Análisis coste-efectividad del implante percutáneo de válvula aórtica SAPIEN 3 en pacientes con estenosis aórtica grave sintomática / Cost-effectiveness analysis of the SAPIEN 3 transcatheter aortic valve implant in patients with symptomatic severe aortic stenosis

Introducción y objetivos: El implante percutáneo de la válvula aórtica se ha consolidado como tratamiento de la estenosis aórtica grave inoperable o de alto riesgo quirúrgico. Recientemente las indicaciones se han ampliado a riesgo intermedio y bajo. Nuestro objetivo es evaluar la eficiencia de SAPIEN 3 frente al tratamiento médico conservador (TMC) o el reemplazo quirúrgico de válvula aórtica (RVA) en pacientes sintomáticos inoperables con riesgo alto e intermedio.´Métodos: Análisis de coste-efectividad de SAPIEN 3 frente a RVA/TMC mediante un modelo de Markov (ciclos mensuales) adaptado con 8 estados definidos por la New York Hearth Association y resultados a 15 años, incluidos las complicaciones mayores y el tratamiento tras el alta hospitalaria, desde la perspectiva del Sistema Nacional de Salud. Los parámetros de efectividad se basan en los estudios PARTNER. Se incluyeron costes sanitarios (en euros de 2019) derivados del procedimiento, hospitalización, complicaciones clínicas y seguimiento. Se aplicó una tasa de descuento anual del 3% en costes y beneficios. El análisis de sensibilidad fue determinístico y probabilístico (Monte Carlo). Resultados: En comparación con el RVA (riesgo alto e intermedio) y el TMC (inoperables), el SAPIEN 3 implicó mejores resultados en las 3 poblaciones y menor estancia. Las tasas de coste-utilidad incremental fueron 5.471 (riesgo alto), 8.119 (riesgo intermedio) y 9.948 (inoperables) euros/años de vida ajustados por calidad ganados. En el análisis probabilístico, el SAPIEN 3 resultó coste-efectivo por encima del 75% de las simulaciones en los 3 perfiles. Conclusiones: En nuestro medio, el SAPIEN 3 permite un tratamiento eficiente de la estenosis aórtica grave tanto en pacientes inoperables como en riesgo alto e intermedio (AU)

Introduction and objectives: Transcatheter aortic valve implant has become a widely accepted treatment for inoperable patients with aortic stenosis and patients at high surgical risk. Its indications have recently been expanded to include patients at intermediate and low surgical risk. Our aim was to evaluate the efficiency of SAPIEN 3 vs conservative medical treatment (CMT) or surgical aortic valve replacement (SAVR) in symptomatic inoperable patients at high or intermediate risk. Methods: We conducted a cost-effectiveness analysis of SAPIEN 3 vs SAVR/CMT, using a Markov model (monthly cycles) with 8 states defined by the New York Heart Association and a time horizon of 15 years, including major complications and management after hospital discharge, from the perspective of the National Health System. Effectiveness parameters were based on the PARTNER trials. Costs related to the procedure, hospitalization, complications, and follow-up were included (euros in 2019). An annual discount rate of 3% was applied to both costs and benefits. Deterministic and probabilistic sensitivity analyses (Monte Carlo) were performed. Results: Compared with SAVR (high and intermediate risk) and CMT (inoperable), SAPIEN 3 showed better clinical results in the 3 populations and lower hospital stay. Incremental cost-utility ratios (€/quality-adjusted life years gained) were 5471 (high risk), 8119 (intermediate risk) and 9948 (inoperable), respectively. In the probabilistic analysis, SAPIEN 3 was cost-effective in more than 75% of the simulations in the 3 profiles. Conclusions: In our health system, SAPIEN 3 facilitates efficient management of severe aortic stenosis in inoperable and high- and intermediate-risk patients (AU)

[Oral antibiotic request without prescription in community pharmacies. Description of pharmacists' intervention]. / Demanda de antibióticos sin prescripción en la farmacia comunitaria. Descripción de la intervención del farmacéutico.

OBJECTIVES: To quantify the proportion of oral antibiotics requests without prescription in Community Pharmacy (CP) and to analyse it causes. METHOD: Cross-sectional multicentre study carried out in Spanish community pharmacies during 4 weeks, one in each season of the year. Oral J01 antibiotics (Anatomical Therapeutic Chemical classification, ATC) requested for self-medication were analysed. RESULTS: 247 pharmacies and 365 pharmacists participated in the study, 1172 antibiotic requests were recorded. More frequent requests for antibiotic self-medication were: previous treatment for the same symptoms (63.1%), insufficient time for a general practitioner (GP) consultation (12.1%) and patient belief that GP is going to prescribe the antibiotic (4.9%). Higher number of generic medication were requested compared to brand medication (41.1 versus 34.9%). Active ingredients commonly requested were amoxicillin (28.2%), amoxicillin-clavulanic (14.9%) and phosphomycin (21.8%) to treat upper respiratory related infections (35.1%), urinary infections (28.1%) and teeth infections (20.2%). 2406 pharmacists' interventions were carried out: referring to the GP (40.8%), information for correct use of medication (31.3%), non-pharmacological treatment (15.7%), and recommendation of a different medication (6.9%) or a different product (5.3%). CONCLUSIONS: Nowadays higher number of active ingredients than brands are requested when selecting a treatment for an infection, mainly ß-lactams and macrolides. Majority of self-medication tried to treat upper respiratory infections, urinary and teeth infections. Most frequent pharmacists' intervention was referring to the GP to obtain a correct diagnosis and treatment.

[Characteristics of private and irregular prescription for oral antibiotics in Spanish community pharmacies]. / Perfil de las solicitudes de antibióticos en farmacia comunitaria con receta privada y prescripción irregular.

OBJECTIVE: To quantify the proportion of oral antibiotics through private prescription (PP) and irregular prescription (IP) in the Community Pharmacy (CP). MATERIAL AND METHODS: Cross-sectional multicentre study carried out in Spanish community pharmacies over a 4week period, one in each season of the year. An analysis was made of private and irregular prescriptions of oral J01 antibacterials for systemic use (Anatomical Therapeutic Chemical [ATC] classification). The study variables used were prescription and consultation characteristics. RESULTS: A total of 3569 PP (71% followed legislation) and 833 IP were recorded by 365 pharmacists working in 247 CP. PP were prescribed by dentists (43.7%), general practitioners (GP) (26.20%), and paediatricians (10.3%), to treat teeth infections (39.8%), upper respiratory infections (25.6%), lower respiratory infections (10.3%), and urinary infections (7.7%). The most prescribed antibiotics were amoxicillin (27.9%) and amoxicillin-clavulanic (25.2%). IP came from Emergency Departments (32.8%), oral/phone prescriptions (20.4%), and patient demand due to insufficient quantity of antibiotic to complete treatment (10%). Prescriptions came from GP (25.2%), dentists (24.7%), and paediatricians (12%) to treat upper respiratory infections (32.5%), teeth infections (25.8%), urinary infections (14.2%), and lower respiratory infections (10.8%). The most prescribed antibiotics were amoxicillin-clavulanic (27.4%) and amoxicillin (21.6%). Since every patient with IP was referred to the GP, 45.4% of them accepted the recommendations of the pharmacists. CONCLUSIONS: This study obtained PP and IP characteristics, unknown and needed data in Spain for future health policy plans.

Pathophysiology of bronchial smooth muscle remodelling in asthma.

Whereas the role of bronchial smooth muscle remains controversial in healthy subjects its role is well established in asthmatics. Bronchial smooth muscle contraction induces airway narrowing. The smooth muscle also contributes to bronchial inflammation by secreting a range of inflammatory mediators, recruiting and activating inflammatory cells, such as mast cells or T-lymphocytes. In addition, bronchial smooth muscle mass is significantly increased in asthma. Such an increase has been related to a deposition of extracellular matrix proteins, and an increase in both cell size and number. However, the mechanisms of this smooth muscle remodelling are complex and not completely understood. The article will review recent data regarding the pathophysiology of bronchial smooth muscle remodelling in asthma.

Comprensión de la información recibida por el paciente en la primera prescripción: intervención farmacéutica / Understanding of the information received by the patient in the first prescription of a medicine: pharmacist intervention

INTRODUCCIÓN.- Nuestro objetivo ha sido valorar el conocimiento que tiene el paciente del tratamiento prescrito por primera vez, en función de la información recibida en la consulta médica. MATERIAL Y MÉTODOS.- Estudio observacional transversal, realizado en 10 oficinas de farmacia de las provincias de Albacete y Jaén del 1 de abril al 31 de mayo del 2009 entre pacientes o cuidadores que acudieron con un inicio de tratamiento. A dichos sujetos se les realizó una encuesta para cada uno de los medicamentos prescritos y los datos se analizaron con SPSS. RESULTADOS.- Tuvieron validez un total de 318 encuestas y, de éstas, sólo un 44% de los casos demostraron tener un total conocimiento del tratamiento. La intervención del farmacéutico fue requerida principalmente para aclarar posología (35,4%) y duración del tratamiento (33,9%). El grado de conocimiento aumentó cuando la información era escrita, apreciándose un aumento significativo si se acompañaba de oral, y cuando se la proporcionaba el especialista. Disminuyó a mayor edad del paciente y menor nivel de estudios. DISCUSIÓN.- El moderado conocimiento del tratamiento podría ser debido a la presión ejercida por la masificación de las consultas, que provocaría que el médico general no pueda atender al paciente el tiempo suficiente. Además, el paciente acude al especialista para ser tratado de patologías más graves y lo hace con menor frecuencia, lo que podría suponer que ponga mayor interés en conocer el tratamiento. El menor conocimiento de los ancianos se explicaría porque se trata de pacientes habitualmente polimedicados y con problemas cognitivos(AU)

INTRODUCTION.- Our aim has been to evaluate the knowledge that a patient has regarding a treatment newly prescribed, according to the information given in the medical consultation. METHODOLOGY.- Cross-sectional study, carried out in 10 community pharmacies of Albacete and Jaén, from 1st of April to 31st of May 2009. Data was obtained from a survey completed by the patients or their carers for each one of the new treatments started. Information obtained was analyzed with SPSS. RESULTS.- 318 valid surveys, only 44% of these cases proved a total knowledge of the treatment. Pharmacist intervention was mainly needed to clarify the dosage (35,4%) and the duration of the treatment (33,9%). The degree of knowledge increased when the information was given by a consultant and also when was written information. More over it was seen a significant increase of knowledge when written information was accompanied by verbal. In the other hand, it decreased in elderly patients and in them with lower level of education. DISCUSION.- The moderate knowledge of the treatment could be due to the limited time GP have for each patient. Also, patients normally attend to the consultant for more serious illness and less often, probably paying more attention to the information about the treatment prescribed. The lower level of knowledge in the elderly could be explained for the high number of medicines they take and the cognitive problems(AU)

Perfil del tratamiento con Levotiroxina: interacciones farmacológicas detectadas / Levothyroxine treatment profile: pharmacological interactions detected

INTRODUCCIÓN.- Nuestro objetivo ha sido determinar el perfil del tratamiento con levotiroxina, incidiendo en las posibles interacciones que se pueden producir en pacientes polimedicados. METODOLOGÍA.- Estudio observacional transversal a partir de los datos obtenidos en 10 farmacias comunitarias de Albacete y provincia, durante los meses de enero a marzo de 2008. Se incluyeron un total de 184 pacientes (33 varones y 151 mujeres) que acudieron a la oficina de farmacia con una prescripción de levotiroxina. Se diseñó una hoja registro que contenía diversos datos acerca del paciente y del tratamiento. RESULTADOS.- El perfil más frecuente del paciente fue el siguiente: mujer de más de 60 años que hace más de un año que comenzó el tratamiento con levotiroxina y la posología más habitual la siguiente: 50-100 mcg/día tomados en ayunas antes del desayuno. Un 58,7% de los encuestados tomaban levotiroxina y algún otro fármaco y de éstos más de la mitad lo hacían en la misma toma,detectando una posible interacción en prácticamente un tercio de los mismos, siendo la principal consecuencia el aumento de los niveles de levotiroxina. DISCUSIÓN.- La elevada probabilidad de interacción obliga a que se recomiende analizar los tratamientos concomitantes con levotiroxina, especialmente en pacientes ancianos habitualmente polimedicados. Llama la atención que el farmacéutico tuvo que intervenir en prácticamente la mitad de las dispensaciones, principalmente para indicar que el medicamento se debe tomar en ayunas y a la hora indicada, hecho que refuerza que se trata de un profesional clave en la adherencia al tratamiento(AU)

INTRODUCTION.- Our aim has been to determine the treatment profile with levothyroxine, focusing on the possible interactions that can occur in polymedicated patients. METHODOLOGY.- Cross-sectional study, with data obtained from 10 community pharmacies of Albacete and its county from January to March 2008. 184 patients (33 men and 151 women) were included in the study. These patients obtained the levothyroxine from one of the 10 pharmacies collaborating in the study. Data log sheet contained a variety of information about the patient and the treatment. RESULTS.- The most frequent profile of the patients was: women over sixty years age, who had been taking levothyroxine for over a year, with the most common dosage being 50-100 mcg/day before breakfast. A 58,7% of the patients were taking levothyroxine and another drug. More than half of these patients, were taking levothyroxine at the same time of other medicines. We detected a possible interaction in one third of the cases, resulting in an increase of levothyroxine blood levels. DISCUSION.- Due to the high probability of drug interactions, concomitant treatments with levothyroxine need to be analyzed, specially in elderly patients very often polymedicated. It was surprising the fact that the pharmacist had to intervene in practically half of the cases, mainly to indicate that levothyroxine has to be taking on an empty stomach. This reinforces the important role that pharmacists play to ensure adherence to the treatment(AU)

Grado de satisfacción en función de la información recibida por el paciente en la primera prescripción / Satisfaction degree regarding to the information received by the patient in the first prescription

INTRODUCCIÓN.- El objetivo ha sido reflejar el grado de satisfacción del paciente con la información recibida cuando se le prescribe un medicamento por primera vez, en función del tipo de información y del grado de capacitación del que se la proporciona. MATERIAL Y MÉTODOS.- Estudio observacional transversal, realizado en 10 oficinas de farmacia de las provincias de Albacete y Jaén del 1 de abril al 31 de mayo del 2009 entre pacientes o cuidadores que acudieron con un inicio de tratamiento. A dichos sujetos se les realizó una encuesta de satisfacción para cada uno de los medicamentos prescritos y los datos se analizaron con SPSS. RESULTADOS.- Se recogieron un total de 318 encuestas válidas. En el 76,7% de los casos, los pacientes manifestaron estar satisfechos con la información recibida. Cuando la información que se da al paciente es únicamente escrita a mano, el grado de satisfacción es superior al manifestado cuando se da oral o escrita informatizada, destacando el aumento significativo de este grado de satisfacción cuando la información escrita se acompaña de la oral. La satisfacción es mayor en el caso de tratamientos puntuales frente a crónicos y cuando la información la da el médico especialista, aunque la diferencia no es estadísticamente significativa. DISCUSIÓN.- Cuando la información es únicamente escrita informatizada, casi en la mitad de los casos los encuestados no están satisfechos y sólo un tercio comprende todo el tratamiento, cobrando especial relevancia este tema si consideramos que la prescripción informatizada es la que prevalece en nuestro medio(AU)

INTRODUCTION.- The objective has been to reflect the degree of satisfaction shown by the patient with the information received when starting a new treatment. It was based on the type of information and the level of training of the person who provides the information. METHODOLOGY.- Cross-sectional study, carried out in 10 community pharmacies of Albacete and Jaén from the 1st of April to the 31st of May 2009. Patients or their carers completed a survey about satisfaction for each one of the new medicines prescribed. Data obtained was analyzed with SPSS. RESULTS.- 318 valid surveys were collected. In 76,7% of the cases, patients stated to be satisfied with the information received. The level of satisfaction was higher when information was given hand written to the patient in comparison with verbal or computerized written. More over a significant increase of satisfaction was seen when written information was accompanied by verbal one. Satisfaction was greater in acute treatments than in chronic treatments and also when information was given by a consultant. However this difference was found not to be statiscally significant. DISCUSION.- When only computerized written information is supplied, nearly half of the patients are not satisfied and only one third of them understand everything about the new treatment. These findings are very significant for us due to the high number of computerized prescriptions we have to deal within our pharmacies(AU)

Mast cell adhesion to bronchial smooth muscle in asthma specifically depends on CD51 and CD44 variant 6.

BACKGROUND: Mast cells infiltrate the bronchial smooth muscle (BSM) in asthmatic patients, but the mechanism of mast cell adhesion is still unknown. The adhesion molecules CD44 (i.e. hyaluronate receptor) and CD51 (i.e. vitronectin receptor) are widely expressed and bind to many extracellular matrix (ECM) proteins. The aims of the study are (i) to identify the role of ECM in mast cell adhesion to BSM and (ii) to examine the role of CD51 and CD44 in this adhesion. METHODS: Human lung mast cells, human mast cell line (HMC-1), and BSM cells from control donors or asthmatic patients were cultured in the presence/absence of various cytokines. Mast cell-BSM interaction was assessed using (3)H-thymidine-pulsed mast cells, confocal immunofluorescence, or electron microscopy. Adhesion molecules expression and collagen production on both cell types were evaluated by quantitative RT-PCR, western blot, and flow cytometry. RESULTS: Mast cell adhesion to BSM cells mostly involved type I collagen of the ECM. Such an adhesion was increased in normal BSM cells under inflammatory condition, whereas it was maximal in asthmatic BSM cells. Blockade of either CD51 or CD44 significantly decreased mast cell adhesion to BSM. At the molecular level, protein and the transcriptional expression of type I collagen, CD51 or CD44 remained unchanged in asthmatic BSM cells or in mast cells/BSM cells under inflammatory conditions, whereas that of CD44 variant isoform 6 (v6) was increased. CONCLUSIONS: Mast cell-BSM cell adhesion involved collagen, CD44, and CD51, particularly under inflammatory conditions. CD44v6 expression is increased in asthmatic BSM cells.

Langevin simulation of rf collisional multipactor breakdown of gases.

The thresholds for the electron multiplication in both multipactor and the so-called collisional multipactor microwave discharges are calculated by means of an individual particle model. The simulations are restricted to low and intermediate gas pressures, where the collisional mean-free path of electrons is of the same order or larger than the characteristic dimension of the system. Thus, the charge multiplication is caused by both the electron impact ionization of the neutral gas and the secondary electron emission by electron collisions at the surfaces. The charge avalanche is simulated by the numerical integration of the trajectories of electrons up to the characteristic time for the space-charge buildup. The electron dynamics is described by the stochastic Langevin equations where the collisional scatter of electrons is incorporated by means of a random force, while the microwave electric field and the friction are deterministic forces. The physical properties of materials at the walls are considered by means of realistic models deduced from experimental data fitting, while the constant collision frequency model is used for elastic and inelastic electron collisions with neutral atoms. Previous results for low pressure electron multipactor are recovered, and for pressures corresponding to collisional multipactor the predictions of this simple model are in agreement with both the experimental results and particle in cell and Monte Carlo simulations. Finally, physical conditions under which the charge multiplication develops and the limitations for higher pressures of the proposed model are also discussed.

Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. OBJECTIVES: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. METHODS: A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. RESULTS: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. CONCLUSIONS: Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

[Atopic dermatitis aggravates the allergic airways inflammation in acute viral bronchiolitis]. / La dermatite atopique aggrave l'inflammation allergique dans la bronchiolite aiguë virale.

INTRODUCTION: Exhaled nitric oxide (FeNO) is a putative non-invasive marker of eosinophilic airway inflammation with a good predictive value for allergic asthma in preschool children. The aim of the present study was to compare FeNO after acute viral bronchiolitis (AVB) in children aged less than 2 years without atopic dermatitis (AD) vs those with atopic dermatitis, as well as children with AD without any history of AVB. METHODS: Forty-two children (mean age +/- SD: 12.3 +/- 5.2 months; range 5.0-23.5; sex-ratio M: F=1.3: 1) were included in this prospective study, > 8 wks after an episode of AVB. The patients' atopic status was assessed both by clinical phenotype and IgE- mediated response to inhaled and/or food allergens. FeNO (ppb) was measured off-line by the chemoluminescence method on samples obtained from gas collected in a balloon during tidal breathing. RESULTS: There was a significant difference between the AVB/AD (23.4 +/- 14.3 ppb, n=15) vs the AVB without AD group (13.5 +/- 10. 1 ppb, n=13) or the AD without AVB group (11.0 +/- 8.3 ppb, n=14). Maternal feeding for more than 2 months decreased FeNO by 50%. CONCLUSION: Atopic children below 2 years with AD produce more NO after AVB than non-atopic children or atopic children without any history of AVB. Maternal feeding decreases FeNO.

Sublingual-swallow immunotherapy with standardized 3-grass pollen extract: a double-blind, placebo-controlled study.

BACKGROUND: Sublingual immunotherapy (SLIT) is accepted as a safe and effective route for the treatment of grass pollen allergy, but clarification of its clinical and biological efficacy requires more study. OBJECTIVE: To evaluate the efficacy, safety, and compliance of SLIT with a standardized 3-grass pollen extract in patients with grass pollen seasonal allergic rhinoconjunctivitis, with or without mild asthma. METHODS: This multicenter, randomized, double-blind study included 127 patients (aged 12-41 years; mean age, 24.9 years) with grass pollen seasonal allergic rhinoconjunctivitis, with or without mild asthma. They received either SLIT with a high-dose, standardized, 3-grass pollen extract or placebo for 10 months before and during the grass pollen season. The efficacy evaluation compared weekly clinical scores (defined as the sum of the symptom score and rescue medication score) to measure rhinoconjunctivitis and asthma for the first 8 weeks of the pollen season. We also evaluated safety and compliance and measured changes in anti-Dactylis specific IgG4 antibody levels. RESULTS: There was a trend in favor of the study group in the mean adjusted clinical score. The groups were not comparable on inclusion (P = .02): the SLIT group included more subjects with asthma and had a higher mean IgG4 serum level. Additional exploration according to subgroups with and without asthma found that among the patients without asthma, the SLIT group had a significantly better clinical score (P = .045). Anti-Dactylis specific IgG4 levels increased significantly in the SLIT group. CONCLUSION: SLIT with a standardized, high-dose, 3-grass pollen extract is safe and significantly improves the clinical score in patients with hay fever and without asthma during the pollen season.

Bone fractures after cardiac transplantation.

OBJECTIVE: Bone loss and bone fractures are disabling complications after heart transplantation. Severe bone loss happens mainly during the first year posttransplantation. Steroids and cyclosporine alter bone metabolism in several ways. To counterbalance these effects, antiresorptive therapy is provided to these patients. The objective of this study was to assess the frequency of bone fractures after heart transplantation, considering previous comorbidities, immunosuppressive therapy, and osteoprotective treatment. METHODS: From 1993 to 2005, 443 consecutive heart transplant recipients were followed for the occurrence of bone fractures, immunosuppressive therapy, clinical conditions, and antiresorptive treatment. RESULTS: There were 41 fractures in 34 patients (7.6%, group I). The remainder of patients formed group II. Fractures commonly involved the lumbar spine. Postmenopausal women had more fractures than other patients (20.6% vs 7.8%, P = .02). When the initial immunosuppressive regimen included tacrolimus, fractures did not happen (P = .01, vs other regimens). Osteoprotective therapy was administered to 91.2% of patients in group I and 79% in group II (P = .08). Mean interval from transplantation to the first fracture was 1131.5 days. Overweight patients had a 61.8% incidence of fracture. CONCLUSIONS: Our series showed a low frequency of bone fractures. Postmenopausal women and overweight patients had more fractures. An initial immunosuppressive regimen using tacrolimus was associated with lower fracture rates.

Omalizumab decreases nonspecific airway hyperresponsiveness in vitro.

BACKGROUND: In asthmatic patients, both symptoms and hyperresponsiveness are related to immunoglobulin E (IgE) concentration in serum. The anti-IgE monoclonal antibody omalizumab improved the control of asthma, but its effect on airway hyperresponsiveness is controversial. Passive sensitization reproduced in vitro a bronchial hyperresponsiveness, an increase in IgE bearing cells, and a mast cell degranulation. This study was designed to examine the effect of omalizumab on passive sensitization-induced hyperresponsiveness, alterations in IgE positive inflammatory cells and mast cell degranulation within the bronchial wall. METHODS: Proximal (3-5 mm diameter) and distal (0.5-1.5 mm diameter) human bronchi dissected out from 10 lung specimens were incubated in normal or asthmatic serum containing various concentrations of omalizumab. Contractile responses to histamine or Dermatophagoides pteronyssinus (D. pter) were recorded using an organ bath system and expressed as percentage of maximal contractile response to acetylcholine (ACh). Immunohistochemistry was performed using monoclonal antibodies directed against IgE or tryptase. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). RESULTS: The specific bronchial hyperresponsiveness to D. pter and the nonspecific bronchial hyperresponsiveness to histamine following passive sensitization were significantly inhibited by omalizumab in both distal and proximal airways. Passive sensitization-induced increase in IgE positive cells was also abolished by omalizumab in a concentration dependent manner. Mast cell degranulation which was inhibited by omalizumab was positively correlated with the contractile response to D. pter. CONCLUSIONS: Omalizumab blocks specific and nonspecific bronchial hyperresponsiveness. Anti-IgE also decreases IgE bearing cell number and mast cell degranulation.

Inflammation of bronchial smooth muscle in allergic asthma.

BACKGROUND: Recent observations in asthma suggest that bronchial smooth muscle is infiltrated by inflammatory cells including mast cells. Such an infiltration may contribute to airway remodelling that is partly due to an increase in smooth muscle mass. Whether muscle increase is the result of smooth muscle cell hypertrophy remains controversial and has not been studied by ultrastructural analysis. A morphometric analysis of airway smooth muscle (ASM) was undertaken in asthmatic patients using electron microscopy to examine the interactions between ASM cells and inflammatory cells. METHODS: ASM specimens were obtained from 14 asthmatic subjects and nine non-asthmatic controls undergoing fibreoptic endoscopy. Inflammatory cell counts were assessed by immunohistochemistry, and ultrastructural parameters were measured using electron microscopy in a blinded fashion on smooth muscle cells and inflammatory cells. RESULTS: ASM from asthmatic patients was infiltrated by an increased number of mast cells and lymphocytes. Smooth muscle cells and their basal lamina were thicker in asthmatic patients (9.5 (0.8) and 1.4 (0.2) microm) than in controls (6.7 (0.4) and 0.7 (0.1) microm). In asthmatics the extracellular matrix was frequently organised in large amounts between ASM cells. Myofibroblasts within smooth muscle bundles were only observed in asthmatics, some of them displaying a close contact with ASM cells. CONCLUSION: In asthma, airway myositis is characterised by a direct interaction between ASM cells and mast cells and lymphocytes. Smooth muscle remodelling was present, including cell hypertrophy and abnormal extracellular matrix deposition moulding ASM cells.

Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma.

Human airway smooth muscle cells (HASMC) secrete fractalkine (FKN), a chemokine the concentration of which is increased in asthmatic patients. HASMC also induce mast cell chemotaxis, as a component of asthma inflammation. We therefore evaluated the role of smooth muscle-derived FKN in mast cell migration. We assessed the capacity of recombinant FKN to induce human mast cell chemotaxis. This effect implicates a calcium-independent pathway involving actin reorganization and protein kinase C-delta. We found that HASMC constitutively produce FKN, the synthesis of which is reinforced upon proinflammatory stimulation. Under basal experimental conditions, FKN production by HASMC is not sufficient to induce mast cell chemotaxis. However, pretreatment of mast cells with the neuropeptide vasoactive intestinal peptide (VIP) increases FKN potency to attract mast cells. Since we observed, in asthmatic patients, an increase in both FKN and VIP expression by airway smooth muscle and a positive correlation between VIP staining and mast cell infiltration of the smooth muscle layer, we conclude that HASMC-derived FKN may contribute to mast cell recruitment in asthma.

RNA interference decreases PAR-2 expression and function in human airway smooth muscle cells.

Asthma is characterized by bronchial inflammation and hyperresponsiveness that involves mast cell tryptase and potentially its specific receptor protease activated receptor 2 (PAR-2). Tryptase increases free intracellular calcium concentration ([Ca2+]i), a key step in activation of human airway smooth muscle cells (HASMC). The aim of this study was to analyze the effect of PAR-2 gene silencing on HASMC, in terms of calcium response, since no antagonist is available for this receptor. Five siRNA against PAR-2 were synthesized and transfected in HASMC using lipid agents, and PAR-2 expression was examined using Western blot, fluorescence-activated cell sorter, immunocytochemistry and RT-PCR. [Ca2+]i was measured using microspectrofluorimetry in response to tryptase, the activating peptide SLIGKV, trypsin, or caffeine. Two siRNA significantly inhibited PAR-2 expression in terms of both total and surface protein expression, as well as mRNA levels. Tryptase- and SLIGKV-induced transient increase in [Ca2+]i was significantly inhibited after transfection with the most appropriate siRNA, whereas neither trypsin nor caffeine response was altered. Two control siRNA had no effect in terms of both PAR-2 expression and calcium response. Transfection efficiency was maximal after 24 h and disappeared after 48 h. Gene silencing using siRNA can thus be used in vitro to assess the function of PAR-2 in HASMC.

[IgE and respiratory disease]. / Immunoglobuline E et maladies respiratoires.

INTRODUCTION: IgE is known to provide the biological basis for allergy and immediate hypersensitivity. However, recent data provide some evidence that IgE responses are involved in other inflammatory processes apart from allergy, including several respiratory diseases. STATE OF THE ART: IgE binds to mast cells and basophils but also to other inflammatory cells, which are involved in non-allergic processes. IgE has a role in antigen presentation and is implicated in a number of other immune mechanisms. In the airways, IgE plays an important role in bronchial hyperactivity, even in the absence of an allergen. Epidemiological studies have demonstrated that IgE response is related not only to allergy but also to asthma symptoms, in the presence or absence of atopy, as well as exposure to cigarette smoke. IgE response is altered in several respiratory diseases including extrinsic and intrinsic asthma and allergic bronchopulmonary aspergillosis. CONCLUSION AND PERSPECTIVES: Since anti-IgE monoclonal antibodies are now available for administration to humans, a better understanding of the IgE response may allow the identification of novel therapeutic targets in the field of respiratory disease.