IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods.

BACKGROUND: The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods. METHODS: Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis). RESULTS: Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis. CONCLUSIONS: Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

[Complete response to tyrosine kinase inhibitors in metastatic renal cancer. Report of four cases]. / Respuesta completa a los inhibidores de la tirosin kinasa en cáncer renal metastásico. Aportacion de 4 casos.

OBJECTIVSE: To describe the complete responses in our patients with metastatic renal cancer treated with tyrosine kinase inhibitors. MATERIAL AND METHODS: Between June 2007 and December 2014 we treated in our department 43 patients with metastatic renal cancer with antiangiogenic drugs. RESULTS: 9.3% (4/43) of the patients treated with antiangiogenic drugs obtained complete response according to RECIST 1.1 criteria. In 3 of the 4 patients, complete response was obtained during the first-line treatment with sunitinib at doses of 50 mgr/day in a 4/2 scheme and the remaining patient obtained it with second line axitinib at doses of 10 mgr/day. CONCLUSIONS: Tyrosine kinase inhibitors can induce complete responses in patients with metastatic renal cancer. Discontinuation of treatment with tyrosine kinase inhibitors after a complete response may be an option.

Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy.

BACKGROUND: Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and 2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent. We sought to identify key pathways and mediators critically involved in the induction of allergic sensitization to peanut. METHODS: Comprehensive metabolomics analysis with liquid chromatography-mass spectrometry was used to detect metabolite changes in mice (C57BL/6) undergoing sensitization. Loss-of-function and gain-of-function studies were performed in mice subjected to two models of peanut sensitization and anaphylaxis that involved either oral or epicutaneous sensitization. Flow cytometric analyses on dendritic cells (DCs) in vitro and in vivo were used to investigate the mechanisms of immune activation. RESULTS: Elevated levels of uric acid (UA) were detected in mice undergoing sensitization as well as in peanut-allergic children who were not challenged with peanut. In mice, the depletion of UA during sensitization prevented the development of peanut-specific immunoglobulins IgE and IgG1 as well as anaphylaxis while exogenous delivery of UA crystals (monosodium urate, MSU) restored the allergic phenotype. Monosodium urate enhanced CD86 and OX40L expression on DCs, independent of Toll-like receptors 2 and 4, the NLRP3 inflammasome, and IL-1ß, via a PI3K signaling pathway. CONCLUSION: Overproduction of the UA alarmin in the local microenvironment plays a critical role in the induction of peanut-allergic sensitization, likely due to its ability to activate DCs. These finding suggest that cellular damage or tissue injury may be an essential requisite for the development of allergic sensitization to foods.

Implementation and assessment of a fast-track programme to improve communication between primary and specialized care in patients with suspected cancer: how to shorten time between initial symptoms of cancer, diagnosis and initiation of treatment

Purpose. This study aims to asses a cancer fast-track programme (CFP) to shorten the time since a patient with suspicion of cancer is referred by the primary care (PC) physician to the specialized medical team. Methods. Guidelines for main suspected tumours were designed to help PC physicians to detect and rapidly refer cases to the CFP oncology coordinator, who sent them to the appropriate department to accelerate diagnosis, staging and therapy. All patients analysed in this report were referred from June 2009 to July 2012. Results. A total of 897 suspected cancer cases were submitted and finally 705 were studied. In 205 (29 %) a cancer diagnosis was confirmed within 23 days (median). Therapy was initiated within 46 days after referral (median). Early diagnoses with a potential curative approach were made in 166 (82 %). Conclusions. This CFP decreased the waiting time for cancer diagnosis, by improving communication between PC physician and specialized care teams. Most patients included in this program could get therapy with curative intent (AU)

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Implementation and assessment of a fast-track programme to improve communication between primary and specialized care in patients with suspected cancer: how to shorten time between initial symptoms of cancer, diagnosis and initiation of treatment.

PURPOSE: This study aims to asses a cancer fast-track programme (CFP) to shorten the time since a patient with suspicion of cancer is referred by the primary care (PC) physician to the specialized medical team. METHODS: Guidelines for main suspected tumours were designed to help PC physicians to detect and rapidly refer cases to the CFP oncology coordinator, who sent them to the appropriate department to accelerate diagnosis, staging and therapy. All patients analysed in this report were referred from June 2009 to July 2012. RESULTS: A total of 897 suspected cancer cases were submitted and finally 705 were studied. In 205 (29 %) a cancer diagnosis was confirmed within 23 days (median). Therapy was initiated within 46 days after referral (median). Early diagnoses with a potential curative approach were made in 166 (82 %). CONCLUSIONS: This CFP decreased the waiting time for cancer diagnosis, by improving communication between PC physician and specialized care teams. Most patients included in this program could get therapy with curative intent.

T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes.

Intestinal T helper type 2 (Th2) immunity in food allergy results in IgG1 and IgE production, and antigen re-exposure elicits responses such as anaphylaxis and eosinophilic inflammation. Although interleukin-4 (IL-4) is critically required for allergic sensitization, the source and control of IL-4 during the initiation of Th2 immunity in vivo remains unclear. Non-intestinal and non-food allergy systems have suggested that natural killer-like T (NKT) or γδ T-cell innate lymphocytes can supply the IL-4 required to induce Th2 polarization. Group 2 innate lymphoid cells (ILCs) are a novel IL-4-competent population, but their contribution to initiating adaptive Th2 immunity is unclear. There are also reports of IL-4-independent Th2 responses. Here, we show that IL-4-dependent peanut allergic Th2 responses are completely intact in NKT-deficient, γδ T-deficient or ILC-deficient mice, including antigen-specific IgG1/IgE production, anaphylaxis, and cytokine production. Instead, IL-4 solely from CD4(+) Th cells induces full Th2 immunity. Further, CD4(+) Th cell production of IL-4 in vivo is dependent on OX40L, a costimulatory molecule on dendritic cells (DCs) required for intestinal allergic priming. However, both Th2 cells and ILCs orchestrated IL-13-dependent eosinophilic inflammation. Thus, intestinal Th2 priming is initiated by an autocrine/paracrine acting CD4(+) Th cell-intrinsic IL-4 program that is controlled by DC OX40L, and not by NKT, γδ T, or ILC cells.

Parâmetros genéticos para características de carcaça avaliadas por ultrassonografia em bovinos da raça Guzerá / Genetic parameters for body weight and real-time ultra sound carcass traits of Guzera cattle

A partir das observações de 1.325 animais (90,4 por cento de machos e 9,6 por cento de fêmeas) e do pedigree de 6.642 animais da raça Guzerá foram estimados os parâmetros genéticos para o peso corporal e as características área de olho de lombo e espessura de gordura na costela e na garupa, avaliadas por meio da técnica de ultrassonografia. Os componentes de (co)variância foram estimados pelo método da máxima verossimilhança restrita, utilizando-se o aplicativo MTDFREML. Foram utilizados, para as estimativas de repetibilidade e herdabilidade, modelos unicaracterística e, para as correlações genéticas e fenotípicas entre as características, modelos bicaracterísticas. As estimativas de repetibilidade (erros-padrão) foram 0,44(0,10) para peso corporal, 0,39(0,10) para área de olho de lombo, 0,75(0,06) para espessura de gordura na costela e 0,49(0,08) para espessura de gordura na garupa. As estimativas de herdabilidade, respectivamente a partir de modelos uni e bicaracterísticas, foram 0,42(0,11) e 0,41(0,11) para peso corporal, 0,35(0,09) e 0,34(0,09) para área de olho de lombo, 0,20(0,08) e 0,32(0,02) para espessura de gordura na garupa e 0,05(0,06) e 0,10(0,08) para espessura de gordura na costela. As estimativas de correlações genéticas foram 0,79(0,09) entre o peso corporal e a área de olho de lombo; 0,20(0,08) entre o peso corporal e a espessura de gordura na garupa; 0,05(0,06) entre a área de olho de lombo e a espessura de gordura na costela; 0,02(0,27) entre a área de olho de lombo e a espessura de gordura na garupa; e 0,64(0,22) entre as duas medidas de espessura de gordura. Os resultados indicam que é uma mensuração suficiente para a adequada avaliação das características área de olho de lombo e espessura de gordura na carcaça e que a seleção direta para essas características pode resultar em carcaças mais musculosas e de melhor acabamento. Indica, ainda, ausência de antagonismo genético entre a seleção para peso corporal e características ...

Genetic parameters were estimated for body weight and real-time ultra-sound loin-eye area, rump fat thickness, and back fat thickness using data from 1,325 yearling Guzera cattle (90.4 percent bulls and 9.6 percent heifers) and pedigree structure with 6,642 animals. Variance and covariance components were estimated using REML methodology and MTDFREML software. Single trait animal models were used to estimate repeatability and heritability for the four traits. Multiple traits animal models were used to estimate genetic correlations among the traits. Repeatability estimates (standard errors) were 0.44(0.10) for body weight, 0.39(0.10) for loin-eye area, 0.75(0.06) for rump fat thickness, and 0.49(0.08) for back fat thickness. Heritability estimates were 0.42(0.11) and 0.41(0.11) for body weight, 0.35(0.09) and 0.34(0.09) for loin-eye area, 0.20(0.08) and 0.32(0.08) for back fat thickness, and 0.05(0.06) and 0.10(0.08) for rump fat thickness, respectively from single and multiple traits models. Genetic correlation estimates were 0.79(0.09) between body weight and loin-eye area, 0.20(0.08) between body weight and back fat thickness, 0.05(0.06) between loin-eye area and rump fat thickness, 0.02(0.27) between loin-eye area and back fat thickness and 0.64(0.22) between the two measurements of fat thickness. In order to evaluate carcass traits, results suggested that repeated real-time ultra-sound measurements are not needed and that direct selection for these traits might be effective. In addition, there is no genetic antagonism between selection for body weight and carcass traits.

Estudio sobre el conocimiento de factores de riesgo cardiovascular en estudiantes de medicina / Medical students’ knowledge of cardiovascular risk factors

Objetivos: Valorar el conocimiento de los estudiantes de Medicina de la Universidad de Navarra sobre la enfermedad cardiovascular y susfactores de riesgo.Material y métodos: Estudio descriptivo transversal en una muestra de 334 alumnos de 1º, 4º y 6º curso, autocumplimentando un cuestionario anónimo. Se utilizó el programa estadístico SPSS 11.0Resultados: La mayoría de los alumnos de 4º y 6º identifi caron correctamente los factores de riesgo cardiovascular (FRCV). Los de 4º identifi canmejor los valores lipídicos y los de 6º reconocen mejor la hipertensión arterial y el aumento del índice de masa corporal como FRCV. Un 97,8% considera la dieta mediterránea como factor protector. Conclusión: Existe un buen conocimiento de los FRCV entre los estudiantes de Medicina de la Universidad de Navarra y va aumentando a lo largo de la carrera

Objectives: To evaluate cardiovascular risk factor awareness among medical students at the University of Navarra.Material and Methods: A descriptive cross-sectional study including 334 students of the 1st, 4th and 6th year. They answered an anonymous structuredquestionnaire, and the results were analyzed using SPSS 11.0.Results: Most 4th and 6th year students correctly identifi ed the cardiovascular risk factors (CVRF). The 4th year students obtained better results on lipid values while the 6th year students performed better on body mass index and arterial hypertension. 97.8% of the sample considered the Mediterranean diet to be a protective factor.Conclusion: University of Navarra’s medical students are well informed about CVRF and their knowledge increases along the degree course

[Medical students' knowledge of cardiovascular risk factors]. / Estudio sobre el conocimiento de factores de riesgo cardiovascular en estudiantes de medicina.

OBJECTIVES: To evaluate cardiovascular risk factor awareness among medical students at the University of Navarra. MATERIAL AND METHODS: A descriptive cross-sectional study including 334 students of the 1st, 4th and 6th year. They answered an anonymous structured questionnaire, and the results were analyzed using SPSS 11.0. RESULTS: Most 4th and 6th year students correctly identified the cardiovascular risk factors (CVRF). The 4th year students obtained better results on lipid values while the 6th year students performed better on body mass index and arterial hypertension. 97.8% of the sample considered the Mediterranean diet to be a protective factor. CONCLUSION: University of Navarra's medical students are well informed about CVRF and their knowledge increases along the degree course.

Association between the T29-->C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: The Study of Osteoporotic Fractures.

CONTEXT: Transgenic animal experiments suggest that increased expression of transforming growth factor beta1 (TGF-beta1) is protective against early tumor development, particularly in breast cancer. A T-->C (thymine to cytosine) transition in the 29th nucleotide in the coding sequence results in a leucine to proline substitution at the 10th amino acid and is associated with increased serum levels of TGF-beta1. OBJECTIVE: To determine whether an association exists between this TGF-beta1 polymorphism and breast cancer risk. DESIGN, SETTING, AND PARTICIPANTS: The Study of Osteoporotic Fractures, a prospective cohort study of white, community-dwelling women aged 65 years or older who were recruited at 4 US centers between 1986 and 1988. Three thousand seventy-five women who provided sufficient clinical information, buffy coat samples, and adequate consent for genotyping are included in this analysis. MAIN OUTCOME MEASURE: Breast cancer cases during a mean (SD) follow-up of 9.3 (1.9) years, verified by medical chart review and compared by genotype. RESULTS: Risk of breast cancer was similar in the 1124 women with the T/T genotype (56 cases; 5.4 per 1000 person-years) and the 1493 women with the T/C genotype (80 cases; 5.8 per 1000 person-years) but was significantly lower (P =.01) in the 458 women with the C/C genotype (10 cases; 2.3 per 1000 person-years). In analyses that adjusted for age, age at menarche, age at menopause, estrogen use, parity, body mass index, and bone mineral density, women with the C/C genotype had a significantly lower risk of developing breast cancer compared with women with the T/T or T/C genotype (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.17-0.75). There was no significant difference between the risk for women with the T/C genotype compared with women with the T/T genotype (adjusted HR, 1.04; 95% CI, 0.73-1.48). CONCLUSIONS: Our findings suggest that TGF-beta1 genotype is associated with risk of breast cancer in white women aged 65 years or older. Because the T allele is the common variant and confers an increased risk, it may be associated with a large proportion of breast cancer cases.

Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease.

Genetic linkage analysis in families with multiple cases of inflammatory bowel disease (IBD) has mapped a gene which confers susceptibility to IBD to the pericentromeric region of chromosome 16 (IBD1). The linked region includes the interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are abnormal in IBD, the IL4R gene is thus both a positional and functional candidate for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with IBD in 355 families, which included 435 cases of Crohn's disease and 329 cases of ulcerative colitis. No association was observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) and either the Crohn's disease or ulcerative colitis phenotypes using the transmission disequilibrium test. There was also no evidence for association when the four markers were analyzed individually. The results indicate that these variants are not significant genetic determinants of IBD, and that the IL4R gene is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants are in complete equilibrium with each other, although they are separated by only about 21 kilobases of genomic DNA. This suggests that a very dense SNP map may be required to exclude or detect disease associations with some candidate genes.

Linkage of inflammatory bowel disease to human chromosome 6p.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Given the immunologic dysregulation in IBD, the human-leukocyte-antigen region on chromosome 6p is of significant interest. Previous association and linkage analysis has provided conflicting evidence as to the existence of an IBD-susceptibility locus in this region. Here we report on a two-stage linkage and association analysis of both a basic population of 353 affected sibling pairs (ASPs) and an extension of this population to 428 white ASPs of northern European extraction. Twenty-eight microsatellite markers on chromosome 6 were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of five single-nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for association of these important candidate genes with IBD. In summary, we provide firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.

High-throughput single nucleotide polymorphism genotyping by fluorescent 5' exonuclease assay.

Single nucleotide polymorphisms (SNPs) are the class of DNA variants that are most common in the genome. Technologies are needed that allow relatively high-throughput, high-quality genotyping of SNPs, with rapid assay development for individual SNPs of interest. We have implemented an accurate and high-throughput SNP genotyping system using a commercially available fluorescent 5' exonuclease assay. Optimization of the assay system for low-volume reactions and low-probe concentrations has reduced assay costs by 75%. Using a simple assay optimization process, we successfully developed genotyping assays for 92% of assays attempted (309 out of 335) and have generated over 200,000 genotypes.

Numerous length polymorphisms at short tandem repeats in human cytomegalovirus.

We show the presence of numerous short tandem repeats in the human cytomegalovirus (HCMV) genome and assess their usefulness as molecular markers. The genome is shown to contain at least 24 microsatellite regions that exhibit length polymorphisms. Insertion-deletion polymorphisms at these short tandem repeats are common (80% of repeats examined are polymorphic among two laboratory strains and 10 clinical isolates). This is the first report of widespread microsatellite length polymorphism in a viral genome. Some regions are highly polymorphic: one was revealed by DNA sequencing to contain length variants at five closely linked sites, which combined resulted in 10 variants for this region among the 12 strains and isolates examined. This study not only provides a new molecular marker system for this virus but also extends our understanding of microsatellite polymorphism in two important ways. First, variable-length repeats in HCMV can be considerably shorter than polymorphic repeats previously found in other organisms. Second, highly variable microsatellite repeats are not confined to prokaryotes and eukaryotes, as previously assumed. This variation provides a useful marker system for distinguishing viral isolates, and similar markers are also likely to be found in other large-genome DNA viruses.

[Epidemiologic study of cardiovascular risk factors in Alcala de Henares, Madrid]. / Estudio epidemiológico de los factores de riesgo cardiovascular en Alcalá de Henares (Madrid).

We studied the prevalence of cardiovascular risk factors (included arterial hypertension, tobacco, diabetes, dyslipemias) in Alcalá de Henares population during the period 1992-1993, following the WHO criterias and protocols. The results upon 12,000 analyzed individuals showed dates similar to other spanish studies in relationship with arterial hypertension and diabetes (factors with known genetic determinants) and, in lesser degree, with tabaquism and hypercholesterolemia.

[Acute abdomen of urologic origin]. / Abdomen agudo de origen urológico.

Presentation of one case of bladder carcinoma which caused acute abdomen following spontaneous perforation. This presentation is extremely rare and should be taken into account when haematuria and abdominal pain appear simultaneously.

[Ogilvie's syndrome. Benefits of repeat colonoscopic decompression on its developmental course]. / Síndrome de Ogilvie. Beneficios de la descompresión colonoscópic repetida sobre su curso evolutivo.

Seven cases of Ogilvie's syndrome are described. In six of ther good recovery was related to repeated endoscopic colonic decompressions. This is the safest and most precise procedure in the diagnosis and treatment of the disease. We emphasize the usefulness of repeated decompressions in the outcome of Ogilvie's syndrome. One of patients in which decompression was not attempted died of a colonic rupture.