The Mast Cell Degranulator Compound 48/80 Directly Activates Neurons

Background Compound 48/80 is widely used in animal and tissue models as a “selective” mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. Methodology/Principal Findings We used in vivo recordings from extrinsic intestinal afferents together with Ca++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H1 and H2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca++ transients in mast cell-free enteric neuron cultures. Conclusions/Significance The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL

WET SILICA GELS : TEXTURAL CHARACTERIZATION

La thermoporométrie et la microscopie électronique ont été adaptées à l'étude texturale de gels de silice encore humides, obtenus par une méthode sol-gel. L'évolution de la texture poreuse de ces gels en fonction des conditions de préparation d'une part, et après un séchage en conditions hypercritiques d'autre part, a ainsi pu être mis en évidence.Still-wet silica gels, obtained by sol-gel methods, are studied by thermoporometry and electronic microscopy to determine their porous texture. The influence of preparation methods on the pore size is shown. The effect of hypercritical drying on the texture of the gel is also studied

Profil énergétique de l'adsorption d'eau à 25°C sur montmorillonites homoioniques (K+, Na+, H+, Ca++)

The variations in the heat of adsorption during the hydration, of homoionic montmorillonites are obtained by direct calorimetric measurements. The curves can show two important maxima ; the latter represent, in the course of successive swellings of the clay minerals, the initial hydration of the balance cation and of its solvation complement, when passing into the adsorbed phasis. The form, importance and position of these maxima depend on the nature of the cation and on the preliminary thermal treatment of the sample. They do not only inform about the necessary hydration energy but also about the transformations of the solid (swelling migration of the cation).Les variations de la chaleur d'adsorption au cours de l'hydratation des montmorillonites homoioniques sont obtenues par mesures directes calorimétriques. Les courbes peuvent présenter deux maxima importants qui traduisent au cours des gonflements successifs de l'argile l'hydratation première du cation compensateur et son complément de solvation quand il passe dans la phase adsorbée. La forme, l'importance et la position de ces maxima dépendent de la nature du cation et du traitement thermique préalable subi par l'échantillon. Ils renseignent non seulement sur l'énergie d'hydratation mise enjeu, mais également sur les transformations du solide (gonflement, migration du cation).Quinson J. F., Escoubes M., Blanc R. Profil énergétique de l'adsorption d'eau à 25°C sur montmorillonites homoioniques (K+, Na+, H+, Ca++). In: Bulletin du Groupe français des argiles. Tome 24, fascicule 1, 1972. pp. 49-67

Changement d’état liquide [math] solide dans les milieux poreux

Les relations thermodynamiques appliquées aux corps finement divisés conduisent à des expressions liant la température du point triple et l’énergie de changement d’état d’un corps dans un milieu poreux aux courbures des interphases. Un examen de la solidification d’un corps saturant un milieu poreux qu’il mouille, permet d’envisager trois processus de changement d’état. A chacun de ces mécanismes correspond une relation particulière entre la variation de la température du point triple et le rayon du capillaire dans lequel a lieu la transformation. La confrontation de l’étude théorique et des résultats expérimentaux permet de faire un choix parmi les processus envisagés. Cette comparaison met également en évidence la présence, à la paroi, d’un certain nombre de couches de molécules qui ne participent pas au changement d’état

Étude microcalorimétrique de la sorption d'eau sur des fibres et des grains de polytéréphtalate d'éthylène-glycol

Le couplage microcalorimétrie-gravimétrie a été utilisé pour déterminer le profil énergétique de la sorption d'eau sur des grains et des fibres de polytéréplitalate d'éthylène-glycol à 25 °C.Les résultats obtenus ont mis en évidence l'hétérogénéité de la surface du polymère vis-à-vis de l'eau et l'apparition d'un phénomène de gonflement avec nouvelle accessibilité du solvant. Cette nouvelle accessibilité apparaît à une pression relative d'autant plus forte que le taux de cristallinité, élevé par traitement thermique, est plus important.Des études de rétention de vapeurs et de cinétique de diffusion ont permis de mieux préciser le mécanisme de sorption de la vapeur d'eau

Evolution of the porous volume during the aerogel-glass transformation

The evolution of the texture of a silica aerogel during sintering is studied by thermoporometry. During the first stages of the densification the macroporous volume drops strongly while the mesoporous volume seems to be constant. This behavior is in contradiction with sintering models which predict that the sintering rate is faster for bodies with smaller particles or pores. In fact the analysis of the micropore size distribution shows that the sintering of the mesopores is responsible for macropore decrease