[Use of targeting therapy in Erdheim-Chester disease: A case report with neurologic involvement]. / Utilisation de thérapie ciblée dans la maladie d'Erdheim-Chester : à propos d'un cas avec atteinte du système nerveux central.

INTRODUCTION: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68+ CD1a- histiocytes. The clinical and radiological presentation is very variable. CASE REPORT: We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity. CONCLUSION: Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

[Specific antibodies against Plasmodium falciparum antigens in immune subjects: I. Comparison of detection/titration methods]. / Anticorps spécifiques d'antigènes de Plasmodium falciparum chez les sujets immuns: I. Comparaison de méthodes de détection/titration.

We report a comparative study of specific antibody levels to the blood stages of P. falciparum in individuals living in two different areas with different transmission levels of malaria. We have compared 2 techniques for the detection/titration of antibodies i.e. ELISA and IFI, ELISA being particularly suitable for immuno-epidemiological related studies. A schizont lysate from P. falciparum infected red blood cells from FUP/CB Marburg strain as antigen proved usefullness, as compared with an antigen extracted from a local strain recently adapted to in vitro culture. Using these techniques, high specific antibody responses were found in the villagers' sera and mean levels of antibodies increased with age. Levels of specific IgG were comparable between those two locations, in spite of a ten fold higher level of transmission between the two villages. In contrast, a significantly higher level of IgM in adults living in holoendemic.

Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir.

PURPOSE: The retinal toxicity of single and repeated intravitreal injections of foscarnet was investigated. In addition, the effects of a combination of foscarnet and ganciclovir were studied, and a pharmacokinetic study to determine the ocular pharmacokinetics of foscarnet after intravitreal injection was carried out. METHODS: Forty rabbits (both albino and pigmented) were used in this study. The electroretinographic (ERG) a-waves and b-waves and oscillatory potentials (OP) were used as as indicators of retinal toxicity. Potential toxicity was also assessed by ophthalmoscopy and histologic studies (light and electron microscopy). RESULTS: The a-wave and b-wave were not deteriorated with 2.4 mg foscarnet after single or repeated injections. The OP remained unchanged. There was no ERG change after intravitreal injection of a combination of both drugs. No evidence of retinal toxicity was observed by indirect ophthalmoscopy in any case. Light and electron microscopy on semithin sections of retina failed to demonstrate any adverse effects, and showed normal organization and cytoarchitecture of all the layers of the retina without evidence of cytopathology. The ocular pharmacokinetics of foscarnet determined by noncompartmental analysis showed a 34-hour terminal elimination half-life and an apparent volume of distribution of 1.9 ml. CONCLUSIONS: Based on these results, high doses of foscarnet were not judged toxic to the rabbit retina, with single or repeated injections. Moreover, concomitant injection of the two drugs did not induce any retinal toxicity. These findings suggest that when systemic treatment is to be stopped in patients with AIDS for toxic side effects, either ganciclovir or foscarnet may be used intravitreally as an alternative. Because a combination of the two drugs has been shown to be synergistic, both ganciclovir and foscarnet might be simultaneously injected into the vitreous cavity to block progression of cytomegalovirus retinitis.

CD3 monoclonal antibodies evoke the same cytochrome P450-regulated capacitative entry of calcium as thapsigargin in Jurkat T cells.

In T cells CD3 monoclonal antibodies mediate an elevation of cytosolic Ca2+ concentration due to a release from internal stores and also due to an entry from extracellular medium, the mechanism of which is not clearly elucidated. Previous studies on several cell types have reported that depleting intracellular Ca2+ stores with inhibitors of the reticulum Ca(2+)-ATPase resulted in an increased plasma membrane permeability to calcium ions. It has been suggested that emptying the reticulum triggers a Ca2+ influx from extracellular medium, independent of phosphoinositide hydrolysis. To document the physiological relevance of such a mechanism, we compared CD3- and thapsigargin-induced sustained increase of cytosolic Ca2+ concentration in Jurkat T cells with regard to their sensitivity to internal and external Ca2+ level and to several inhibitors which do not affect the release of internal stores. We show that (1) there was no additivity of the two effects; (2) both CD3- and thapsigargin-evoked Ca2+ influx were inhibited when membrane was depolarized by either gramicidin or a high potassium concentration; and (3) Ca2+ influx was abrogated by cytochrome P450 inhibitors such as lipoxygenase inhibitors or imidazole antimicotic drugs. CD3 mAb and thapsigargin thus triggered the same signaling events, probably involving a cytochrome P450, to transmit information from depleted endoplasmic reticulum to the plasma membrane.

Intracellular Ca2+ regulation in CD3 stimulated Jurkat T cells involves H+ fluxes.

Triggering the CD3/TCR complex of T lymphocytes induces a rapid rise in cytosolic free calcium followed by a slowly declining plateau. The level of this plateau depends on external pH, the more alkalinized media leading to higher values. Neither a pH-dependent binding of mAb, nor a perturbation of internal pH can account for this effect. In a sodium-free medium, or in the presence of dimethylamiloride Ca2+, elevation is accompanied by an acidification of the cells; both of them depend, to the same extent, on external calcium concentration. TPA inhibits CD3-, but not ionomycin-induced Ca2+ and H+ raises, indicating that it acts more probably on Ca2+ influx, rather than on its efflux. These results suggest that intracellular calcium could be regulated by a Ca2+/H+ ATPase which drives H+ in and Ca2+ out. In the presence of external Na+, H+ should return to the medium by the Na+/H+ exchanger.