Investigation of Rabies virus in wild mammals of the atlantic forest in Rio de Janeiro, Brazil.

With the successful control of rabies transmitted by dogs in Brazil, wild animals have played a relevant epidemiological role in the transmission of rabies virus (RABV). Bats, non-human primates and wild canines are the main wild animals that transmit RABV in the country. It is worth highlighting the possibility of synanthropic action of these species, when they become adapted to urban areas, causing infections in domestic animals and eventually in humans. This work aimed to evaluate the circulation of RABV in the Pedra Branca Forest, an Atlantic Forest area, located in the state of Rio de Janeiro, Southeast Brazil. Saliva and blood samples were obtained from 60 individuals of eight species of bats, captured with mist nets, and 13 individuals of callitrichid primates, captured with tomahawk traps. Saliva samples were subjected to Reverse Transcription Polymerase Chain Reaction (RT-PCR), targeting the RABV N gene, with all samples being negative. Blood samples of all animals were submitted to the Rapid Fluorescent Focus Inhibition Test (RFFIT) to detect neutralizing antibodies (Ab) for RABV. Six bat samples (8%) were seropositive for RABV with antibody titers greater than or equal to 0.1 IU/mL. The detection of Ab but not viral RNA indicates exposure rather than current RABV transmission in the analyzed populations. The results presented here reinforce the importance of serological studies in wildlife to access RABV circulation in a region.

Real-time reflectance anisotropy spectroscopy of GaAs homoepitaxy.

Reflectance anisotropy spectroscopy (RAS) is a highly sensitive optical probe for the real-time study of the epitaxial growth of zincblende semiconductors. Here we report on (1) non-equilibrium RAS spectra acquired in real time during the homoepitaxial growth of GaAs, and (2) RAS spectra for GaAs surfaces under equilibrium with several arsenic overpressures. We show that in both cases RAS spectra can be decomposed into two basic components, each with a characteristic line shape. We further show that both dynamic and equilibrium RAS spectra are described by the same pair of basic components. We conclude that the time evolution of non-equilibrium RAS spectra acquired during the epitaxial growth can be described in terms of RAS spectra for equilibrium surfaces. The results reported here should be useful for the interpretation of the physics underlying the rapid time evolution of dynamic RAS spectra during the first monolayer growth. Thus, we show that RAS constitutes a valuable tool for the study of epitaxial growth mechanisms.

Cuidado de enfermería postoperación de Tromboendarterectomia Pulmonar Bilateral. Estudio de caso fundamentado en los principios de Henderson / Nursing care after Bilateral Pulmonary Thromboendarterectomy. Case study based on Henderson's principles / Cuidados de enfermagem após tromboendarterectomia pulmonar bilateral. Estudo de caso baseado nos princípios de Henderson

Resumen Introducción La tromboembolia pulmonar (TEP) es un padecimiento que se presenta con frecuencia de manera silenciosa, el 50 % o más de los casos no se diagnostica. Se define como la oclusión total o parcial de la circulación pulmonar, ocasionada por un coágulo sanguíneo proveniente de la circulación venosa sistémica, incluidas las cavidades derechas y que, de acuerdo a su magnitud, puede o no originar síntomas. Está considerada como una urgencia cardiovascular y constituye una de las principales causas de morbimortalidad en pacientes hospitalizados. Objetivo Desarrollar un Estudio de caso basado en el Proceso de Atención de Enfermería en la persona postoperada de Tromboendarterectomía Pulmonar Bilateral en Unidad de cuidados intensivos postquirúrgica de un Instituto Nacional de Tercer Nivel de la Ciudad de México. Método Estudio de caso basado en las etapas del proceso enfermero, se utilizó una Guía de valoración de las 14 necesidades de Virginia Henderson, jerarquización de Diagnósticos enfermeros, se ofreció una atención integral enfocada en cuidados especializados para cubrir las necesidades más afectadas en la persona. Conclusiones La aplicación del proceso de atención enfermero con base en la valoración de las 14 necesidades de Virginia Henderson, identificó que las necesidades más afectadas fueron; Oxigenación/Circulación y Evitar peligros, con la jerarquización se determinó que es imprescindible el conocimiento de enfermería en intervenciones especificas en el proceso postoperatorio de Tromboendarterectomía como: la detección del riesgo de alteraciones del ritmo cardiaco, valoración e intervenciones en insuficiencia respiratoria aguda, la propensión a eventos trombóticos secundarios a afección genética, para el logro de la recuperación de la salud de manera exitosa.

Abstract Introduction Since a pulmonary embolism (PE) can develop silently, more than 50 % of cases are not diagnosed until clear signs and symptoms are present. It is defined as the partial or total blockage of pulmonary circulation due to a blood clot which originated from the venous circulation elsewhere. Considered a cardiovascular urgency, it is a main cause of morbidity and mortality among hospitalized patients. Objective Based on the Nursing Process, to carry out a study case on a person who underwent surgery for Bilateral Pulmonary Thromboendarterectomy in the ICU of a Third Level of Care National Institute of Mexico City. Method This is a study case which followed the stages of the Nursing Process. An assessment guide of the 14 needs proposed by Virginia Henderson was utilized. Nursing diagnoses were ranked. An integral and specialized care addressing the patient's most important needs was offered. Conclusions The most important needs identified were: promoting oxygenation and circulation, and preventing risks. From the diagnoses analysis, it was determined that nursing knowledge is crucial in post thromboendarterectomy interventions, in terms of heart rate alteration risk detection, acute respiratory insufficiency assessment, and secondary thrombotic events prevention, all these in order to achieve a successful recovery.

Resumo Introdução A trombo embolia pulmonar (TEP) é uma doença que se apresenta com frequência de maneira silenciosa, o 50 % ou mais dos casos não se diagnostica. Define-se como a oclusão total ou parcial da circulação pulmonar, ocasionada por um coágulo sanguíneo proveniente da circulação venosa sistémica, incluídas as cavidades direitas e que, conforme sua magnitude, pode ou não originar sintomas. É considerada como uma urgência cardiovascular e constitui uma das principais causas de morbimortalidade em pacientes hospitalizados. Objetivo Desenvolver um Estudo de caso baseado no Processo de Atenção de Enfermagem na pessoa pós-perada de Tromboendarterectomia Pulmonar Bilateral na Unidade de cuidados intensivos post-cirúrgica de um Instituto Nacional de Terceiro Nível da Cidade do México. Método Estudo de Caso baseado nas etapas do processo enfermeiro, utilizou-se uma Guia de avaliação das 14 necessidades de Virginia Henderson, hierarquização de Diagnósticos enfermeiros, ofereceu-se uma atenção integral focalizada em cuidados especializados para cobrir as necessidades mais afetadas na pessoa. Conclusões A aplicação do processo de atenção enfermeiro com base na avaliação das 14 necessidades de Virginia Henderson, identificou que as necessidades mais afetadas foram; Oxigenação/Circulação e Evitar perigos, com a hierarquização determinou-se que é imprescindível o conhecimento de enfermagem em intervenções especificas no processo pós-operatório de Tromboendarterectomia como: a detecção do risco de alterações do ritmo cardíaco, avaliação e intervenções em insuficiência respiratória aguda, a propensão a eventos trombóticos secundários a afecção genética, para o sucesso da recuperação da saúde de maneira bem-sucedida.

The Significant Role of c-Abl Kinase in Barrier Altering Agonists-mediated Cytoskeletal Biomechanics.

Exploration of human pulmonary artery endothelial cell (EC) as a prototypical biomechanical system has important pathophysiologic relevance because this cell type plays a key role in the development of a wide variety of clinical conditions. The complex hierarchical organization ranging from the molecular scale up to the cellular level has an intimate and intricate relationship to the barrier function between lung tissue and blood. To understand the innate molecule-cell-tissue relationship across varied length-scales, the functional role of c-Abl kinase in the cytoskeletal nano-biomechanics of ECs in response to barrier-altering agonists was investigated using atomic force microscopy. Concurrently, the spatially specific arrangement of cytoskeleton structure and dynamic distribution of critical proteins were examined using scanning electron microscopy and immunofluorescence. Reduction in c-Abl expression by siRNA attenuates both thrombin- and sphingosine 1-phosphate (S1P)-mediated structural changes in ECs, specifically spatially-defined changes in elastic modulus and distribution of critical proteins. These results indicate that c-Abl kinase is an important determinant of cortical actin-based cytoskeletal rearrangement. Our findings directly bridge the gap between kinase activity, structural complexity, and functional connectivity across varied length-scales, and suggest that manipulation of c-Abl kinase activity may be a potential target for the treatment of pulmonary barrier disorders.

[Conversion of arthrodesis to total hip replacement in Mexico. Case report]. / Conversión de artrodesis a prótesis total de cadera en México. Reporte de un caso.

Since 1900, hip fusion was considered a definitive treatment, being the method of choice for osteoarthritis (OA) of the hip in young patients, and others as infections or sequelae of childhood illnesses, although today it has been migrated to the use of prostheses with non-cemented implants. Currently orthopedic management of osteoarthritis in the hip of the young patient has changed dramatically in part derived from the consequences of long-term arthrodesis in adjacent joints, so we present this case where we perform the conversion to total hip arthroplasty.

Desde 1900, la artrodesis de cadera se consideraba como un tratamiento definitivo, siendo el método de elección para la osteoartritis (OA) de cadera en pacientes jóvenes y otros padecimientos como infecciones o secuelas de enfermedades infantiles, aunque hoy día se ha migrado al uso de prótesis con implantes no cementados. Actualmente, el manejo ortopédico de la osteoartritis en la cadera del paciente joven ha cambiado de forma impresionante, en parte derivado de las consecuencias de la artrodesis a largo plazo en las articulaciones vecinas, por ello presentamos este caso en el que se realiza la conversión a una artroplastía total de cadera (ATC).

Imatinib Alters Agonists-mediated Cytoskeletal Biomechanics in Lung Endothelium.

The endothelium serves as a size-selective barrier and tightly controls the fluid exchange from the circulation to the surrounding tissues. In this study, a multiplexed microscopy characterization is developed to study the spatio-temporal effects of Abl kinases on endothelial cytoskeletal structure using AFM, SEM, and immunofluorescence. Sphingosine 1-phosphate (S1P) produces significant endothelial barrier enhancement by means of peripheral actin rearrangement. However, Abl kinase inhibition by imatinib reduces rapid redistribution of the important cytoskeletal proteins to the periphery and their association with the cortical actin ring. Herein, it moderates the thickness of the cortical actin ring, and diminishes the increase in elastic modulus at the periphery and cytoplasm. These findings demonstrate that imatinib attenuates multiple cytoskeletal changes associated with S1P-mediated endothelial barrier enhancement and suggest a novel role for Abl kinases in mediating these S1P effects. These observations bridge the gap between molecule dynamics, structure complexity and function connectivity across varied length-scales to improve our understanding on human pulmonary endothelial barrier regulation. Moreover, our study suggests a framework for understanding form-function relationships in other biomechanical subsystems, wherein complex hierarchical organization programmed from the molecular scale to the cellular and tissue levels has an intimate relationship to the overall physiological function.

Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.

BACKGROUND: The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund's adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. METHODS: Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15-day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. RESULTS: Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints. CONCLUSION: Results suggest that mazindol via D2-like receptors has an antinociceptive role in mice with CFA-induced knee arthritis without modifying the bone health negatively.

[Localized pigmented vellonodular sunovitis, cause of knee hemarthrosis]. / Sinovitis vellonodular pigmentada localizada, causa de hemartrosis en rodilla.

The pigmented vellonodular sinovitis (PVNS) is benign neoplasm with synovial proliferation and hemosiderin deposit, characterized by large compromising joints, especially the knee. At present, two variants of clinics, the diffuse form (PVNSD) and the localized (PVNSL) are described. Arthroscopic synovectomy and radiosynoviorthesis (RSO) is the treatment that has shown the best functional results. Nuclear magnetic resonance is an appropriate method for conducting the diagnosis of PVNSL.

La sinovitis vellonodular pigmentada (SVP) es una neoplasia benigna con proliferación sinovial y depósito de hemosiderina, se caracteriza por comprometer grandes articulaciones, en especial la rodilla. En la actualidad se describen dos variantes clínicas, la forma difusa (SVPD) y la localizada (SVPL). La sinovectomía artroscópica y sinovectomía por radiación conforman el tratamiento que ha demostrado mejores resultados funcionales. La resonancia magnética nuclear es un método adecuado para establecer el diagnóstico de la SVPL.

Differential elastic responses to barrier-altering agonists in two types of human lung endothelium.

Vascular integrity is primarily determined by endothelial cell (EC) cytoskeletal structure that is differentially regulated by various stimuli. In this study, atomic force microscopy (AFM) was used to characterize structural and mechanical properties in the cytoskeleton of cultured human pulmonary artery EC (HPAEC) and human lung microvascular EC (HLMVEC) by determining elastic properties (Young's modulus) in response to endogenous barrier protective agents sphingosine 1-phosphate (S1P) and hepatocyte growth factor (HGF), or the barrier disruptive molecule thrombin. Initial studies in unstimulated cells indicate higher baseline peripheral elastic modulus values in HPAEC (mean 2.9 KPa) than in HLMVEC (1.8 KPa). After 30 min of stimulation, S1P induced the highest Young's modulus increase (6.1 KPa) compared to the other barrier enhancing stimuli, HGF (5.8 KPa) and the pharmaceutical agent and S1P analog FTY720 (4.1 KPa). In contrast, the barrier disruptive agent thrombin decreased values from 2.5 KPa to 0.7 KPa depending on the cell type and treatment time. AFM topographical imaging supports these quantitative biophysical data regarding differential peripheral elastic properties in EC. Overall, these AFM studies provide novel insights into the biomechanical properties of human lung EC that regulate vascular barrier function and have potential applicability to pathophysiologic vascular leak syndromes such as acute lung injury.

PO-07 - Excluding pulmonary embolism in cancer patients using the Wells rule and age-adjusted D-dimer testing: an individual patient data meta-analysis.

INTRODUCTION: Among patients with clinically suspected pulmonary embolism (PE), imaging and anticoagulant treatment can be safely withheld in approximately one-third of patients based on the combination of a "PE unlikely" Wells score and a D-dimer below the age-adjusted threshold. The clinical utility of this diagnostic approach in cancer patients is less clear. AIM: To evaluate the efficiency and failure rate of the original and simplified Wells rules in combination with age-adjusted D-dimer testing in patients with active cancer. MATERIALS AND METHODS: Individual patient data were used from 6 large prospective studies in which the diagnostic management of PE was guided by the original Wells rule and D-dimer testing. Study physicians classified patients as having active cancer if they had new, recurrent, or progressive cancer (excluding basal-cell or squamous-cell skin carcinoma), or cancer requiring treatment in the last 6 months. We evaluated the dichotomous Wells rule and its simplified version (Table). The efficiency of the algorithm was defined as the proportion of patients with a "PE unlikely" Wells score and a negative age-adjusted D-dimer, defined by a D-dimer below the threshold of a patient's age times 10 µg/L in patients aged ≥51 years. A diagnostic failure was defined as a patient with a "PE unlikely" Wells score and negative age-adjusted D-dimer who had symptomatic venous thromboembolism during 3 months follow-up. A one-stage random effects meta-analysis was performed to estimate the efficiency and failure. RESULTS: The dataset comprised 938 patients with active cancer with a mean age of 63 years. The most frequent cancer types were breast (13%), gastrointestinal tract (11%), and lung (8%). The type of cancer was not specified in 42%. The pooled PE prevalence was 29% (95% CI 25-32). PE could be excluded in 122 patients based on a "PE unlikely" Wells score and a negative age-adjusted D-dimer (efficiency 13%; 95% CI 11-15). Two of 122 patients were diagnosed with non-fatal symptomatic venous thromboembolism during follow-up (failure rate 1.5%; 95% CI 0.13-14.8). The simplified Wells score in combination with a negative age-adjusted D-dimer had an efficiency of 3.9% (95% CI 2.0-7.6) and a failure rate of 2.4% (95% CI 0.3-15). CONCLUSIONS: Among cancer patients with clinically suspected PE, imaging and anticoagulant treatment can be withheld in 1 out of every 8 patients by the original Wells rule and age-adjusted D-dimer testing. The simplified Wells rule was neither efficient nor safe in this population.

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury.

Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and anti-inflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.

B-vitamin mixture improves the analgesic effect of diclofenac in patients with osteoarthritis: a double blind study.

According to the high consumption of the mixture of B vitamins and diclofenac in several countries, this combination has constituted a frequently used option in pain therapy from inflammatory origin. Although the evidence obtained from inflammatory pain animal models has shown the existence of analgesic synergy between diclofenac and the B vitamins mixture, the corresponding clinical evidence is scarce. A double-blind, randomized clinical trial study was designed to characterize the analgesic effect and safety of diclofenac and B vitamins against diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to total knee arthroplasty with a pain level ≥7 in a 1-10 cm visual analogue scale were allocated to receive a single intramuscular injection of sodium diclofenac (75 mg) alone or combined with thiamine (100 mg), pyridoxine (100 mg) and cyanocobalamin (5 mg), and the pain level was evaluated during 12 h post-injection. Diclofenac+B vitamins mixture showed a superior analgesic effect during the assessed period and also a better assessment of the pain relief perception by patients than diclofenac alone. This study constitutes a clinical support on the improvement of the analgesic effect of diclofenac by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical model of inflammatory pain.

Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis.

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

[Efficacy of parenteral glutamine in patients undergoing bone marrow transplantation]. / Eficacia de la glutamina parenteral en pacientes sometidos a trasplante autólogo de médula ósea.

INTRODUCTION: Autologous bone marrow transplant (ABMT) represents a high metabolic stress. Glutamine has proven to be effective in severe catabolic states, although there are controversial studies. OBJECTIVES: To assess the effect of parenteral nutrition (PN) therapy supplemented with glutamine on the occurrence of mucositis and mean hospital stay in patients submitted to ABMT. METHODS: Retrospective study of patients submitted to ABMT between 2006 and 2009. In 2008, one vial of L-alanyl-L-glutamine (20 g) was added by protocol to the PN formulations of these patients. Thirteen clinical charts since that date (glutamine group) and 13 previous charts (control group) were randomly selected (n = 26). We compared the degree of mucositis and hospital stay in both groups. In the subgroup of glutamine-treated patients, we compare the glutamine dose in the patients developing some degree of mucositis with that of those not having this complication. RESULTS: Mean hospital stay: 27.8 ± 7.4 days (control group) vs. 20.3 ± 5.3 days (glutamine group) (p = 0.01). The severity of mucositis was lower in the glutaminetreated group (p = 0.02). The weight-adjusted dose of L-alanyl-L-glutamine in the patients not developing mucositis was higher than in the other ones (0.32 vs. 0.24 g/kg/day; p = 0.02). CONCLUSIONS: Glutamine supplementation reduces the degree of mucositis and hospital stay in patients submitted to autologous bone marrow transplantation. The degree of mucositis is lower in the subgroup of patients receiving higher doses of glutamine.

FTY720-induced human pulmonary endothelial barrier enhancement is mediated by c-Abl.

Strategies to improve pulmonary endothelial barrier function are needed to reverse the devastating effects of vascular leak in acute respiratory distress syndrome. FTY720 is a pharmaceutical analogue of the potent barrier-enhancing phospholipid sphingosine 1-phosphate (S1P). FTY720 decreases vascular permeability by an incompletely characterised mechanism that differs from S1P. Here, we describe its barrier-promoting effects on intracellular signalling and junctional assembly formation in human pulmonary endothelium. Permeability of cultured human pulmonary endothelial cells was assessed using transendothelial electrical resistance and dextran transwell assays. Junctional complex formation was assessed using membrane fractionation and immunofluorescence. Pharmacological inhibitors and small interfering (si)RNA were utilised to determine the effects of individual components on permeability. Unlike S1P, FTY720 failed to induce membrane translocation of adherens junction or tight junction proteins. ß-catenin, occludin, claudin-5 or zona occludens protein (ZO)-1/ZO-2 siRNAs did not alter FTY720-induced barrier enhancement. FTY720 induced focal adhesion kinase (FAK) phosphorylation and focal adhesion formation, with FAK siRNA partially attenuating the prolonged phase of barrier enhancement. Inhibition of Src, protein kinase (PK)A, PKG, PKC or protein phosphatase 2A failed to alter FTY720-induced barrier enhancement. FTY720 increased c-Abl tyrosine kinase activity and c-Abl siRNA attenuated peak barrier enhancement after FTY720. FTY720 enhances endothelial barrier function by a novel pathway involving c-Abl signalling.

Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro.

Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 microM) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via G(i)-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.

Amifostine reduces lung vascular permeability via suppression of inflammatory signalling.

Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-kappaB pathway. In vivo, concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury.

Características del asma infantil en Atención Primaria. Mejora del seguimiento / The asthma in children is the second cause of infantile chronic morbidity, consuming great part of the sanitary resources

El asma infantil es la segunda causa de morbilidad crónica infantil consumiendo gran parte de los recursos sanitarios. Material y métodos: estudiamos de forma transversal 1.509 historias de pacientes de 6 a14 años, seguidos en un centro de salud de la meseta castellana (España). Resultados: la edad media de los niños con asma fue 8,9 años con un ligero predominio en varones, la prevalencia acumulada de 11,9% y en los últimos 3 años del 9%. La edad de inicio fue de 3,5 años. Presentaban antecedentes familiares de enfermedad atópica el 39,4% y personales en el 54,7%. Otra patología respiratoria se halló en el 51,4%. El 89,8% de los niños erancontrolados en Atención Primaria, las pruebas de estudio de sensibilización alérgica se realizaron en el 44,1% y la función pulmonar en el 48,8%. Conclusiones: el seguimiento mayoritario de estos pacientes se ha realizado en Atención Primaria y ha permitido una mejora en el control de los pacientes (AU)

The asthma in children is the second cause of infantile chronic morbidity, consuming greatpart of the sanitary resources. Methodology: we made of cross-sectional study of 1,509 histories of patients of 6 to 14 years, followed in Primary Care in the Castilian plateau (Spain). Results: the average age was 8.9 years with a slight predominance of males, accumulated prevalence of 11.9% and in the last 3 years of 9%. The age of onset was 3.5 years. Familiar atopic disease was present in 39.4% and personal antecedents in 54.7%. Another respiratory condition was present in 51.4%. Eighty-nine point eight percent of the children were controlled in primary care. Forty-four point one percent of children had sensitization tests performedand 48.8% had undergone tests of pulmonary function. Conclusions: most of the follow up of these patients takes place in Primary Care and thisfact has allowed an improvement in the control of the patients (AU)

[Bortezomib in relapsed or refractory multiple myeloma: results in a cohort of 39 patients]. / Bortezomib en mieloma múltiple en recidiva o refractario: resultados en una cohorte de 39 pacientes.

INTRODUCTION: Bortezomib has presently become a significant rescue treatment in multiple myeloma (MM) due to its observed effectiveness and safety in multicenter trials. We have aimed to verify both aspects in a setting of non-selected patients. PATIENTS AND METHODS: This is an observational, prospective study of the cohort of relapsed or refractory MM patients treated with bortezomib in our Department. The variables analyzed were response, its duration, time to the treatment failure (TTF), overall survival (OS), response related conditions and toxicity. Statistical methods used were Fisher's exact test, log rank-test and Kaplan-Meier survival tables. RESULTS: A total of 39 patients, 25 relapsed and 14 refractory to chemotherapy, started the treatment. The mean number of previous treatment was 2.3 and they received an average of 5.8 cycles of bortezomib. Complete response was achieved in 14 patients (36%), partial response in 12 (31%) and minor or no response in 13 ones (33%). Median duration of response was 8 months, median TTF was 10 months and median OS, from the onset of bortezomib was 16.5 months, with a median observation of live patients of 12.5 months. The response was more frequent in males (p = 0.019) and in patients with one previous treatment (p = 0.15). There were no significant differences regarding to TTF when we considered the cause of treatment (relapse or no response to chemotherapy) nor in the number of previous treatment regimes. The most frequent adverse events were reversible thrombocytopenia (31%), polyneuropathy (28%) and asthenia-anorexia (23%). CONCLUSIONS: In our cohort of non-selected, relapsed or refractory MM patients, the observations found in the multicenter randomized trials results regarding response rate and duration, TTF OS and safety of bortezomib therapy were verified.