Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma.

BACKGROUND:: Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients. METHODS:: The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit. RESULTS:: Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a peroperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula. CONCLUSION:: Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy.

Traces of functions in Fock spaces on lattices of critical density

Following a scheme of Levin we describe the values that functions in Fock spaces take on lattices of critical density in terms of both the size of the values and a cancelation condition that involves discrete versions of the Cauchy and Beurling-Ahlfors transforms.

Uniform estimates in the Poincare-Aronszajn theorem on the separation of singularities of analytic functions

We study the possibility of splitting any bounded analytic function $f$ with singularities in a closed set $E\cup F$ as a sum of two bounded analytic functions with singularities in $E$ and $F$ respectively. We obtain some results under geometric restrictions on the sets $E$ and $F$ and we provide some examples showing the sharpness of the positive results.

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver.

Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.

On the retinal toxicity of intraocular glucocorticoids.

Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids is used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular edema, inflammation and neovascularization. The most commonly used glucocorticoid is triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied, non-common, but deleterious effects of glucocorticoids on the retina. We found that the intravitreal administration of TA is beneficial in the treatment of neovascularization because it triggers cell death of endothelial cells of neovessels by a caspase-independent mechanism. However, this treatment is toxic for the retina because it induces a non-apoptotic, caspase-independent cell death related to paraptosis, mostly in the retinal pigmented epithelium cells and the Müller cells.

Hardy’s inequalities for monotone functions on partly ordered measure spaces

We characterize the weighted Hardy inequalities for monotone functions in Rn +. In dimension n = 1, this recovers the standard theory of Bp weights. For n > 1, the result was previously only known for the case p = 1. In fact, our main theorem is proved in the more general setting of partly ordered measure spaces.

Distinct profiles of cytotoxic granules in memory CD8 T cells correlate with functions, differentiation stage, and antigen exposure

RAPPORT DE SYNTHÈSE : Les profils des granules cytotoxiques des cellules T CD8 mémoires sont corrélés à la fonction, à leur état de différentiation et à l'exposition à l'antigène. Les lymphocytes T-CD8 cytotoxiques exercent leur fonction antivirale et antitumorale surtout par la sécrétion des granules cytotoxiques. En général, ce sont l'activité de dégranulation et les granules cytotoxiques (contenant perforine et différentes granzymes) qui définissent les lymphocytes T-CD8 cytotoxiques. Dans cette étude, nous avons investigué l'expression de granzyme K par cytométrie en flux, en comparaison avec l'expression de granzyme A, granzyme B et de perforine. L'expression des granules cytotoxiques a été déterminée dans lymphocytes T-CD8 qui étaient spécifiques pour des différents virus, en particulier spécifique pour le virus d'influenza (flu), le virus Ebstein Barr (EBV), le virus de cytomégalie (CMV) et le virus de l'immunodéficience humaine (HIV). Nous avons observé une dichotomie entre l'expression du granzyme K et de la perforine dans les lymphocytes T-CD8 qui étaient spécifiques aux virus mentionnés. Les profils des lymphocytes T-CD8 spécifiques à flu étaient positifs soit pour granzyme A et granzyme K soit pour le granzyme K seul, mais dans l'ensemble négatifs pour perforine et granzyme B. Les cellules spécifiques à CMV étaient dans la plupart positives pour perforine, granzyme B et A, mais négatives pour le granzyme K. Les cellules spécifiques à EBV et HIV étaient dans la majorité positives pour granzyme A, B et K, et dans la moitié des cas négatives pour la perforine. Nous avons également analysé, selon les marqueurs de mémoire de CD45 et CD127, les profils de différentiation cellulaire: Les cellules avec les granules cytotoxiques contenant exclusivement le granzyme K, étaient associées à un état de différentiation précoce. Au contraire, les protéines cytolytiques perforine, granzyme A et B, correspondent à une différentiation avancée. En outre, les protéines perforine et granzyme B, mais pas les granzymes A et K, sont corrélées à une activité cytotoxique. Finalement, des changements dans l'exposition d'antigène in vitro et in vivo suivant une infection primaire d' HIV ou une vaccination modulent le profil de granules cytotoxiques. Ces résultats nous permettent d'étendre la compréhension de la relation entre les différents profils de granules cytotoxiques des lymphocytes T-CD8 et leur fonction, leur état de différentiation et l'exposition à l'antigène.

Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions.

The peroxisome proliferator-activated receptors (PPARs) are fatty acid and eicosanoid inducible nuclear receptors, which occur in three different isotypes. Upon activator binding, they modulate the expression of various target genes implicated in several important physiological pathways. During the past few years, the identification of both PPAR ligands, natural and synthetic, and PPAR targets and their associated functions has been one of the most important achievements in the field. It underscores the potential therapeutic application of PPAR-specific compounds on the one side, and the crucial biological roles of endogenous PPAR ligands on the other.

Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions.

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+ T-lymphocyte subsets, RA+CCR7-27+28+ and RA+CCR7-27+28-, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon gamma, and tumor necrosis factor alpha. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

Depistage mutationnel des genes de la peripherine/RDS, rhodopsine et ROM-1 dans 69 cas index de retinite pigmentaire et autres dystrophies retiniennes [Mutational screening of peripherin/RDS genes, rhodopsin and ROM-1 in 69 index cases with retinitis pigmentosa and other retinal dystrophies]

PURPOSE: Phenotypic, genetic and molecular characterization of 69 index patients with retinitis pigmentosa (RP) and various inherited retinal diseases. PATIENTS AND METHOD: patients went through complete ocular examination and blood samples were drawn for mutational screening of three candidate genes: rhodopsin (RHO), peripherin/RDS, and ROM-1. RESULTS: the most frequent type of RP among our population was the autosomal dominant (43.6%). Three RHO mutations were found among the RP patients. A RDS mutation was detected in three unrelated families segregating dominant macular dystrophy. DISCUSSION AND CONCLUSIONS: 18% of the autosomal dominant RP patients presented a RHO mutation; RDS R172W mutation was present in 25% of the dominant macular dystrophies.

Functions for estimating stem diameter and tree age using tree height, crown width and existing stand database information

Abstract