Validation of an ion selective electrode system for the analysis of serum fluoride ion

A high impedance unit was developed for use with a fluoride/pH electrode system for the measurement of serum fluoride. The linearity, accuracy, precision and detection limit of the system is reported. At a pH of 1.55, the system was linear over a range of serum fluoride concentrations up to 100 μmol l-1, with a lower limit of detection of 0.3 μmol l-1. Recoveries at this pH were 94-105% in the range 2.6-100 μmol l-1. Within-run CVs ranged from 4.2% at a level of 2.3 μmol l-1 to 1.2% at a level of 55.7 μmol l-1, while day-to-day CVs ranged from 12.8% at a level of 2.2 μmol l-1 to 4.6% at a level of 51.7 μmol l-1. The system demonstrated a rapid response time and has the potential for a smaller sample size requirement with alternative electrode shape. Continued development of this unit into an automated fluoride ion selective electrode system is recommended, since the measurement of serial serum fluoride samples is of greatest importance in assessing the impact of new anaesthetic agents on renal function

Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia

High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a "mix-and-match" principle where BsAbs were selected on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia

The loss of P2X7 receptor expression leads to increase intestinal glucose transit and hepatic steatosis

In intestinal epithelial cells (IEC), it was reported that the activation of the P2X7 receptor leads to the internalization of the glucose transporter GLUT2, which is accompanied by a reduction of IEC capacity to transport glucose. In this study, we used P2rx7−/− mice to decipher P2X7 functions in intestinal glucose transport and to evaluate the impacts on metabolism. Immunohistochemistry analyses revealed the presence of GLUT2 at the apical domain of P2rx7−/− jejunum enterocytes. Positron emission tomography and biodistribution studies demonstrated that glucose was more efciently delivered to the circulation of knockout animals. These fndings correlated with increase blood glucose, insulin, triglycerides and cholesterol levels. In fact, P2rx7−/− mice had increased serum triglyceride and cholesterol levels and displayed glucose intolerance and resistance to insulin. Finally, P2rx7−/− mice developed a hepatic steatosis characterized by a reduction of Acaca, Acacb, Fasn and Acox1 mRNA expression, as well as for ACC and FAS protein expression. Our study suggests that P2X7 could play a central role in metabolic diseases

Pratique des endocrinologues français en lipidologie : évaluation lors des situations complexes à la frontière des recommandations

National audienceIl existe de nombreuses recommandations récentes sur le traitement des dyslipidémies (SFC-EAS/AHA-ACC/IAS), parfois contradictoires. Certaines situations cliniques se situant à la frontière du champ traité par les recommandations, nous avons souhaité évaluer le comportement des endocrinologues français face à ces situations. Cinq cent seize endocrinologues (289 femmes et 212 hommes) ont répondu à 6 cas cliniques soumis en ligne via un sondage effectué en juillet et septembre 2015. Selon la méthode Delphi, 10 experts ont attribué une note sur 10 à chaque item de chaque cas clinique appréciant la conformité escomptée par rapport aux recommandations thérapeutiques et l’agressivité thérapeutique. Les variables explicatives prises en compte en analyse univariée puis multivariée ont été : sexe, âge, inter-région d’exercice, lieu d’exercice, mode d’exercice et lecture régulière d’au moins une revue internationale. La conformité est en moyenne de 6,2 (± 2,0) et l’agressivité de 5,1 (± 1,7), proches des valeurs moyennes établies par les experts. Le score de conformité et celui de l’agressivité sont étroitement corrélés (r = 0,669, p < 10−3). Seuls l’âge (le score le plus bas étant observé chez les plus de 50 ans, p = 0,0038) et le mode d’exercice non libéral vs libéral (moyenne 6,5 ± 2,0 vs 5,8 ± 1,9, p = 0,0001) sont associés avec le score de conformité. En analyse multivariée, ces deux variables explicatives demeurent indépendantes mais le meilleur modèle explique moins de 10 % de la variabilité des scores. Les tranches d’âges extrêmes et l’exercice libéral sont des facteurs associés avec une moindre conformité aux recommandations, toutefois cette enquête suggère que de nombreux facteurs additionnels non explorés sont susceptibles d’interveni