Human fetal bone cells in delivery systems for bone engineering.

The aim of this study was to culture human fetal bone cells (dedicated cell banks of fetal bone derived from 14 week gestation femurs) within both hyaluronic acid gel and collagen foam, to compare the biocompatibility of both matrices as potential delivery systems for bone engineering and particularly for oral application. Fetal bone cell banks were prepared from one organ donation and cells were cultured for up to 4 weeks within hyaluronic acid (Mesolis(®)) and collagen foams (TissueFleece(®)). Cell survival and differentiation were assessed by cell proliferation assays and histology of frozen sections stained with Giemsa, von Kossa and ALP at 1, 2 and 4 weeks of culture. Within both materials, fetal bone cells could proliferate in three-dimensional structure at ∼70% capacity compared to monolayer culture. In addition, these cells were positive for ALP and von Kossa staining, indicating cellular differentiation and matrix production. Collagen foam provides a better structure for fetal bone cell delivery if cavity filling is necessary and hydrogels would permit an injectable technique for difficult to treat areas. In all, there was high biocompatibility, cellular differentiation and matrix deposition seen in both matrices by fetal bone cells, allowing for easy cell delivery for bone stimulation in vivo. Copyright © 2011 John Wiley & Sons, Ltd.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis.

BACKGROUND: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. METHODS AND FINDINGS: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. CONCLUSIONS: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.

Harmonisation of short-term in vitro culture for the expansion of antigen-specific CD8(+) T cells with detection by ELISPOT and HLA-multimer staining.

Ex vivo ELISPOT and multimer staining are well-established tests for the assessment of antigen-specific T cells. Many laboratories are now using a period of in vitro stimulation (IVS) to enhance detection. Here, we report the findings of a multi-centre panel organised by the Association for Cancer Immunotherapy Immunoguiding Program to investigate the impact of IVS protocols on the detection of antigen-specific T cells of varying ex vivo frequency. Five centres performed ELISPOT and multimer staining on centrally prepared PBMCs from 3 donors, both ex vivo and following IVS. A harmonised IVS protocol was designed based on the best-performing protocol(s), which was then evaluated in a second phase on 2 donors by 6 centres. All centres were able to reliably detect antigen-specific T cells of high/intermediate frequency both ex vivo (Phase I) and post-IVS (Phase I and II). The highest frequencies of antigen-specific T cells ex vivo were mirrored in the frequencies following IVS and in the detection rates. However, antigen-specific T cells of a low/undetectable frequency ex vivo were not reproducibly detected post-IVS. Harmonisation of the IVS protocol reduced the inter-laboratory variation observed for ELISPOT and multimer analyses by approximately 20 %. We further demonstrate that results from ELISPOT and multimer staining correlated after (P < 0.0001 and R (2) = 0.5113), but not before IVS. In summary, IVS was shown to be a reproducible method that benefitted from method harmonisation.

Detection of smuggled cocaine in cargo using MDCT.

OBJECTIVE: Smuggling dissolved drugs, especially cocaine, in bottled liquids is an ongoing problem at borders. Common fluoroscopy of packages at the border cannot detect contaminated liquids. The objective of our study was to develop an MDCT screening method to detect cocaine-containing vessels that are hidden between uncontaminated ones in a shipment. MATERIALS AND METHODS: Studies were performed on three wine bottles containing cocaine solutions that were confiscated at the Swiss border. Reference values were obtained by scans of different sorts of commercially available wine and aqueous solutions of dissolved sugar. All bottles were scanned using MDCT, and data evaluation was performed by measuring the mean peak of Hounsfield units. To verify the method, simulated testing was performed. RESULTS: Using measurements of the mean peak of Hounsfield units enables the detection of dissolved cocaine in wine bottles in a noninvasive and rapid fashion. Increasing opacity corresponds well with the concentration of dissolved cocaine. Simulated testing showed that it is possible to distinguish between cocaine-contaminated and uncontaminated wine bottles. CONCLUSION: The described method is an efficacious screening method to detect cocaine-contaminated bottles that are hidden between untreated bottles in cargo. The noninvasive examination of cargo allows a questionable delivery to be tracked without arousing the suspicion of the smugglers.

Food-dependent Cushing's syndrome: possible involvement of leptin in cortisol hypersecretion.

Stimulation ofcortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing's syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing's syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing's syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing's syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Expression of brain-derived neurotrophic factor is not modulated by chronic mild stress in the rat hippocampus and amygdala.

Accumulating evidence supports a role for brain-derived neurotrophic factor (BDNF) in depression. However, most of these studies have been performed in animal models that have a low face validity with regard to the human disease. Here, we examined the regulation of BDNF expression in the hippocampus and amygdala of rats subjected to the chronic mild stress (CMS) model of depression, a paradigm that induces anhedonia, a core symptom of depression. We found that exposure of rats to the CMS paradigm did not modulate BDNF mRNA expression in the hippocampus and amygdala. In addition, chronic administration of imipramine, which reversed CMS-induced anhedonia, did not alter BDNF mRNA expression in these limbic structures.

Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.

Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Detection of Leishmania RNA virus in Leishmania parasites.

BACKGROUND: Patients suffering from cutaneous leishmaniasis (CL) caused by New World Leishmania (Viannia) species are at high risk of developing mucosal (ML) or disseminated cutaneous leishmaniasis (DCL). After the formation of a primary skin lesion at the site of the bite by a Leishmania-infected sand fly, the infection can disseminate to form secondary lesions. This metastatic phenotype causes significant morbidity and is often associated with a hyper-inflammatory immune response leading to the destruction of nasopharyngeal tissues in ML, and appearance of nodules or numerous ulcerated skin lesions in DCL. Recently, we connected this aggressive phenotype to the presence of Leishmania RNA virus (LRV) in strains of L. guyanensis, showing that LRV is responsible for elevated parasitaemia, destructive hyper-inflammation and an overall exacerbation of the disease. Further studies of this relationship and the distribution of LRVs in other Leishmania strains and species would benefit from improved methods of viral detection and quantitation, especially ones not dependent on prior knowledge of the viral sequence as LRVs show significant evolutionary divergence. METHODOLOGY/PRINCIPAL FINDINGS: This study reports various techniques, among which, the use of an anti-dsRNA monoclonal antibody (J2) stands out for its specific and quantitative recognition of dsRNA in a sequence-independent fashion. Applications of J2 include immunofluorescence, ELISA and dot blot: techniques complementing an arsenal of other detection tools, such as nucleic acid purification and quantitative real-time-PCR. We evaluate each method as well as demonstrate a successful LRV detection by the J2 antibody in several parasite strains, a freshly isolated patient sample and lesion biopsies of infected mice. CONCLUSIONS/SIGNIFICANCE: We propose that refinements of these methods could be transferred to the field for use as a diagnostic tool in detecting the presence of LRV, and potentially assessing the LRV-related risk of complications in cutaneous leishmaniasis.

A biophysical model of atrial fibrillation ablation: what can a surgeon learn from a computer model?

AIMS: Surgical ablation procedures for treating atrial fibrillation have been shown to be highly successful. However, the ideal ablation pattern still remains to be determined. This article reports on a systematic study of the effectiveness of the performance of different ablation line patterns. METHODS AND RESULTS: This study of ablation line patterns was performed in a biophysical model of human atria by combining basic lines: (i) in the right atrium: isthmus line, line between vena cavae and appendage line and (ii) in the left atrium: several versions of pulmonary vein isolation, connection of pulmonary veins, isthmus line, and appendage line. Success rates and the presence of residual atrial flutter were documented. Basic patterns yielded conversion rates of only 10-25 and 10-55% in the right and the left atria, respectively. The best result for pulmonary vein isolation was obtained when a single closed line encompassed all veins (55%). Combination of lines in the right/left atrium only led to a success rate of 65/80%. Higher rates, up to 90-100%, could be obtained if right and left lines were combined. The inclusion of a left isthmus line was found to be essential for avoiding uncommon left atrial flutter. CONCLUSION: Some patterns studied achieved a high conversion rate, although using a smaller number of lines than those of the Maze III procedure. The biophysical atrial model is shown to be effective in the search for promising alternative ablation strategies.

Evaluation des résultats du traitement chirurgical des luxations acromio-claviculaires de type III selon un score cinématique

Introduction : Le traitement des entorses acromio-claviculaires (AC) est aujourd'hui encore controversé. Les luxations AC avec lésion du fascia delto-trapézoidale (grade IV, V et VI) sont généralement traitées par une chirurgie de stabilisation. A l'inverse les entorses sans luxation de la clavicule (grade I et II) sont traitées conservativement avec de bons résultats. Il reste une interrogation concernant le traitement des luxations AC sans lésion du fascia delto-trapézoidale (grade III). Le but de notre étude est d'évaluer les résultats du traitement chirurgical des entorses AC de grade III selon un score cinématique. Matériel et Méthode : 30 patients avec une entorse AC de grade III ont été opérés d'une stabilisation de la clavicule entre 2003 et 2011 par le service d'Orthopédie et traumatologie du CHUV. Tous ont été cliniquement évalués selon le score de Constant. L'évaluation cinématique a été effectuée à l'aide d'un iPod touch, fixé sur l'humérus. Cet outil de mesure, décrit et validé par l'EPFL, prend en considération l'accélération et la vitesse angulaire du membre supérieur pour 7 différents mouvements des deux bras. L'évaluation cinématique a été effectuée en comparant le côté opéré par rapport au côté sain selon 2 scores (RAV et P) provenant de ces variables. Les scores RAV et P sont calculés par l'application installée sur l'iPod touch, ils sont donnés en pourcentage par rapport à l'épaule saine. Nous avons défini un score de Constant relatif de plus de 60 et un score cinématique de plus de 75% comme satisfaisant. Résultats : Nous avons revus dix patients avec un recul moyen de 36 mois (6 à 72 mois) d'un âge moyen de 42 ans (27 à 62 ans). Le score de Constant moyen est de 75.9 ± 21.7. Le score P moyen est de 89.3% ± 23.4 et le score RAV moyen est de 91.8% ± 15.8 (tab.1). Quatre sujets obtiennent un excellent score de Constant pour le bras opéré, 2 sujets obtiennent un bon score et un sujet obtient un score moyen, tandis que 3 sujets obtiennent un mauvais score. Huit patients obtiennent un score cinématique satisfaisant alors que nous observons 2 résultats non satisfaisants. Les mauvais résultats tant cliniques que cinématiques ont été observés chez des patients travailleurs de force, nécessitant d'effectuer des mouvements de l'épaule au-dessus du niveau du buste. Discussion et Conclusion : Sur la base d'une évaluation clinique et cinématique, le traitement chirugical des entorses AC de grade III donne des résultats satisfaisants. Notre étude ne comportant pas de groupe contrôle et notre série étant non homogène, avec un nombre limité de sujet, nous ne pouvons conclure que le traitement chirurgical est le traitement le mieux adapté aux patients avec une entorse acromio-claviculaires de type III. Nous recommandons toutefois un traitement chirugical chez les patients actifs, et les patients exerçant un métier avec nécessité de mobilisation de l'épaule au dessus du buste. Un travail manuel lourd représente un facteur de mauvais pronostic.

Contribution of major cardiovascular risk factors to familial premature coronary artery disease : the GENECARD project

Résumé: Objectifs: Cette étude relève la prévalence des principaux facteurs de risque cardiovasculaire dans les coronaropathies précoces (P-CAD) familiales, survenant chez au moins deux frères et/ou soeurs d'une même fratrie. Méthodes: Nous avons recruté 213 survivants atteints de P-CAD, issus de 103 fratries, diagnostiqués avant l'âge de 50 ans chez les hommes et 55 ans chez les femmes. La présence ou non d'hypertension, d'hypercholestérolémie, d'obésité et de tabagisme a été documentée au moment de l'événement chez 163 de ces patients (145 hommes et 18 femmes). Chaque patient a été comparé à deux individus de même âge et sexe, chez qui un diagnostic de P-CAD «sporadique» (non familiale) était posé, et à trois individus choisis au hasard parmi la population générale. Résultats: En comparaison de la population générale, les patients atteints de P-CAD sporadique avaient une prévalence supérieure pour 1 'hypertension (29% vs. 14%, p<0.001), le cholestérol (54% vs. 33%, p<0.001), l'obésité (20% vs. 13%, p<0.001) et le tabagisme (76% vs. 39%, p<0.001). Ces facteurs de risque étaient de prévalences similaires, voire supérieures chez les patients atteints de P-CAD familiale (43% [p<0.05 vs. P-CAD sporadiques], 58% [p=0.07], 21% et 72%) respectivement). Seulement 7 (4%) des 163 patients atteints de P-CAD familiale et 22 (7%) des 326 patients atteints de P-CAD sporadique, ne présentaient aucun facteur de risque cardiovasculaire, comparés à 167 (34%) des 489 patients issus de la population générale. Conclusions: Les facteurs de risque cardiovasculaire classiques et réversibles ont une haute prévalence chez les patients atteints de P-CAD familiale. Ce fait rend improbable une contribution génétique prédominante, agissant en l'absence de facteurs de risque. Abstract: Objectives: This study was designed to assess the prevalence of major cardiovascular risk factors in familial premature coronary artery disease (P-CAD), affecting two or more siblings within one sibship. Background: Premature CAD has a genetic component. It remains to be established whether familial P-CAD is due to genes acting independently from major cardiovascular risk factors. Methods: We recruited 213 P-CAD survivors from 103 sibships diagnosed before age ?50 (men) or ?55 (women) years old. Hypertension, hypercholesterolemia, obesity, and smoking were documented at the time of the event in 163 patients (145 men and 18 women). Each patient was compared with two individuals of the same age and gender, diagnosed with sporadic (nonfamilial) P-CAD, and three individuals randomly sampled from the general population. Results: Compared with the general population, patients with sporadic P-CAD had a higher prevalence of hypertension (29% vs. 14%, p < 0.001), hypercholesterolemia (54% vs. 33%, p < 0.001), obesity (20% vs. 13%, p < 0.001), and smoking (76% vs. 39%, p < 0.001). These risk factors were equally or even more prevalent in patients with familial P-CAD (43% [p < 0.05 vs. sporadic P-CAD], 58% [p = 0.07], 21% and 72%, respectively). Overall, only 7 (4%) of 163 of patients with familial P-CAD and 22 (7%) of 326 of patients with sporadic P-CAD had none of these conditions, as compared with 167 (34%) of 489 patients in the general population. Conclusions: Classic, remediable risk factors are highly prevalent in patients with familial P-CAD. Accordingly, a major contribution of genes acting in the absence of these risk factors is unlikely

Lignes ferroviaires régionales : ouvrir, fermer ou moderniser? : obstacles juridiques, techniques, géopolitiques ou absence de volonté politique? : études de quatre lignes ferroviaires franco-belges et franco-suisses

L'objectif de la présente étude est de cerner les facteurs de succès et d'échec des réouvertures et modernisations de lignes ferroviaires transfrontalières dans les zones limitrophes. L'enquête prend pour base deux lignes franco-belges (Mons-Valenciennes et Namur- Charleville-Mézières) et deux lignes franco-suisses (Delémont-Belfort et Neuchâtel- Besançon). Le problème public réside dans l'absence de moyens de transports publics exploitant le potentiel existant dans le bassin de vie concerné (sous-exploitation du marché des transports). Les obstacles à franchir dans le domaine des transports ferroviaires peuvent être de nature juridique. Ainsi, des prescriptions légales telles que certains standards d'interopérabilité, l'absence d'une définition de l'expression «train régional» au niveau européen, la sécurité (passages à niveau) ou des mesures en faveur des personnes à mobilité réduite, peuvent entraver, voire empêcher des réouvertures ou modernisations de lignes régionales, car ces standards ne sont pas adaptés à la réalité des lignes dont le potentiel est faible en termes de voyageurs et de fret. À un autre niveau, il est rare que les aspects techniques constituent des obstacles. C'est cependant le cas lorsque deux réseaux ferroviaires nourrissent des philosophies antagonistes (réseau cadencé et non cadencé). Pour la réouverture des lignes, on constate l'absence de définitions claires, au niveau politique, de la desserte de base et des seuils de fréquentation minimale. Il y a parfois un contraste marqué entre une infrastructure dégradée et un matériel roulant très moderne, signe d'absence de sensibilisation à l'entretien des infrastructures ferroviaires. Pourtant, ces infrastructures jouent un rôle important à l'échelon géopolitique. Correctement aménagées (offre, temps de parcours, correspondances), elles permettent le désenclavement de toute une région. La réouverture d'un chaînon manquant peut changer la position géopolitique d'une région, comme dans le cas de Mons-Valenciennes; mais en même temps, l'argument de l'impact géopolitique peut entraver une réouverture, même lorsqu'il n'est pas fondé, comme le montre le cas de Dinant-Givet qui semble concurrencer une autre ligne existante. L'impact des lignes à grande vitesse sur les régions limitrophes est souvent surestimé. En revanche, la praticabilité du concept des quatre capitaux (capital manufacturé, social, naturel et humain) est sous-estimée dans le domaine des transports publics. Les grilles d'analyse des quatre capitaux nous ont en effet permis de prouver l'applicabilité du concept aux lignes ferroviaires transfrontalières, en dépit du manque de me- surabilité de certains indicateurs. L'évaluation des lignes retenues à l'aide de notre grille d'analyse montre que les lignes régionales françaises accusent un lourd retard en termes de performance. Ce fait est confirmé dans les quatre capitaux. En appliquant notre méthode de planification à des lignes ferroviaires (transfrontalières), on observe que les lignes actuelles n'exploitent pas suffisamment leur potentiel. L'approche proposée se base sur le triangle «offre - infrastructure - matériel roulant» et s'articule autour des usagers. Avant toute planification, il faut développer une vision pour la région et la ligne concernée, dans laquelle la voie ferrée servira d'axe structurant. La vision se manifeste par un horaire qui traduit l'offre sou-haitée à long terme avec des temps de parcours idéaux, et des noeuds de correspondance avec d'autres moyens de transport. Alors, les lignes régionales peuvent contribuer à un changement de paradigme qui favorise un mode de vie axé davantage sur les services des transports publics que sur le transport individuel, également dans les régions limitrophes. - Het doel van deze Studie is het onderzocken von de redenen van het succès en van het falen van de heropening of modernisering van al of niet grensoverschrijdende spoorlijnen. Het on- derzoek is gebaseerd op twee Frans-Belgische lijnen (Bergen-Yalenciennes en Namen- Charleville-Mezières) en twee Frans-Zwitserse lijnen (Delémont-Belfort en Neuchâtel- Besançon). Het probleem is de afwezigheid van openbare transportmogelijkheden in de uitbating van de betrokken woongebieden (onderbenutting van de transportmarkt). De te overschrijden hindernissen op het gebied van spoorwegvervoer kunnen van juridische oorsprong zijn. Dat wil zeggen dat wettelijke vereisten zoals bepaalde standaarden voor inte- roperabiliteit, het ontbreken van een definitie van «regionale trein» op Europees niveau, de beveiliging (spoorwegovergangen) of maatregelen voor mensen met verminderde mobiliteit de heropening of modernisering van de regionale lijnen kunnen verhinderen, aangezien deze normen niet zijn aangepast aan de realiteit op aan de lijnen waarvan het potenti eel laag is, zowel voor reizigers als voor goederen. Op een ander niveau is het zeldzaam dat de technische as-pecten voor obstakels zorgen. Het is nochtans het geval wanneer twee spoorwegnetten zorgen voor tegenstrijdige ideeën (regelmatig of onregelmatig bezet net). Om de lijnen te he- ropenen, is er een gebrek aan duidelijke afspraken op politiek niveau, voor een minimale be- diening en een minimale opkomst. Soms is er een groot contrast tussen een verouderde infras- tructuur en een zeer modem rollend materieel, een teken van gebrek aan gezond verstand bij het onderhoud van de spoorweginfrastructuur. Deze infrastructuur speelt echter een belan- grijke roi in het geopolitieke niveau. Goed beheerd (aanbod, reistijd, verbindingen) zorgen ze voor een heropening van een hele regio. De heropening van een ontbrekende schakel kan de geopolitieke positie van een regio veranderen, zoals in het geval van Bergen-Valenciennes, maar terzelfder tijd kan het argument van de geopolitieke impact een heropening verhinderen, zelfs als het ongegrond is, zoals in het geval van Dinant-Givet dat blijkt te concurreren met een andere bestaande lijn. De impact van hogesnelheidslijnen op grensoverschrijdende regio's wordt vaak overschat. Daartegenover wordt de haalbaarheid van het concept van de vier kapi- taalvlakken (opbouwend, sociaal, natuurlijk en menselijk kapitaal) onderschat op het gebied van openbaar vervoer. De analyse van de vier kapitaalvlakken heeft ons toegelaten de toepas- baar-heid van het concept van de grensoverschrijdende spoorlijnen aan te tonen, ondanks het ge-brek aan meetbaarheid van bepaalde indicatoren. Evaluatie van de lijnen, geselecteerd met behulp van ons analysekader, heeft aangetoond dat Franse regionale lijnen achterblijven op het gebied van prestaties. Dit wordt bevestigd op de vier kapitaalvlakken. Door het toepassen van onze planningsmethode op spoorlijnen (in grenszones), zien we dat de huidige lijnen hun potentieel onvoldoende benutten. De voorgestelde aanpak is gebaseerd op de driehoek «aan- bieding - infrastructuur - rollend materieel» en rieht zieh op de gebruikers. Vooraleer een planning opgesteld kan worden, moeten we een visie ontwikkelen voor de betrokken lijn en de regio waarin de spoorweg zal dienen als structurele as. De visie baseert zieh op een diens- tregeling die uitgaat van een aanbod op lange termijn met ideale rijtijden en knooppunten met an-dere transportmiddelen. Zodoende kunnen regionale lijnen bijdragen aan een paradigma- vers-chuiving die een levensstijl promoot die meer gericht is op het openbaar vervoer dan op het individueel vervoer, ook in naburige regio's. - Das Ziel der Studie ist die Identifizierung von Erfolgs- und Misserfolgsfaktoren bei Wiedereröffnungen und Modernisierungen von (grenzüberschreitenden) Regionalverkehrslinien in Randregionen. Die Untersuchung stützt sich auf zwei belgisch-französische (Mons- Valenciennes und Namur-Charleville-Mézières) sowie zwei schweizerisch-französische Linien (Delémont-Belfort und Neuchâtel-Besançon). Das öffentliche Problem besteht im Fehlen eines öffentlichen Verkehrsmittels, welches das vorhandene Potential im Einzugsbereich der betrachteten Linien vollständig ausnützt (unvollständige Ausnützung des vorhandenen Transportmarktes). Die zu überwindenden Hindernisse auf dem Gebiet des Eisenbahnwesens können juristischer Natur sein. Es handelt sich dabei um gewisse juristische Vorschriften w. z. B. Interoperabili- tätsstandards, die Abwesenheit einer klaren Definition des Begriffes «Regionalverkehr» auf europäischer Ebene, Sicherheitsstandards (Bahnübergänge) oder Massnahmen zu Gunsten von Behinderten, die Wiedereröffnungen behindern können, weil diese Standards keine Rücksicht auf die Gegebenheiten von Regionallinien mit einem geringen Nachfragepotential nehmen. Technische Vorgaben stellen nur selten ein Hindernis bei Wiedereröffnungen dar. Dies kann dann der Fall sein, wenn zwei Eisenbahnnetze mit unterschiedlichen Betriebsphilosophien aufeinander treffen (Netz mit Taktverkehr und unvertaktete Netze). Bei Wiedereröffnung von Eisenbahnlinie ist festzustellen, dass auf politischer Ebene keine Definitionen in Bezug auf Basisangebot und der minimalen Nachfrage bestehen. Bisweilen ist ein starker Kontrast zwischen einem schlechten Infrastrukturzustand und einem darauf verkehrenden modernem Rollmaterial festzustellen. Gerade diese Infrastruktur spielt auf geopolitischer Ebene eine wichtige Rolle. Wird diese korrekt betrieben (attraktives Angebot, Fahrzeit, Umsteigeverbindungen), erlaubt sie einer ganzen Region eine Lösung aus der Isolation. Die Wiedereröffnung eines fehlenden Teilstücks kann die geopolitische Situation einer Region positiv verändern, wie das Beispiel der Linie Mons-Valenciennes zeigt. Gleichzeitig kann das Argument der geopolitischen Position eine Wiedereröffnung behindern, auch wenn die vorgebrachten Argumente nicht stichhaltig sind, wie das Beispiel der Linie Dinant-Givet beweist, die angeblich einen bestehenden Eisenbahgüterverkehrskorridor konkurrenzieren soll. Der Einfluss von Hochgeschwindigkeitsstrecken auf Randregionen wird oft überschätzt. Im Gegensatz dazu wird die Anwendbarkeit des Konzeptes der vier Kapitalien (konstruiertes, soziales, natürliches und Human-Kapital) bei der Anwendbarkeit im öffentlichen Verkehr unters-chätzt. Der verwendete Analyseraster der vier Kapitalien erlaubt die Anwendbarkeit dieses Ansatzes auf grenzüberschreitende Eisenbahnlinien, trotz des Fehlens von Daten für zahlreiche Indikatoren, zu untermauern. Die Evaluation der betrachteten Linien hat gezeigt, dass die französischen Schienenregionalverkehrslinien einen bedeutenden Rückstand in Bezug auf die Leistungsfähigkeit vorweisen. Dies wird durch die Anwendung des Analyseraster der vier Kapitalien bestätigt. Der Einsatz, der in dieser Arbeit entwickelten Planungsmethode auf die vier grenzüberschreitenden Regionalverkehrslinien hat gezeigt, dass die heutige Betriebsweise von Regionalverkehrslinien das vorhandene Potential nicht ausschöpft. Der vorgeschlagene Ansatz basiert auf dem Dreieck «Angebot - Infrastruktur - Rollmaterial» in dem die Benützerlnnen im Zentrum stehen. Jedoch steht die Entwicklung einer Vision für die betroffene Region und Linie vor dem Beginn jeder Planung im Zentrum, bei der die Eisenbahnlinie als strukturierende Achse benützt wird. Diese manifestiert sich in einer Fahrplanstruktur, die das langfristig gewünschte Angebot mit idealen Fahrzeiten und Umsteigeknoten mit anderen Verkehrsmitteln beinhaltet. In dieser Weise können die Regionalverkehrslinien einen Beitrag zu einem Paradigmawechsel beitragen, der auch in Randregionen einen Lebensstil fördert, der vermehrt auf den öffentlichen Verkehr als auf den motorisierten Individualverkehr setzt. - L'obiettivo di questo studio è quello di identificare i fattori di successo e di fallimento relativi alla riapertura e modernizzazione di linee ferroviarie transfrontaliere e non in aree limitrofe. L'indagine si basa su due linee franco-belghe (Mons-Valenciennes e Namur-Charleville- Mézières) e due linee franco-svizzere (Delémont-Belfort e Neuchâtel-Besançon). Il problema pubblico è la mancanza di mezzi di trasporto pubblico che sfruttino il potenziale esistente nel bacino d'utenza interessato (sottoutilizzazione del mercato dei trasporti). Gli ostacoli da superare nel settore del trasporto ferroviario possono essere di natura giuridica - vale a dire, requisiti legali come alcuni standard d'interoperabilità, l'assenza di una definizione del termine «treno regionale» a livello europeo, la sicurezza (passaggi a livello) o misure a favore di persone a mobilità ridotta, che possono ostacolare o impedire la riapertura o modernizzazione di linee regionali poiché queste norme non vengono adattate alla realtà delle linee il cui potenziale è basso in termini di viaggiatori e merci. A un altro livello è raro che aspetti tecnici costituiscano degli ostacoli. Tuttavia è il caso quando due reti ferroviarie perseguono filosofie antagoniste (rete cadenzata e non cadenzata). Per riaprire le linee si rileva una mancanza di definizioni chiare, a livello politico, del collegamento di base e delle soglie minime di frequentazione. A volte vi è un netto contrasto tra un'infrastruttura degradata e un modernissimo materiale rotabile, segno della mancanza di sensibilizzazione per la manutenzione delle infrastrutture ferroviarie. Eppure queste strutture svolgono un ruolo importante a livello geopolitico. Correttamente gestite (offerta, tempi di percorrenza, coincidenze), permettono l'apertura verso l'esterno di un'intera regione. La riapertura di un tassello mancante può cambiare la posizione geopolitica di una regione, come nel caso di Mons-Valenciennes. Allo stesso tempo, tuttavia, l'argomento dell'impatto geopolitico, anche se infondato, può ostacolare una riapertura - come nel caso di Dinant-Givet che sembra fare concorrenza a un'altra linea esistente. L'impatto delle linee ad alta velocità sulle regioni limitrofe è spesso sovrastimato. In compenso, l'attuabilità del concetto dei quattro capitali (capitale fabbricato, sociale, naturale e umano) è sottovalutata nel settore dei trasporti pubblici. Le griglie d'analisi dei quattro capitali ci hanno effettivamente permesso di dimostrare l'applicabilità del concetto alle linee ferroviarie transfrontaliere, nonostante la mancanza di misurabilità di alcuni indicatori. La valutazione delle linee selezionate in supporto alla nostra griglia d'analisi mostra che le linee regionali francesi accusano un pesante ritardo in termini di prestazioni. Questo dato di fatto è confermato nei quattro capitali. Applicando il nostro metodo di pianificazione alle linee ferroviarie (transfrontaliere), si osserva che le attuali linee non sfruttano a sufficienza il loro potenziale. L'approccio proposto è basato sul triangolo «offerta / infrastrutture / materiale rotabile» e si articola attorno agli utenti. Prima di qualsiasi pianificazione, è necessario sviluppare una visione per la regione e la linea coinvolta, in cui la ferrovia servirà come asse strutturale. La visione si manifesta attraverso un orario che rifletta l'offerta desiderata a lungo termine, con tempi di percorrenza ideali e nodi di coincidenza con altri mezzi di trasporto. In questo modo, le linee regionali possono contribuire a un cambiamento di paradigma che favorisca uno stile di vita più focalizzato sui servizi di trasporto pubblico che sul trasporto individuale - anche nelle regioni limitrofe.