Natural and Induced Tolerance to Hymenoptera Venom: A Single Mechanism?

Inducing tolerance in Hymenoptera-allergic patients, bee venom immunotherapy (BVIT) is a widely accepted method to treat severe allergy to bee stings. In order to increase the existing knowledge on the underlying immunological mechanisms and look for possible biomarkers predictive of efficacy, a group of 20 bee-venom-allergic patients (AG) were thoroughly examined during their first year of BVIT. In addition, the results of treated patients with those of an untreated group of 20 tolerant beekeepers (TG) who had previously shown a firm suppressor-regulatory profile were compared. Tolerance in AG patients was invariably associated with a significant regulatory response characterised by the expansion of Helios- subpopulation and increased IL-10, specific IgG4 (sIgG4), and kynurenine levels. Although specific IgE (sIgE) levels increased transiently, surprisingly, the T helper type 2 (Th2) population and IL-4 levels rose significantly after one year of immunotherapy. Thus, the picture of two parallel phenomena emerges: a tolerogenic response and an allergenic one. Comparing these results with those obtained from the TG, different immunological mechanisms appear to govern natural and acquired tolerance to immunotherapy. Of particular interest, the kynurenine levels and T regulatory (Treg) Helios- population could be proposed as new biomarkers of response to BVIT.

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man.

Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and UGT1A6 genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance (p < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men (p < 0.001). UGT1A6 genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant UGT1A6 alleles showed a 22.5% increase in t1/2 values and a 22.8 increase in drug exposure (p < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the UGT1A6*2 and UGT1A6*4 variant alleles, whereas no effect of UGT1A6*3 and UGT1A9*3 alleles, BMI, or drug−drug interaction was identified in this study. We conclude that sex and UGT1A6 variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs.

Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

Identification of Novel Biomarkers for Drug Hypersensitivity After Sequencing of the Promoter Area in 16 Genes of the Vitamin D Pathway and the High-Affinity IgE Receptor.

The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including FCER1A, MS4A2, FCER1G, VDR, GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, RXRA, RXRB, RXRG, IL4, IL4R, IL13, and IL13RA1. The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes FCER1G (rs36233990 and rs2070901), and GC (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter FCER1G rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases.

Análisis Probabilista de Seguridad de tratamientos de radioterapia con un acelerador lineal de uso médico / Probabilistic safety assessment of the radiotherapy treatment with a linear accelerator for medical use

RESUMEN El trabajo presenta los resultados del Análisis Probabilista de Seguridad al proceso de tratamiento de radioterapia con un acelerador lineal de uso médico desarrollado por el Foro Iberoamericano de Organismos Reguladores Radiológicos y Nucleares. Se evaluaron las exposiciones accidentales potenciales durante el proceso de tratamiento del paciente, los trabajadores y miembros del público, aunque el énfasis del estudio se orientó hacia los pacientes. El método de análisis de modos de fallos y efectos se utilizó para definir los sucesos iniciadores de accidentes y los métodos de árboles de sucesos y árboles de fallo para determinar las secuencias accidentales que se pueden producir. Una vez cuantificada la frecuencia de ocurrencia de las secuencias accidentales se realizaron análisis de importancia para determinar los sucesos más significativos desde el punto de vista de la seguridad y se identificaron los principales contribuyentes al riesgo, así como las recomendaciones de seguridad más apropiadas para reducirlo.

ABSTRACT This paper presents the results of the Probabilistic Safety Assessment to the radiotherapy treatment with an Electron Linear Accelerator for Medical Use, which was conducted in the framework of the Iberian-American Forum of Radiological and Nuclear Regulatory Agencies. Potential accidental exposures during the treatment of patients, workers and members of the public were assessed, although the study was mainly focused on patients. The methodology of failure modes and effects analysis was used to define accident initiating events and methods of event tree and fault tree analysis to determine the accident sequences that may occur. After quantifying the frequency of occurrence of the accident sequences, an important analysis was carried out in order to determine the most significant events from the point of view of safety. The major contributors to risk were identified as well as the most appropriate safety recommendations to reduce it.

Diabetes en la vejez / Diaabetes in senility

Existen dos tipos de diabetes en la vejez: la diabetes de la vejez propiamente dicha, o "senil", que comienza después de los 65 ó 70 años y la diabetes"envejecida" que comienza años atrás y llega a la edad provecta después de varios años de evolución. Los factoares a tener en cuenta para su correcto tratamiento son el estado de nutrición, la patología coexistente, las complicaciones, los trastornos psiquiátricos, las funciones intelectuales, el entorno familiar y la expectativa de vida. La hipertensión arterial, la dislipidemia y la disfunción eréctil son patologías agregadas pevalentes en este tipo de enfermos.

Hemorragia y tromboembolismo en oncología

Contenido: Visión hematológica del manejo de en - . Visión de un oncólogo clínico - Mecanismos patogénicos de : implicaciones terapéuticas - Visión clínica del manejo de eventos trombóticos en en pacientes con cáncer - Complicaciones trombóticas del en - y - en los - Papel de la heparina en la supervivencia de pacientes con cáncer