Urban health: l'irrémédiable urbanisation de la vie et de la médecine [Urban health: the irremediable urbanization of life and medicine].

Since 2007, the number of people living in cities exceeds that of rural areas. Thus, cities and their organizations have a major influence on all spheres of human life, especially health. This influence may generate inequality, suffering and disease, but also represent an opportunity for health and well-being. This paper introduces the concept of urban health, particularly in terms of primary care medicine and presents solutions that encompass a wide field (politics, urban planning, social inequality, education). Improving urban health requires collaboration of medical with non-medical actors, in order to become of development (re-) urban structure and promotes the health of all.

Generalized food-deceptive orchid species flower earlier and occur at lower altitudes than rewarding ones

Aims Food-deceptive pollination, in which plants do not offer any food reward to their pollinators, is common within the Orchidaceae. As food-deceptive orchids are poorer competitors for pollinator visitation than rewarding orchids, their occurrence in a given habitat may be more constrained than that of rewarding orchids. In particular, the success of deceptive orchids strongly relies on several biotic factors such as interactions with co-flowering rewarding species and pollinators, which may vary with altitude and over time. Our study compares generalized food-deceptive (i.e. excluding sexually deceptive) and rewarding orchids to test whether (i) deceptive orchids flower earlier compared to their rewarding counterparts and whether (ii) the relative occurrence of deceptive orchids decreases with increasing altitude. Methods To compare the flowering phenology of rewarding and deceptive orchids, we analysed data compiled from the literature at the species level over the occidental Palaearctic area. Since flowering phenology can be constrained by the latitudinal distribution of the species and by their phylogenetic relationships, we accounted for these factors in our analysis. To compare the altitudinal distribution of rewarding and deceptive orchids, we used field observations made over the entire Swiss territory and over two Swiss mountain ranges. Important Findings We found that deceptive orchid species start flowering earlier than rewarding orchids do, which is in accordance with the hypotheses of exploitation of naive pollinators and/or avoidance of competition with rewarding co-occurring species. Also, the relative frequency of deceptive orchids decreases with altitude, suggesting that deception may be less profitable at high compared to low altitude.

The European Board of Physical and Rehabilitation Medicine : the past, the present and the future [Europejska Rada Medycyny Fizykalnej i Rehabilitacji: przeszłość, teraźniejszość i perspektywy]

Right from the beginning of the development of the medical specialty of Physical and Rehabilitation Medicine (PRM) the harmonization of the fields of competence and the specialist training across Europe was always an important issue. The initially informal European collaboration was formalized in 1963 under the umbrella of the European Federation of PRM. The European Academy of PRM and the UEMS section of PRM started to contribute in 1969 and 1974 respectively. In 1991 the European Board of Physical and Rehabilitation Medicine (EBPRM) was founded with the specific task of harmonizing education and training in PRM in Europe. The EBPRM has progressively defined curricula for the teaching of medical students and for the postgraduate education and training of PRM specialists. It also created a harmonized European certification system for medical PRM specialists, PRM trainers and PRM training sites. European teaching initiatives for PRM trainees (European PRM Schools) were promoted and learning material for PRM trainees and PRM specialists (e-learning, books and e-books, etc.) was created. For the future the Board will have to ensure that a minimal specific undergraduate curriculum on PRM based on a detailed European catalogue of learning objectives will be taught in all medical schools in Europe as a basis for the general medical practice. To stimulate the harmonization of national curricula, the existing postgraduate curriculum will be expanded by a syllabus of competencies related to PRM and a catalogue of learning objectives to be reached by all European PRM trainees. The integration of the certifying examination of the PRM Board into the national assessment procedures for PRM specialists will also have to be promoted.

Improved detection of microbial ureteral stent colonisation by sonication.

PURPOSE: The diagnosis of microbial ureteral stent colonisation (MUSC) is difficult, since routine diagnostic techniques do not accurately detect microorganisms embedded in biofilms. New methods may improve diagnostic yield and understanding the pathophysiology of MUSC. The aim of the present study was to evaluate the potential of sonication in the detection of MUSC and to identify risk factors for device colonisation. METHODS: Four hundred and eight polyurethane ureteral stents of 300 consecutive patients were prospectively evaluated. Conventional urine culture (CUC) was obtained prior to stent placement and device removal. Sonication was performed to dislodge adherent microorganisms. Data of patient sex and age, indwelling time and indication for stent placement were recorded. RESULTS: Sonicate-fluid culture detected MUSC in 36%. Ureteral stents inserted during urinary tract infection (UTI) were more frequently colonised (59%) compared to those placed in sterile urine (26%; P < 0.001). Female sex (P < 0.001) and continuous stenting (P < 0.005) were significant risk factors for MUSC; a similar trend was observed in patients older than 50 years (P = 0.16). MUSC and indwelling time were positively correlated (P < 0.005). MUSC was accompanied by positive CUC in 36%. Most commonly isolated microorganisms were Coagulase-negative staphylococci (18.3%), Enterococci (17.9%) and Enterobacteriaceae (16.9%). CONCLUSIONS: Sonication is a promising approach in the diagnosis of MUSC. Significant risk factors for MUSC are UTI at the time of stent insertion, female sex, continuous stenting and indwelling time. CUC is a poor predictor of MUSC. The clinical relevance of MUSC needs further evaluation to classify isolated microorganism properly as contaminants or pathogens.

Combining MAR elements and transposable vectors for more reliable transgene integration and expression

Integration without cytotoxic effects and long-term expression of a transgene constitutes a major challenge in gene therapy and biotechnology applications. In this context, transposons represent an attractive system for gene transfer because of their ability to promote efficient integration of a transgene in a variety of cell lines. However, the transgene integration can lead to insertional mutagenesis and/or unstable transgene expression by epigenetic modifications. These unwanted events may be limited by the use of chromatin control elements called MARs (matrix attachment regions). Indeed, the insertion of these DNA elements next to the transgene usually results in higher and more stable expression by maintaining transgene chromatin in an active configuration and preventing gene silencing. In this study, we tested if the inclusion of the MAR 1-68 in the piggyBac transposon system may lead to efficient and safer transgene integration and ensure reliable stable and long-term expression of a transgene. The MAR-containing transposon construct was tested in CHO cells, for biotechnology applications, and in mesoangioblast cells that can differentiate into muscle cells and are important candidates for potential stem cell therapies of myopathies. We showed that the addition of the MAR 1 -68 in the piggyBac transposon did not interfere with transposition, thereby maintaining high frequency of transgene integrations in these cells. Moreover, the MAR allowed higher transgene expression from fewer transposon integration events. We also found that enriched transgene-expressing cell populations could be obtained without the need of selection pressure. Since antibiotic-enforced selection protocols often result in a higher integrated copy number and mosaic expression patterns, this strategy could benefit many applications in which a low copy number of integrated transgenes and antibiotic-free conditions are desired. In addition, the intramuscular transplantation of mouse tibialis anterior muscles with mesoangioblasts containing the transposon led to widespread and sustained myofiber transgene expression after differentiation of these cells in vivo. These findings indicated that piggyBac vectors may provide a viable approach to achieve stable gene transfer in the context of Duchenne muscular dystrophy therapy. - L'intégration sans effets cytotoxiques et l'expression à long terme d'un transgène constituent un défi majeur en thérapie génique et en biotechnologie. Dans ce contexte, les transposons représentent un système attrayant pour le transfert de gènes en raison de leur capacité à promouvoir l'intégration efficace d'un transgène dans une variété de lignées cellulaires. Toutefois, l'intégration d'un transgène peut conduire à une mutagénèse insertionnelle et/ou à une expression instable due au silençage du transgène suite à des modifications épigénétiques. Ces événements indésirables de silençage génique peuvent être diminués par l'utilisation d'éléments de contrôle de la chromatine appelés MAR (matrix attachment region). En effet, l'insertion de ces éléments d'ADN à proximité du transgène se traduit généralement par une expression plus élevée et plus stable de celui-ci, en permettant le maintien d'une chromatine dans une configuration active autour du transgène et en empêchant l'inactivation du gène. Dans cette étude, nous avons testé si l'inclusion du MAR 1-68 dans le système transposon piggyBac peut améliorer l'efficacité d'intégration de façon sécuritaire et l'expression à long terme d'un transgène. Le transposon contenant l'élément MAR a été testé dans les cellules CHO, couramment utilisées en biotechnologie, et dans des cellules progénitrices appelées mésoangioblastes, qui peuvent se différencier en cellules musculaires, et qui constituent ainsi des candidats prometteurs pour la thérapie à partir de cellules souches de patients souffrant de myopathie. Nous avons montré que l'addition du MAR 1-68 dans le transposon piggyBac n'interfère pas avec la transposition et permet de maintenir une fréquence élevée d'intégration du transgène dans ces deux types cellulaires. De plus, il semble que cette association mène à une meilleure expression du transgène à partir de peu d'événements d'intégration du transposon. En outre, ces populations enrichies en cellules exprimant de façon stable le transgène ont pu être obtenues sans avoir recours à une pression de sélection. Etant donné que les protocoles de sélection basée sur l'utilisation d'antibiotiques conduisent souvent à un nombre plus élevé de copies intégrées et à la variégation de l'expression du transgène et qu'ils impliquent une longue culture in vitro, cette stratégie pourrait profiter à des applications pour lesquelles on souhaite un faible nombre de copies intégrées et/ou l'utilisation d'antibiotiques n'est pas souhaitable. De plus, la transplantation intramusculaire de mésoangioblastes contenant le transposon dans le muscle tibial antérieur de souris a conduit, après la différentiation de ces cellules in vivo, à une expression constante et étendue du transgène dans les myofibres. Ces résultats indiquent que les vecteurs piggyBac pourraient fournir une approche viable pour assurer un transfert de gènes stables dans le contexte d'un traitement de la dystrophic musculaire de Duchenne.

CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy.

European guidelines for sclerotherapy in chronic venous disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guideline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidocanol and sodium tetradecyl sulphate. Other sclerosants are not discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations.

Early Variscan I-type pluton in the pre-Alpine basement of the Western Alps: The ca. 360 Ma Cogne diorite (NW-Italy)

Located at the internal border of the Grand-Saint-Bernard Zone, the diorite and its aureole lie on top of intensively studied Alpine eclogitic units but this pluton, poorly studied yet, has kept locally almost undeformed. The pluton intruded, at similar to 360 Ma, country-rocks mostly composed of dark shales with Na2O > K2O and minor mafic intercalations of tholeiitic basalt affinity. This association is characteristic of the Vanoise (France) basement series, where available age determinations suggest an Early Paleozoic age. Parts of the pluton, and of its hornfels aureole that is evidenced here for the first time, in the Punta Bioula section of Valsavaranche valley (NW-Italy), have been well-preserved from the Alpine deformation. Syn-emplacement hardening, dehydration-induced, probably prevented strain-enhanced Alpine recrystallization. Magmatic rock-types range continuously from subordinate mafic types at SiO2 similar to 48%, of hornblendite with cumulative or appinite affinities, to the main body of quartz diorite to quartz monzonite (SiO2 up to 62%). P-T estimates for the pluton emplacement, based on the abundance of garnet in the hornfelses, using also zircon and apatite saturation thermometry and Al-in-hornblende barometry, suggest T similar to 800-950 degrees C and minimum P in the 0.2-0.5 GPa range, with records of higher pressure conditions (up to 1-2 GPa?) in hornblendite phlogopite-cored amphibole. The high-K, Na > K, calcalkaline geochemistry is in line with a destructive plate-margin setting. Based on major element data and radiogenic isotope signature (epsilon Nd-360 Ma from -1.2 to + 0.9, Sr-87/Sr-86(360 MA) from 0.7054 to 0.7063), the parental magmas are interpreted in terms of deep-seated metabasaltic partial melts with limited contamination from shallower sources, the low radiogenic Nd-content excluding a major contribution from Vanoise tholeiites. There is no other preserved evidence for Variscan magmatism of similar age and composition in the Western Alps, but probable analogs are known in the western and northern parts of French Massif Central. Regarding the Alpine tectonics, not only the age of the pluton and its host-rocks (instead of the Permo-Carboniferous age previously believed), but also its upper mylonitic contact, suggest revisions of the Alpine nappe model. The Cogne diorite allegedly constituted the axial part of the E-verging ``pli en retour [backfold] du Valsavaranche'', a cornerstone of popular Alpine structural models: in fact, the alleged fold limbs, as attested here by field and geochemical data, do not belong to the same unit, and the backfold hypothesis is unfounded. (C) 2012 Elsevier B.V. All rights reserved.

Pathologies mimicking deep venous thrombosis of the legs: pictorial review of US findings : P27

Purpose: Precise diagnosis of DVT of the legs is a challenging problem, not only in front of suspicion of PE, but also in all status of leg pain, warmth and swelling. Clinical diagnosis has a low accuracy and further investigations are mandatory in order to diagnose DVT. Amongst the possible investigations, US has a high specificity and a good NPV. However, many pathologies unrelated to the veins may mimic the signs and symptoms of DVT and have to be recognized in order to make the correct diagnosis. The purpose of this paper is to review the results of the US investigations of the legs performed in our Department during the last three years for a suspicion of DVT and describe alternative diagnoses mimicking DVT. Methods and materials: Through a RIS-based search, we retrospectively reviewed all the cases of US of the legs performed in our Department between January 2006 and December 2008 for a suspicion of DVT. We selected the cases of positive findings unrelated to the veins and illustrated these findings with characteristic images. Results: 419 US of the legs were performed between December 2006 and December 2008 for a suspicion of DVT. Among these, 75 were positive for DVT, and 79 for alternative diagnosis. The most common alternative diagnosis was edema of the legs (31%), followed by hematoma (23%). Other findings were Baker cysts (13%), cellulitis (10%) and lymphoceles (5%). Rare diagnoses were arterio-venous malformations, pseudoaneurysms, pelvic masses, necrosing fasciitis, intramuscular abscesses, subcutaneous seromas, sarcoma and ganglion cysts. Conclusion: A greater knowledge of the US appearance of the pathologies mimicking DVT may help to make the correct diagnosis, avoiding further expensive investigations or inappropriate anticoagulant therapy.

Retrospective research: What are the ethical and legal requirements?

Retrospective research is conducted on already available data and/or biologic material. Whether such research requires that patients specifically consent to the use of "their" data continues to stir controversy. From a legal and ethical point of view, it depends on several factors. The main criteria to be considered are whether the data or the sample is anonymous, whether the researcher is the one who collected it and whether the patient was told of the possible research use. In Switzerland, several laws delineate the procedure to be followed. The definition of "anonymous" is open to some interpretation. In addition, it is debatable whether consent waivers that are legally admissible for data extend to research involving human biological samples. In a few years, a new Swiss federal law on human research could clarify the regulatory landscape. Meanwhile, hospital-internal guidelines may impose stricter conditions than required by federal or cantonal law. Conversely, Swiss and European ethical texts may suggest greater flexibility and call for a looser interpretation of existing laws. The present article provides an overview of the issues for physicians, scientists, ethics committee members and policy makers involved in retrospective research in Switzerland. It aims at provoking more open discussions of the regulatory problems and possible future legal and ethical solutions.

Evolutionary impact assessment: accounting for evolutionary consequences of fishing in an ecosystem approach to fisheries management

Managing fisheries resources to maintain healthy ecosystems is one of the main goals of the ecosystem approach to fisheries (EAF). While a number of international treaties call for the implementation of EAF, there are still gaps in the underlying methodology. One aspect that has received substantial scientific attention recently is fisheries-induced evolution (FIE). Increasing evidence indicates that intensive fishing has the potential to exert strong directional selection on life-history traits, behaviour, physiology, and morphology of exploited fish. Of particular concern is that reversing evolutionary responses to fishing can be much more difficult than reversing demographic or phenotypically plastic responses. Furthermore, like climate change, multiple agents cause FIE, with effects accumulating over time. Consequently, FIE may alter the utility derived from fish stocks, which in turn can modify the monetary value living aquatic resources provide to society. Quantifying and predicting the evolutionary effects of fishing is therefore important for both ecological and economic reasons. An important reason this is not happening is the lack of an appropriate assessment framework. We therefore describe the evolutionary impact assessment (EvoIA) as a structured approach for assessing the evolutionary consequences of fishing and evaluating the predicted evolutionary outcomes of alternative management options. EvoIA can contribute to EAF by clarifying how evolution may alter stock properties and ecological relations, support the precautionary approach to fisheries management by addressing a previously overlooked source of uncertainty and risk, and thus contribute to sustainable fisheries.

Haben selektive COX-2-Hemmer unerwünschte renale und kardiovaskuläre Wirkungen [Do selective COX-2 inhibitors have adverse renal and cardiovascular effects?].

Selective cyclooxygenase-2-inhibitors (COX-2) were developed as an alternative to the non-steroidal anti-inflammatory drugs (NSAID) in order to reduce their known gastrointestinal and renal toxicity. Several recent studies have shown the complex mechanism of the cyclooxygenase-2. The inhibition of the COX-2 has effects on renal hemodynamics, renal salt and water retention and may increase the thromboembolic and therefore the cardiovascular risk. The renal toxicity of the COX-2 inhibitors is similar to that of traditional NSAID. Regarding these data, COX-2 inhibitors should be prescribed with much caution to high risk patients, that is, patients with renal failure and/or cardiovascular diseases.

Pharmacological stimulation of edar signaling in the adult enhances sebaceous gland size and function.

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED.

Participation in a population-based physical activity programme as an aid for smoking cessation: a randomised trial.

OBJECTIVES: Exercise combined with nicotine therapy may help smoking cessation and minimise weight gain after quitting. Low participation in vigorous-intensity physical activity programmes precludes their population-wide applicability. In a randomised controlled trial, we tested whether a population-based moderate-intensity physical activity programme increases quit rates among sedentary smokers receiving nicotine therapy. METHODS: Participants (n=481; 57% male; mean age, 42.2 years (SD 10.1); mean cigarette consumption, 27 (SD 10.2) per day) were offered a nine-week smoking cessation programme consisting of a weekly 15-minute counselling session and the prescription of nicotine replacement therapy. In addition, participants in the physical activity group (n=229) also took part in a programme of moderate-intensity physical activity implemented at the national level, and offering nine weekly 60-minute sessions of physical activity. To ensure equal contact conditions, participants in the control group (n=252) attended weekly 60-minute health behaviour education sessions unrelated to physical activity. The primary outcome was continuous CO-verified smoking abstinence rates at 1-year follow-up. RESULTS: Continuous smoking abstinence rates were high and similar in the physical activity group and the control group at the end of the intervention (47% versus 46%, p=0.81) and at 1-year follow-up (27% versus 29%, p=0.71). The mean weight gain after one year was 4.4 kg and 6.2 kg among sustained quitters of the physical activity and control groups, respectively (p=0.06). CONCLUSION: Participation in a population-based moderate-intensity physical activity programme for 9 weeks in addition to a comprehensive smoking cessation programme did not significantly increase smoking cessation rates. A non-significant reduction in weight gain was observed among participants who quit smoking in the physical activity group. TRIAL REGISTRATION: ClinicalTrials.gov; US National Institutes for Health (available online at http://clinicaltrials.gov/; CLINICAL TRIAL REGISTRATION NUMBER: NCT00521391).

Patient with syncope and LQTS carrying a mutation in the PAS domain of the hERG1 channel.

We report the case of a woman with syncope and persistently prolonged QTc interval. Screening of congenital long QT syndrome (LQTS) genes revealed that she was a heterozygous carrier of a novel KCNH2 mutation, c.G238C. Electrophysiological and biochemical characterizations unveiled the pathogenicity of this new mutation, displaying a 2-fold reduction in protein expression and current density due to a maturation/trafficking-deficient mechanism. The patient's phenotype can be fully explained by this observation. This study illustrates the importance of performing genetic analyses and mutation characterization when there is a suspicion of congenital LQTS. Identifying mutations in the PAS domain or other domains of the hERG1 channel and understanding their effect may provide more focused and mutation-specific risk assessment in this population.