Donor Lung Preservation at 10°C: Clinical and Logistical Impact.

INTRODUCTION: Cold static donor lung preservation at 10°C appears to be a promising method to safely extend the cold ischemic time (CIT) and improve lung transplant (LTx) logistics. METHODS: LTx from November 2021 to February 2023 were included in this single institution, prospective, non-randomized study comparing prolonged preservation at 10°C versus standard preservation on ice. The inclusion criteria for 10°C preservation were suitable grafts for LTx without any donor retrieval concerns. PRIMARY ENDPOINT: primary graft dysfunction (PGD) grade-3 at 72-h. Secondary endpoints: clinical outcomes, cytokine profile and logistical impact. RESULTS: Thirty-three out of fifty-seven cases were preserved at 10°C. Donor and recipient characteristics were similar across the groups. Total preservation times (h:min) were longer (p<0.001) in the 10°C group [1st lung: median 12:09 (IQR 9:23-13:29); 2nd: 14:24 (12:00-16:20)] vs. standard group [1st lung: median 5:47 (IQR 5:18-6:40); 2nd: 7:15 (6:33-7:40)]. PGD grade-3 at 72-h was 9.4% in 10°C group vs. 12.5% in standard group (p=0.440). Length of mechanical ventilation (MV), ICU and hospital stays were similar in both groups. Thirty and ninety-day mortality rates were 0% in 10°C group (vs. 4.2% in standard group). IL-8 concentration was significantly higher 6-h post-LTx in the standard group (p=0.025) and IL-10 concentration was increased 72-h post-LTx in the 10°C group (p=0.045). CONCLUSIONS: Preservation at 10°C may represent a safe and feasible strategy to intentionally prolong the CIT. In our center, extending the CIT at 10°C may allow for semi-elective LTx and improve logistics with similar outcomes compared to the current standard preservation on ice.

[The need for an integrated approach to rhinitis and asthma] / La necesidad de un abordaje integrado de la rinitis y el asma.

Introduction: Several evidences support the concept of united airway and its pathophysiological, clinical, and therapeutic implications. The existence of rhinitis can generate greater difficulty in asthma control and higher direct and indirect health care costs, which is not sufficiently recognized by the majority of physicians who often treat them as separate entities. Objective: To examine witness evidence of the relationship between rhinitis and asthma that contributes to the integrated approach to both pathologies. Methods: A bibliographic search was carried out in the PubMed (Medline), EBSCO, Scielo, and Google Scholar databases using MeSH and DeCS terms related to the clinical and therapeutic relationship between rhinitis and asthma. Results: Finally, 46 references describing the impact of rhinitis on the quality of life of patients with asthma and its therapeutic correlate were included. Conclusions: The treatment of both diseases based on this integrated model is imperative. Both, the endo-phenotypic recognition and the consequent therapeutic approach allow to the concomitant control of asthma and rhinitis and a decrease in their morbidity. Complementary therapeutic measures based on the concept "one airway, one disease" support the good clinical practices necessary to achieve the best therapeutic result.

INTRODUCCIÓN: Numerosas evidencias sustentan el concepto de unidad de la vía aérea y sus consiguientes implicancias fisiopatológicas, clínicas y terapéuticas. La existencia de rinitis puede generar una mayor dificultad para el control del asma y mayores costos sanitarios directos e indirectos, lo que no es suficientemente reconocido por la mayoría de los médicos que las tratan, generalmente, como entidades separadas. OBJETIVO: Examinar evidencias testigos de la relación entre rinitis y asma que favorezcan el abordaje integrado de ambas patologías. Métodos: Se realizó una búsqueda bibliográfica en bases de datos PubMed (Medline), EBSCO, Scielo, Google Scholar utilizando términos MeSH y DeCS vinculados a la relación clínica y terapéutica entre rinitis y asma. RESULTADOS: Finalmente se incluyeron 46 referencias bibliográficas que describen el impacto de la rinitis sobre la calidad de vida de pacientes con asma y su correlato terapéutico. CONCLUSIONES: El tratamiento de ambas enfermedades fundamentado en un modelo integrado es imperativo. El reconocimiento endo-fenotípico conjunto y la decisión terapéutica consecuente permite en control simultáneo del asma y la rinitis y una disminución de su morbilidad. La adopción de medidas terapéuticas complementarias basadas en el concepto "una vía aérea, una única enfermedad" se corresponde con las buenas prácticas clínicas necesarias para lograr el mejor resultado terapéutico.

Metastatic Crohn's disease: a difficult diagnosis from different perspectives

Metastatic Crohn's disease (MCD) is a rare cutaneous manifestation of Crohn's disease (CD). The simultaneous involvement of the vulva and oral region is uncommon in clinical presentations of MCD. We present the case of a middle-aged woman with a family history of autoimmunity who initially presented with oral and vulvoperineal involvement. Initially, Behçet's disease was ruled out, but histopathological studies of the vulva revealed findings compatible with MCD. The patient had no gastrointestinal symptoms, and fecal calprotectin levels were normal. Upper and lower endoscopic examinations and capsule endoscopy of the small intestine (SI) did not reveal any significant findings. Treatment with anti-tumor necrosis factor (anti-TNF) agents was initiated but resulted in paradoxical psoriasis with adalimumab and infliximab. Cyclosporine was also used, but the patient experienced intolerable tachycardia. After 18 months, the patient developed episcleritis and experienced diarrhea accompanied by cramp-like abdominal pain. Repeat upper and lower endoscopic examinations showed normal results, while capsule endoscopy of the SI revealed CD enteritis. The patient was diagnosed with CD of the small intestine, along with extraintestinal manifestations of vulvoperineal MCD, oral involvement, and episcleritis. Management with azathioprine and ustekinumab was initiated, resulting in significant clinical improvement. MCD poses a diagnostic challenge due to its unusual manifestations. It may present without gastrointestinal tract involvement, mimicking other conditions. Therefore, timely diagnosis and the selection of the most appropriate therapeutic strategy are crucial.

La enfermedad de Crohn metastásica (ECM) es una entidad rara, es una manifestación cutánea en enfermedad Crohn (EC), y en su presentación clínica es inusual el compromiso vulvar y oral de modo concomitante. Se describe el caso de una mujer de edad media que tiene historia familiar de autoinmunidad, presenta inicialmente compromiso oral y vulvoperineal. En su abordaje inicial se descartó enfermedad de Behçet, pero los estudios histopatológicos a nivel vulvar tuvieron hallazgos compatibles para ECM. Hubo ausencia de síntomas gastrointestinales y sus niveles de calprotectina fecal eran normales. Los estudios endoscópicos altos y bajos, y la cápsula endoscópica del intestino delgado (ID) no tuvieron hallazgos relevantes. Se inició el tratamiento con antifactor de necrosis tumoral (anti-TNF) y presentó una psoriasis paradójica con adalimumab e infliximab. También se utilizó ciclosporina y presentó una taquicardia intolerable. 18 meses después de estos síntomas tuvo epiescleritis e inició con diarrea asociada a dolor abdominal tipo cólico, por lo que se repitieron los estudios endoscópicos altos y bajos, que resultaron normales, y cápsula endoscópica de ID mostró una enteritis por EC. Se consideró EC de ID con manifestaciones extraintestinales y con ECM vulvoperineal, compromiso oral y epiescleritis. Se requirió manejo con azatioprina y ustekinumab, con una mejoría clínica significativa. La ECM es un reto diagnóstico, pues es una manifestación inusual; en su debut puede haber ausencia de compromiso en el tracto gastrointestinal y también simular otras entidades. Debe buscarse lograr el diagnóstico oportuno y la estrategia terapéutica más segura.

Relationship between exhaled nitric oxide and biomarkers of atopy in children and adolescents with allergic rhinitis.

INTRODUCTION: Measurement of the exhaled nitric oxide fraction (FeNO) has been proposed as an indirect and non-invasive method to detect eosinophilic airway inflammation. Allergic rhinitis (AR) is frequently associated with high levels of FeNO. Allergic sensitization can contribute to the recruitment of eosinophils in the airway and the consequent increase in FeNO. OBJECTIVE: To correlate FeNO values with inflammatory and atopic sensitization biomarkers in patients with AR. PATIENTS AND METHODS: Observational, analytical, cross-sectional study. Children and adolescents with AR without asthma were included. FeNO, blood eosinophil count, total serum IgE were determined and skin tests with aeroallergens were performed by calculating the scores for PPC1 (number of positive allergens), STS2 (sum of millimeters of positive papules) and the atopy index (ratio between STS2/STS1). Spearman's correlation test was used between FeNO and variables of inflammation and atopy. RESULTS: Twenty-eight patients between 6 and 17 years old were included. There was a significant positive correlation between FeNO and blood eosinophils (r=.38; p=.047) and between FeNO and the atopy index (r=.40; p=.03). No correlation was found between FeNO and total serum IgE (r=.24; p=.21), STS1 (r=.20; p=.32) and STS2 (r=.34; p=.08). CONCLUSION: In children and adolescents with AR, FeNO was correlated with the atopy index and the blood eosinophil count. These last biomarkers could be used as alternatives for FeNO as biomarkers of lower airway inflammation in patients with AR.

Relationship between exhaled nitric oxide and biomarkers of atopy in children and adolescents with allergic rhinitis

Introduction: Measurement of the exhaled nitric oxide fraction (FeNO) has been proposed as an indirect and non-invasive method to detect eosinophilic airway inflammation. Allergic rhinitis (AR) is frequently associated with high levels of FeNO. Allergic sensitization can contribute to the recruitment of eosinophils in the airway and the consequent increase in FeNO.ObjectiveTo correlate FeNO values with inflammatory and atopic sensitization biomarkers in patients with AR.Patients and methodsObservational, analytical, cross-sectional study. Children and adolescents with AR without asthma were included. FeNO, blood eosinophil count, total serum IgE were determined and skin tests with aeroallergens were performed by calculating the scores for PPC1 (number of positive allergens), STS2 (sum of millimeters of positive papules) and the atopy index (ratio between STS2/STS1). Spearman's correlation test was used between FeNO and variables of inflammation and atopy.ResultsTwenty-eight patients between 6 and 17 years old were included. There was a significant positive correlation between FeNO and blood eosinophils (r=.38; p=.047) and between FeNO and the atopy index (r=.40; p=.03). No correlation was found between FeNO and total serum IgE (r=.24; p=.21), STS1 (r=.20; p=.32) and STS2 (r=.34; p=.08).ConclusionIn children and adolescents with AR, FeNO was correlated with the atopy index and the blood eosinophil count. These last biomarkers could be used as alternatives for FeNO as biomarkers of lower airway inflammation in patients with AR. (AU)

Antecedentes: La determinación de la fracción exhalada de óxido nítrico (FeNO) ha sido propuesta como un método indirecto no invasivo para detectar la inflamación eosinofílica de la vía aérea. La rinitis alérgica (RA) se asocia frecuentemente con la FeNO elevada. La sensibilización a alérgenos puede contribuir al reclutamiento de eosinófilos en la vía aérea y el consiguiente incremento de la FeNO.ObjetivosCorrelacionar los valores de la FeNO con los biomarcadores inflamatorios y de sensibilización atópica en los pacientes con RA.Pacientes y métodosEstudio observacional, analítico y transversal. Se incluyeron niños y adolescentes con RA, sin asma. Se determinó la FeNO, el recuento de eosinófilos en sangre, la IgE sérica total, y se realizaron pruebas cutáneas con aeroalérgenos calificando los puntajes PPC1 (número de alérgenos positivos), PPC2 (suma de los milímetros de las pápulas positivas) y el índice de atopia (cociente entre milímetros de pápulas positivas/número de antígenos positivos). Se utilizó la prueba de correlación de Spearman entre la FeNO y las variables de inflamación y atopia.ResultadosSe incluyeron 28 pacientes entre 6 y 17 años. Se comprobó una correlación positiva significativa entre la FeNO y los eosinófilos en sangre (r=0,38; p=0,047), y el índice de atopia (r=0,40; p=0,03). No hubo correlación entre la FeNO con IgE sérica total (r=0,24; p=0,21) y con PPC1 (r=0,20; p=0,32) y PPC2 (r=0,34; p=0,08).ConclusionesEn niños y adolescentes con RA, la FeNO se correlacionó con el recuento de eosinófilos hemáticos y el índice de atopia. Estos últimos podrían utilizarse como sustitutos de la FeNO como biomarcadores de inflamación bronquial en pacientes con RA. (AU)

SARS-COV-2 seroprevalence among all healthcare workers in a tertiary hospital in Spain.

BACKGROUND: Healthcare workers (HCWs) have been a critical and vulnerable population during SARS-CoV-2 pandemic. The aim of this study was to determine the overall seroprevalence and to evaluate occupational risk factors among HCWs in one of the countries most affected by this pandemic. METHODS: We conducted a seroprevalence study for SARS-CoV-2 in a tertiary hospital in Madrid (Spain) between 24 April and 8 May 2020. A total of 4894 HCWs were invited for serologic testing. Serum samples were tested for SARS-CoV-2 IgM and IgG antibodies using Enzyme Immunoassay (ELISA) and Electro-Chemiluminescence Immunoassay (ECLIA) techniques. We calculated odds ratios to assess association between demographic and occupational characteristics with SARS-CoV-2 seroconversion. RESULTS: We processed 4324 serum samples. Overall, seroprevalence was of 16.6% (95% CI: 15.5-17.7). We found statistically significant differences in SARS-CoV-2 seroprevalence by type of employee, professional category, department and type of activity performed during the pandemic period, while no differences were identified between the personnel working in the COVID-19 wards compared to those working in non-COVID-19 wards. We confirmed 268 (26.7%) infections among 1005 hospital staff members tested by PCR. 60.5% of HCWs infected by SARS-CoV-2, assessed either by PCR or serology, could be considered asymptomatic or paucisymptomatic. CONCLUSIONS: HCWs have an increased risk of SARS-CoV-2 infection but COVID-19 patient exposure was not a determining factor. Universal mask wearing should be mandatory in healthcare settings given the important number of asymptomatic and paucisymptomatic cases.

Assessment of nasal obstruction by subjective methods and peak nasal inspiratory flow in children and adolescents with chronic rhinitis. / Evaluación de la obstrucción nasal por métodos subjetivos y pico flujo inspiratorio nasal en niños y adolescentes con rinitis crónica.

INTRODUCTION: Nasal obstruction (NO) is the most irritating symptom of chronic rhinitis (CR). The results of studies that correlated subjective and objective methods of NO in children and adults were contradictory. OBJECTIVES: To analyze the correlation between subjective NO scales and peak nasal inspiratory flow (PNIF) measurements and compare the subjective NO assessment and PNIF in children by age. POPULATION AND METHODS: Participants were patients with CR. The correlation between the subjective NO assessment using a visual analog scale (NO-VAS) and the Nasal Obstruction Symptom Evaluation (NOSE) and nasal airflow measurement pre- and post-vasoconstrictor administration using the PNIF was estimated. The differences in the subjective NO assessment and PNIF between children aged 8-11 years and 12-15 years were analyzed. RESULTS: A total of 79 patients aged 8-15 years were included. No correlation was established between the NO-VAS and the PNIF before and after vasoconstrictor administration (r = -0.19; p = 0.11 and r = -0.18; p = 0.15 respectively) or between the NOSE and the baseline PNIF (r = -0.23; p = 0.07). Differences were observed in the PNIF between children aged 8-11 years and 12-15 years (p =<0.0001), but there were no differences in the subjective perception assessed with the NO-VAS (p = 0.7591). CONCLUSION: No correlation was demonstrated between the subjective NO score and the PNIF in children and adolescents with CR. Older children have a lower perception of NO than younger ones. Subjective NO scales cannot replace the PNIF measurement in patients with rhinitis.

Introducción. La obstrucción nasal (ON) es el síntoma más molesto de la rinitis crónica (RC). Los estudios que correlacionaron métodos subjetivos y objetivos de ON realizados en niños y adultos produjeron resultados contradictorios. Objetivos. Analizar la correlación entre escalas subjetivas de ON con determinaciones de pico flujo inspiratorio nasal (PFIN) y comparar la valoración subjetiva de la ON y el PFIN en niños según su edad. Población y métodos. Participaron pacientes con RC. Se estimó la correlación entre la evaluación subjetiva de la ON mediante una escala visual análoga (ON-EVA, por su sigla en inglés) y la Escala de evaluación de los síntomas de obstrucción nasal (NOSE, por su sigla en inglés) y medición del flujo aéreo nasal pre- y posvasoconstrictor, mediante PFIN. Se analizaron las diferencias entre los grupos de 8 a 11 años y los de 12 a 15 años para la valoración subjetiva de la ON y PFIN. Resultados. Se incluyeron 79 pacientes entre 8 y 15 años. No se comprobó correlación entre ON-EVA y PFIN antes y después del vasoconstrictor (r = -0,19; p = 0,11 y r = -0,18; p = 0,15 respectivamente) ni entre NOSE y PFIN basal (r = -0,23; p = 0,07). Hubo diferencias en el PFIN entre niños de 8-11 años y 12 a 15 años (p =<0,0001), pero no se demostraron diferencias en la percepción subjetiva por ONEVA (p = 0,7591). Conclusión. No se demostró correlación entre puntajes subjetivos de ON y PFIN en niños y adolescentes con RC. Los niños mayores perciben menos la ON que los de menor edad. Las escalas subjetivas de ON no reemplazan su medición con PFIN en pacientes con rinitis.

Evaluación de la obstrucción nasal por métodos subjetivos y pico flujo inspiratorio nasal en niños y adolescentes con rinitis crónica / Assessment of nasal obstruction by subjective methods and peak nasal inspiratory flow in children and adolescents with chronic rhinitis

Introducción. La obstrucción nasal (ON) es el síntoma más molesto de la rinitis crónica (RC). Los estudios que correlacionaron métodos subjetivos y objetivos de ON realizados en niños y adultos produjeron resultados contradictorios. Objetivos. Analizar la correlación entre escalas subjetivas de ON con determinaciones de pico flujo inspiratorio nasal (PFIN) y comparar la valoración subjetiva de la ON y el PFIN en niños según su edad. Población y métodos. Participaron pacientes con RC. Se estimó la correlación entre la evaluación subjetiva de la ON mediante una escala visual análoga (ON-EVA, por su sigla en inglés) y la Escala de evaluación de los síntomas de obstrucción nasal (NOSE, por su sigla en inglés) y medición del flujo aéreo nasal pre- y posvasoconstrictor, mediante PFIN. Se analizaron las diferencias entre los grupos de 8 a 11 años y los de 12 a 15 años para la valoración subjetiva de la ON y PFIN. Resultados. Se incluyeron 79 pacientes entre 8 y 15 años. No se comprobó correlación entre ON-EVA y PFIN antes y después del vasoconstrictor (r = -0,19; p = 0,11 y r = -0,18; p = 0,15 respectivamente) ni entre NOSE y PFIN basal (r = -0,23; p = 0,07). Hubo diferencias en el PFIN entre niños de 8-11 años y 12 a 15 años (p = <0,0001), pero no se demostraron diferencias en la percepción subjetiva por ON-EVA (p = 0,7591). Conclusión. No se demostró correlación entre puntajes subjetivos de ON y PFIN en niños y adolescentes con RC. Los niños mayores perciben menos la ON que los de menor edad. Las escalas subjetivas de ON no reemplazan su medición con PFIN en pacientes con rinitis.

Introduction. Nasal obstruction (NO) is the most irritating symptom of chronic rhinitis (CR). The results of studies that correlated subjective and objective methods of NO in children and adults were contradictory. Objectives. To analyze the correlation between subjective NO scales and peak nasal inspiratory flow (PNIF) measurements and compare the subjective NO assessment and PNIF in children by age. Population and methods. Participants were patients with CR. The correlation between the subjective NO assessment using a visual analog scale (NO-VAS) and the Nasal Obstruction Symptom Evaluation (NOSE) and nasal airflow measurement pre- and post-vasoconstrictor administration using the PNIF was estimated. The differences in the subjective NO assessment and PNIF between children aged 8-11 years and 12-15 years were analyzed. Results. A total of 79 patients aged 8-15 years were included. No correlation was established between the NO-VAS and the PNIF before and after vasoconstrictor administration (r = -0.19; p = 0.11 and r = -0.18; p = 0.15 respectively) or between the NOSE and the baseline PNIF (r = -0.23; p = 0.07). Differences were observed in the PNIF between children aged 8-11 years and 12-15 years (p = < 0.0001), but there were no differences in the subjective perception assessed with the NO-VAS (p = 0.7591). Conclusion. No correlation was demonstrated between the subjective NO score and the PNIF in children and adolescents with CR. Older children have a lower perception of NO than younger ones. Subjective NO scales cannot replace the PNIF measurement in patients with rhinitis

Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines.

Rationale: Gastric cancer (GC) is a solid tumor that contains subpopulations of cancer stem cells (CSCs), which are considered drivers of tumor initiation and metastasis; responsible for therapeutic resistance; and promoters of tumor relapse. The balance between symmetric and asymmetric division is crucial for stem cell maintenance. The objective of this study is to evaluate the role of MAD2, a key protein for proper mitotic checkpoint activity, in the tumorigenesis of GC. Methods: Gastric cancer stem cells (GCSCs) were obtained from MKN45, SNU638 and ST2957 cell lines. Pluripotency and stemness markers were evaluated by RT-qPCR and autofluorescence and membrane markers by flow cytometry. Relevant signal transduction pathways were studied by WB. We analysed cell cycle progression, migration and invasion after modulation of MAD2 activity or protein expression levels in these in vitro models. In vivo assays were performed in a nude mouse subcutaneous xenograft model. Results: We found that NANOG, CXCR4 and autofluorescence are common and consistent markers for the GCSCs analysed, with other markers showing more variability. The three main signalling pathways (Wnt/ß-catenin; Hedgehog and Notch) were activated in GCSCs. Downregulation of MAD2 in MKN45CSCs decreased the expression of markers CXCR4, CD133, CD90, LGR5 and VIM, without affecting cell cycle profile or therapy resistance. Moreover, migration, invasion and tumor growth were clearly reduced, and accordingly, we found that metalloprotease expression decreased. These results were accompanied by a reduction in the levels of transcription factors related with epithelial-to-mesenchymal transition. Conclusions: We can conclude that MAD2 is important for GCSCs stemness and its downregulation in MKN45CSCs plays a central role in GC tumorigenesis, likely through CXCR4-SNAI2-MMP1. Thus, its potential use in the clinical setting should be studied as its functions appear to extend beyond mitosis.

Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population-Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures.

Inhibitory Killer-cell Immunoglobulin-like Receptors (KIR) specific for HLA class I molecules enable human natural killer cells to monitor altered antigen presentation in pathogen-infected and tumor cells. KIR genes display extensive copy-number variation and allelic polymorphism. They organize in a series of variable arrangements, designated KIR haplotypes, which derive from duplications of ancestral genes and sequence diversification through point mutation and unequal crossing-over events. Genomic studies have established the organization of multiple KIR haplotypes-many of them are fixed in most human populations, whereas variants of those have less certain distributions. Whilst KIR-gene diversity of many populations and ethnicities has been explored superficially (frequencies of individual genes and presence/absence profiles), less abundant are in-depth analyses of how such diversity emerges from KIR-haplotype structures. We characterize here the genetic diversity of KIR in a sample of 414 Spanish individuals. Using a parsimonious approach, we manage to explain all 38 observed KIR-gene profiles by homo- or heterozygous combinations of six fixed centromeric and telomeric motifs; of six variant gene arrangements characterized previously by us and others; and of two novel haplotypes never detected before in Caucasoids. Associated to the latter haplotypes, we also identified the novel transcribed KIR2DL5B*0020202 allele, and a chimeric KIR2DS2/KIR2DL3 gene (designated KIR2DL3*033) that challenges current criteria for classification and nomenclature of KIR genes and haplotypes.

Estado actual del uso de medicamentos biológicos en asma grave / Biologic therapy for severe asthma: an update

Asma es una enfermedad heterogénea que se manifiesta con diferentes fenotipos y endotipos de fisiopatología compleja. El asma grave resistente al tratamiento con altas dosis de esteroides inhalatorios es una entidad infrecuente pero que plantea un gran desafío para el médico. Los progresos en los conocimientos de la fisiopatogenia del asma han permitido el desarrollo de nuevas terapias con inmunobiológicos que permiten una terapia más individualizada en el contexto de la medicina de precisión. La mayoría de estas nuevas terapias han sido desarrolladas para el asma T2 alta, principalmente eosinofílica, pero son menos los desarrollos para el asma T2 baja, cuyos mecanismos no están completamente dilucidados. Esta revisión intenta recopilar las más recientes evidencias acerca del uso de medicamentos biológicos en el asma grave, con especial énfasis en sus mecanismos de acción, indicaciones, eficacia clínica y posibles efectos adversos. (AU)

Asthma is a heterogeneous disease with a complex pathophysiology that manifests with different phenotypes and endotypes. Severe asthma, resistant to treatment with high doses of inhaled steroids, is an uncommon entity but it implies a great medical challenge. Progress in the knowledge of the pathophysiology of asthma has allowed the development of new and more individualized therapy with biologics in the context of precision medicine. Most of these targeted biologic therapies for have been developed for asthma type-2 high, mainly eosinophilic, but there are fewer developments for non-T2 asthma, whose mechanisms are not completely elucidated. This review attempts to compile the most recent evidence about the use of biologic therapies in severe asthma, with special emphasis on its mechanisms of action, indications, clinical efficacy and possible adverse effects. (AU)

[Comparative analysis of exhaled nitric oxide in children and teenagers with allergic and non-allergic rhinitis]. / Análisis comparativo de la fracción exhalada de óxido nítrico en niños y en adolescentes con rinitis alérgica y no alérgica.

BACKGROUND: There is subclinical bronchial inflammation in patients with allergic rhinitis (AR). There is less evidence of inflammation of the lower airway in non-allergic rhinitis (NAR). OBJECTIVE: To investigate the inflammation of the lower airway by exhaled nitric oxide (FeNO) in patients with AR and NAR without asthma and its link to lung function, the severity of rhinitis, and biomarkers of atopy. METHODS: A cross-sectional study of patients aged 6 to 18 years, with AR or NAR without asthma. Spirometry, serum IgE, blood eosinophil count and FeNO were carried out. Rhinitis was classified according to the ARIA guide. RESULTS: Forty patients were included; 28 with AR and 12 with NAR. Patients with AR showed higher FeNO levels (medium 36.5 ppb; range 5-114) than those with NAR (medium 7 ppb; range 5-24) (p = 0.0011). Elevated FeNO was linked to spirometric abnormalities [OR= 7.14 (95 % CI 1.04-49.04), p = 0.049)]. In AR, there was correlation between FeNO and blood eosinophils (r = 0.41, p = 0-33). CONCLUSIONS: Both children and teenagers with AR showed higher FeNO than patients with NAR, which was correlated with blood eosinophilia and altered lung function.

Antecedentes: Existe inflamación bronquial subclínica en pacientes con rinitis alérgica. Son menos las evidencias de inflamación de la vía aérea inferior en rinitis no alérgica. Objetivo: Investigar inflamación de la vía aérea inferior por la fracción exhalada de óxido nítrico (FeNO) en pacientes con rinitis alérgica y rinitis no alérgica sin asma y su asociación con función pulmonar, gravedad de la rinitis y biomarcadores de atopia. Métodos: Estudio transversal de pacientes entre seis y 18 años, con rinitis alérgica o rinitis no alérgica sin asma. Se realizó espirometría, IgE sérica, recuento de eosinófilos hemáticos y FeNO. Se clasificó la rinitis según guía ARIA. Resultados: Se incluyeron 40 pacientes, 28 con rinitis alérgica y 12 con rinitis no alérgica. Los pacientes con rinitis alérgica tuvieron niveles de FeNO más elevados (mediana 36.5 ppb, rango 5-114) que aquellos con rinitis no alérgica (mediana 7 ppb, rango 5-24) (p = 0.0011). La FeNO elevada se asoció con anormalidad espirométrica (RM = 7.14 [IC 95 % = 1.04-49.04], p = 0.049). En la rinitis alérgica, existió correlación entre FeNO y eosinófilos en sangre (r = 0.41, p = 0-33). Conclusiones: Los niños y adolescentes con rinitis alérgica tuvieron FeNO más elevada que los pacientes con rinitis no alérgica, que se correlacionó con eosinofilia hemática y función pulmonar alterada.

Síndrome de fiebre periódica: serie de casos / Periodic fever syndrome: Case series

El síndrome de fiebre periódica (SFP) se caracteriza clínicamente por episodios repetidos y variables de inflamación sistémica en donde no se encuentra causa infecciosa, neoplásica ni evidencia de autoantígenos o autoanticuerpos. Los síntomas alternan con períodos de remisión total. La manifestación clínica cardinal es la presencia de fiebre, que se acompaña de síntomas sistémicos (artritis, serositis, exantema y afectación ocular) y similares entre una crisis y otra, que duran días a semanas. Presentan como características generales inicio en la infancia y duración autolimitada de los síntomas. SFP se ubican en el grupo VII de la clasificación de inmunodeficiencias primarias, en estos se debe diferenciar las enfermedades vinculados a mutaciones monogénicas, con pronóstico complejo, de las formas benignas denominadas "fiebre periódica, aftas, faringitis y adenopatías" (PFAPA). Para clasificar a pacientes con SFP se usan los criterios establecidos por Eurofever Classification Criteria (ECC)6 y en las formas benignas, los criterios de Thomas. (AU)

Periodic fever syndrome (PFS) is clinically characterized by repeated and variable episodes of systemic inflammation in which there is no infectious, neoplastic cause or evidence of autoantigens or autoantibodies. Symptoms alternate with periods of total remission. The cardinal clinical manifestation is the presence of fever, which is accompanied by systemic symptoms (arthritis, serositis, exanthema and ocular involvement) and that they are similar between one crisis and another, lasting days to weeks. They present as general characteristics, childhood onset and self-limited duration of symptoms. PFS is in group VII of the classification of primary immunodeficiencies, in which it is important to differentiate the diseases linked to monogenic mutations, with complex prognosis, from the benign forms called "periodic fever, aphthous, pharyngitis and adenopathy" (PFAPA). The criteria established by Eurofever Classification Criteria (ECC) are used to classify patients with PFS and for the benign forms, the Thomas criteria. (AU)

Relationship between rhinitis severity and lung function in children and adolescents without asthma. / [Relación entre grado clínico de rinitis y función pulmonar en niños y adolescentes sin asma.]

Background: The link between upper and lower airways is recognized clinically as a "unique airway". Subclinical spirometric abnormalities have been observed in patients with rhinitis without asthma, which could be proportional to rhinitis severity. Objectives: To investigate possible subclinical alterations in lung function and bronchodilator reversibility in children and adolescents with allergic (AR) and non-allergic rhinitis (NAR) without asthma, according to the clinical grade of rhinitis classified by ARIA (Allergic Rhinitis and Its Impact on Asthma). Methods: In a cross-sectional analytical study, we included patients aged 5 to 18 years with symptoms of AR and NAR without asthma. Spirometry was performed by flow-volume curve and we analyzed the abnormalities in respiratory function and bronchodilator response in relation to clinical grade of rhinitis by ARIA using an adjusted logistic model. Results: We studied 193 patients; 42 (21.7%) had some spirometric abnormalities. Patients with moderate-severe persistent rhinitis had greater impairment of lung function compared to the other grades of rhinitis (p=0.009). This defect was associated with both frequency (p=0.03) and severity of rhinitis (p=0.04) but not with atopic status (p=0.28). A positive bronchodilator response was more frequent in grades moderate-severe of rhinitis than in mild forms (p=0.04). Conclusion: Abnormalities of lung function was more prevalent in moderate-severe persistent rhinitis and was associated with the frequency and severity of rhinitis but not to atopic status. The bronchodilator reversibility was observed in patients with intermittent and persistent moderate-severe rhinitis.

Introducción: Las vías aéreas superior e inferior se comportan como una unidad. Se han observado alteraciones espirométricas subclínicas en pacientes con rinitis, sin asma, que podrían ser proporcionales a la magnitud de la rinitis. Objetivos: Investigar las posibles alteraciones de la función pulmonar y reversibilidad al broncodilatador en niños y adolescentes con rinitis alérgica (RA) y no alérgica (RNA), sin asma, según el grado clínico de rinitis establecido por ARIA (Rinitis Alérgica y su Impacto en Asma). Población y métodos: Estudio transversal analítico. Se incluyeron pacientes entre 5 y 18 años con RA y RNA, sin asma. Se analizó la existencia de anormalidades en la función pulmonar (curva flujo-volumen) y la respuesta broncodilatadora en relación al grado clínico de rinitis por ARIA ajustando un modelo logístico.Resultados: Se estudiaron 193 pacientes; 42 (21,7%) tuvieron al menos un parámetro espirométrico alterado. Los pacientes con rinitis persistente moderada-grave presentaron mayor afectación de la función pulmonar respecto a otros grados de rinitis (p=0,009). El defecto se asoció a la frecuencia (p=0,03) y a la gravedad de la rinitis (p=0,04) pero no con la atopia (p=0,28). La respuesta broncodilatadora positiva fue más frecuente en los grados de rinitis moderada-grave que en los leves (p=0,04). Conclusiones: La alteración de la función pulmonar fue más prevalente en la rinitis persistente moderada-grave y se asoció a la frecuencia y la gravedad de la rinitis pero fue independiente de la condición de atopia. La reversibilidad al broncodilatador se observó en pacientes con rinitis intermitente y persistente moderada-grave.

Estructura de la placenta y su impacto en la transferencia de la inmunidad materno-fetal: revisión en mamíferos domésticos / Structure of the placenta and its impact on the transfer of maternal-fetal immunity: a review in domestic mammals

La placenta es un órgano imprescindible para llevar adelante la gestación en mamíferos domésticos. Está constituida por tejidos maternos y fetales y cumple numerosas funciones: intercambio de gases, nutrientes y excreción de productos de desecho, función inmune a nivel de tolerancia y transferencia, función endócrina sintetizando hormonas y factores de crecimiento. Existe una gran diversidad estructural en las placentas de diferentes especies animales. Las clasificaciones de mayor relevancia son la que dependen de la descripción morfológica macroscópica, basada en la distribución de las vellosidades placentarias en el corion del feto y la clasificación histológica, fundamentada en el número de capas que se interponen entre la sangre materna y la fetal, determinando la transferencia de inmunoglobulinas (Igs) a través de este órgano. El objetivo del presente trabajo es describir la estructura placentaria en diferentes especies y su impacto en la transferencia de la inmunidad materno-fetal. (AU)

The placenta is an essential organ for pregnancy in domestic mammals. It is constituted by maternal fetal tissues and fulfills numerous functions: exchange of gases, nutrients and excretion of waste products, prevents the immune system from identifying the embryo as a foreign body and synthesizes hormones and growth factors. There is great structural diversity in placentas of different animal species, and those can be classified in different ways. The most relevant is the macroscopic morphological classification, which is based on the distribution of the placental villi in the corium of the fetus, and the histological, that relies on the number of layers between maternal and fetal blood, determining if there is immunoglobulin (Ig) transfer or it is carried out through the colostrum. The objective of the work is to describe the placental structure in different species and its impact on the transfer of maternal-fetal immunity. (AU)

Inducción de tolerancia en alergia a la proteína de leche de vaca: modelo desde un caso clínico / Tolerance induction in cow' s milk protein allergy: a clinical case model

La prevalencia de la alergia alimentaria en pediatría presenta un incremento en los últimos años; el alimento más frecuentemente involucrado es la leche de vaca. La alergia a proteína de leche de vaca (APLV) afecta la calidad de vida del paciente y su familia porque requiere dieta de exclusión y medicación de rescate por probables reacciones frente a ingesta accidental del alimento. Actualmente se está avanzando en el estudio de la inmunoterapia oral (ITO) con leche de vaca (LV) como alternativa de tratamiento. Algunos estudios demuestran descenso de la IgE específica (IgEs) para LV4, mientras otros autores refieren que no hay cambios posteriores al tratamiento con ITO3.

The prevalence of food allergy in paediatrics has increased in recent years; the most frequent food involved is cow's milk1. Allergy to cow's milk protein (CMPA) affects the quality of life of the patient and his or her family because it requires exclusion diet and rescue medication for probable reactions to accidental food intake1. There are currently advances in the study of oral immunotherapy (OIT) with cow's milk (CM). Some studies show a decrease in specific IgE (IgEs) for CM, while other authors refer no changes after treatment with OIT3.

The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation.

Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin-angiotensin system (RAS) heptapeptide angiotensin (Ang)-(1-7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence-associated galactosidase (SA-ß-gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein-coupled receptor Mas, Ang-(1-7) inhibited the pro-senescence action of Ang II, but also of a non-RAS stressor such as the cytokine IL-1ß. Moreover, Ang-(1-7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti-senescence action of the heptapeptide. Indeed, both Ang-(1-7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase-1 (HO-1) pathway. The HO-1 inhibitor tin protoporphyrin IX prevented the anti-senescence action evoked by Ang-(1-7) or recombinant klotho. Overall, the present study identifies Ang-(1-7) as an anti-senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO-1. Ang-(1-7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.

New Findings in the Signaling Pathways of cis and trans Platinum Iodido Complexes' Interaction with DNA of Cancer Cells.

We have selected a series of aliphatic amine platinum compounds bearing chloride and/or iodide as the leaving groups. The complexes' cytotoxicity and interaction with DNA indicated differences in the reactivity. Now, we are reporting on the analysis of their molecular mechanism of action on gastric cancer cells. Our data reveals differences between them. Chlorido drugs showed similar behavior to cisplatin; they both required p53 to induce apoptosis but only cis-ipa showed DNA damage requirement for apoptosis induction. On the contrary, cis and trans iodido induced cell death independent of p53 activity, and they induced cell death through Bid activation, so their toxicity could be enhanced in a combined treatment with novel Bcl-2 protein family inhibitors. We also report the structural features of the DNA adduct for one of the complexes by X-ray diffraction. These findings represent a step forward in the search for new platinum-derived agents more specific and effective in the treatment of cancer.

Diagnóstico de enfermedad granulomatosa crónica (EGC): perspectiva desde la resolución de un caso clínico / Diagnosis of chronic granulomatous disease (CGD): perspective from the resolution of a clinical case

La EGC es una patología de baja prevalencia incluida en el grupo de los defectos congénitos de los fagocitos. Existen dos formas de transmisión genética: ligada a X, la más frecuente y grave, y autosómica recesiva. Se debe a mutaciones de los genes que codifican para las proteínas que constituyen el complejo NADP oxidasa lo que induce incapacidad en fagocitos para realizar el estallido respiratorio. El diagnóstico se fundamenta en el fenotipo clínico y de laboratorio; la prueba de dihidrorodamina (DHR) con estímulo de PMA por citometría de flujo es el método diagnóstico de elección. El diagnóstico definitivo es la identificación de la mutación genética por secuenciación del ADN. La terapéutica curativa de esta patología es el trasplante de células madres hematopoyéticas (TCHP). (AU)

CGD is a low prevalence pathology included in the group of congenital phagocyte defects. There are two forms of genetic transmission: the X-linked, the most frequent and severe, and autosomal recessive. It is due to a mutation of the genes coding for proteins that constitute the NADP oxidase complex, which induces inability of phagocytes to perform respiratory burst. The initial diagnosis is based on the clinical and laboratory phenotype; the dihydrorhodamine (DHR) test with PMA stimulation by flow cytometry is a diagnostic method of choice. The demonstration of the genetic mutation by DNA sequencing is the definitive diagnosis. The haemopoietic stem-cell transplantation (HSCT) is the curative therapy of this pathology. (AU)