Ocular and systemic bio-distribution of rhodamine-conjugated liposomes loaded with VIP injected into the vitreous of Lewis rats.

PURPOSE: Local delivery of therapeutic molecules encapsulated within liposomes is a promising method to treat ocular inflammation. The purpose of the present study was to define the biodistribution of rhodamine-conjugated liposomes loaded with vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, following their intravitreal (IVT) injection in normal rats. METHODS: Healthy seven- to eight-week-old Lewis male rats were injected into the vitreous with empty rhodamine-conjugated liposomes (Rh-Lip) or with VIP-loaded Rh-Lip (VIP-Rh-Lip; 50 mM of lipids with an encapsulation efficiency of 3.0+/-0.4 mmol VIP/mol lipids). Twenty-four h after IVT injection, the eyes, the cervical, mesenteric, and inguinal lymph nodes (LN), and spleen were collected. The phenotype and distribution of cells internalizing Rh-Lip and VIP-Rh-Lip were studied. Determination of VIP expression in ocular tissues and lymphoid organs and interactions with T cells in cervical LN was performed on whole mounted tissues and frozen tissue sections by immunofluorescence and confocal microscopy. RESULTS: In the eye, 24 h following IVT injection, fluorescent liposomes (Rh-Lip and VIP-Rh-Lip) were detected mainly in the posterior segment of the eye (vitreous, inner layer of the retina) and to a lesser extent at the level of the iris root and ciliary body. Liposomes were internalized by activated retinal M��ller glial cells, ocular tissue resident macrophages, and rare infiltrating activated macrophages. In addition, fluorescent liposomes were found in the episclera and conjunctiva where free VIP expression was also detected. In lymphoid organs, Rh-Lip and VIP-Rh-Lip were distributed almost exclusively in the cervical lymph nodes (LN) with only a few Rh-Lip-positive cells detected in the spleen and mesenteric LN and none in the inguinal LN. In the cervical LN, Rh-Lip were internalized by resident ED3-positive macrophages adjacent to CD4 and CD8-positive T lymphocytes. Some of these T lymphocytes in close contact with macrophages containing VIP-Rh-Lip expressed VIP. CONCLUSIONS: Liposomes are specifically internalized by retinal M��ller glial cells and resident macrophages in the eye. A limited passage of fluorescent liposomes from the vitreous to the spleen via the conventional outflow pathway and the venous circulation was detected. The majority of fluorescent liposomes deposited in the conjunctiva following IVT injection reached the subcapsular sinus of the cervical LN via conjuntival lymphatics. In the cervical LN, Rh-Lip were internalized by resident subcapsular sinus macrophages adjacent to T lymphocytes. Detection of VIP in both macrophages and T cells in cervical LN suggests that IVT injection of VIP-Rh-Lip may increase ocular immune privilege by modulating the loco-regional immune environment. In conclusion, our observations suggest that IVT injection of VIP-loaded liposomes is a promising therapeutic strategy to dampen ocular inflammation by modulating macrophage and T cell activation mainly in the loco-regional immune system.

A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.

PURPOSE: To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU). METHODS: EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues. RESULTS: After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13. CONCLUSIONS: This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.

Shorter time to diagnosis and improved stage at presentation in Swiss patients with retinoblastoma treated from 1963 to 2004

Rapport de synth��se : Le r��tinoblastome est la tumeur de l'oeil la plus fr��quente chez l'enfant. Un diagnostic pr��coce est important pour sauver le globe oculaire et la survie du patient. Le but de notre ��tude est de d��terminer l'��volution de l'intervalle diagnostique, c'est-��-dire le d��lai entre les premiers sympt��mes et la date du diagnostic officiel du r��tinoblastome, sur une p��riode de 40 ans en Suisse. Mat��riel et m��thode : Il s'agit d'une ��tude r��trospective faite sur 139 patients suisses trait��s pour r��tinoblastome durant trois diff��rentes p��riodes : (1) 1963-1983 ; (2) 1984-1993 ; et (3) 1994-2004. On compare certaines caract��ristiques : le sexe du patient, la lat��ralit�� de la maladie, les premiers sympt��mes, leurs observateurs, l'intervalle diagnostique, l'��ge au diagnostic, le stade de la maladie, l'histoire familiale. R��sultats : 37 patients (26.6%) ont ��t�� trait��s dans la premi��re p��riode ; 44 (31.7%) dans la p��riode 2 et 58 (41.7%) dans la p��riode 3. L'intervalle diagnostique diminue de fa��on significative de 6.97 mois dans la p��riode 1 �� 3.58 dans la p��riode 2 �� 2.25 dans la p��riode 3 pour le total des malades. Ceci reste significatif pour les r��tinoblastomes unilat��raux. De plus, dans ce m��me groupe, on observe une diminution significative des stades avanc��s de la maladie, groupe E selon Murphree (61.5% dans la p��riode 1 ; 46.7% dans la p��riode 2 et 22.2 % dans la p��riode 3). Lorsque la maladie est bilat��rale, les m��mes observations se font de fa��on un peu moins marqu��e. Il n'y a aucun patient diagnostiqu�� au stade E de la maladie en pr��sence d'une anamn��se familiale positive. Leucocorie (48.2%) et strabisme (20.1 %) sont les sympt��mes les plus fr��quents durant les 3 p��riodes. Les seuls facteurs qui influencent significativement le risque d'avoir un stade E de la maladie sont la dur��e de l'intervalle diagnostic et la p��riode de diagnostic. Conclusion : On constate un progr��s dans le diagnostic du r��tinoblastome en Suisse, surtout lors de maladie unilat��rale. De m��me, des am��liorations sont not��es dans la maladie bilat��rale mais de fa��on non significative. Il est donc important de mieux enseigner aux m��decins �� reconna��tre les sympt��mes oculaires de la maladie et �� r��f��rer les patients plus t��t aux sp��cialistes. Abstract : OBECTIVES : Retinoblastoma is the most frequent intraocular malignancy in children. Early diagnosis is essential for globe salvage and patient survival. The aim of our study was to determine how time to diagnosis of retinoblastoma has evolved over a 40-year period in Switzerland. METHOD AND PATIENTS : A retrospective study of 139 Swiss patients with retinoblastoma was performed comparing 3 periods: (1) 1963-1983; (2) 1984-1993; and (3) 1994-2004. Factors taken into account were gender, laterality of ret��noblastoma, age at first symptoms, type and first observer of symptoms, time to diagnosis, age at diagnosis, disease stage, and family history. RESULTS : Thirty-seven patients (26.6%) were treated in period 1, 44 (31.7%) in period 2, and S8 (41.7%) in period 3.Overall, the diagnostic interval decreased in a significant way from 6.97 months in period 1 to 3.58 in period 2 and to 2.25 in period 3. When looking separately at unilateral and bilateral disease, the decrease o�� the diagnostic interval remained statistically significant in unilateral retinoblastoma; there was also a significant reduction in the number of patients with advanced group E disease (Murphree classification) (61.5% in period 1, 46.7% in period 2, 22.2% in period 3). In bilateral disease, the same observations were made to a lesser extent. However, there were no cases with group E disease in 10 patients with positive family history. Leukornria (48.2%) and strabismus (20.1 %) were the 2 most frequent symptoms throughout the 3 periods. The only factors that statistically influenced the chances of having a diagnosis of group E disease were the diagnostic interval and period of diagnosis. Conclusion : Progress has been made in the diagnosis of retinoblastoma in Switzerland, notably in unilateral disease. Improvement to a lesser extent has also been observed in bilateral cases but without statistical significance. Greater effort is needed to teach physians-in-training to recognize the importance of ocular symptoms and refer patients earlier.

Subconjunctival Injection of XG-102, a c-Jun N-Terminal Kinase Inhibitor Peptide, in the Treatment of Endotoxin-Induced Uveitis in Rats.

Abstract Purpose: XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design. METHODS: EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot. RESULTS: XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina. CONCLUSION: These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.

Entre hybris et m��lancolie : po��tique, esth��tique et usages de la liste dans le roman fran��ais contemporain (1963-2013)

Forme archa��que, pr��sente d��s l'aube de l'��criture; forme ergonomique, pr��sente autour de nous de mani��re bien plus courante que toute narration; la liste est un objet fascinant, qui ne d��voile jamais autant sa complexit�� que lorsqu'elle appara��t dans un cadre litt��raire. Un cadre permettant de questionner, en les confrontant, la liste et son ��nonciateur - son sujet. Qui parle quand une liste se dit? Que dit-elle de celui qui l'��nonce? Qui parle, lorsque la syntaxe se bouleverse au point de d��truire les hi��rarchies permettant habituellement de fixer au discours une origine, une destination, une reprise en charge? Il s'agira de r��pondre �� ces questions et donc de passer d'une po��tique �� une ��thique de la liste, afin de montrer que la description d'un tel objet est indissociable de sa contextualisation discursive, sa subjectivisation. Celle-ci traverse, par une constante m��talepse (glissement entre les instances de responsabilit�� du discours), tout le spectre des actants du texte-liste - de la figure d'auteur �� celle du lecteur. La sp��cificit�� de la liste litt��raire se d��porte alors dans un espace ��thique, puis bient��t thymique, constitu�� par un faisceau d'oppositions : par exemple, la liste peut ��tre ferm��e ou ouverte, hyper- ou hypolisible ; signe d'ordre (c'est l'inventaire, o�� �� l'item correspond la chose) comme de d��sordre (c'est l'accumulation prolif��rante). Mais le couple oppositionnel le plus f��cond est constitu�� par l'hybris et la m��lancolie: hybris, ou l'orgueil de croire �� une r��invention du monde par le pouvoir d'une juxtaposition sans limites. M��lancolie, ou miroitement du mot manquant, ��vidence de l'absence. C'est sous l'��gide de cette opposition que je traite un vaste corpus constitu�� de huit auteurs contemporains, marqu��s par un XXe si��cle catastrophique, o�� �� l'hybris pl��thorique de l'expression de la monstruosit�� et de l'abondance (J-M.G. Le Cl��zio, Georges Perec, Eric Chevillard) r��pond la m��lancolie d'une absence ontologique : identitaire (Patrick Modiano), ��pist��mologique (Pierre Senges) langagi��re (Pascal Quignard, Olivia Rosenthal), voire politique (Antoine Volodine).

R��union et d��sunions autour du cin��ma-v��rit�� : le MIPE-TV 1963 de Lyon

Au d��but des ann��es 1960, les documentaristes Jean Rouch, Mario Ruspoli, Richard Leacock, Robert Drew et Michel Brault se r��clament d'une proximit�� in��dite avec le r��el film�� et oeuvrent activement �� la cr��ation de nouvelles cam��ras l��g��res et synchrones: c'est le temps du �� cin��ma-v��rit�� �� qui d��cha��ne en France de vives pol��miques. En mars 1963, constructeurs d'appareils, cin��astes et journalistes sont invit��s par Pierre Schaeffer �� discuter de ces questions lors des Journ��es d'Etudes du MIPE-TV. Cette manifestation, moment nodal du �� cin��ma-v��rit�� ��, est l'occasion de se r��unir autour des nouvelles techniques l��g��res, mais aussi de d��battre des enjeux ��thiques et moraux de ce cin��ma et de prendre position sur la controverse terminologique qui oppose les partisans de l'expression consensuelle �� cin��ma direct �� aux adeptes de la notion pol��mique �� cin��ma-v��rit�� ��.

�� Saturer les esprits �� việt cộng par la propagande : l'incitation �� la d��fection dans le programme chi��u hồi

Lanc�� en 1963 par le pr��sident Ng�� ����nh Diệm, le programme chi��u hồi visait �� susciter des d��fections dans les rangs Vi��t cộng. Sa premi��re phase, dite de persuasion, consistait en un intense effort de propagande r��alis�� par le largage de milliards de tracts, la diffusion de messages par haut-parleur a��rien, l'affichage de banderoles ou de posters et plus g��n��ralement l'utilisation de tous les canaux de communication possibles. S'y ajoutait le d��ploiement d'unit��s de propagande arm��es, compos��es d'anciens Vi��t cộng, charg��es de plus particuli��rement cibler les groupes prioritairement vis��s par les messages du programme. Le programme chi��u hồi fut la plus massive des op��rations psychologiques conduites lors de la guerre du Vietnam et sans doute la plus importante des actions de guerre psychologique de l'histoire.