Patients with AIDS-defining cancers are not universally screened for HIV: a 10-year retrospective analysis of HIV-testing practices in a Swiss university hospital.

OBJECTIVES: Kaposi's sarcoma (KS), invasive cervical carcinoma (ICC) and non-Hodgkin lymphoma (NHL) have been listed as AIDS-defining cancers (ADCs) by the Centers for Disease Control and Prevention since 1993. Despite this, HIV screening is not universally mentioned in ADC treatment guidelines. We examined screening practices at a tertiary centre serving a population where HIV seroprevalence is 0.4%. METHODS: Patients with KS, ICC, NHL and Hodgkin lymphoma (HL), treated at Lausanne University Hospital between January 2002 and July 2012, were studied retrospectively. HIV testing was considered part of the oncology work-up if performed between 90 days before and 90 days after the cancer diagnosis date. RESULTS: A total of 880 patients were examined: 10 with KS, 58 with ICC, 672 with NHL and 140 with HL. HIV testing rates were 100, 11, 60 and 59%, and HIV seroprevalence was 60, 1.7, 3.4 and 5%, respectively. Thirty-seven patients (4.2%) were HIV-positive, of whom eight (22%) were diagnosed at oncology work-up. All newly diagnosed patients had CD4 counts < 200 cells/μL and six (75%) had presented to a physician 12-236 weeks previously with conditions warranting HIV testing. CONCLUSIONS: In our institution, only patients with KS were universally screened. Screening rates for other cancers ranged from 11 to 60%. HIV seroprevalence was at least fourfold higher than the population average. As HIV-positive status impacts on cancer patient medical management, HIV screening should be included in oncology guidelines. Further, we recommend that opt-out screening should be adopted in all patients with ADCs and HL.

"Tanti e sì fatti suoni un suono esprime" : metrica e stile della Gerusalemme Liberata

La prima parte della ricerca è un approfondito studio dell'endecasillabo della Gerusalemme Liberata: in particolar modo, analizzo con un metodo statistico-quantitativo morfologia prosodica e tipologie del verso epico tassiano e distribuzione dei diversi tipi ritmici all'interno dell'ottava, tenendo naturalmente conto della necessaria connessione tra fisionomia ritmico-prosodica del verso e le strutture retoriche e sintattiche. Tale analisi, condotta con una prospettiva comparativa nei confronti di altre opere tassiane (Rinaldo, Conquistata) e della precedente tradizione in ottave, porta a riscontrare delle linee evolutive coerenti nella direzione di un progressivo innalzamento verso il modello lirico petrarchesco e dellacasiano e di un complessivo 'aggravamento' delle strutture stilistiche. I risultati permettono di mettere in discussione la vulgata critica che considererebbe monotono l'endecasillabo della Liberata: questo è negato, oltre che dall'evidenza delle statistiche, dal piano melodico e intonativo del verso, dato che diversi fattori stilistici interagenti (inarcature; struttura prevalentemente paratattica; dispositio molto mossa; moltiplicazione delle pause interne al verso) contribuiscono a minare la stabilità intonativa dell'endecasillabo, nella direzione del contrappunto tra movimento della frase e cadenze del verso. Analogamente, lo studio della fisionomia dell'ottava (seconda parte della ricerca) mostra da un lato il mantenimento di un modello di stanza 'pari', sostanzialmente affine al modello ariostesco, dall'altro una disposizione dei materiali verbali tesa a sommuovere internamente l'incedere per distici. Questo è legato alla strategia narrativa, di disposizione delle sequenze diegetiche: si possono infatti notare sovente aggregazioni di distici la cui continuità logico-argomentativa travalica la misura dell'ottava, rinnovando il rapporto dinamico e contrappuntistico tra forme metriche e fluire della narrazione. Ciò ha una funzione solidale proprio con lo sviluppo narrativo, dato che diversi espedienti stilistici paiono concorrere alla realizzazione di quella varietà nell'unità aristotelicamente centrale nell'elaborazione teorica tardocinquecentesca e tassiana in particolare. Nella terza parte del lavoro, infine, provo ad allontanare la lente dalla microscopia metrica e cerco di porre in relazione i dati metrico-stilistici con quelli sintattico-retorici già studiati dalla critica, provando a verificare nella concreta prassi poetica la teoria della commistione degli stili, così come viene progressivamente definendosi nella ricca produzione teorica del Tasso: centrale è la questione del dosaggio di artifici simmetrici, tipici del genere lirico, e asimmetrici, caratteristici dello stile grave, dosaggio coerente che si rivela in grado di illuminare da una prospettiva appunto stilistica le oscillazioni e le screziature del più grande poema tardorinascimentale.

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Patients with AIDS-defining cancers are not universally screened for HIV: a 10-year retrospective analysis of HIV-testing practices in a Swiss university hospital.

OBJECTIVES: Kaposi's sarcoma (KS), invasive cervical carcinoma (ICC) and non-Hodgkin lymphoma (NHL) have been listed as AIDS-defining cancers (ADCs) by the Centers for Disease Control and Prevention since 1993. Despite this, HIV screening is not universally mentioned in ADC treatment guidelines. We examined screening practices at a tertiary centre serving a population where HIV seroprevalence is 0.4%. METHODS: Patients with KS, ICC, NHL and Hodgkin lymphoma (HL), treated at Lausanne University Hospital between January 2002 and July 2012, were studied retrospectively. HIV testing was considered part of the oncology work-up if performed between 90 days before and 90 days after the cancer diagnosis date. RESULTS: A total of 880 patients were examined: 10 with KS, 58 with ICC, 672 with NHL and 140 with HL. HIV testing rates were 100, 11, 60 and 59%, and HIV seroprevalence was 60, 1.7, 3.4 and 5%, respectively. Thirty-seven patients (4.2%) were HIV-positive, of whom eight (22%) were diagnosed at oncology work-up. All newly diagnosed patients had CD4 counts < 200 cells/μL and six (75%) had presented to a physician 12-236 weeks previously with conditions warranting HIV testing. CONCLUSIONS: In our institution, only patients with KS were universally screened. Screening rates for other cancers ranged from 11 to 60%. HIV seroprevalence was at least fourfold higher than the population average. As HIV-positive status impacts on cancer patient medical management, HIV screening should be included in oncology guidelines. Further, we recommend that opt-out screening should be adopted in all patients with ADCs and HL.

Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.

Summary.  Background and objectives: Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. Methods: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. Results: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated MGP levels. Phosphorylated MGP was also found to be present in the first KS patient originally described. Conclusions: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.

Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death.

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS). HHV-8 encodes an antiapoptotic viral Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (vFLIP/K13). The antiapoptotic activity of vFLIP/K13 has been attributed to an inhibition of caspase 8 activation and more recently to its capability to induce the expression of antiapoptotic proteins via activation of NF-kappaB. Our study provides the first proteome-wide analysis of the effect of vFLIP/K13 on cellular-protein expression. Using comparative proteome analysis, we identified manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant and an important antiapoptotic enzyme, as the protein most strongly upregulated by vFLIP/K13 in endothelial cells. MnSOD expression was also upregulated in endothelial cells upon infection with HHV-8. Microarray analysis confirmed that MnSOD is also upregulated at the RNA level, though the differential expression at the RNA level was much lower (5.6-fold) than at the protein level (25.1-fold). The induction of MnSOD expression was dependent on vFLIP/K13-mediated activation of NF-kappaB, occurred in a cell-intrinsic manner, and was correlated with decreased intracellular superoxide accumulation and increased resistance of endothelial cells to superoxide-induced death. The upregulation of MnSOD expression by vFLIP/K13 may support the survival of HHV-8-infected cells in the inflammatory microenvironment in KS.

Prioritizing genetic testing in patients with kallmann syndrome using clinical phenotypes.

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment.

Objective: To evaluate the degree of E-2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments.Design: Retrospective and prospective studies.Setting: Academic institution.Patient(s): Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Intervention(s): Serum sex hormone-binding globulin (SHBG) and total E-2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined.Main Outcome Measure(s): Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS.Result(s): TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n = 91) than in controls (n = 63) and in patients with KS (n = 45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E-2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E-2 were very significantly higher in patients with CHH receiving T enanthate (n = 101) or the FSH-hCG combination (n = 88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCGtherapy significantly and prospectively increased TE2 levels in patients with CHH.Conclusion(s): Contrary to KS, the male hypogonadism observed in CHH is associated with profound E-2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy. (Fertil Steril (R) 2011; 95: 2324-29. (C) 2011 by American Society for Reproductive Medicine.)

Understanding mutational and selective processes that govern gene duplication in mammals

Abstract : Gene duplication is an essential source of material for the origin of genetic novelties. The reverse transcription of source gene mRNA followed by the genomic insertion of the resulting cDNA - retroposition - has provided the human genome with at least ~3600 detectable retrocopies. We find that ~30% of these retrocopies are transcribed, generally in testes. Their transcription often relies on preexisting regulatory elements (or open chromatin) close to their insertion site, which is illustrated by mRNA molecules containing retrocopies fused to their neighboring genes. Retrocopies appear to have been profoundly shaped by selection. Consistently, human retrocopies with an intact open reading (ORF) are more often transcribed than retropseudogenes, which leads to a minimal estimate of 120 functional retrogenes present in our genome. We also performed an analysis of Ka/Ks for human retrocopies. This analysis demonstrates that several intact retrocopies evolved under purifying selection and yields an estimated formation rate of ~1 retrogene per million year in the primate lineage. Using DNA sequencing and evolutionary simulations, we have identified 7 such primate-specific retrogenes that emerged on the lineage leading to humans In therian genomes, we found an excess of retrogenes with X-linked parents. Expression analyses support the idea that this "out of X" movement was driven by natural selection to produce autosomal functional counterparts for X-linked genes, which are silenced during male meiosis. Phylogenetic dating of this "out of X" movement suggests that our sex chromosomes arose about 180 MYA ago and are thus much younger than previously thought. Finally, we have also analyzed young gene duplications (and deletions) that arose by non allelic-homologous recombination and are not fixed in species. Using wild-caught and laboratory animals, we detected thousands of DNA segments that are polymorphic in copy number in mice. These copy number variants were found to profoundly alter the transcriptome of several mouse tissues. Strikingly, their influence on gene expression is not limited to the gene they contain but seems to extend to genes located up to 1.5 million bases away.

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.

BACKGROUND: The advent of highly active antiretroviral therapy (HAART) in 1996 led to a decrease in the incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL), but not of other cancers, among people with HIV or AIDS (PWHA). It also led to marked increases in their life expectancy. METHODS: We conducted a record-linkage study between the Swiss HIV Cohort Study and nine Swiss cantonal cancer registries. In total, 9429 PWHA provided 20,615, 17,690, and 15,410 person-years in the pre-, early-, and late-HAART periods, respectively. Standardised incidence ratios in PWHA vs the general population, as well as age-standardised, and age-specific incidence rates were computed for different periods. RESULTS: Incidence of KS and NHL decreased by several fold between the pre- and early-HAART periods, and additionally declined from the early- to the late-HAART period. Incidence of cancers of the anus, liver, non-melanomatous skin, and Hodgkin's lymphoma increased in the early- compared with the pre-HAART period, but not during the late-HAART period. The incidence of all non-AIDS-defining cancers (NADCs) combined was similar in all periods, and approximately double that in the general population. CONCLUSIONS: Increases in the incidence of selected NADCs after the introduction of HAART were largely accounted for by the ageing of PWHA.

Distribution of arm velocity and frequency of arm usage during daily activity: objective outcome evaluation after shoulder surgery.

In clinical settings, functional evaluation of shoulder movement is primarily based on what the patient thinks he/she is able to do rather than what he/she is actually performing. We proposed a new approach for shoulder assessment based on inertial sensors to monitor arm movement in the daily routine. The detection of movement of the humerus relative to the trunk was first validated in a laboratory setting (sensitivity>95%, specificity>97%). Then, 41 control subjects and 21 patients suffering from a rotator cuff tear were evaluated (before and after surgery) using clinical questionnaires and a one-day measurement of arm movement. The quantity of movement was estimated with the movement frequency and its symmetry index (SIFr). The quality of movement was assessed using the Kolmogorov-Smirnov distance (KS) between the cumulative distribution of the arm velocity for controls and the same distribution for each patient. SIFr presented differences between patients and controls at 3 month follow-up (p<0.05) while KS showed differences also after 6 months (p<0.01). SIFr illustrated a change in dominance due to the disorder whereas KS, which appeared independent of the dominance and occupation, showed a change in movement velocity. Both parameters were correlated to clinical scores (R(2) reaching 0.5). This approach provides clinicians with new objective parameters for evaluating the functional ability of the shoulder in daily conditions, which could be useful for outcome assessment after surgery.

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. Design and Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

Variations in PROKR2, But Not PROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia.

Context:Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).Objective:We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.Results:We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C-the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2(-/-) mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2(-/-) mice.Conclusions:The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.

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.