Ophtalmologie. Thérapie génique des rétinopathies héréditaires: premiers résultats [Gene therapy for hereditary eye diseases: where are we?]

Les résultats préliminaires de trois essais cliniques de thérapie génique d'une forme agressive de rétinite pigmentaire (l'amaurose congénitale de Leber) ont prouvé que le traitement des maladies dégénératives de la rétine par transfert de gène peut être sûr et efficace pour rétablir une fonction visuelle. Il faudra encore attendre les résultats à long terme de ces études pour que soit définitivement validée cette approche thérapeutique. Dans l'intervalle, il importe de se préparer à son introduction en ophtalmologie de façon à la rendre accessible à nos malades. Pratiquement cela revient à promouvoir: 1) le recrutement; 2) la caractérisation du phénotype et du génotype des sujets atteints et 3) la constitution d'un registre des rétinopathies héréditaires. Recently, preliminary results of three clinical gene therapy trials for early onset retinitis pigmentosa--Leber congenital amaurosis--suggested that treating this degenerative retinal disease by gene transfection can be safe and efficient to restore a visual function. The definitive validation of this therapeutic approach depends on the long-term results. The forthcoming availability of gene therapy in ophthalmology prompts the implementation: of 1) recruitment, 2) phenotyping and genotyping of affected patients, 3) and creation of a hereditary retinopathy registry.

Substance use and suicidal conduct: a study of adolescents hospitalized for suicide attempt and ideation.

AIM: To study the prevalence of psychoactive substance use disorder (PSUD) among suicidal adolescents, psychoactive substance intoxication at the moment of the attempt, and the association between PSUD at baseline and either occurrence of suicide or repetition of suicide attempt(s). METHODS: 186 adolescents aged 16 to 21 y hospitalized for suicide attempt or overwhelming suicidal ideation were included (T0); 148 of them were traced again for evaluations after 6 mo (T1) and/or 18 mo (T2). DSM-IV diagnoses were assessed each time using the Mini International Neuropsychiatric Interview. RESULTS: At T0, 39.2% of the subjects were found to have a PSUD. Among them, a significantly higher proportion was intoxicated at the time of the attempt than those without PSUD (44.3% vs 25.4%). Among the 148 adolescents who could be traced at either T1 or T2, two died from suicide and 30 repeated suicide attempts once or more times. A marginally significant association was found between death by suicide/repetition of suicide attempt and alcohol abuse/dependence at baseline (OR=3.3, 95% CI 0.7-15.0; OR=2.6, 95% CI 0.7-9.3). More than one suicide attempt before admission to hospital at T0 (OR=3.2, 95% CI 1.1-10.0) and age over 19 y at T0 (OR=3.2, 95% CI 1.1-9.2) were independently associated with the likelihood of death by suicide or repetition of suicide attempt. CONCLUSION: Among adolescents hospitalized for suicide attempt or overwhelming suicidal ideation, the risk of death or repetition of attempt is high and is associated with previous suicide attempts--especially among older adolescents--and also marginally associated with PSUD; these adolescents should be carefully evaluated for such risks and followed up once discharged from the hospital.

Length of hospital stay and postdischarge mortality in patients with pulmonary embolism: a statewide perspective

BACKGROUND: The optimal length of stay (LOS) for patients with pulmonary embolism (PE) is unknown. Although reducing LOS is likely to save costs, the effects on patient safety are unclear. We sought to identify patient and hospital factors associated with LOS and assess whether LOS was associated with postdischarge mortality. METHODS: We evaluated patients discharged with a primary diagnosis of PE from 186 acute care hospitals in Pennsylvania (January 2000 through November 2002). We used discrete survival models to examine the association between (1) patient and hospital factors and the time to discharge and (2) LOS and postdischarge mortality within 30 days of presentation, adjusting for patient and hospital factors. RESULTS: Among 15 531 patient discharges with PE, the median LOS was 6 days, and postdischarge mortality rate was 3.3%. In multivariate analysis, patients from Philadelphia were less likely to be discharged on a given day (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.73-0.93), as were black patients (OR, 0.88; 95% CI, 0.82-0.94).The odds of discharge decreased notably with greater patient severity of illness and in patients without private health insurance. Adjusted postdischarge mortality was significantly higher for patients with an LOS of 4 days or less (OR, 1.55; 95% CI, 1.21-2.00) relative to those with an LOS of 5 to 6 days. CONCLUSIONS: Several hospital and patient factors were independently associated with LOS. Patients with a very short LOS had greater postdischarge mortality relative to patients with a typical LOS, suggesting that physicians may inappropriately select patients with PE for early discharge who are at increased risk of complications

A cross-cultural study of the higher-order structures underlying personality disorders in French-speaking Africa and Switzerland

Most studies about the higher-order dimensions to be considered in order to parsimoniously describe Personality Disorders (PDs) have identified between two and four factors but there is still no consensus about their exact number. In this context, the cultural stability of these structures might be a criterion to be considered. The aim of this study was to identify stable higher-order structures of PD traits in a French-speaking African and Swiss sample (N = 2,711). All subject completed the IPDE screening questionnaire. Using Everett's criterion and conducting a series of principal component analyses, a cross-culturally stable two- and four-factor structure were identified, associated with a total congruence coefficient of respectively .98 and .94 after Procrustes rotation. Moreover, these two structures were also highly replicable across the four African regions considered, North Africa, West Africa, Central Africa, and Mauritius, with a mean total congruence coefficient of respectively .97 and .87. The four-factor structure presented the advantage of being similar to Livesely's four components and of describing the ten PDs more accurately.

Magnetic resonance imaging determinants of intraindividual variability in the elderly: combined analysis of grey and white matter.

Elderly individuals display a rapid age-related increase in intraindividual variability (IIV) of their performances. This phenomenon could reflect subtle changes in frontal lobe integrity. However, structural studies in this field are still missing. To address this issue, we computed an IIV index for a simple reaction time (RT) task and performed magnetic resonance imaging (MRI) including voxel based morphometry (VBM) and the tract based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in 61 adults aged from 22 to 88 years. The age-related IIV increase was associated with decreased fractional anisotropy (FA) as well as increased radial (RD) and mean (MD) diffusion in the main white matter (WM) fiber tracts. In contrast, axial diffusion (AD) and grey matter (GM) densities did not show any significant correlation with IIV. In multivariate models, only FA has an age-independent effect on IIV. These results revealed that WM but not GM changes partly mediated the age-related increase of IIV. They also revealed that the association between WM and IIV could not be only attributed to the damage of frontal lobe circuits but concerned the majority of interhemispheric and intrahemispheric corticocortical connections.

Analysis of organic volatile residues in 9 mm spent cartridges

Determining the time since discharge of spent cartridges found on a crime scene may be very useful in firearm investigations. The potential of small calibre munitions was barely studied before and this work did therefore focus on that problematic. The first step was to optimize the detection potential of solidphase microextraction (SPME) followed by gas chromatography coupled to a mass spectrometry detector (GC/MS). This allowed determining the organic volatile composition of empty cartridges immediately after a gunshot. Identification of 32 detected compounds was confirmed by the analysis of reference substances. Preliminary aging studies over 32 hours were carried out on selected target compounds to evaluate their potential for the dating of shotguns.

Positive control of swarming, rhamnolipid synthesis, and lipase production by the posttranscriptional RsmA/RsmZ system in Pseudomonas aeruginosa PAO1.

In Pseudomonas aeruginosa, the small RNA-binding, regulatory protein RsmA is a negative control element in the formation of several extracellular products (e.g., pyocyanin, hydrogen cyanide, PA-IL lectin) as well as in the production of N-acylhomoserine lactone quorum-sensing signal molecules. RsmA was found to control positively the ability to swarm and to produce extracellular rhamnolipids and lipase, i.e., functions contributing to niche colonization by P. aeruginosa. An rsmA null mutant was entirely devoid of swarming but produced detectable amounts of rhamnolipids, suggesting that factors in addition to rhamnolipids influence the swarming ability of P. aeruginosa. A small regulatory RNA, rsmZ, which antagonized the effects of RsmA, was identified in P. aeruginosa. Expression of the rsmZ gene was dependent on both the global regulator GacA and RsmA, increased with cell density, and was subject to negative autoregulation. Overexpression of rsmZ and a null mutation in rsmA resulted in quantitatively similar, negative or positive effects on target genes, in agreement with a model that postulates titration of RsmA protein by RsmZ RNA.

Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis.

BACKGROUND: Anti-TNFα agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. METHODS: We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFα agents. Appropriateness of the first-line anti-TNFα treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. RESULTS: Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. CONCLUSION: Appropriateness of first-line anti-TNFα therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFα agents.

Colposcopic evaluation after a repeat atypical squamous cells of undetermined significance (ASCUS) smear.

OBJECTIVES: Management of patients with atypical squamous cells of undetermined significance (ASCUS) remains controversial. We chose to repeat the Pap smear after four months. If ASCUS persisted in this second test, the patient was advised to undergo colposcopy. Our objective is to determine the clinical significance and the prediction of neoplasia among these patients through a colposcopic examination. METHODS: Of 29,827 patients who had a Pap smear, ASCUS were detected in 1387 (5%) and persisted in the repeat smear of 225 (16%). Colposcopy and an additional Pap smear were performed on 186 patients. RESULTS: Out of 186 colposcopic evaluations, 91 (49%) were normal and the patients had a negative Pap smear. Colposcopy was abnormal in 95/186 patients (51%) (Table 1). Histology of the directed biopsies revealed 38 (21%) low-grade squamous intraepithelial lesions (LSIL) and 17 (9%) high-grade squamous intraepithelial lesions (HSIL). Forty patients (21%) with normal biopsies had ASCUS for the third time in the Pap smear. CONCLUSIONS: Colposcopic evaluation after a repeated Pap smear with ASCUS is an appropriate cost-effective management. Finding 30% of LSIL or HSIL justifies this additional investigation.

Les stratégies politiques et foncières des grands propriétaires fonciers en action : études de cas

Ce cahier présente une analyse comparée de quatre études de cas menées au sein du projet consacré aux stratégies politiques et foncières des grands propriétaires fonciers suisses à l'IDHEAP en 2007-2008. Ces études de cas concernent le complexe immobilier de « La Maladière » à Neuchâtel, le pôle de développement économique du Wankdorf à Berne, le « Centre Boujean » à Bienne ainsi que la place d'armes de Thoune. De chacun de ces cas sont présentés la chronologie des événements, les étapes et régimes du projet, les configurations et stratégies des acteurs, les impacts sur la durabilité ainsi qu'une discussion des résultats à la lumière des hypothèses du projet. L'analyse comparée fait le point des configurations et stratégies des acteurs qui sont ensuite mises en relation avec les régimes institutionnels et la durabilité des usages du sol. L'un des messages principaux est que, aujourd'hui, on ne peut plus séparer l'aménagement du territoire du foncier si l'on veut atteindre les objectifs politiques du développement du territoire. Die vorliegende Publikation enthält eine vergleichende Analyse von vier Fallstudien, die im Rahmen des Projektes zu den Strategien der grossen Grundeigentümer der Schweiz im Bereich der Ausübung ihrer Eigentumsrechte und ihrer Interventionen auf der Ebene der Raumplanung durchgeführt wurden. Sie betreffen den Immobilienkomplex ,,La Maladière" in Neuenburg, den Entwicklungsschwerpunkt Wankdorf in Bern, das ,,Centre Boujean" in Biel und den Waffenplatz Thun. Die Zusammenfassungen der Fallstudien enthalten Angaben zur Chronologie der Ereignisse, zu den verschiedenen Etappen der Projektentwicklung und der entsprechenden Regime, zu den Akteurkonfigurationen und -strategien, zu den Auswirkungen der Projekte auf die nachhaltige Entwicklung sowie eine Diskussion der empirischen Befunde im Lichte der Projekthypothesen. Die vergleichende Analyse nimmt eine Typologie der Akteurkonfigurationen vor und diskutiert deren Folgen für die institutionellen Regime und für die nachhaltige Entwicklung der Ressource Boden. Eines der Hauptergebnisse liegt in der Feststellung, dass sich heute Raumplanung mehr den je mit den Bodeneigentumsverhältnissen befassen muss, um die beabsichtigten politischen Entwicklungsziele zu erreichen.

PchC thioesterase optimizes nonribosomal biosynthesis of the peptide siderophore pyochelin in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, the antibiotic dihydroaeruginoate (Dha) and the siderophore pyochelin are produced from salicylate and cysteine by a thiotemplate mechanism involving the peptide synthetases PchE and PchF. A thioesterase encoded by the pchC gene was found to be necessary for maximal production of both Dha and pyochelin, but it was not required for Dha release from PchE and could not replace the thioesterase function specified by the C-terminal domain of PchF. In vitro, 2-aminobutyrate, a cysteine analog, was adenylated by purified PchE and PchF proteins. In vivo, this analog strongly interfered with Dha and pyochelin formation in a pchC deletion mutant but affected production of these metabolites only slightly in the wild type. Exogenously supplied cysteine overcame the negative effect of a pchC mutation to a large extent, whereas addition of salicylate did not. These data are in agreement with a role for PchC as an editing enzyme that removes wrongly charged molecules from the peptidyl carrier protein domains of PchE and PchF.

Weekend versus weekday admission and mortality after acute pulmonary embolism.

BACKGROUND: Optimal management of acute pulmonary embolism (PE) requires medical expertise, diagnostic testing, and therapies that may not be available consistently throughout the entire week. We sought to assess whether associations exist between weekday or weekend admission and mortality and length of hospital stay for patients hospitalized with PE. METHODS AND RESULTS: We evaluated patients discharged with a primary diagnosis of PE from 186 acute care hospitals in Pennsylvania (January 2000 to November 2002). We used random-effect logistic models to study the association between weekend admission and 30-day mortality and used discrete survival models to study the association between weekend admission and time to hospital discharge, adjusting for hospital (region, size, and teaching status) and patient factors (race, insurance, severity of illness, and use of thrombolytic therapy). Among 15 531 patient discharges with PE, 3286 patients (21.2%) had been admitted on a weekend. Patients admitted on weekends had a higher unadjusted 30-day mortality rate (11.1% versus 8.8%) than patients admitted on weekdays, with no difference in length of stay. Patients admitted on weekends had significantly greater adjusted odds of dying (odds ratio 1.17, 95% confidence interval 1.03 to 1.34) than patients admitted on weekdays. The higher mortality among patients hospitalized on weekends was driven by the increased mortality rate among the most severely ill patients. CONCLUSIONS: Patients with PE who are admitted on weekends have a significantly higher short-term mortality than patients admitted on weekdays. Quality-improvement efforts should aim to ensure a consistent approach to the management of PE 7 days a week.