Can customized implants correct enophthalmos and delayed diplopia in post-traumatic orbital deformities? A volumetric analysis.

The purpose of this study was to determine whether orbital reconstruction with customized implants can correct post-traumatic orbital deformities such as late enophthalmos and delayed diplopia. The hypothesis proposed was that an overcorrection of the orbital volume is needed to resolve enophthalmos. A retrospective observational descriptive study was conducted. Patients with a major trauma who required customized orbital implants for the delayed treatment of unilateral orbital fractures that had initially been operated on using titanium mesh and/or osteosynthesis plates were included. The orbital volumes of the unaffected contralateral side, of the affected orbit after initial reconstruction with mesh, and of the affected orbit subsequently reconstructed with the customized implant were calculated. All of the patients included in this study had diplopia in the gaze position prior to the installation of the implant. In addition, they all had severe enophthalmos. After surgery, no patient with a customized implant showed diplopia. The enophthalmos was corrected in all but one case. On average, orbits reconstructed with customized implants had lower volumes compared to the unaffected contralateral side. In cases where the enophthalmos was resolved, the volume was reduced by an average of 8.55%. Further studies using a larger number of cases and with controlled volumetric corrections using CAD/CAM are needed.

Tolerability during double-blind randomized phase I trials with the house dust mite allergy immunotherapy tablet in adults and children.

BACKGROUND AND OBJECTIVE: The orodispersible house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of HDM respiratory allergic disease. The objective of the 2 phase I trials was to investigate tolerability and the acceptable dose range of HDM SLIT-tablet treatment in adults and children with HDM respiratory allergic disease. PATIENTS AND METHODS: The trials were randomized, multiple-dose, dose-escalation, double-blind, placebo-controlled phase I trials including patients with HDM-induced asthma, with or without rhinoconjunctivitis. Both trials were registered in EudraCT (Trial 1: 2005-002151-41; Trial 2: 2007-000402-67). Trial 1 included 71 adults (18-63 years) and trial 2 included 72 children (5-14 years). Both trials included 6 dose groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in MedDRA (version 8.1 or later). Immunological variables included specific IgE and IgE-blocking factor. RESULTS: No serious AEs were reported. In trial 1 (maximum dose, 32 development units [DU]), 1 patient in the 16 DU group discontinued due to AEs. The entire 32 DU group was discontinued as 1 patient had a severe adverse reaction. In trial 2 (maximum dose, 12 DU), no patients discontinued prematurely. The most frequently reported AEs were mild application-site related events. The total number of events was dose-related within each trial. HDM SLIT-tablet treatment induced changes in immunological parameters in a dose-dependent manner. CONCLUSIONS: These trials demonstrate that doses up to 12 DU of HDM SLIT-tablet were tolerated in the selected populations, and thus are suitable for further clinical investigations in adults and children with HDM respiratory allergic disease.

Tolerability during double-blind randomized phase I trials with the house dust mite allergy immunotherapy tablet in adults and children

Background and Objective: The orodispersible house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of HDM respiratory allergic disease. The objective of the 2 phase I trials was to investigate tolerability and the acceptable dose range of HDM SLIT-tablet treatment in adults and children with HDM respiratory allergic disease. Patients and Methods: The trials were randomized, multiple-dose, dose-escalation, double-blind, placebo-controlled phase I trials including patients with HDM-induced asthma, with or without rhinoconjunctivitis. Both trials were registered in EudraCT (Trial 1: 2005-002151-41; Trial 2: 2007-000402-67). Trial 1 included 71 adults (18-63 years) and trial 2 included 72 children (5-14 years). Both trials included 6 dose groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in MedDRA (version 8.1 or later). Immunological variables included specific IgE and IgE-blocking factor. Results: No serious AEs were reported. In trial 1 (maximum dose, 32 development units [DU]), 1 patient in the 16 DU group discontinued due to AEs. The entire 32 DU group was discontinued as 1 patient had a severe adverse reaction. In trial 2 (maximum dose, 12 DU), no patients discontinued prematurely. The most frequently reported AEs were mild application-site related events. The total number of events was dose-related within each trial. HDM SLIT-tablet treatment induced changes in immunological parameters in a dose-dependent manner. Conclusions: These trials demonstrate that doses up to 12 DU of HDM SLIT-tablet were tolerated in the selected populations, and thus are suitable for further clinical investigations in adults and children with HDM respiratory allergic disease (AU)

Introducción y Objetivo: La tableta orodispersable para inmunoterapia sublingual del ácaro del polvo de casa (SLIT-tablet) se ha desarrollado para el tratamiento de la alergia respiratoria frente al ácaro. El objetivo de la fase I de estos 2 ensayos clínicos fue investigar la tolerancia y el rango de aceptación de la dosis de tratamiento en adultos y niños con alergia respiratoria al ácaro del polvo de casa. Los ensayos randomizados, con dosis múltiple escalonada, doble ciego controlados con placebo incluyeron a pacientes con asma inducida por el ácaro del polvo de casa, con o sin rinoconjuntivitis. Se registraron en EudraCT (Ensayo 1: 2005-002151-41; Ensayo 2: 2007-000402-67). Pacientes y Métodos: El ensayo 1 incluyó a 71 pacientes adultos (18-63 años) y el ensayo 2 incluyó a 72 niños (5-14 años). Ambos ensayos clínicos incluían 6 grupos de dosis que fueron randomizados 3:1 para tratamiento activo o placebo, una vez al día durante 28 días. Las reacciones adversas (RAs) fueron codificadas en MedDRA (versión 8.1 or later). Las variables inmunológicas incluían IgE específica y factor bloqueante de la IgE. No se registraron RAs importantes. En el ensayo 1 (con la dosis máxima y 32 unidades de desarrollo [UD])un paciente del grupo 16-UD tuvo que dejar el tratamiento por RAs. El grupo 32-UD completo abandonó el tratamiento debido a que un paciente manifestó RAs graves. Resultados: En el ensayo 2 (dosis máxima ,12 UD) ningún paciente abandonó el tratamiento de forma prematura. Las RAs más frecuentemente registradas fueron de tipo local relacionadas con el lugar de aplicación del tratamiento. El número total de reacciones estaba relacionado con la dosis administrada en cada ensayo. Por otra parte, este tratamiento indujo cambios en los parámetros inmunológicos de forma dosis-dependiente. Conclusiones: Estos ensayos demuestran que el aumento de dosis por encima de 12 UD se tolera bien en las poblaciones estudiadas en estos ensayos, dato a tener en cuenta para futuras investigaciones en adultos y niños con alergia respiratoria por polvo de casa (AU)

Clinical evolution of patients with respiratory allergic disease due to sensitisation to Alternaria alternata being treated with subcutaneous immunotherapy

Introduction: Sensitisation to Alternaria is a cause of respiratory disease in Spain, particularly in childhood, but it is also a significant marker of the severity of this disease. Therefore, the use of an aetiological treatment (allergen specific immunotherapy) is essential, and both subjective and objective clinical parameters should be used to follow up this treatment. Objective: This open-label, uncontrolled, observational, prospective study was designed inorder to study the evolution of these patients on allergen specific immunotherapy therapy in daily clinical practice and to assess the use of different monitoring tools. Material and Methods: A total of 99 patients were included. They were monosensitised to this perennial allergen and treated with subcutaneous allergen specific immunotherapy. Afterone year of follow-up, these patients were assessed for the presence of symptoms, use of medication, clinical incidents, quality of life and asthma control. Results: After one year of treatment a significant fall was observed in the use of concomitant medication ( 2-agonists: p = 0.0278, inhaled corticosteroids: p = 0.0007, anti-leukotrienes:p = 0.0495), nasal symptoms (p = 0.0081), quality of life (PAQLQ, p < 0.0001) and asthma control (ACQ, p < 0.0001). Twenty-one patients had to attend emergency department due to exacerbation of their allergic disease, and only one of them had to be admitted to hospital. Conclusion: respiratory allergic disease due to Alternaria alternata is a disease which is hard to control, and in our daily practice, the use of specific subcutaneous immunotherapy can be of significant benefit in our paediatric patients (AU)

Clinical evolution of patients with respiratory allergic disease due to sensitisation to Alternaria alternata being treated with subcutaneous immunotherapy.

INTRODUCTION: Sensitisation to Alternaria is a cause of respiratory disease in Spain, particularly in childhood, but it is also a significant marker of the severity of this disease. Therefore, the use of an aetiological treatment (allergen specific immunotherapy) is essential, and both subjective and objective clinical parameters should be used to follow up this treatment. OBJECTIVE: This open-label, uncontrolled, observational, prospective study was designed in order to study the evolution of these patients on allergen specific immunotherapy therapy in daily clinical practice and to assess the use of different monitoring tools. MATERIAL AND METHODS: A total of 99 patients were included. They were monosensitised to this perennial allergen and treated with subcutaneous allergen specific immunotherapy. After one year of follow-up, these patients were assessed for the presence of symptoms, use of medication, clinical incidents, quality of life and asthma control. RESULTS: After one year of treatment a significant fall was observed in the use of concomitant medication (ß2-agonists: p=0.0278, inhaled corticosteroids: p=0.0007, anti-leukotrienes: p=0.0495), nasal symptoms (p=0.0081), quality of life (PAQLQ, p<0.0001) and asthma control (ACQ, p<0.0001). Twenty-one patients had to attend emergency department due to exacerbation of their allergic disease, and only one of them had to be admitted to hospital. CONCLUSION: respiratory allergic disease due to Alternaria alternata is a disease which is hard to control, and in our daily practice, the use of specific subcutaneous immunotherapy can be of significant benefit in our paediatric patients.

Localization of intracellular compartments that exchange Na,K-ATPase molecules with the plasma membrane in a hormone-dependent manner.

BACKGROUND AND PURPOSE: Dopamine is a major regulator of sodium reabsorption in proximal tubule epithelia. By binding to D1-receptors, dopamine induces endocytosis of plasma membrane Na,K-ATPase, resulting in a reduced capacity of the cells to transport sodium, thus contributing to natriuresis. We have previously demonstrated several aspects of the molecular mechanism by which dopamine induces Na,K-ATPase endocytosis; however, the location of intracellular compartments containing Na,K-ATPase molecules has not been identified. EXPERIMENTAL APPROACH: In this study, we used different approaches to determine the localization of Na,K-ATPase-containing intracellular compartments. By expression of fluorescent-tagged Na,K-ATPase molecules in opossum kidney cells, a cell culture model of proximal tubule epithelia, we used fluorescence microscopy to determine cellular distribution of the fluorescent molecules and the effects of dopamine on this distribution. By labelling cell surface Na,K-ATPase molecules from the cell exterior with either biotin or an epitope-tagged antibody, we determined the localization of the tagged Na,K-ATPase molecules after endocytosis induced by dopamine. KEY RESULTS: In cells expressing fluorescent-tagged Na,K-ATPase molecules, there were intracellular compartments containing Na,K-ATPase molecules. These compartments were in very close proximity to the plasma membrane. Upon treatment of the cells with dopamine, the fluorescence labelling of these compartments was increased. The labelling of these compartments was also observed when the endocytosis of biotin- or antibody-tagged plasma membrane Na,K-ATPase molecules was induced by dopamine. CONCLUSIONS AND IMPLICATIONS: The intracellular compartments containing Na,K-ATPase molecules are located just underneath the plasma membrane.

Predictive factors in infraorbital sensitivity disturbances following zygomaticomaxillary fractures.

The aim of this study was to define if the alterations in sensory modalities could be a predictive factor in the prognostic recovery of the ION. Ten patients that had suffered facial trauma, associated with sensitivity alterations of the ION were evaluated prospectively. Touch detection thresholds (TD) were measured using Von Frey's filaments aesthesiometer. A warm/cold discrimination (W/C) was also done to the patients, on the same areas. The patients were examined in both sides of the face, using the non-traumatized side as control. The tests were done before surgery and several times postoperatively. For statistical analysis of the results, the two-sample t test was used. A significant difference (P < 0.0001) in the mean tactile recovery time between the areas without thermal sensitivity before surgery and those with normal thermal sensitivity before surgery was observed. Therefore, we propose that during the preoperative examination, the surgeon examines the thermal discrimination in order to establish prognosis and approximate recovery times.

Evaluation of paediatric tolerance to an extract of Alternaria alternata under two treatment regimes. A multicentre study.

In order to evaluate the efficacy and safety of an extract of Alternaria alternata in a paediatric population, a two phase study plan has been elaborated that in the first place consists of a retrospective analysis of tolerance under the standard treatment regimes used by the clinical groups involved. This was achieved by analysing the records of 94 patients that have been treated with this extract, these being consecutive patients included at 7 clinics over a period of 6 months. Two regimes were used: a conventional short regime of 7 doses and a cluster regime. Under neither of these two regimes were any serious reactions registered. The percentage of local reactions was significantly greater using the short conventional regime than with the cluster regime (1.9% and 0.4% respectively, p = .035). In contrast, no significant differences were observed with respect to the systemic reactions (0.5% and 1.2%), these percentages also being similar to those registered with other extracts in which identical regimes have been used. In conclusion, we can confirm that a very satisfactory tolerance profile was observed, with the advantage that through using shorter regimes than the conventional regime of 13 doses, a considerable saving is made both in the number of visits and the doses necessary to reach the maintenance dose.

Evaluation of paediatric tolerance to an extract of Alternaria alternata under two treatment regimes. A multicentre study

In order to evaluate the efficacy and safety of an extract of Alternaria alternata in a paediatric population, a two phase study plan has been elaborated that in the first place consists of a retrospective analysis of tolerance under the standard treatment regimes used by the clinical groups involved. This was achieved by analysing the records of 94 patients that have been treated with this extract, these being consecutive patients included at 7 clinics over a period of 6 months. Two regimes were used: a conventional short regime of 7 doses and a cluster regime. Under neither of these two regimes were any serious reactions registered. The percentage of local reactions was significantly greater using the short conventional regime than with the cluster regime (1.9 % and 0.4 % respectively, p = .035). In contrast, no significant differences were observed with respect to the systemic reactions (0.5 % and 1.2 %), these percentages also being similar to those registered with other extracts in which identical regimes have been used. In conclusion, we can confirm that a very satisfactory tolerance profile was observed, with the advantage that through using shorter regimes than the conventional regime of 13 doses, a considerable saving is made both in the number of visits and the doses necessary to reach the maintenance dose

Con el fin de evaluar la eficacia y la seguridad de un extracto de Alternaria alternata en una población pediátrica, se realizó un plan de estudio en dos fases, que consistió en primer lugar en un análisis retrospectivo de la tolerancia bajo las pautas de tratamiento convencionales empleadas por los grupos clínicos estudiados. A este fin se analizaron los historiales de 94 pacientes que habían recibido tratamiento con este extracto. Se trataba de pacientes consecutivos tratados en 7 clínicas durante un período de 6 meses. Se emplearon dos pautas: una pauta breve convencional de 7 dosis y una pauta agrupada o "cluster". No se observaron reacciones de consideración bajo ninguna de las dos pautas. El porcentaje de reacciones locales fue significativamente superior al usar la pauta breve convencional que al usar la pauta agrupada (1,9 % y 0,4 % respectivamente, p = 0,035). En cambio, no se observaron diferencias significativas en lo relativo a reacciones sistémicas (0,5 % y 1,2 %), siendo estos porcentajes similares a los obtenidos con otros extractos y siguiendo pautas idénticas. En conclusión, podemos confirmar la observación de un perfil de tolerancia muy satisfactorio, con la ventaja de que con pautas más breves que la convencional de 13 dosis se obtiene un ahorro considerable tanto en número de visitas como en las dosis necesarias para llegar a la de mantenimiento

[Sublingual immunotherapy in children. Immunotherapy Committee of the Spanish Society for Clinical Immunology and Pediatric Allergology]. / Inmunoterapia sublingual en niños. Comité de Inmunoterapia de la Sociedad Española de Inmunología Clínica y Alergología Pediátrica (SEICAP).

Sublingual immunotherapy is currently attracting growing interest because of its ease of administration and, according to previous studies, its infrequent and mild adverse effects. However, at least in children, the efficacy of this therapy has not been completely demonstrated. In addition, the mechanisms of action remain to be elucidated since few studies have been published and the results have been contradictory and sometimes inconclusive. For this reason, we performed a literature review through the MEDLINE database, selecting double-blind studies carried out in children. Only 10 studies meeting these requirements were retrieved. All the studies were performed by European researchers and nine were published in European journals. Efficacy was evaluated by clinical parameters and by reduction in medication use. The results on efficacy are not homogeneous, although most support the utility of this route of administration. Moreover, reports of allergens other than those used in these studies dust mites and grass pollens are lacking. In conclusion, further studies evaluating the efficacy of this therapy in children are required. Among the general population, if the efficacy of sublingual immunotherapy in the treatment of sensitization to hymenoptera venoms were demonstrated, as has been the case with subcutaneous immunotherapy, the utility of this route of administration would be definitively confirmed. Finally, sublingual immunotherapy could be used in children who have shown systemic reactions to subcutaneous immunotherapy or who refuse to undergo injections.

Inmunoterapia sublingual en niños

En la actualidad hay un creciente interés en el uso de la inmunoterapia por vía sublingual (ITSL) por su fácil administración y, según estudios previos, los escasos y leves efectos secundarios. Sin embargo, al menos en niños, la eficacia aún no está totalmente demostrada, y por otra parte, los mecanismos de acción no están aclarados, pues los estudios son escasos, contradictorios a veces y no concluyentes. Por este motivo, se ha efectuado una revisión bibliográfica, mediante la búsqueda en MEDLINE, seleccionando trabajos efectuados en niños, doble ciego. Sólo se han localizado 10 trabajos con esas características. Todos están realizados por investigadores europeos, nueve de los cuales están publicados en revistas del continente. La eficacia se valora por parámetros clínicos y por la reducción del uso de medicación. En cuanto a la eficacia, los resultados no son homogéneos, aunque en su mayoría finalmente se acepta la utilidad de la vía de administración. Además, faltan estudios con alérgenos distintos de los usados en esos estudios, que lo han sido con ácaros y pólenes de gramíneas. En conclusión, faltan más trabajos que valoren la eficacia en niños. En población general, se considera que si se demostrase la eficacia en el tratamiento de la sensibilización a veneno de himenópteros, como está demostrado con la IT subcutánea, podría afirmarse con certeza la utilidad de esta vía de administración. Finalmente, se considera que podría utilizarse la ITSL niños que hayan tenido reacciones sistémicas con IT subcutánea, o que manifiesten algún rechazo a la administración de inyecciones (AU)

Sublingual immunotherapy is currently attracting growing interest because of its ease of administration and, according to previous studies, its infrequent and mild adverse effects. However, at least in children, the efficacy of this therapy has not been completely demonstrated. In addition, the mechanisms of action remain to be elucidated since few studies have been published and the results have been contradictory and sometimes inconclusive. For this reason, we performed a literature review through the MEDLINE database, selecting double-blind studies carried out in children. Only 10 studies meeting these requirements were retrieved. All the studies were performed by European researchers and nine were published in European journals. Efficacy was evaluated by clinical parameters and by reduction in medication use. The results on efficacy are not homogeneous, although most support the utility of this route of administration. Moreover, reports of allergens other than those used in these studies ­ dust mites and grass pollens ­ are lacking. In conclusion, further studies evaluating the efficacy of this therapy in children are required. Among the general population, if the efficacy of sublingual immunotherapy in the treatment of sensitization to hymenoptera venoms were demonstrated, as has been the case with subcutaneous immunotherapy, the utility of this route of administration would be definitively confirmed. Finally, sublingual immunotherapy could be used in children who have shown systemic reactions to subcutaneous immunotherapy or who refuse to undergo injections (AU)

Cytoplasmic segment interactions in the alpha1-subunit of the rat Na+, K+-atpase.

The currently accepted topographical model for the organization of the alpha-subunit of the Na+, K+-ATPase in the membrane considers that the protein has ten transmembrane segments and six cytoplasmic loops. Evidence of interaction between the cytoplasmic regions may contribute to a better understanding of the structure/function relationship of this protein. In this study, the first four cytoplasmic segments (C1, C2, C3 and C4) of the rat alpha1 subunit were expressed in Escherichia Coli. The large cytoplasmic loop between transmembrane segments four and five (C3) retained its native structure as demonstrated by the ability of ATP to protect against chemical modification by Fluorescein 5-isothiocyanate (FITC). Interaction studies were conducted by an overlay assay (Far Western blots) and surface plasmon resonance technology. We observed that C3 interacts with the N-terminal segment of the Na+, K+-ATPase, C1; and that both C1 and C3 interact with the cytoplasmic segments C2 and C4.

Simultaneous phosphorylation of Ser11 and Ser18 in the alpha-subunit promotes the recruitment of Na(+),K(+)-ATPase molecules to the plasma membrane.

Renal sodium homeostasis is a major determinant of blood pressure and is regulated by several natriuretic and antinatriuretic hormones. These hormones, acting through intracellular second messengers, either activate or inhibit proximal tubule Na(+),K(+)-ATPase. We have shown previously that phorbol ester (PMA) stimulation of endogenous PKC leads to activation of Na(+),K(+)-ATPase in cultured proximal tubule cells (OK cells) expressing the rodent Na(+), K(+)-ATPase alpha-subunit. We have now demonstrated that the treatment with PMA leads to an increased amount of Na(+),K(+)-ATPase molecules in the plasmalemma, which is proportional to the increased enzyme activity. Colchicine, dinitrophenol, and potassium cyanide prevented the PMA-dependent stimulation of activity without affecting the increased level of phosphorylation of the Na(+), K(+)-ATPase alpha-subunit. This suggests that phosphorylation does not directly stimulate Na(+),K(+)-ATPase activity; instead, phosphorylation may be the triggering mechanism for recruitment of Na(+),K(+)-ATPase molecules to the plasma membrane. Transfected cells expressing either an S11A or S18A mutant had the same basal Na(+),K(+)-ATPase activity as cells expressing the wild-type rodent alpha-subunit, but PMA stimulation of Na(+),K(+)-ATPase activity was completely abolished in either mutant. PMA treatment led to phosphorylation of the alpha-subunit by stimulation of PKC-beta, and the extent of this phosphorylation was greatly reduced in the S11A and S18A mutants. These results indicate that both Ser11 and Ser18 of the alpha-subunit are essential for PMA stimulation of Na(+), K(+)-ATPase activity, and that these amino acids are phosphorylated during this process. The results presented here support the hypothesis that PMA regulation of Na(+),K(+)-ATPase is the result of an increased number of Na(+),K(+)-ATPase molecules in the plasma membrane.

Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+, K+-ATPase alpha subunit and regulates its trafficking.

Endocytosis of Na(+),K(+)-ATPase molecules in response to G protein-coupled receptor stimulation requires activation of class I(A) phosphoinositide-3 kinase (PI3K-I(A)) in a protein kinase C-dependent manner. In this paper, we report that PI3K-I(A), through its p85alpha subunit-SH3 domain, binds to a proline-rich region in the Na(+),K(+)-ATPase catalytic alpha subunit. This interaction is enhanced by protein kinase C-dependent phosphorylation of a serine residue that flanks the proline-rich motif in the Na(+),K(+)-ATPase alpha subunit and results in increased PI3K-I(A) activity, an effect necessary for adaptor protein 2 binding and clathrin recruitment. Thus, Ser-phosphorylation of the Na(+),K(+)-ATPase catalytic subunit serves as an anchor signal for regulating the location of PI3K-I(A) and its activation during Na(+),K(+)-ATPase endocytosis in response to G protein-coupled receptor signals.

Inmunoterapia sublingual con un extracto de Dermatophagoides pteronyssinus valorado en unidades de masa: evaluación del grado de cumplimiento, seguridad y mejoría clínica / Sublingual immunotherapy with a Dermatophagoides pteronyssinus extract in mass units: assessment of efficacy, safety and degree of compliance

Fundamento: El uso de vacunas alergénica administradas por vía sublingual (SLIT) e cada vez mayor. y con numerosos los estudios en los que e demuestra su eficacia y seguridad. El objetivo del presente estudio era establecer, en dos grupos de pacientes (niños y adultos) con enfermedad alérgica respiratoria por sensibilización a Dermatophagoides pteronyssinus, además de los dos parámetros anteriores, el grado de cumplimiento de los pacientes hacia el tratamiento. Métodos: Se analizó la evolución clínica de los pacientes tras 1 año de tratamiento, mediante puntuación de síntomas y medicación. El grado de cumplimiento e valoró correlacionando el cumplimiento del estudio con un cuestionario que contenía un juicio crítico del paciente respecto a SLIT. Resultados: El 84% de los pacientes e encontró mejor o mucho mejor al finalizar el año de tratamiento: se encontraron diferencias estadísticamente significativas en lo síntomas nasales, oculares. Síntomas totales y puntuación del conjunto de Síntomas y medicación. El porcentaje de reacciones sistémicas por do i fue de 0,3. El grado de cumplimiento del protocolo fue bueno o muy bueno en el 72% de los paciente; en estos paciente la correlación entre este parámetro y la existencia de un juicio crítico positivo fue significativa. Conclusión: Las vacunas alergénicas administradas por vía sublingual han demostrado ser un tratamiento seguro y eficaz. Se ha objetivado en lo paciente un alto grado de cumplimiento hacia esta forma de inmunoterapia (AU)

Background: Allergenic vaccines administered by sublingual route (SLIT) are being increase ingly ued in clinical practice, being their efficacy and safety well documented. The aim of this study was lo assess both parameters in two groups of parients, adults and children, unitized to a perennial allergen (D. pteronyssinus), and to establi h the degree of compliance of treatment. Methods: Syrnptorns and medication score was measured before end after 1 year of treatment. The degree of cornpliance was evaluared through correlarion between the compliance of protocol and a questionnaire based on the critica! opinion towards SLIT. Results: Most of patients (84C/t) were better or much better after J year of treatment. Statistical differences were found in ocular.na al and total symptoms score, a well as in total (symptoms plus medication) score. The percentage of systemic reactions was 0.3. The degree of protocol compliance was good or very good in 72% of patients. existing in these patients a significant correlation between this parameter and a positive opinion towards SLIT. Conclusion: SLIT is an effective and well tolerated treatment, showing the patients a high degree of compliance (AU)

G protein-coupled receptors regulate Na+,K+-ATPase activity and endocytosis by modulating the recruitment of adaptor protein 2 and clathrin.

Inhibition of Na(+),K(+)-ATPase (NKA) activity in renal epithelial cells by activation of G protein-coupled receptors is mediated by phosphorylation of the catalytic alpha-subunit followed by endocytosis of active molecules. We examined whether agonists that counteract this effect do so by dephosphorylation of the alpha-subunit or by preventing its internalization through a direct interaction with the endocytic network. Oxymetazoline counteracted the action of dopamine on NKA activity, and this effect was achieved not by preventing alpha-subunit phosphorylation, but by impaired endocytosis of alpha-subunits into clathrin vesicles and early and late endosomes. Dopamine-induced inhibition of NKA activity and alpha-subunit endocytosis required the interaction of adaptor protein 2 (AP-2) with the catalytic alpha-subunit. Phosphorylation of the alpha-subunit is essential because dopamine failed to promote such interaction in cells lacking the protein kinase C phosphorylation residue (S18A). Confocal microscopy confirmed that oxymetazoline prevents incorporation of NKA molecules into clathrin vesicles by inhibiting the ability of dopamine to recruit clathrin to the plasma membrane. Dopamine decreased the basal levels of inositol hexakisphosphate (InsP(6)), whereas oxymetazoline prevented this effect. Similar increments (above basal) in the concentration of InsP(6) induced by oxymetazoline prevented AP-2 binding to the NKA alpha-subunit in response to dopamine. In conclusion, inhibition of NKA activity can be reversed by preventing its endocytosis without altering the state of alpha-subunit phosphorylation; increased InsP(6) in response to G protein-coupled receptor signals blocks the recruitment of AP-2 and thereby clathrin-dependent endocytosis of NKA.

Dermatomiosistis Juvenil (DMJ) y vitiligio: una nueva asociacion? / Dermatomyositis and vitiligo: a new autoimmune association?

La DMJ y el vitiligo son enfermedades consideradas de origen autoinmune, que puede presentarse en forma aislada o asociada a otras patologias. No hemos hallado descripta su asociacion en un mismo paciente. Presentamos el caso de un adolescente varon de 14 años, portador de ambas entidades. El analisis del mismo no nos permitio hallar una etiopatogenia comun, pudiendo tratarse de una asociacion casual

Dermatomiosistis Juvenil (DMJ) y vitiligio: una nueva asociacion? / Dermatomyositis and vitiligo: a new autoimmune association?

La DMJ y el vitiligo son enfermedades consideradas de origen autoinmune, que puede presentarse en forma aislada o asociada a otras patologias. No hemos hallado descripta su asociacion en un mismo paciente. Presentamos el caso de un adolescente varon de 14 años, portador de ambas entidades. El analisis del mismo no nos permitio hallar una etiopatogenia comun, pudiendo tratarse de una asociacion casual

Insulin-induced stimulation of Na+,K(+)-ATPase activity in kidney proximal tubule cells depends on phosphorylation of the alpha-subunit at Tyr-10.

Phosphorylation of the alpha-subunit of Na+,K(+)-ATPase plays an important role in the regulation of this pump. Recent studies suggest that insulin, known to increase solute and fluid reabsorption in mammalian proximal convoluted tubule (PCT), is stimulating Na+,K(+)-ATPase activity through the tyrosine phosphorylation process. This study was therefore undertaken to evaluate the role of tyrosine phosphorylation of the Na+,K(+)-ATPase alpha-subunit in the action of insulin. In rat PCT, insulin and orthovanadate (a tyrosine phosphatase inhibitor) increased tyrosine phosphorylation level of the alpha-subunit more than twofold. Their effects were not additive, suggesting a common mechanism of action. Insulin-induced tyrosine phosphorylation was prevented by genistein, a tyrosine kinase inhibitor. The site of tyrosine phosphorylation was identified on Tyr-10 by controlled trypsinolysis in rat PCTs and by site-directed mutagenesis in opossum kidney cells transfected with rat alpha-subunit. The functional relevance of Tyr-10 phosphorylation was assessed by 1) the abolition of insulin-induced stimulation of the ouabain-sensitive (86)Rb uptake in opossum kidney cells expressing mutant rat alpha1-subunits wherein tyrosine was replaced by alanine or glutamine; and 2) the similarity of the time course and dose dependency of the insulin-induced increase in ouabain-sensitive (86)Rb uptake and tyrosine phosphorylation. These findings indicate that phosphorylation of the Na+,K(+)-ATPase alpha-subunit at Tyr-10 likely participates in the physiological control of sodium reabsorption in PCT.

PKC-beta and PKC-zeta mediate opposing effects on proximal tubule Na+,K+-ATPase activity.

Dopamine (DA) inhibits rodent proximal tubule Na+,K+-ATPase via stimulation of protein kinase C (PKC). However, direct stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) results in increased Na+,K+-ATPase. LY333531, a specific inhibitor of the PKC-beta isoform, prevents PMA-dependent activation of Na+,K+-ATPase, but has no effect on DA inhibition of this activity. A similar result was obtained with a PKC-beta inhibitor peptide. Concentrations of staurosporine, that inhibits PKC-zeta, prevent DA-dependent inhibition of Na+,K+-ATPase and a similar effect was obtained with a PKC-zeta inhibitor peptide. Thus, PMA-dependent stimulation of Na+,K+-ATPase is mediated by activation of PKC-beta, whereas inhibition by DA requires activation of PKC-zeta.