Successful treatment of Trichosporon asahii fungemia with isavuconazole in a patient with hematologic malignancies

International audienceTrichosporon spp. are yeast-like microorganisms responsible for skin, urinary, pulmonary, or bloodstream infections. Due to intrinsic resistance to echinocandins, poor susceptibility to polyenes, and preferred occurrence in immunocompromised patients, such infections are often of poor prognosis. Yet no consensual therapeutic guidelines are presently available. Several clinical cases of Trichosporon infections have been successfully treated with azole therapy, including voriconazole which appeared frequently effective against Trichosporon both in vitro and in vivo. However, the low efficacy associated with some Trichosporon genotypes, complex pharmacokinetics, and the side effects of voriconazole represent limitations for its use and has prompted a search for other therapeutic options. Here, we report a case of T. asahii fungemia in a patient with B-cell acute lymphoblastic leukemia which was successfully treated with isavuconazole consecutive to stopping voriconazole therapy due to severe side effects. This observation suggests that isavuconazole with a similar spectrum to voriconazole, fewer pharmacology interactions, and side effects may be considered as a valuable therapeutic option against Trichosporon infections

Évaluation du test de génération de thrombine au cours des pathologies érythrocytaires constitutionnelles

Les pathologies érythrocytaires constitutionnelles regroupent un ensemble de pathologies. Elles peuvent entrainer une instabilité des hématies, pouvant être à l’origine d’hémolyse. Ces anomalies érythrocytaires présentent un état d’hypercoagulabilité multifactorielle caractérisé par un déséquilibre des facteurs pro et anticoagulants. Nous avons souhaité explorer cette hypercoagulabilité par un test d’exploration global de l’hémostase : le test de génération de thrombine (TGT). Matériels et méthodes : Nous avons inclus 20 patients avec une sphérocytose héréditaire, 113 drépanocytoses, 36 A/S, 23 thalassémies et 9 enzymopathies. Nous avons utilisé du plasma pauvre en plaquettes avec 1pM de facteur tissulaire et 4μM de phospholipides. Résultats : Un état d’hypercoagulabilité est observé sur plusieurs paramètres du TGT au cours de la sphérocytose héréditaire, des thalassémies, du trait drépanocytaire et des enzymopathies. Concernant la drépanocytose, bien que nous rapportions une hypercoagulabilité sur la plupart des paramètres du TGT, l’ETP ne diffère pas significativement quel que soit le génotype ou l’état basal vs crises vaso-occlusives (CVO). Des corrélations entre le TGT avec les réticulocytes et monocytes sont rapportées chez ces patients. Enfin, l’ETP et le pic de thrombine sont susceptibles de prédire le risque de faire une CVO dans l’année. Conclusion : Ces résultats confirment l’hypercoagulabilité acquise au cours des pathologies érythrocytaires constitutionnelles. Nos résultats doivent être confirmés sur une cohorte plus importante. Le TGT peut présenter un intérêt dans la prédiction du risque de CVO. Ce test permet une compréhension globale de la thrombophilie acquise au cours de ces pathologies

Acute hemolysis crisis revealed a Wilson disease

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Determination of Lipoxygenase, CYP450, and Non-Enzymatic Metabolites of Arachidonic Acid in Essential Hypertension and Type 2 Diabetes

Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling

Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential therapeutic targets in CVD. For this objective, plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) were monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS2) in different rat models of CVD, i.e., angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there were modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4, LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after multiple testing corrections. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in LPA 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on cultured human pulmonary smooth muscle cells (PA-SMCs) with an increase in their proliferation. Finally, plasma level of LPA(16:0) was positively associated with the increase in pulmonary artery systolic pressure in patients with cardiac dysfunction. This study demonstrates that circulating LPA may contribute to the pathophysiology of PH. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure

International audienceIntroduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure

Introduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease

Inhibition of Soluble Epoxide Hydrolase Does Not Promote or Aggravate Pulmonary Hypertension in Rats

Inhibitors of soluble epoxide hydrolase (sEH), which catalyzes the hydrolysis of various natural epoxides to their corresponding diols, present an opportunity for developing oral drugs for a range of human cardiovascular and inflammatory diseases, including, among others, diabetes and neuropathic pain. However, some evidence suggests that their administration may precipitate the development of pulmonary hypertension (PH). We thus evaluated the impact of chronic oral administration of the sEH inhibitor TPPU (N-[1-(1-Oxopropyl)-4-piperidinyl]-N′-[4-(trifluoromethoxy)phenyl]-urea) on hemodynamics, pulmonary vascular reactivity, and remodeling, as well as on right ventricular (RV) dimension and function at baseline and in the Sugen (SU5416) + hypoxia (SuHx) rat model of severe PH. Treatment with TPPU started 5 weeks after SU5416 injection for 3 weeks. No differences regarding the increase in pulmonary vascular resistance, remodeling, and inflammation, nor the abolishment of phenylephrine-induced pulmonary artery constriction, were noted in SuHx rats. In addition, TPPU did not modify the development of RV dysfunction, hypertrophy, and fibrosis in SuHx rats. Similarly, none of these parameters were affected by TPPU in normoxic rats. Complementary in vitro data demonstrated that TPPU reduced the proliferation of cultured human pulmonary artery-smooth muscle cells (PA-SMCs). This study demonstrates that inhibition of sEH does not induce nor aggravate the development of PH and RV dysfunction in SuHx rats. In contrast, a potential beneficial effect against pulmonary artery remodeling in humans is suggested