Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travellers with fever

Si le tableau clinique évoque une malaria et que le résultat des examens parasitologiques n?est pas disponible ou est négatif, le praticien n?a pas d?information basée sur l?évidence pour savoir s?il doit donner ou non un traitement présomptif. Afin d?identifier les facteurs cliniques et paracliniques prédictifs d?une parasitémie à Plasmodium, nous avons mené une étude prospective chez les voyageurs ou migrants en provenance d?une zone tropicale ou subtropicale et qui consultaient pour de la fièvre. Le questionnaire comprenait 49 items explorant les données démographiques, les caractéristiques du voyage, les éléments de l?anamnèse et de l?examen clinique ainsi que les résultats de laboratoire. 336 sujets avec données complètes ont été recrutés (97 patients atteints de malaria et 239 contrôles avec fièvre et examen parasitologique négatif). L?analyse de régression multivariée a permis d?identifier les facteurs prédictifs de maiaria suivants : prophylaxie inadéquate, sudations, absence de douleur abdominale, température )38"C, mauvais état général, splénomégalie, compte leucocytaire (1 O x 1 03/L, plaquettes ~ 1 5 0 x l 03/L, taux d?hémoglobine <12 g/dL et éosinophiles (5%. La présence d?une splénomégalie avait le coefficient de probabilité positif pour un diagnostic de malaria le plus élevé (1 3.6) ; venait ensuite la présence d?une thrombopénie (1 1 .O). Dans le contexte de la consultation ambulatoire de la Policlinique Médicale Universitaire (prévalence de malaria de 29%), la probabilité post- test d?avoir un examen parasitologique positif était de 85% pour la splénomégalie et de 82% pour la thrombopénie. Même si le seuil thérapeutique n?est pas absolument défini, il semble raisonnable d?envisager un traitement présomptif lorsque la probabilité post- test est >80%. Si le médecin est réticent à administrer un traitement sans documentation parasitologique, il devrait au moins se retenir d?entreprendre d?autres investigations coûteuses, et plutôt répéter l?examen parasitologique après 12-24 heures.

Biomedical risk assessment as an aid for smoking cessation.

BACKGROUND: A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. OBJECTIVES: To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. SEARCH STRATEGY: We systematically searched the Cochrane Collaboration Tobacco Addiction Group Specialized Register, Cochrane Central Register of Controlled Trials 2008 Issue 4, MEDLINE (1966 to January 2009), and EMBASE (1980 to January 2009). We combined methodological terms with terms related to smoking cessation counselling and biomedical measurements. SELECTION CRITERIA: Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. DATA COLLECTION AND ANALYSIS: Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. Results were expressed as a relative risk (RR) for smoking cessation with 95% confidence intervals (CI). Where appropriate a pooled effect was estimated using a Mantel-Haenszel fixed effect method. MAIN RESULTS: We included eleven trials using a variety of biomedical tests. Two pairs of trials had sufficiently similar recruitment, setting and interventions to calculate a pooled effect; there was no evidence that CO measurement in primary care (RR 1.06, 95% CI 0.85 to 1.32) or spirometry in primary care (RR 1.18, 95% CI 0.77 to 1.81) increased cessation rates. We did not pool the other seven trials. One trial in primary care detected a significant benefit of lung age feedback after spirometry (RR 2.12; 95% CI 1.24 to 3.62). One trial that used ultrasonography of carotid and femoral arteries and photographs of plaques detected a benefit (RR 2.77; 95% CI 1.04 to 7.41) but enrolled a population of light smokers. Five trials failed to detect evidence of a significant effect. One of these tested CO feedback alone and CO + genetic susceptibility as two different intervention; none of the three possible comparisons detected significant effects. Three others used a combination of CO and spirometry feedback in different settings, and one tested for a genetic marker. AUTHORS' CONCLUSIONS: There is little evidence about the effects of most types of biomedical tests for risk assessment. Spirometry combined with an interpretation of the results in terms of 'lung age' had a significant effect in a single good quality trial. Mixed quality evidence does not support the hypothesis that other types of biomedical risk assessment increase smoking cessation in comparison to standard treatment. Only two pairs of studies were similar enough in term of recruitment, setting, and intervention to allow meta-analysis.

Implication of TNF family members in the immune response to the infection with the intracellular protozoan parasite "Leishmania major"

Suite à une infection avec le protozoaire Leishmania major (L. major), les souris sensibles de souche BALB/c développent des lésions progressives associées à une maturation des cellules CD4+ TH2 sécrétant de l'IL-4. A l'inverse, les souris résistantes de souche C57BL/6 guérissent à terme, sous l'influence de l'expansion des cellules CD4+ TH1 produisant de l'IFNy qui a un effet synergique avec le TNF ("tumor necrosis factor") sur l'activation des macrophages et leur fonction leishmanicide. Lors de notre étude nous avons montré que des souris C57BL/6 doublement déficientes en TNF et FasL ("Fas ligand") infectées par L. major ne guérissaient ni leur lésions ni ne contrôlaient la réplication de parasites malgré une réponse de type TH1. Bien que l'activité de synthétase inductible de l'oxyde nitrique ("iNOs") soit comparable chez les souris doublement ou simplement déficientes, seules celles déficientes en FasL ont démontré une incapacité à contrôler la réplication parasitaire. De surcroît il est apparu que le FasL a un effet synergique avec l'IFNy. L'adjonction de FasL à une culture cellulaire de macrophages stimulés par l'IFNy conduit à une activation de ces cellules. Celle-ci est démontrée par l'augmentation de la production de TNF et de NO par les macrophages ainsi que par l'élimination des parasites intracellulaires par ces mêmes cellules. Alors que le FasL et l'IFNy semblent essentiels au contrôle de la réplication des pathogènes intracellulaires, la contribution de TNF s'oriente davantage vers le contrôle de l'inflammation. L'activation macrophagique via Fas précède la mort cellulaire qui survient quelques jours plus tard. Cette mort cellulaire programmée était indépendante de la cascade enzymatique des caspases, au vu de l'absence d'effet de l'inhibiteur non-spécifique ZVAD-fmk des caspases. Ces résultats suggèrent que l'interaction Fas-FasL agit comme une costimulation nécessaire à une activation efficace des macrophages, la mort cellulaire survenant consécutivement à l'activation des macrophages.¦-¦Upon infection with the protozoan parasite Leishmania major (L. major), susceptible BALB/c mice develop non healing lesions associated with the maturation of CD4+ TH2 cells secreting IL-4. In contrast, resistant C57BL/6 mice are able to heal their lesions, because of CD4+ TH1 cell expansion and production of high levels of IFNy, which synergizes with tumour necrosis factor (TNF) in activating macrophages to their microbicidal state. In our study we showed that C57BL/6 mice lacking both TNF and Fas ligand (FasL) infected with L. major neither resolved their lesions nor controlled L. major replication despite a strong TH1 response. Although comparable inducible nitric oxide synthase (iNOs) was measured in single or double deficient mice, only mice deficient in FasL failed to control the parasite replication. Moreover FasL synergized with IFNy for the induction of leishmanicidal activity within macrophages infected with L. major in vitro. Addition of FasL to IFNy stimulated macrophages led to their activation, as reflected by the secretion of tumour necrosis factor and nitrite oxide, as well as the induction of their microbicidal activity, resulting in the killing of intracellular L. major. While FasL along with IFNy and iNOs appeared to be essential for the complete control of intracellular pathogen replication, the contribution of TNF appeared more important in controlling the inflammation on the site of infection. Macrophage activation via Fas pathway preceded cell death, which occurred a few days after Fas mediated activation. This program cell death was independent of caspase enzymatic activities as revealed by the lack of effect of ZVAD-fmk, a pan-caspase inhibitor. These results suggested that the Fas-FasL pathway, as part of the classical activation pathway of the macrophages, is essential in the stimulation of macrophage leading to a microbicidal state and to AICD, and may thus contribute to the pathogenesis of L. major infection.

Clinical characteristics and outcome of patients admitted to a medico-surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction: Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic respiratory failure (HRF). Whether this approach is equally successful for all categories of HRF patients is however debated. We assessed if any clinical characteristics of HRF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods: Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HRF (defined as PaCO2 >50 mm Hg), and receiving NIV between January 2009 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU and hospital mortality were recorded. Results are reported as median [IQR]. Comparisons with Chi2 or Kruskal-Wallis tests, p <0.05 (*). Results: 164 patients were included, 45 (27.4%) of whom were intubated after 10 [2-34] hours, after having received 7 [2-19] hours of NIV. NIV successful patients received 15 [5-22] hours of NIV for up to 5 days. Intubation was correlated with increased ICU (20% vs. 3%, p <0.001) and hospital (46.7% vs. 30.2, p >0.05) mortality. Conclusions: A majority of patients requiring NIV for hypercapnic respiratory failure in our ICU have no diagnosed chronic pulmonary disease. These patients tend to have increased ICUand hospital mortality. The majority of patients were non-surgical, a feature correlated with increased hospital mortality. Beside usual predictors of severity such as age and SAPS II, absence of diagnosed chronic pulmonary disease and non-operative state appear to be associated with increased mortality. Further studies should explore whether these patients are indeed more prone to an adverse outcome and which therapeutic strategies might contribute to alter this course.

Resting-State Functional Connectivity Emerges from Structurally and Dynamically Shaped Slow Linear Fluctuations.

Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.

Biomedical risk assessment as an aid for smoking cessation.

BACKGROUND: A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. OBJECTIVES: To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. SEARCH METHODS: For the most recent update, we searched the Cochrane Collaboration Tobacco Addiction Group Specialized Register in July 2012 for studies added since the last update in 2009. SELECTION CRITERIA: Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. DATA COLLECTION AND ANALYSIS: Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. Results were expressed as a relative risk (RR) for smoking cessation with 95% confidence intervals (CI). Where appropriate, a pooled effect was estimated using a Mantel-Haenszel fixed-effect method. MAIN RESULTS: We included 15 trials using a variety of biomedical tests. Two pairs of trials had sufficiently similar recruitment, setting and interventions to calculate a pooled effect; there was no evidence that carbon monoxide (CO) measurement in primary care (RR 1.06, 95% CI 0.85 to 1.32) or spirometry in primary care (RR 1.18, 95% CI 0.77 to 1.81) increased cessation rates. We did not pool the other 11 trials due to the presence of substantial clinical heterogeneity. Of the remaining 11 trials, two trials detected statistically significant benefits: one trial in primary care detected a significant benefit of lung age feedback after spirometry (RR 2.12, 95% CI 1.24 to 3.62) and one trial that used ultrasonography of carotid and femoral arteries and photographs of plaques detected a benefit (RR 2.77, 95% CI 1.04 to 7.41) but enrolled a population of light smokers and was judged to be at unclear risk of bias in two domains. Nine further trials did not detect significant effects. One of these tested CO feedback alone and CO combined with genetic susceptibility as two different interventions; none of the three possible comparisons detected significant effects. One trial used CO measurement, one used ultrasonography of carotid arteries and two tested for genetic markers. The four remaining trials used a combination of CO and spirometry feedback in different settings. AUTHORS' CONCLUSIONS: There is little evidence about the effects of most types of biomedical tests for risk assessment on smoking cessation. Of the fifteen included studies, only two detected a significant effect of the intervention. Spirometry combined with an interpretation of the results in terms of 'lung age' had a significant effect in a single good quality trial but the evidence is not optimal. A trial of carotid plaque screening using ultrasound also detected a significant effect, but a second larger study of a similar feedback mechanism did not detect evidence of an effect. Only two pairs of studies were similar enough in terms of recruitment, setting, and intervention to allow meta-analyses; neither of these found evidence of an effect. Mixed quality evidence does not support the hypothesis that other types of biomedical risk assessment increase smoking cessation in comparison to standard treatment. There is insufficient evidence with which to evaluate the hypothesis that multiple types of assessment are more effective than single forms of assessment.

Biomedical risk assessment as an aid for smoking cessation.

BACKGROUND: A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. We reviewed systematically data on smoking cessation rates from controlled trials that used biomedical risk assessment and feedback. OBJECTIVES: To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. SEARCH STRATEGY: We systematically searched he Cochrane Collaboration Tobacco Addiction Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to 2004), and EMBASE (1980 to 2004). We combined methodological terms with terms related to smoking cessation counselling and biomedical measurements. SELECTION CRITERIA: Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. DATA COLLECTION AND ANALYSIS: Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. MAIN RESULTS: From 4049 retrieved references, we selected 170 for full text assessment. We retained eight trials for data extraction and analysis. One of the eight used CO alone and CO + Genetic Susceptibility as two different intervention groups, giving rise to three possible comparisons. Three of the trials isolated the effect of exhaled CO on smoking cessation rates resulting in the following odds ratios (ORs) and 95% confidence intervals (95% CI): 0.73 (0.38 to 1.39), 0.93 (0.62 to 1.41), and 1.18 (0.84 to 1.64). Combining CO measurement with genetic susceptibility gave an OR of 0.58 (0.29 to 1.19). Exhaled CO measurement and spirometry were used together in three trials, resulting in the following ORs (95% CI): 0.6 (0.25 to 1.46), 2.45 (0.73 to 8.25), and 3.50 (0.88 to 13.92). Spirometry results alone were used in one other trial with an OR of 1.21 (0.60 to 2.42).Two trials used other motivational feedback measures, with an OR of 0.80 (0.39 to 1.65) for genetic susceptibility to lung cancer alone, and 3.15 (1.06 to 9.31) for ultrasonography of carotid and femoral arteries performed in light smokers (average 10 to 12 cigarettes a day). AUTHORS' CONCLUSIONS: Due to the scarcity of evidence of sufficient quality, we can make no definitive statements about the effectiveness of biomedical risk assessment as an aid for smoking cessation. Current evidence of lower quality does not however support the hypothesis that biomedical risk assessment increases smoking cessation in comparison with standard treatment. Only two studies were similar enough in term of recruitment, setting, and intervention to allow pooling of data and meta-analysis.

New insights into the regulatory mechanisms of the NALP3 inflammasome

Résumé : Les vertébrés ont recours au système immunitaire inné et adaptatif pour combattre les pathogènes. La découverte des récepteurs Toll, il y a dix ans, a fortement augmenté l'intérêt porté à l'immunité innée. Depuis lors, des récepteurs intracellulaires tels que les membres de la famille RIG-like helicase (RLHs) et NOD-like receptor (NLRs) ont été décrits pour leur rôle dans la détection des pathogènes. L'interleukine-1 beta (IL-1β) est une cytokine pro-inflammatoire qui est synthétisée sous forme de précurseur, la proIL-1β. La proIL-1β requiert d'être clivée par la caspase-1 pour devenir active. La caspase-1 est elle-même activée par un complexe appelé inflammasome qui peut être formé par divers membres de la famille NLR. Plusieurs inflammasomes ont été décrits tels que le NALP3 inflammasome ou l'IPAF inflammasome. Dans cette étude nous avons identifié la co-chaperone SGT1 et la chaperone HSP90 comme partenaires d'interaction de NALP3. Ces deux protéines sont bien connues chez les plantes pour leurs rôles dans la régulation des gènes de résistance (gène R) qui sont structurellement apparentés à la famille NLR. Nous avons pu montrer que SGT1 et HSP90 jouent un rôle similaire dans la régulation de NALP3 et des protéines R. En effet, nous avons démontré que les deux protéines sont nécessaires pour l'activité du NALP3 inflammasome. De plus, la HSP90 est également requise pour la stabilité de NALP3. En se basant sur ces observations, nous avons proposé un modèle dans lequel SGT1 et HSP90 maintiennent NALP3 inactif mais prêt à percevoir un ligand activateur qui initierait la cascade inflammatoire. Nous avons également montré une interaction entre SGT1 et HSP90 avec plusieurs NLRs. Cette observation suggère qu'un mécanisme similaire pourrait être impliqué dans la régulation des membres de la famille des NLRs. Ces dernières années, plusieurs PAMPs mais également des DAMPs ont été identifiés comme activateurs du NALP3 inflammasome. Dans la seconde partie de cette étude, nous avons identifié la réponse au stress du réticulum endoplasmique (RE) comme nouvel activateur du NALP3 inflammasome. Cette réponse est initiée lors de l'accumulation dans le réticulum endoplasmique de protéines ayant une mauvaise conformation ce qui conduit, en autre, à l'arrêt de la synthèse de nouvelles protéines ainsi qu'une augmentation de la dégradation des protéines. Les mécanismes par lesquels la réponse du réticulum endoplasmique induit l'activation du NALP3 inflammasome doivent encore être déterminés. Summary : Vertebrates rely on the adaptive and the innate immune systems to fight pathogens. Awarness of the importance of the innate system increased with the identification of Toll-like receptors a decade ago. Since then, intracellular receptors such as the RIG-like helicase (RLH) and the NOD-like receptor (NLR) families have been described for their role in the recognition of microbes. Interleukin- 1ß (IL-1ß) is a key mediator of inflammation. This proinflammatory cytokine is synthesised as an inactive precursor that requires processing by caspase-1 to become active. Caspase-1 is, itself, activated in a complex termed the inflammasome that can be formed by members of the NLR family. Various inflammasome complexes have been described such as the IPAF and the NALP3 inflammasome. In this study, we have identified the co-chaperone SGT1 and the chaperone HSP90 as interacting partners of NALP3. SGT1 and HSP90 are both known for their role in the activity of plant resistance proteins (R proteins) which are structurally related to the NLR family. We have shown that HSP90 and SGT1 play a similar role in the regulation of NALP3 and in the regulation of plant R proteins. Indeed, we demonstrated that both HSP90 and SGT1 are essential for the activity of the NALP3 inflammasome complex. In addition, HSP90 is required for the stability of NALP3. Based on these observations, we have proposed a model in which SGT1 and HSP90 maintain NALP3 in an inactive but signaling-competent state, ready to receive an activating ligand that induces the inflammatory cascade. An interaction between several NLR members, SGTI and HSP90 was also shown, suggesting that similar mechanisms could be involved in the regulation of other NLRs. Several pathogen-associated molecular patterns (PAMPs) but also danger associated molecular patterns (DAMPs) have been identified as NALP3 activators. In the second part of this study, we have identified the ER stress response as a new NALP3 activator. The ER stress response is activated upon the accumulation of unfolded protein in the endoplasmic reticulum and results in a block in protein synthesis and increased protein degradation. The mechanisms of ER stress-mediated NALP3 activation remain to be determined.

Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages.

Peripheral arterial disease (PAD) is a common disease with increasing prevalence, presenting with impaired walking ability affecting patient's quality of life. PAD epidemiology is known, however, mechanisms underlying functional muscle impairment remain unclear. Using a mouse PAD model, aim of this study was to assess muscle adaptive responses during early (1 week) and late (5 weeks) disease stages. Unilateral hindlimb ischemia was induced in ApoE(-/-) mice by iliac artery ligation. Ischemic limb perfusion and oxygenation (Laser Doppler imaging, transcutaneous oxygen pressure assessments) significantly decreased during early and late stage compared to pre-ischemia, however, values were significantly higher during late versus early phase. Number of arterioles and arteriogenesis-linked gene expression increased at later stage. Walking ability, evaluated by forced and voluntary walking tests, remained significantly decreased both at early and late phase without any significant improvement. Muscle glucose uptake ([18F]fluorodeoxyglucose positron emission tomography) significantly increased during early ischemia decreasing at later stage. Gene expression analysis showed significant shift in muscle M1/M2 macrophages and Th1/Th2 T cells balance toward pro-inflammatory phenotype during early ischemia; later, inflammatory state returned to neutrality. Muscular M1/M2 shift inhibition by a statin prevented impaired walking ability in early ischemia. High-energy phosphate metabolism remained unchanged (31-Phosphorus magnetic resonance spectroscopy). Results show that rapid transient muscular inflammation contributes to impaired walking capacity while increased glucose uptake may be a compensatory mechanisms preserving immediate limb viability during early ischemia in a mouse PAD model. With time, increased ischemic limb perfusion and oxygenation assure muscle viability although not sufficiently to improve walking impairment. Subsequent decreased muscle glucose uptake may partly contribute to chronic walking impairment. Early inflammation inhibition and/or late muscle glucose impairment prevention are promising strategies for PAD management.

Comparison of indices proposed as criteria for assigning skin notation

OBJECTIVES: Skin notations are used as a hazard identification tool to flag chemicals associated with a potential risk related to transdermal penetration. The transparency and rigorousness of the skin notation assignment process have recently been questioned. We compared different approaches proposed as criteria for these notations as a starting point for improving and systematizing current practice. METHODS: In this study, skin notations, dermal acute lethal dose 50 in mammals (LD(50)s) and two dermal risk indices derived from previously published work were compared using the lists of Swiss maximum allowable concentrations (MACs) and threshold limit values (TLVs) from the American Conference of Governmental Industrial Hygienists (ACGIH). The indices were both based on quantitative structure-activity relationship (QSAR) estimation of transdermal fluxes. One index compared the cumulative dose received through skin given specific exposure surface and duration to that received through lungs following inhalation 8 h at the MAC or TLV. The other index estimated the blood level increase caused by adding skin exposure to the inhalation route at kinetic steady state. Dermal-to-other route ratios of LD(50) were calculated as secondary indices of dermal penetrability. RESULTS: The working data set included 364 substances. Depending on the subdataset, agreement between the Swiss and ACGIH skin notations varied between 82 and 87%. Chemicals with a skin notation were more likely to have higher dermal risk indices and lower dermal LD(50) than chemicals without a notation (probabilities between 60 and 70%). The risk indices, based on cumulative dose and kinetic steady state, respectively, appeared proportional up to a constant independent of chemical-specific properties. They agreed well with dermal LD(50)s (Spearman correlation coefficients -0.42 to -0.43). Dermal-to-other routes LD(50) ratios were moderately associated with QSAR-based transdermal fluxes (Spearman correlation coefficients -0.2 to -0.3). CONCLUSIONS: The plausible but variable relationship between current skin notations and the different approaches tested confirm the need to improve current skin notations. QSAR-based risk indices and dermal toxicity data might be successfully integrated in a systematic alternative to current skin notations for detecting chemicals associated with potential dermal risk in the workplace. [Authors]

INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma.

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.

Patterns in the situated activity of substance use in the careers of elite doping athletes

Objectives This article presents a psychological approach to substance use in sport using a dynamic and situated activity framework. The aim was to analyze the various relationships between activity and the consumption of substances during the sporting life course of athletes who recognized doping violation. Design Data were collected from secondary sources and biographical and self-confrontational interviews to build traces of the past activity. Method Twelve doping athletes or those admitting to having used banned substances volunteered to participate. The data were coded and compared to identify typical activities and their intrinsic dynamics. Results Six activities were identified: "Agree to use," "Drop out of a non-viable state," Return to a former state," "Prevent a potential deficiency," "Maintain an acquired state," and "Balance the sporting life with substance use," comprising 11 patterns. Conclusions The athletes' activity embedded substance use in reciprocal relationships that consisted of freezing, exploring and exploiting fields of possible actions created and offered by the situation dynamics. Recommendations for situated and dynamic prevention are provided.

Eretria - Nea Psara : eine klassizistische Stadtanlage über der antiken Polis

Résumé: Le présent ouvrage propose une histoire de l'Erétrie moderne, de la redécouverte du site antique au projet urbanistique de 1834 pour une ville nouvelle destinée à accueillir les réfugiés de l'île de Psara - anéantie en 1824 par les Ottomans - et au développement urbain d'Erétrie/Nea Psara au XIXe et au XXe siècles. Le nom d'Erétrie englobe trois couches historiques distinctes: la cité antique, la ville néoclassique, dessinée par l'architecte allemand Eduard Schaubert (1804-1860), et le village moderne, issu de son projet. Chacune de ces strates - vestiges antiques, tissu urbain néoclassique et constructions plus récentes - est perceptible au sein de cet ensemble urbain et se trouve en relation constante avec les autres. L'exposé des recherches archéologiques - depuis la redécouverte du site antique par Ciriaco de' Pizzicolli d'Ancona (Cyriaque d'Ancône) en 1436 déjà, puis de manière systématique par des voyageurs-archéologues dès le XIXe siècle - comble une lacune dans l'historiographie de la cité antique. Cette approche met également en lumière la relation étroite entre archéologie et urbanisme au XIXe siècle. Si l'exploration de la Grèce avait été jusqu'à son indépendance en 1827 essentiellement le fait des archéologues, des historiens et des philologues, après cette date, des géologues, des ingénieurs et des topographes travaillant pour le développement économique du jeune Etat se mirent également à parcourir le pays, le regard tourné non plus seulement vers l'Antiquité, mais aussi vers l'avenir. L'histoire de la redécouverte d'Erétrie permet ainsi d'éclairer divers aspects liés à la gestation de l'Etat grec. Le projet conçu en 1834 par Ecluard Schaubert de ville néoclassique superposée aux ruines de la cité antique d'Erétrie s'inscrit dans un réseau de créations de villes nouvelles et de modernisations de villes existantes par le nouvel Etat grec, qui cherchait à fonder sa légitimité et son identité, après la domination ottomane, sur les valeurs idéales (ou idéalisées) de l'Antiquité classique. Dans le projet de développement urbain d'Erétrie, la relation étroite entre archéologie et urbanisme et, par conséquent, la référence à l'Antiquité sont évidentes: Eduard Schaubert commença par tracer sur son plan toutes les ruines antiques, dressant ainsi l'état des connaissances archéologiques du site. Sur cette base, l'architecte conçut la ville néoclassique en y incluant les principales ruines, qui devaient servir de repères visuels et qui concrétisaient ainsi le lien idéologique de la monarchie absolue avec l'Antiquité. A Erétrie, deux perspectives principales reliaient le port à l'acropole et l'Ecole navale au théâtre antique. L'intégration de ruines antiques dans un projet urbanistique avait été réalisée par Stamatios Kleanthes et Eduard Schaubert en 1831-1832 dans le plan de l'Athènes moderne, avant que celle-ci n'ait été promue capitale de la Grèce. Les deux architectes ont ainsi anticipé le caractère idéal d'Athènes dans le processus de gestation de l'Etat grec. L'importance de ce plan et de celui qu'ifs ont établi sur le même modèle pour le Pirée a été reconnue par les historiens de l'urbanisme. En revanche, le plan d'Erétrie, qui suit pourtant les mêmes principes, n'a été que partiellement étudié. Cette monographie montre que le projet d'Erétrie était le plus abouti des trois, qui tous se caractérisent par un système de routes rayonnant depuis le siège du gouvernement (résidences royales à Athènes et au Pirée, mairie à Erétrie). Cet éventail de rues ou u patte d'oie» embrasse à Athènes l'acropole et au Pirée fa baie du port, alors qu'a Erétrie il est double, axé en raison de la topographie sur l'acropole et sur Pa baie du port. Cette double patte d'oie crée ainsi le lien idéologique avec l'Antiquité et témoigne, par son ouverture sur le port, de l'essor économique souhaité par le gouvernement. Le plan d'Erétrie représente de manière exemplaire l'urbanisme programmatique de la Grèce sous Othon ler (1832-1862). L'ouvrage s'intéresse ensuite à la réalisation du projet de Schaubert, dont la mise en oeuvre n'a pas répondu aux attentes du Gouvernement. Le faible développement d'Erétrie s'explique principalement par le surdimensionnement du projet, des finances publiques modestes, la malaria endémique et une politique économique inadaptée aux traditions commerciales des Psariotes. Les lenteurs dans la réalisation du projet et même des régressions au cours du XIXe siècle et au début du XXe siècle, puis l'urbanisation accélérée d'Erétrie à partir des années 1960, ont eu pour conséquence que les historiens de l'urbanisme et les urbanistes ont sous-estimé, voire ignoré la valeur historique de ce concept Cependant, l'exécution du projet néoclassique s'est poursuivie de manière continue et des références au plan de Schaubert peuvent être observées dans l'aménagement récent de la localité aujourd'hui encore. Ainsi, des arbres ont été plantés dans les années 1960 le long de l'enceinte urbaine antique, à l'emplacement où Schaubert avait prévu la création d'une promenade arborée. Au centre d'Erétrie, là où l'agora principale aurait dû être aménagée, une grande place publique servant au marché hebdomadaire a été créée. Dans le quartier oriental, une petite église dédiée à la Pan hagia Paravouniotissa a été construite en 2001 sur la parcelle où Schaubert en avait prévue une. D'importants éléments des projets de Schaubert, qui ne sont actuellement plus guère perceptibles à Athènes et au Pirée, le sont toujours à Erétrie. Les espaces verts, par exemple, occupent une place importante dans le domaine privé: malgré la densification du tissu urbain, des parcelles caractéristiques contiennent encore des maisons isolées d'un ou de deux niveaux côté rue, avec un grand jardin à l'arrière, séparé des parcelles voisines par un mur en pierre ou en brique crue. Erétrie mérite donc une reconnaissance plus considérable dans l'histoire de l'urbanisme, puisqu'elle contribue à faire mieux comprendre les projets de ses deux villes soeurs. L'étude du projet urbanistique est complétée par une approche typologique des constructions néoclassiques d'Erétrie qui souligne encore la valeur historique de cet ensemble. Comme la plupart des édifices sont, menacés de démolition, à l'exception d'un petit nombre d'entre eux qui bénéficient d'un bon entretien, un inventaire photographique des constructions d'Erétrie datant du XIXe et du début du XXe siècle a été constitué entre 1994 et 2005, complété par des photographies anciennes. Il en ressort que les formes et les techniques de construction sont représentatives de l'architecture privée à l'époque de la création de l'Etat. Enfin, le plan directeur d'Erétrie, réalisé en 1975-1976 par un séminaire du Département d'architecture de l'Ecole polytechnique fédérale de Zurich avec l'appui de l'Ecole suisse d'archéologie en Grèce, est publié ici intégralement pour la première fois. Le présent ouvrage rend ses lettres de noblesse à un ensemble urbain néoclassique, certes modeste, mais issu d'un projet urbanistique ambitieux, témoin significatif du programme politique du nouvel Etat grec. SUMMARY Translated by William Eisler This book gives an account of the history of modern Eretria. It encompasses the rediscovery of the ancient city, the 1834 urban plan for the new town designed to accommodate the refugees from the island of Psara - destroyed by the Ottomans in 1824 - and also the urban development of Eretria/Nea Psara in the 19th and 20th centuries. The name Eretria carries a rich heritage: the ancient city, the neoclassical town designed by the Germen architect Eduard Schaubert (1804-1860), and the modern village. These three distinct historical layers ancient ruins, neoclassical plan and more recent constructions - can be seen within this urban area and are interlinked with each other. The account of the archeological investigations fills a gap in the historiography of the ancient city. This started with the early rediscovery of the ancient site by Ciriaco de'Pizzicolli d'Ancona in 1436, and was followed by systematic research by travellers/ archeologists from the 19th century onward. Furthermore, this shows the close relationship between archeology and urbanism in the 19th century. The exploration of Greece prier te its independence in 1827 was mainly red by archeologists, historians and philologists. Subsequently, geologists, engineers and topographers working for the young state's economic development travelled across the country, with their attention focused not only on Antiquity but are on the future. The history of Eretria's rediscovery gives new insights on various aspects related to the development of the Greek state. In 1834, Eduard Schaubert's project, planning a neoclassical town built upon the ancient Eretria, took place alongside the development of other new cities and the modernization of existing ones du ring the Ottoman domination. By doing so, the new Greek state wanted to build its legitimacy and identity, based upon the ideal (or idealized) values of Classical Antiquity. In the urban development of Eretria, the close connection between archeology and urbanism, and the reference to Antiquity, are obvious. Eduard Schaubert began by tracing on his plan ail of the ancient ruins, thus showing the knowledge of the archeological site at that time. On this basis, the architect planned the neoclassical town, incorporating the principal ruins which were to serve as visual references embodying the ideological link between Antiquity and King Otto's absolute monarchy. In Eretria, two principal visual axes linked the port to the acropolis and the Naval School to the ancient theatre. The integration of ancient ruins in an urban project had already been achieved by Stamatios Kleanthes and Eduard Schaubert in 1831-1832 in their plan for modern Athens, before it became the capital of Greece. The two architects had therefore anticipated the ideal character of Athens at the beginning of the Greek state. The importance of this plan and that of Piraeus (designed along the same model) has long been recognized by urban historians. By contrast, the plan of Eretria based open the same principles has been only partly studied. This book explains clearly that the Eretria project was the most elaborate. The three cities are characterized by a system of roads radiating from the seat of government (the royal residences in Athens and Piraeus, the town hall in Eretria). This fan-like arrangement of streets includes the Acropolis in Athens and the harbour in Piraeus, whereas in Eretria it is twofold, orientated towards the acropolis and the harbour on account of the topography. This double fan-like arrangement shows the ideological link with Antiquity and, with its opening onto the harbour, the government's desire for economic development. The plan of Eretria is a typical ex- ample of the programmatic urbanism of Greece under Otto I (1832-1862). The book discusses the completion of Schaubert's project, which was not fully carried out as expected by the government. The poor development of Eretria can be explained primarily by the excessive scale of the project, the modest public finances, the endemic malaria and an economic policy unsuitable to the commercial traditions of the Psariotes. Delays, even regressions in the implementation of the project in the course of the 19th and the beginning of the 20th centuries, followed by the growing urbanization of Eretria starting in the 1960's, led urban historians and town planners to underestimate or even to ignore the historical value of this concept. Nevertheless, the neoclassical project was carried out steadfastly, and references to the Schaubert plan can still be seen in the modern layout of the town. Trees were planted in the 1960's all along the circumference of the ancient city, where Schaubert had planned a tree-lined promenade. A big public square serving as a weekly market place was created in the centre of Eretria, where the principal agora had been originally planned. In 2001 a small church dedicated to the Panhagia Paravouniotissa was built on a plot of land in the eastern district, where this had been intended by Schaubert. Important elements of Schaubert's projects, which are barely perceptible in modern-day Athens and Piraeus, remain visible in Eretria. Green areas, for example, occupy a significant place within the private properties. In spite of the urban densification, characteristic plots still include isolated houses of one or two stories facing the street, with large gardens in the rear, separated from neighbours by stone or mudbrick walls. Eretria therefore deserves a more prominent position in the history of urbanism, as it contributes to a better understanding of ifs two sister cities. The study of the urban project is enriched by a typological approach to the neoclassical constructions of Eretria, underlining once again the historical value of this heritage. Since only a small number of the buildings have benefited from good maintenance and the greater part is threatened with demolition, a photographic inventory of the constructions of Eretria dating from the 19tIt and early 20th centuries was produced between 1994 and 2005, supplemented by old photographs. This documentation clearly shows that the forms and techniques of construction are characteristic of private architecture at the beginning of modern Greece. Finally, the master plan of Eretria drafted in 1975-1976 by a seminar of the Department of Architecture of the Swiss Federal Institute of Technology, Zurich, with the support of the Swiss School of Archeology in Greece, is published here in full for the first time. This book gives credit to a neoclassical urban heritage which, although modest in scale, derives from an ambitious project that embodies the political programme of the new Greek state. ΠΕΡΙΛΗΨΗ Μετάβραση Ελενή Δημητρακοπούλου Η παρούσα εργασία προτείνει μια. ιστορία της σύγχρονης πόλης της Ερέτριας, ξεκινώντας από την αποκάλύψη του αρχαιολογικού χώρου, περνώντας από την σύνταξη, το 1834, του ρυμοτομικού σχεδίου για μια νέα. πόλη που σκοπό είχε να υποδεχθεί τούς πρόσφυγες από τα Ψαρά. - που καταστράφηκαν ολοσχερώς το 1824 από τούς Οθωμανούς - και εξετάζοντας τέλος την πολεοδομική εξέλιξη της Ερέτριας/Νέων Ψαρών κατά τον 19° και τον 20° αι. Πίσω από το όνομα της Ερέτριας κρύβονται τρία διαφορετικά. ιστορικά στρώματα,: η αρχαία πόλη, η νεοκλασική πόλη πού σχεδιάστηκε από τον γερμανό αρχιτε κτονα "Εντοναρντ Σάουμπερτ (1804-1860) και η σύγχρονη πόλη που κτίστηκε πάνω στά. σχέδια του τελευταίού. Κάθε ένα από αυτά τα στρώματα - αρχαία κατάλοιπα. νεοκλασικός πολεοδομικός ιστός και νεώτερα κτίσματα - γίνεται αντιληπτό στο πλαίσιο αυτού του πολεοδομικού συνόλου και βρίσκεται σε άμεση σχέση με τα άλλα δύο. Ηπαρονσίαση των αρχαιολογικών ερευνών, που ξεκινούν το 1436 με την αποκάλυψη τον αρχαιολογικού χώρού από τον Ciriaco de' Pizzicolli d'Ancona (Κυριάκος ο Αγκωνίτης) και συνεχίζονται συστηματικά. από περιηγητές_αρχαιολόγούς κατά το 19° αι., καλύπτει ένα κενό στην ιστοριογραφία της έρεύνας της αρχαίας πύλης. Η προσέγγιση αυτή φωτίζει επίσης τη στενή σχέσημεταξύαρχαιολογίας και πολεοδομίας κατά τον 190 αι. Αν η εξερεύνηση της Ελλάδος, ως την ανεξαρτησία της το 1827, ήταν έργο κνρϊως αρχαιολόγων, ιστορικών και φιλολόγων, μετά από αυτήν την χρονολογία., γεωλόγοι, μηχανικοί και τοπογράφοι που εργάζονταν για την οικονομική ανάπτυξη τον νεοσύστατου Ελληνικού Κράτούς, άρχισαν επίσης να περιτρέχονν όλη την χώρα., με το βλέμμα. στραμμένο όχι μόνο προς την Αρχαιότητα, αλλά και προς το μέλλον. Η ιστορία της αποκάλυψης της Ερέτριας φωτίζει έτσι και διάφορες όψεις που συνδέονται με την γένεση του Ελληνικού Κράτους. Το 1834, υ 'Εντοναρντ Σάουμπερτ εκπόνησε το σχέδιο μιας νεοκλασικής πόλης που Θα επικαθόταν στα; ερείπια. της αρχαίας Ερέτριας?το έργο εντάσσεται στο δίκτυο δημιουργίας νέων πόλεων και εκσυγχρονισμού των υπαρχυυσών από το νεοσύστατο Ελληνικό Κράτος. το οποίο, μετά την Οθωμανική κυριαρχία, επεδίωκε να Θεμελιώσει την νομιμότητα και την ταυτότητά του πάνω στις ιδανικές ή εξιδανικευμένες αξίες της κλασικής αρχαιότητας. Στο σχέδιο της πολεοδομικής ανάπτυξης της Ερέτριας, η στενή σχέση μεταξύ αρχαιολογίας και πολεοδομίας και, κατ επέκταση. οι σαφείς αναφορές στην Αρχαιότητα. είναι εμφανείς: ο Εντοναρντ Σάουμπερτ άρχισε σχεδιάζοντας στο τοπογραφικό τον όλα τα αρχαία. ερείπια, καταγράφοντας έτσι τις τότε αρχαιολογικές γνώσεις για, το χώρο. Σε αυτή τη βάση, ο αρχιτέκτονας συνέλαβε την νεοκλασική πόλη εντάσσοντας σε αυτήν τα κυριότερα αρχαία μνημεία, τα οποία χρησίμευαν ως οπτικά σημεία αναφοράς, ενώ συγχρόνως υλοποιούσαν την ιδεολογική σχέση της απόλύτης μοναρχίας με την Αρχαιότητα. Στην Ερέτρια, δυο βασικοί άξονες συνέδεαν το λιμάνι με την Ακρόπολη και τη Ναυτική Σχολή με το Αρχαίο Θέατρο. Η ένταξη αρχαίων ερειπίων σε ένα πολεοδομικό σχέδιο είχε ήδη πραγματοποιηθεί από τούς Σταμάτιο Κλεάνθη και'Εντουαρντ Σάουμπερτ στα 1831-1832, στον σχεδιασμό της νέας Αθήνας, πριν αυτή ανακηρυχθεί σε πρωτεύουσα. της Ελλάδος. Οι δυο αρχιτέκτονες προεξόφλησαν έτσι τον συμβολικό χαρακτήρα της Αθήνας στην διαδικασία. γένεσης του Ελληνικού Κράτούς, Η σημασία αυτού τον σχεδίου καθώς και εκείνου που συνέταξαν, πάνω στο ίδιο πνεύμα, για τον Πειραιά έχει αναγνωριστεί από τους σύγχρονούς πολεοδόμους. Αντίθετα, το σχέδιο της Ερέτριας, παρ όλο που ακολούθεί τις ίδιες αρχές, μελετήθηκε πολύ λίγο. Η παρούσα μονογραφία δείχνει ότι το σχέδιο της Ερέτριας ήταν το πιο ολοκληρωμένο από τα τρία. Βασικό χαρακτηριστικό των σχεδίων αυτών είναι ένα σύστημα οδών που αναπτύσσονται ακτινωτά από το κέντρο εξουσίας (βασιλική κατοικία στην Αθήνα και τον Πειραιά, δημαρχείο στην Ερέτρια). Αυτή η ακτινωτή διάταξη των οδών συμπεριλαμβάνει στην Αθήνα την Ακρόπολη και στον Πειραιά το λιμάνι, ενώ στην Ερέτρια είναι αμφίροπη, προσανατολισμένη, λόγω της τοπογραφίας, προς την ακρόπολη αλλά και προς τον όρμο του λιμανιού. Αυτή η διπλή ακτινωτή διάταξη από τη μια δημιούργεί τον ιδεολογικό δεσμό ιιε την Αρχαιότητα, ενώ από την άλλη τονίζει, με το άνοιγμά της προς το λιμάνι, την οικονομική άνθηση της πόλης που επιθυμούσε η κεντρική εξουσία. Τα σχέδιο της Ερέτριας αποτελεί αντιπροσωπευτικό δείγμα της προγραμματικής πολεοδομίας της Ελλάδος κατά τα, χρόνια της Βασιλείας του "Οθωνος (1832-1862). Η υλοποίηση του σχεδίου του Σάουμπερτ δεν ανταποκρίθηκε στις προσδοκίες της κυβέρνησης. Η μικρή ανάπτύξη της Ερέτριας οφείλεται κυρίως στούς ανεδαφικούς, μεγαλεπί βολονς στόχους του σχεδίού, στα μέτρια δημόσια οικονομικά, στην ενδημική ελονοσία λόγω των υφισταμένων ελών καθώς και σε μια, οικονομική πολιτική που ήταν ξένη στις εμπορικές παραδόσεις των Ψαριανών. Οι αργοί ρυθμοί της πραγματοποίησης του σχεδίού και μάλιστα κάποιες περικοπές τον κατά τη διάρκεια τον 19°ν και στις αρχές του 2θ αι., και στη συνέχεια η ταχεία πολεοδομική εξέλιξη της Ερέτριας από τη δεκαετία του 1960, είχαν σαν συνέπεια να υποτιμηθεί ή κατ να αγνοηθεί η ιστορική αξία του πολεοδομικού σχεδίου από τους ιστορικούς της πολεοδομίας. Ωστόσο, η εκτέλεση τον νεοκλασικού σχεδίου ακολουθήθηκε με συνέπεια, ενώ αναφορές στο σχέδιο του Σάουμπερτ μπορούν να παρατηρηθούν, ακόμα. και σήμερα. στις νεώτερες διευθετήσεις τον χώρου. Ετσι, στη δεκαετία του 1960, κατά μήκος του αρχαίού τείχούς της πόλης φυτεύθηκαν δέντρα, στη Θέση όπού ο Σάουμπερτ είχε προβλέψει τη δημιουργία ενός δεντροφυτεμένου περιπάτου. Στο κέντρο της Ερέτριας, εκεί όπου Θα έπρεπε να διαμορφωθεί η κύρια αγορά της πόλης, δημιουργήθηκε μια μεγάλη δημόσια πλατεία όπου γίνεται η εβδομαδιαία λαϊκή αγορά. Στην ανατολική συνοικία, χτίστηκε, το 2001, μια μικρή εκκλησία αφιερωμένη στην Παναγία, την Παραβοννιώτισσα, στο οικόπεδο όπου ο Σάουμπερτ είχε προβλέψει μια εκκλησία. Σημαντικά στοιχεία των σχεδίων του Σάουμπερτ, που δεν γίνονται πια καθόλου αντιληπτά στην ΑΘήνα και στον Πειραιά, μπορούν να παρατηρηθούν στην Ερέτρια. Το πράσινο, για παράδειγμα, καταλαμβάνει σημαντική Θέση τον ιδιωτικού χώρου: παρά την πύκνωση τον πολεοδομικού ιστού, χαρακτηριστικά είναι τα οικόπεδα που περιέχούν ακόμα μεμονωμένα σπίτια, μονώροφα ή διώροφα, επί προσώπου οδού, με ένα μεγάλο κήπο στο πίσω μέρος, που χωρίζονται από τα, γειτονικά οικόπεδα με ένα μαντρότοιχο πέτρινο ή από ωμές πλίνθους. Η Ερέτρια οφείλει λοιπόν να λάβει τη Θέση που της αξίζει στην ιστορία της Νεοελληνικής πολεοδομίας, εφόσον συμβάλλει στην καλύτερη κατανόηση των σχεδίων των δυο αυτών αδελφών πόλεων. Η μελέτη τον πολεοδομικού σχεδίού συμπληρώνεται από μια τυπολογική προσέγγιση των νεοκλασικών κτηρίων της Ερέτριας, η οποία υπογραμμίζει ακόμα περισσότερο την ιστορική αξία του συνόλου αυτού. Καθώς τα περισσότερα κτήρια απειλούνται με κατεδάφιση, με εξαίρεση λίγα από αυτά που είχαν την τύχη να συντηρούνται σωστά, μεταξύ 1994 και 2005, καταρτίστηκε ένα φωτογραφικό αρχείο των κτιρίων της Ερέτριας που χρονολογούνται στο 19° και στις αρχές τον 200υ αι., συμπληρωμένο και από παλιές φωτογραφίες. Από αυτό προκύπτει ότι οι μορφές κατ οι τεχνικές δομήσεως είναι αντιπροσωπευτικές της ιδιωτικής αρχιτεκτονικής κατά την εποχή της σύστασης τον Ελληνικού Κράτους. Τέλος, το γενικό ρυθμιστικό σχέδιο της Ερέτριας, που εκπονήθηκε στα 1975-1976 από μελετητική ομάδατης σχολής Αρχιτεκτόνων του Ομοσπονδιακού Πολυτεχνείου της Ζυρίχης, με την υποστήριξη της Ελβετικής Αρχαιολογικής Σχολής στην Ελλάδα., δημοσιεύεται εδώ για πρώτη φορά στην πλήρη μορφή του. Η παρούσα εργασία, αφορά ένα νεοκλασικό πολεοδομικό σύνολο, ταπεινό ίσως, αλλά αποτέλεσμα ενός φιλόδοξου πολεοδομικού σχεδιασμού, ο οποίος αποτελεί σημαντικό μάρτυρα του πολιτικού προγράμματος τον νεοσύστατού Ελληνικού Κράτους.

L'hémopéritoine spontané: diagnostic, pronostic et thérapeutiques possibles [Spontaneous hemoperitoneum: diagnosis, prognosis and possible therapeutics]

We report the case of a 58-year-old diabetic man admitted to the hospital in a comatose state due to medicamentous hypoglycemia in a context of hypovolemic acute renal failure. Hypovolemia was due to hemoperitoneum in a alcoholic patient with cirrhotic hepatic failure. CT-scan and arterial angiographies revealed a voluminous isolated hepatic mass with active bleeding suggesting the diagnosis of spontaneous bleeding from a hepatocellular carcinoma. The hemorrhage resolved after selective arterial embolization, but the patient died two weeks later from an infectious cause. The differential diagnosis of a spontaneous hemoperitoneum and possibilities of treatment in the case of ruptured hepatocellular carcinoma are discussed.

Biomarqueurs en immunologie générale [Biomarkers in clinical immunology].

In a current perspective of individualized medicine, biomarkers appear as a simple and readily available aid to assist clinicians in the identification and monitoring of diseases whose diagnosis is difficult. Basically, we know the limited performance of medical history and of clinical examination; therefore, the use of laboratory tests is often seen as the panacea to solve the clinical enigma. The purpose of this article is to analyze a few biomarkers commonly processed in the immunology laboratory (AAN, ANCA, anti-tTG, rheumatoid factor and anti-CCP) and to review the principle, the usefulness and the performance of these tests in specific clinical situations. We will see that, far from supplanting history and physical examination, these immunological biomarkers take their full value as a supplement to clinical information!