Dolor y acortamiento aquíleo en pacientes con marcha de puntillas idiopática / Pain and Achilles tendon shortening in patients with idiopathic toe walking

Introducción: La marcha de puntillas idiopática (MPI) es una entidad heterogénea que asocia acortamientos musculares en las extremidades inferiores, dolor y trastornos del neurodesarrollo. Pretendemos estudiar la frecuencia de ciertas características clínicas en pacientes diagnosticados de MPI. Pacientes y métodos: De un total de 100 pacientes evaluados por marcha de puntillas en una consulta de rehabilitación infantil, se diagnosticó a 77 pacientes (24,7% mujeres) como con MPI con ayuda del cuestionario Toe Walking Tool. Mediante la maniobra de Silfverskiöld pudo determinarse el acortamiento aquíleo y mediante test adaptados también el dolor y la asociación con el trastorno por déficit de atención/hiperactividad (TDAH). En el grupo con dolor (n = 30), estudiamos su evolución mediante encuesta telefónica evaluando la intensidad, la localización, el absentismo escolar asociado y el tratamiento utilizado. Resultados: De los 77 pacientes, el 44,2% presentó antecedentes familiares de marcha de puntillas, el 37,7% tuvo acortamiento aquíleo y el 9,1%, de los flexores de la rodilla. El 9,1% de ellos tuvo TDAH confirmado y el 20,8%, sólo sospecha. A mayor edad, encontramos mayor frecuencia de dolor y menor ángulo de dorsiflexión pasiva del tobillo. El dolor fue de moderada-alta intensidad, produjo un 42,3% de absentismo escolar y se localizó predominantemente en la pantorrilla, el tobillo y el pie, y se prescribió fisioterapia, analgesia oral, ortesis y/o toxina botulínica principalmente. Conclusiones: El dolor en la MPI es frecuente, de intensidad moderada-alta, interfiere en la vida diaria y es más referido en niños más mayores que asocian menor dorsiflexión del tobillo. Encontramos asociación de la MPI y el TDAH con frecuencia, lo que anima a profundizar más su estudio como signo de alerta.(AU)

Introduction: Idiopathic toe walking (ITW) is a heterogeneous disorder, which is associated with muscle shortening in lower limbs, pain and neurodevelopmental disorders. We try to study the frequency of clinical features in patients with ITW. Patients and methods: Out of 100 patients evaluated with toe walking in a pediatric rehabilitation clinic, 77 (24,7% women) patients were diagnosed with ITW by means of TWT questionnaire. Achilles’ tendon shortening with Silfverskiöld manoeuvre, pain and attention deficit hyperactivity disorder (ADHD) were studied. In the group of patients with pain (n = 30), we studied pain evolution by means of a telephonic interview which assessed intensity, location, school absenteeism and used therapies. Results: Out of 77 patients, 44.2% had family history of toe walking. 37.7% and 9.1% showed Achilles’ tendon shortening and Knee flexor shortening, respectively. Confirmed diagnosed of ADHD was present in 9.1% and was suspected in 20.8%. The older the patient was, the higher frequency of pain and the lower passive ankle dorsiflexion. Pain has a moderate-severe intensity, was related with school absenteeism in 42.3% of the patients with pain. Pain was located mainly on the calf, the ankle and the foot. It was treated with physiotherapy, oral pain relievers, orthosis and botulinum toxin type A (BTxA). Conclusions: Pain in ITW is frequent, have a moderate-severe intensity, interferes in normal life and is referred in older children with lower ankle dorsiflexion. We found a common association between ITW and ADHD which points out ITW as alarm sign of learning problems.(AU)

[Pain and Achilles tendon shortening in patients with idiopathic toe walking]. / Dolor y acortamiento aquíleo en pacientes con marcha de puntillas idiopática.

INTRODUCTION: Idiopathic toe walking (ITW) is a heterogeneous disorder, which is associated with muscle shortening in lower limbs, pain and neurodevelopmental disorders. We try to study the frequency of clinical features in patients with ITW. PATIENTS AND METHODS: Out of 100 patients evaluated with toe walking in a pediatric rehabilitation clinic, 77 (24,7% women) patients were diagnosed with ITW by means of TWT questionnaire. Achilles' tendon shortening with Silfverskiold manoeuvre, pain and attention deficit hyperactivity disorder (ADHD) were studied. In the group of patients with pain (n = 30), we studied pain evolution by means of a telephonic interview which assessed intensity, location, school absenteeism and used therapies. RESULTS: Out of 77 patients, 44.2% had family history of toe walking. 37.7% and 9.1% showed Achilles' tendon shortening and Knee flexor shortening, respectively. Confirmed diagnosed of ADHD was present in 9.1% and was suspected in 20.8%. The older the patient was, the higher frequency of pain and the lower passive ankle dorsiflexion. Pain has a moderate-severe intensity, was related with school absenteeism in 42.3% of the patients with pain. Pain was located mainly on the calf, the ankle and the foot. It was treated with physiotherapy, oral pain relievers, orthosis and botulinum toxin type A (BTxA). CONCLUSIONS: Pain in ITW is frequent, have a moderate-severe intensity, interferes in normal life and is referred in older children with lower ankle dorsiflexion. We found a common association between ITW and ADHD which points out ITW as alarm sign of learning problems.

TITLE: Dolor y acortamiento aquíleo en pacientes con marcha de puntillas idiopática.Introducción. La marcha de puntillas idiopática (MPI) es una entidad heterogénea que asocia acortamientos musculares en las extremidades inferiores, dolor y trastornos del neurodesarrollo. Pretendemos estudiar la frecuencia de ciertas características clínicas en pacientes diagnosticados de MPI. Pacientes y métodos. De un total de 100 pacientes evaluados por marcha de puntillas en una consulta de rehabilitación infantil, se diagnosticó a 77 pacientes (24,7% mujeres) como con MPI con ayuda del cuestionario Toe Walking Tool. Mediante la maniobra de Silfverskiöld pudo determinarse el acortamiento aquíleo y mediante test adaptados también el dolor y la asociación con el trastorno por déficit de atención/hiperactividad (TDAH). En el grupo con dolor (n = 30), estudiamos su evolución mediante encuesta telefónica evaluando la intensidad, la localización, el absentismo escolar asociado y el tratamiento utilizado. Resultados. De los 77 pacientes, el 44,2% presentó antecedentes familiares de marcha de puntillas, el 37,7% tuvo acortamiento aquíleo y el 9,1%, de los flexores de la rodilla. El 9,1% de ellos tuvo TDAH confirmado y el 20,8%, sólo sospecha. A mayor edad, encontramos mayor frecuencia de dolor y menor ángulo de dorsiflexión pasiva del tobillo. El dolor fue de moderada-alta intensidad, produjo un 42,3% de absentismo escolar y se localizó predominantemente en la pantorrilla, el tobillo y el pie, y se prescribió fisioterapia, analgesia oral, ortesis y/o toxina botulínica principalmente. Conclusiones. El dolor en la MPI es frecuente, de intensidad moderada-alta, interfiere en la vida diaria y es más referido en niños más mayores que asocian menor dorsiflexión del tobillo. Encontramos asociación de la MPI y el TDAH con frecuencia, lo que anima a profundizar más su estudio como signo de alerta.

Parámetros de marcha en una muestra de referencia de escolares sanos españoles: descripción multivariante y asimetrías entre ciclos izquierdos y derechos / Gait parameters in a reference sample of healthy Spanish schoolchildren: multivariate descriptive statistics and asymmetries observed in left and right cycles

Introducción: El análisis instrumental de marcha (AIM) es una tecnología de uso creciente en la evaluación de trastornos motores infantiles. La evaluación de pacientes requiere una base de referencia de normalidad, pero existen pocas referencias infantiles españolas. Objetivo: Descripción de 16 variables de marcha de relevancia clínica en una muestra de referencia de escolares sanos. Estudio de sus relaciones lineales y asimetrías izquierda-derecha. Sujetos y métodos: Se midieron con AIM 16 variables de marcha en escolares sanos (n = 27, 5-13 años). Se estudiaron las asimetrías en cada variable (t de Student, muestras dependientes) y sus intervalos de confianza (95% de la media de diferencia estandarizada derecha menos izquierda, dz). Se representaron los valores y las asociaciones entre variables mediante «heatmap». Resultados: Se aportan tablas de normalidad para 16 variables del ciclo de marcha. Son significativamente asimétricos los valores medios de flexión mínima de cadera (dz: 0,25 IC del 95%, 0,11-0,39) y de máxima abducción de cadera en el balanceo (dz: -1,05 IC del 95%, —1,71; —0,27). Existen asociaciones funcionales entre las variables de marcha. Conclusiones: Presentamos una muestra de normalidad de escolares españoles donde se observan asimetrías entre los lados izquierdo y derecho y organización funcional entre sus variables (AU)

Introduction: Instrumental gait analysis is an emerging technology used increasingly to evaluate motor disorders in children. Normal reference data is necessary in order to evaluate patients, but there are few reference resources for the Spanish paediatric population. Objective: We aim to describe the values of 16 clinically relevant gait variables in healthy Spanish schoolchildren, and identify any linear associations or left-right asymmetries. Subjects and methods: The values of 16 gait variables were determined in schoolchildren (n = 27, aged 5-13 years) using instrumental gait analysis. We analysed asymmetries for each variable (Student’s t-test for dependent samples) and calculated their confidence intervals (95% of the standardised difference in right and left means [SMD]). Values and associations between variables were represented using a heat map. Results: Our project presents normal values tables for 16 variables in the gait cycle. Significant asymmetries were detected in the mean values for minimum hip flexion (SMD: 0.25 95% CI, 0.11-0.39) and peak hip abduction in swing (SMD: −1.05 95% CI: −1.71- − 0.27). Functional associations among gait variables are present. Conclusions: We present a reference dataset for Spanish school-aged children in which leftright asymmetries and functional associations may be observed for different variables (AU)

Gait parameters in a reference sample of healthy Spanish schoolchildren: multivariate descriptive statistics and asymmetries observed in left and right cycles.

INTRODUCTION: Instrumental gait analysis is an emerging technology used increasingly to evaluate motor disorders in children. Normal reference data is necessary in order to evaluate patients, but there are few reference resources for the Spanish paediatric population. OBJECTIVE: We aim to describe the values of 16 clinically relevant gait variables in healthy Spanish schoolchildren, and identify any linear associations or left-right asymmetries. SUBJECTS AND METHODS: The values of 16 gait variables were determined in schoolchildren (n=27, aged 5-13 years) using instrumental gait analysis. We analysed asymmetries for each variable (Student's t-test for dependent samples) and calculated their confidence intervals (95% of the standardised difference in right and left means [SMD]). Values and associations between variables were represented using a heat map. RESULTS: Our project presents normal values tables for 16 variables in the gait cycle. Significant asymmetries were detected in the mean values for minimum hip flexion (SMD: 0.25 95% CI, 0.11-0.39) and peak hip abduction in swing (SMD: -1.05 95% CI: -1.71--0.27). Functional associations among gait variables are present. CONCLUSIONS: We present a reference dataset for Spanish school-aged children in which left-right asymmetries and functional associations may be observed for different variables.

[Diagnosis of brain death by multislice CT scan: angioCT scan and brain perfusion]. / Diagnóstico de muerte encefálica mediante tomografía computarizada multicorte: angio-TC y perfusión cerebral.

BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations.

Diagnóstico de muerte encefálica mediante tomografía computarizada multicorte: angio-TC y perfusión cerebral / Diagnosis of brain death by multislice CT scan: angioCT scan and brain perfusion

El objetivo del presente estudio fue valorar la perfusión cerebral y la angiografía cerebral mediante tomografía computarizada (TC) multicorte, como método diagnóstico de muerte encefálica (ME). Fueron analizados 6 pacientes ingresados en una Unidad de Cuidados Intensivos, con patología neurológica grave y posterior evolución a ME. El diagnóstico de ME se realizó mediante exploración clínica, electroencefalograma (EEG), doppler transcraneal (DTC) y TC multicorte de 64 detectores. Inicialmente se realizó un estudio de perfusión cerebral, seguido de angiografía de troncos supraaórticos y arterias cerebrales con adquisición de imágenes mediante cortes de 0,5 mm, desde el nacimiento de la raíz de aorta hasta el vértex. En todos los pacientes se confirmó el diagnóstico de ME mediante exploración clínica, EEG y DTC. En ningún caso la perfusión cerebral detectaba flujo sanguíneo cerebral. La angio-TC a través de arterias carótidas internas y arterias vertebrales demostraba una ausencia completa de circulación intracraneal visualizándose circulación en ramas de las arterias carótidas externas. La sensibilidad y especificidad del método comparada con la exploración clínica fue del 100%. Estos hallazgos demuestran que el estudio de perfusión cerebral y la angiografía cerebral mediante TC multicorte es una técnica rápida, mínimamente invasiva, de fácil disponibilidad y que demuestra la ausencia de flujo sanguíneo cerebral a través de los 4 troncos vasculares. Esta técnica permite realizar el diagnóstico de ME con una gran seguridad diagnóstica. Su uso tiene especial interés en pacientes con dificultad diagnóstica clínica por tratamiento con fármacos sedantes y graves alteraciones metabólicas

BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations

The Bispectral Index Scale: its use in the detection of brain death.

OBJECTIVE: To evaluate the Bispectral Index Scale (BIS) monitor as a method of brain death (BD) detection. PATIENTS AND METHODS: We performed an observational prospective study in an intensive care unit (ICU) of a university hospital of 19 patients hospitalized nonconsecutively in the ICU with serious neurologic pathology and evolution toward BD. A BIS monitor, XP model, and the sensor "BIS Quatro" were used to continuously record values: suppression ratio (SR), quality of the signal index, and electromyographic (EMG) activity. RESULTS: The BD diagnosis was made through neurological clinical exploration and electroencephalogram (EEG) in all the cases. Additionally, transcranial Doppler was used in 13 patients. Coincident with clinical worsening, it was observed that there was a gradual decrease of the BIS value, together with a rise in the SR. In all the patients in which the BD diagnosis was confirmed, the BIS showed values of 0 and suppression rates of 100. Only one patient showed interferences, due to EMG activity, the same problem was detected when a conventional EEG was performing. After using a neuromuscular blocker, the values of BIS and SR were 0 and 100, respectively. CONCLUSIONS: The BIS is a noninvasive, simple, and easy to interpret method. All the patients with BD diagnosis except for one had a BIS value of 0 and TS of 100, showing a perfect correlation with the other diagnostic methods. The BIS cannot be used on its own for the confirmation of the BD, but it is a useful tool to detect the beginning of brain herniation.

La esteatosis hepática grave en el donante de órganos: valor diagnóstico de la tomografía computarizada abdominal / Severe hepatic steatosis in organ donors: diagnostic value of abdominal scanning

Fundamento. La esteatosis hepática (EH) grave contraindica el trasplante hepático ante el altísimo riesgo de fracaso del injerto. Los depósitos de grasa en los hepatocitos disminuyen de forma importante la densidad hepática; esta hipodensidad, que no existe en condiciones normales, permite diagnosticar radiológicamente la EH. Nuestro objetivo fue validar la tomografía computarizada (TC) abdominal para el diagnóstico de la EH grave en los donantes de órganos. Métodos. El estudio se realizó en 48 donantes multiorgánicos consecutivos. Para el diagnóstico de la EH grave se comparó la biopsia hepática con la densidad, medida en unidades Hounsfield (UH), del hígado y bazo mediante TC abdominal. Se realizaron cinco mediciones en el hígado y tres en el bazo con el fin de comparar la diferencia de densidades entre ambos órganos, con la densidad esplénica como valor de referencia. Los resultados fueron analizados por dos radiólogos y dos anatomopatólogos de forma independiente, que desconocían la historia clínica del donante. Resultados. A mayor diferencia de densidad entre el hígado y el bazo -por disminución de la densidad hepática-, más esteatosis se demostró en las biopsias. Valores superiores a 20 UH de diferencia de densidad entre el hígado y el bazo presentaron siempre en la biopsia una EH superior al 50 per cent. Los valores entre 10-20 UH se correlacionaron con la presencia de algún grado de esteatosis, aunque no se pudo determinar su grado. Valores inferiores a 9 UH se corresponden con hígados normales. Conclusiones. Nuestros resultados presentan una excelente correlación entre el diagnóstico anatomopatológico y el radiológico en la EH grave. Consideramos necesario incluir la realización de una TC abdominal en el protocolo de selección y mantenimiento del donante de órganos. El estudio radiológico nos permite contraindicar a priori la extracción hepática, evitando de esta forma cargas de trabajo y desplazamientos innecesarios de equipos quirúrgicos, así como gastos técnicos y materiales no justificados (AU)

Dynamic scaling in diluted systems: deactivation through thermal dilution.

Activated scaling is confirmed to hold in transverse field-induced phase transitions of randomly diluted Ising systems. Quantum Monte Carlo calculations have been made not just at the percolation threshold (pc) but also well below and above it. We follow the evolution of the activated scaling at zero temperature in the phase transition from ferromagnetic to quantum Griffiths phase (p>pc) at the phase boundary (p=pc) and for transitions inside the nonferromagnetic quantum Griffiths phase (p

ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses.

We examined the requirement for and cooperation between CD28 and inducible costimulator (ICOS) in effective T helper (TH) cell responses in vivo. We found that both CD28 and ICOS were critical in determining the outcome of an immune response; cytolytic T lymphocyte-associated antigen 4-immunoglobulin (CTLA-4-Ig), ICOS-Ig and/or a neutralizing ICOS monoclonal antibody attenuated T cell expansion, TH2 cytokine production and eosinophilic inflammation. CD28-dependent signaling was essential during priming, whereas ICOS-B7RP-1 regulated TH effector responses, and the up-regulation of chemokine receptors that determine T cell migration. Our data suggests a scenario whereby both molecules regulate the outcome of the immune response but play separate key roles: CD28 primes T cells and ICOS regulates effector responses.

Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-3 and tissue leukocyte apoptosis.

We have used two models of murine pulmonary inflammation to investigate the signals responsible for the resolution of bronchial hyperresponsiveness (BHR). Both protocols involved two sensitizations with OVA followed by serial aerosolized challenge with OVA. We determined that administration of the second sensitization by aerosol (model A) was associated with a transient response, whereas administration by the i.p. route (model B) induced a sustained response, in the form of BHR and eosinophilia. This difference in kinetics was due solely to the route of the second Ag administration and was not associated with Ag dose or adjuvant. Differences in kinetics of lung eosinophilia/BHR were shown to be independent of IgE levels and IL-4 or IL-5. However, IL-3 levels in model A closely correlated with the rate of leukocyte clearance by apoptosis and were observed concomitant with a decline in BHR. Blockage of IL-3 in model B increased leukocyte apoptosis but reduced tissue eosinophilia and BHR. The use of mouse models in which a single different administration of allergen is associated with a failure/success to resolve inflammation and BHR by 72 h postchallenge indicates a link between IL-3 production, leukocyte apoptosis, and BHR responses.

Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation.

Optimal T cell activation requires engagement of CD28 with its counterligands B7-1 and B7-2. Inducible costimulator (ICOS) is the third member of the CD28/CTLA4 family that binds a B7-like protein, B7RP-1. Administration of ICOS-Ig attenuates T cell expansion following superantigen (SAg) administration, but fails to regulate either peripheral deletion or anergy induction. ICOS-Ig, but not CTLA4-Ig, uniquely regulates SAg-induced TNF-alpha production, whereas IL-2 secretion is modulated by CTLA4-Ig, but not ICOS-Ig. In contrast, both ICOS and CD28 are required for complete attenuation of IL-4 production. Our data suggest that ICOS and CD28 regulate T cell expansion and that ligation of either CD28 or ICOS can either uniquely regulate cytokine production (IL-2/TNF-alpha) or synergize for optimal cytokine production (IL-4) after SAg administration.

The CD28-related molecule ICOS is required for effective T cell-dependent immune responses.

While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and IFNgamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses.

Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease.

Stromal cell-derived factor-1alpha/beta (SDF-1alpha/beta) is phylogenetically a primitive chemokine widely expressed in a variety of tissues and cell types. This expression is detectable in the absence of stimuli provided by bacterial or viral infections and allergic or autoimmune disorders. Based on these and other findings, SDF-1alpha has not been considered an inflammatory chemokine, but, rather, has been believed to be involved in certain homeostatic processes, such as leukocyte recirculation. SDF-1alpha is a potent chemoattractant for lymphocytes and monocytes that mediates its activity via the chemokine receptor CXCR4. Study of the role of SDF-1alpha/CXCR4 in vivo during inflammation has been limited by the fact that transgenic mice that have been made deficient in either molecule die early in life due to developmental defects. The present study was aimed at evaluating the functional relevance of the SDF-1alpha/CXCR4 axis during an inflammatory process. Neutralizing Abs to CXCR4 reduced lung eosinophilia (bronchoalveolar lavage fluid and interstitium) by half, indicating that CXCR4-mediated signals contribute to lung inflammation in a mouse model of allergic airway disease (AAD). This reduction in inflammation was accompanied by a significant decrease in airway hyper-responsiveness. SDF-1alpha neutralization resulted in similar reduction in both lung allergic inflammation and airway hyper-responsiveness. Retroviral delivery of a CXCR4 cDNA to leukocytes resulted in greater inflammation when transduced mice were subjected to a mouse model of AAD. These results highlight that, although considered a noninflammatory axis, the involvement of CXCR4 and SDF-1alpha is critical during AAD, and this receptor and its ligand are potentially relevant in other inflammatory processes.

Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung.

The understanding of the relative contribution of particular chemokines to the selective accumulation of leukocyte subsets to an organ site during an inflammatory response is made difficult by the simultaneous presence of multiple chemokines with partially overlapping functions at the inflammatory site. The study of several chemokine pathways (expression and function) during the development of a mouse model of allergic airway disease (AAD) has revealed differential expression regulation with distinct cellular sources for individual chemokines with functional bias for the recruitment/localization of regulatory and/or effector leukocyte subsets. In the present review, we propose that distinct functional groups of chemokines co-operate to generate the complete inflammatory response in the lung during AAD. We will also extend these concepts to the specific recruitment of a key cellular subset such as T helper type 2 (Th2) lymphocytes. We propose that the long term recruitment of antigen-specific Th2 cells to target organs, such as airways during chronic lung inflammation, is the result the sequential involvement of several chemotactic axes. Specifically, the CCR3/eotaxin and the CCR4/MDC pathway act in a coordinated co-operative manner, with the CCR3/eotaxin pathway being critical in the acute/early stages of a response, followed by the CCR4/MDC pathway, which ultimately dominates in the recruitment of antigen-specific Th2 cells. Other chemokines/receptors participate in this process possibly by amplifying/priming the Th2 recruitment response.

Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation.

The cloning, expression, and function of the murine (m) homologue of human (h) monocyte-derived chemokine (MDC) is reported here. Like hMDC, mMDC is able to elicit the chemotactic migration in vitro of activated lymphocytes and monocytes. Among activated lymphocytes, Th2 cells were induced to migrate most efficiently. mMDC mRNA and protein expression is modulated during the course of an allergic reaction in the lung. Neutralization of mMDC with specific Abs in a model of lung inflammation resulted in prevention of airway hyperreactivity and significant reduction of eosinophils in the lung interstitium but not in the airway lumen. These data suggest that mMDC is essential in the transit/retention of leukocytes in the lung tissue rather than in their extravasation from the blood vessel or during their transepithelial migration into the airways. These results also highlight the relevance of factors, such as mMDC, that regulate the migration and accumulation of leukocytes within the tissue during the development of the key physiological endpoint of asthma, airway hyperreactivity.

Selective eosinophil transendothelial migration triggered by eotaxin via modulation of Mac-1/ICAM-1 and VLA-4/VCAM-1 interactions.

We have recently cloned eotaxin, a highly efficacious eosinophilic chemokine involved in the development of lung eosinophilia during allergic inflammatory reactions. To understand more precisely how eotaxin facilitates the specific migration of eosinophils, we have studied which adhesion receptors are essential for eotaxin action both in vivo and in vitro. Experiments using mice genetically deficient in adhesion receptors demonstrated that molecules previously reported to be involved in both leukocyte tethering/rolling (P-selectin and E-selectin) and in sticking/ transmigration (ICAM-1 and VCAM-1) are required for eotaxin action in vivo. To further elucidate the mechanism(s) involved in this process, we have used an in vitro transendothelial chemotaxis model. mAb neutralization studies performed in this system suggest that the integrins Mac-1 (CD11b/18), VLA-4 (alpha4beta1) and LFA-1 (CD11a/18) are involved in the transendothelial chemotaxis of eosinophils to eotaxin. Accordingly, the expression of these integrins on eosinophils is elevated by direct action of this chemokine in a concentration-dependent manner. Taken together, our results suggest that eotaxin-induced eosinophil transendothelial migration in vivo and in vitro relies on Mac-1/ICAM-1 and VLA-4NCAM-1 interactions, the latter ones becoming more relevant at later time points of the eotaxin-induced recruitment process.