3 and 12 17beta-hydroxysteroid dehydrogenases (17beta-HSD3 and 12). Using LET-767 transiently transfected into human embryonic kidney-293 cells, we have found that the enzyme catalyzes the transformation of both 4-androstenedione into testosterone and estrone into estradiol, similar to that of mouse 17beta-HSD12 but different from human and primate enzymes that catalyze the transformation of estrone into estradiol. Previously, we have shown that amino acid F234 in human 17beta-HSD12 is responsible for the selectivity of the enzyme toward estrogens. To assess whether this amino acid position 234 in LET-767 could play a role in androgen-estrogen selectivity, we have changed the methionine M234 in LET-767 into F. The results show that the M234F change causes the loss of the ability to transform androstenedione into testosterone, while conserving the ability to transform estrone into estradiol, thus confirming the role of amino acid position 234 in substrate selectivity. To further analyze the structure-function relationship of this enzyme, we have changed the three amino acids corresponding to lethal mutations in let-767 gene. The data show that these mutations strongly affect the ability of LET-767 to convert estrone in to estradiol and abolish its ability to transform androstenedione into testosterone. The high conservation of the active site and amino acids responsible for enzymatic activity and substrate selectivity strongly suggests that LET-767 shares a common ancestor with human 17beta-HSD3 and 12.

Altered DNA damage response in Caenorhabditis elegans with impaired poly(ADP-ribose) glycohydrolases genes expression.

Poly(ADP-ribosyl)ation is one of the first cellular responses induced by DNA damage. Poly(ADP-ribose) is rapidly synthesized by nick-sensor poly(ADP-ribose) polymerases, which facilitate DNA repair enzymes to process DNA damage. ADP-ribose polymers are rapidly catabolized into free ADP-ribose units by poly(ADP-ribose) glycohydrolase (PARG). The metabolism of poly(ADP-ribose) is a well-defined biochemical process for which a physiological role in animals is just beginning to emerge. Two Caenorhabditis elegans PARGs, PME-3 and PME-4, have been cloned by our group. The pme-3 gene encodes an enzyme of 89kDa having less than 18% overall identity with human PARG but 42% identity with the PARG signature motif. The pme-4 gene codes for a PARG of 55kDa with approximately 22% overall identity with human PARG and 40% identity with the PARG signature motif. Two alternatively spliced forms of PME-3 were identified with an SL1 splice leader on both forms of the mRNA and were found to be expressed throughout the worm's life cycle. Similarly, pme-4 was shown to be expressed in all developmental stages of the worm. Recombinant enzymes that were expressed in bacteria displayed a PARG activity that may partly account for the PARG activity measured in the total worm extract. Reporter gene analysis of pme-3 and pme-4 using a GFP fusion construct showed that pme-3 and pme-4 are mainly expressed in nerve cells. PME-3 was shown to be nuclear while PME-4 localized to the cytoplasm. Worms with pme-3 and pme-4 expression knocked-down by RNAi showed a significant sensitivity toward ionizing radiations. Taken together, these data provide evidence for a physiological role for PARGs in DNA damage response and survival. It also shows that PARGs are evolutionarily conserved enzymes and that they are part of an ancient cellular response to DNA damage.

Malignant transformation of intra-cranial epithelial cysts: systematic article review.

INTRODUCTION: Epidermoid and dermoid cysts are among the most benign intra cranial tumors. Their malignant transformation into squamous cell carcinoma is rare. The authors reviewed the literature. MATERIALS AND METHODS: MEDLINE and SCIENCE DIRECT searches, and examination of the references in the selected articles yielded 74 patients, 52 of whom fulfilled Garcia's criteria and were selected for the study. Survival analyses were performed to determine whether survival differences were of statistical significance, and P < 0.05 was considered as significant. RESULTS: Malignant transformation is characterized by a rapid onset of symptoms, recurrence, leptomeningeal carcinomatosis (LC), and tumor enhancement at Computed Tomography Scan or Magnetic Resonance Imaging (87.8 showed this radiological feature). In this review, the SCCs were classified in five groups: (1) Initial malignant transformation of a benign cyst; (2) malignant transformation from a remnant cyst; (3) malignant transformation of a dermoid and epithelial cyst; (4) malignant transformation with leptomeningeal carcinomatosis; (5) other malignancies arising from benign cysts. The median survival was 9 months. Statistics show that LC was of poor prognosis and radiotherapy, although not statistically significant, seems effective against such lesions, with a median survival of 26 months as opposed to 3 months (P=0.077). CONCLUSION: Although rare, malignant transformation of intracranial epithelial cysts has a poor prognosis and surgery followed by radiotherapy seems to be the best therapeutic modality.

The Caenorhabditis elegans FancD2 ortholog is required for survival following DNA damage.

Fanconi anemia (FA) is an autosomal recessive disease characterized by bone-marrow failure, congenital abnormalities, and cancer susceptibility. There are 11 FA complementation groups in human where 8 genes have been identified. We found that FancD2 is conserved in evolution and present in the genome of the nematode Caenorhabditis elegans. The gene Y41E3.9 (CeFancD2) encodes a structural ortholog of human FANCD2 and is composed of 10 predicted exons. Our analysis showed that exons 6 and 7 were absent from a CeFancD2 EST suggesting the presence of a splice variant. In an attempt to characterize its role in DNA damage, we depleted worms of CeFANCD2 using RNAi. When the CeFANCD2(RNAi) worms were treated with a crosslinking agent, a significant drop in the progeny survival was noted. These worms were also sensitive, although to a lesser extent, to ionizing radiation (IR). Therefore, these data support an important role for CeFANCD2 in DNA damage response as for its human counterpart. The data also support the usefulness of C. elegans to study the Fanconi anemia pathway, and emphasize the biological importance of FANCD2 in DNA damage response throughout evolution.

Effect of stabilized iodized oil emulsion on experimentally induced hepatocellular carcinoma in rats.

PURPOSE: Previous studies have shown that the use of Lipiodol UltraFluid (LUF) emulsified with water leads to an increase in the tumoral uptake of iodine I 131-labeled LUF and reduced pulmonary uptake. Although emulsions containing LUF are currently used for chemoembolization of hepatocellular carcinomas (HCCs), this approach is impossible with intraarterial radiation therapy (RT) because of the problems of radiation protection linked to instability of the emulsions. The aims of this study were to develop stabilized emulsions of radiolabeled LUF of different particle sizes and viscosities and to study its biodistribution in rats with HCC. MATERIALS AND METHODS: An emulsifier made of polyethylene glycol and hydrogenated castor oil was used to stabilize emulsions containing water and technetium Tc 99m-labeled Super Six Sulfur LUF. The various emulsions were injected in the hepatic arteries of rats with HCC. Twenty-four hours after injection, the rats were killed and the liver, tumor, and lungs were removed to perform ex-vivo gamma-counting to quantify tumoral, hepatic, and pulmonary uptake. RESULTS: Emulsions of oil in water and water in oil of different viscosities (0.68-1.06 Pa.S) and particle size distributions (21-45 mum) were prepared and kept stable for more than 24 hours. Whatever the type of emulsion, the observed effect on tumoral uptake was the opposite of that expected. Indeed, a decrease in tumoral activity was observed (P < .05 in three of five cases) and a tendency toward increased pulmonary activity was observed (P < .05 in two of five cases) rather than any significant decrease. CONCLUSIONS: This study made it possible to develop emulsions of radiolabeled iodized oil that remain stable for more than 24 hours. However, studies of biodistribution in rats with HCC failed to demonstrate any improvement in tumoral targeting, but rather showed a decrease in tumoral uptake that renders this approach impractical for intraarterial radiolabeled iodized oil RT as well as for intraarterial iodized oil chemoembolization. These results may possibly be explained by the use of an emulsifier containing lipophilic and hydrophilic components that modify the properties of LUF.

Modelling a decision-support system for oncology using rule-based and case-based reasoning methodologies.

In most hospital medical units, multidisciplinary committees meet weekly to discuss their patients' cases. The medical experts base their decisions on three sources of information. First, they check if their patient complies with existing guidelines. Failing these, the medical experts will base their therapeutic decisions on the cases of similar patients that they have treated in the past. We propose a multi-modal reasoning decision-support system based on both guideline and case series, which will automatically compare the patient's case to the corresponding guideline, then to other cases, and retrieve similar cases. The general structure of the system is presented here, the domain of application being oncology. As the patients' records are not currently stored in a database in a format which is directly accessible, an object-oriented model is proposed, which includes prognosis factors currently tested in clinical trials, well-established ones, and a description of the illness episodes. The system is designed to be a data warehouse. Such a system does not exist in the literature. Future work will be needed to define the similarity measures, and to connect the system to the current database.

Interoperability and medical communication using "patient envelope"-based secure messaging.

The process of transmitting patient medical information between different healthcare parties involves harmonizing multiple elements: addresses, certificates, patient IDs, communication protocol, message format, and documents/EPR to be exchanged. Beyond the work done at the "information structure level" within CEN TC251, ISO TC215, HL7 and DICOM, it is necessary to focus on the "basic medical communication level." An original approach, based on the "Patient Envelope", has been developed and successfully implemented for Oncology. The operator of the National "Réseau Santé Social" is now proposing a new "secure messaging" service supporting the "Envelope"-based communication. The authors are actively involved in standardization organizations' works, including EDI Santé, DICOM, IETF, and ISO TC 215. The current "envelope" format is compatible with all the e-mail clients. It will evolve to be based on the ebXML envelope, extended with a "medical header" containing HL7/EHRCOM Data Types and C-METS/GPICs. This document describes the results from a 3-year experience, as well as the different steps included in the project.

Modelling of a case-based retrieval system for oncology.

When a new patient does not comply with the guidelines, experts base their therapeutic decisions on similar patients' cases they have treated in the past. The case-based reasoning decision-support system we propose will automatically compare the patient's case to the structured guideline, then to other cases, and retrieve similar cases. The general structure of the system is presented here, the domain of application being oncology. As the patients' records are not stored in the current database in a format directly exploitable, an object-oriented model is proposed, that includes prognosis factors currently tested in clinical trials, well-established ones, and a description of the illness' episodes. Such system does not exist in the literature. It can be viewed as a data warehouse. Future work consists in defining the similarity measures, and connecting the system to the current database.

[Update in medical informatics in oncology]. / Actualités en information médicale en cancérologie.

Through the implementation of the French reform of resources allocation, according to the French DRG system (PMSI), all the medical records of French hospitals are currently indexed according to the same rules and classifications. As a by-product, these discharge summaries are merged into huge administrative databases covering both public and private settings. Statistical analysis of these data have begun, and seems to be worthwhile in oncology, e.g. for assessing the burden of cancer treatments in hospitals, for revealing the regional variations in practice or for estimating the incidence of melanoma. However, fully anonymous data leading to double counts, questionable quality of summaries and lack of complete covering in radiotherapy centres, still impede from using the data for epidemiological purpose. Short term improvements are under way: changes in quality assessment and control, possibility of linking successive stays of a patient while respecting privacy, implementation of new classification of procedures and new descriptions of "casemix". The French DRG could then have a place in the monitoring of cancer both at national and regional levels.