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Le traitement par inhibiteurs de l'interleukine (IL)-17 a été associé à des infections fongiques [1,2]. L'ixékizumab (IXE) est un anticorps monoclonal ciblant l'IL-17A approuvé pour le traitement du psoriasis (PsO) chez les adultes et les enfants, du rhumatisme psoriasique (RP) et de la spondyloarthrite axiale (axSpA) chez les adultes. Cette analyse post hoc analyse les infections fongiques apparues sous traitement chez les patients traités par IXE dans ces indications. Les données de tolérance sur les infections fongiques ont été regroupées à partir du programme d'essais cliniques (26 études au total) de l'IXE chez les adultes et les enfants. Nous décrivons ici les types et le nombre d'infections fongiques, leur récurrence (définie comme au moins deux événements distincts, quel que soit l'emplacement), leur sévérité (définie à la discrétion de l'investigateur), les événements ayant mené à l'arrêt du traitement ainsi que les traitements antifongiques. Les données sont présentées en tant que fréquence ou taux d'incidence pour 100 personnes-années (TI). Au total, il y avait 7088 patients atteints de PsO, 1401 de RP et 932 d'axSpA. Des infections fongiques ont été signalées chez les patients atteints de PsO (TI = 4,0), de RP (TI = 4,1) et d'axSpA (TI = 2,7). La plupart de ces infections n'étaient pas récurrentes, et étaient de sévérité légère ou modérée. Quelques infections fongiques sévères sont survenues chez les patients atteints de PsO (TI = 0,1), aucune dans le RP et l'axSpA. La plupart des infections fongiques dans le PsO, le RP et l'axSpA étaient des candidoses (TI = 1,9 ; TI = 2,5 et TI = 1,4, respectivement) et des dermatophytoses superficielles (TI = 1,5 ; TI = 1,0 et TI = 1,0, respectivement). Aucun cas de mycose sous-cutanée ou systémique n'a été signalé. Les proportions de patients atteints de PsO, de RP et d'axSpA ayant reçu un traitement antifongique topique vs systémique étaient de 53,6 % vs 1,1 %, 47,8 % vs 0,0 % et 45,6 % vs 3,5 %, respectivement. La plupart des infections n'ont pas mené à l'arrêt de l'IXE (arrêt du traitement chez 0,0 %, 0,1 % et 0,1 % des patients pour le PsO, le RP et l'axSpA, respectivement). Les données sont cohérentes avec celles précédemment publiées avec l'IXE. La majorité des infections fongiques apparues sous IXE chez les patients atteints de PsO, de RP ou d'axSpA étaient : (i) non récurrentes ; (ii) légères ou modérées ; (iii) des candidoses et des dermatophytoses superficielles ; (iv) majoritairement prises en charge par traitement antifongique topique ; et (v) sans incidence sur l'arrêt du traitement. [ABSTRACT FROM AUTHOR]

The administration of recombinant erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. In the present study, experiments were designed to explore the hypothesis that rHuEpo could enhance vascular resistance through mitogenic effect on vascular smooth muscle cells (VSMCs), and that preexisting hypertension might be a predisposing condition. Cultured VSMCs from the thoracic aortae of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and 3H-inositol phosphate formation, respectively (EC50 approximately 4 U/ml). Exposure of VSMCs to rHuEpo for various times gradually increased the levels of c-myc and junB and transiently induced c-fos expression, as determined by Northern analysis. rHuEpo-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.

The identification of factors associated with breast recurrence as first event (62 cases, 10%) following conservative surgery and radiation therapy are drawn out from a series++ of 618 mammary carcinomas of clinical size less than 40 mm, stage I and II (UICC), with a median follow up of 8 years. The most powerful predictive characteristic associated with the likelihood of breast recurrence is multiple foci of invasion (42.9% vs 8.9, P = 0.0001, relative risk [RR]: 6). After this rarely cited feature, young age, less than 40 years (20% vs 7.3%, P = 0.0001, RR: 2.8), extensive in situ carcinoma more than 25% (19.2% vs 8.7%, P = 0.003, RR: 2.5) were found also persistent in the Cox model, but not histologic size more than 25 mm (18.9% vs 9.1%, P = 0.01, RR: 2.3). The site of recurrence was studied on the 54 salvage mastectomy done. A high rate of recurrence at distance of the initial site was found: 37% whose more than half, 22%, were multicentric. No significant difference in the mean delay of appearance was noted between recurrence near or at distance of the initial cancer (mean delay 52 months vs 64 months). From the recurrence the evolution is not very favourable: excluding simultaneous metastases found at the preoperative investigation, ten cases, mammary recurrence is followed by a metastatic syndrome in 36% of cases against 17% without it (P = 0.01, RR: 1.9). Metastatic evolution is not significantly linked with the time, early or late, of the mammary recurrence (54.5% before 5 years vs 39% after) but with the association of a controlateral cancer (P = 0.03). Locally ten of the 54 mastectomy presented a thoracic recurrence, often in case of multicentric breast recurrence (P = 0.05) and not significantly when skin or areola were invaded by carcinoma.

To gain insight into the mechanisms that could account for the augmentation of cellular reactivity in primary hypertension, we have examined some of the biochemical events which are implicated in the transmission of mitogenic signal as well as in cell reactivity. This study focussed on phospholipase C, protein kinase C and GTP-binding proteins (G-proteins), in response to thrombin or arginin-vasopressin (AVP). Cultured fibroblasts prepared from the adventitia of thoracic aorta of spontaneously hypertensive rat (SHR) were used as cell models and were compared with fibroblasts prepared from controls Wistar-Kyoto (WKY) rats. The mitogenicity of each agonist was estimated by measuring the incorporation of 3H-thymidine into the newly synthesized DNA. The agonist-induced phospholipase C activity was evaluated by measuring the production of 3H-inositol phosphates in cells prelabeled with 3H-inositol. The influence of protein kinase C and that of G proteins on the mitogenesis in cells stimulated by thrombin or AVP was determined by pretreating cells with phorbol 12-myristate, 13-acetate (TPA) and pertussis toxin, respectively. Kinetics and dose response studies have demonstrated that in response to thrombin and AVP, the phospholipase C activity and the incorporation of 3H-thymidine were significantly higher in the fibroblasts derived from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to determine the mechanisms which could be responsible for the hypertrophy of vascular wall associated with primary hypertension, we have investigated the mechanisms involved in the proliferation of aortic cells from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. In this study we have examined the role of phospholipase C which is responsible for the formation of second messengers, the function of protein kinase C and that of GTP-binding proteins (G proteins) which couple membrane receptors to phospholipase C. The adventitial fibroblasts from thoracic aorta were chosen as cell model in culture. The capacity of proliferation in response to 10% serum was analyzed by cell number determination and by measuring the incorporation of 3H-thymidine into newly synthesized DNA. Our results showed that SHR-derived fibroblasts proliferated more rapidly and incorporated more 3H-thymidine than WKY-derived fibroblasts. However, the phospholipase C activity, measured by the serum-stimulated production of 3H-inositol phosphates in cells prelabeled with 3H-inositol, did not differ between SHR- and WKY-derived cells. The desensitization of protein kinase C, by long term (2 d) treatment with high dose (300 nM) of phorbol 12-myristate, 13-acetate (TPA), markedly augmented, but to the same extent, the 3H-thymidine incorporation into DNA of SHR- and WKY-derived fibroblasts. Moreover, protein kinase C activation by TPA caused a parallel reduction (25-30%) of the incorporation of 3H-thymidine into DNA of SHR- and WKY-derived cells. Under the same experimental conditions, the growth of SHR- and WKY-derived fibroblasts was reduced by TPA in a dose-dependent manner (up to 20%) to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)