Compromising between European and US allergen immunotherapy schools: Discussions from GUIMIT, the Mexican immunotherapy guidelines.

BACKGROUND: Allergen immunotherapy (AIT) has a longstanding history and still remains the only disease-changing treatment for allergic rhinitis and asthma. Over the years 2 different schools have developed their strategies: the United States (US) and the European. Allergen extracts available in these regions are adapted to local practice. In other parts of the world, extracts from both regions and local ones are commercialized, as in Mexico. Here, local experts developed a national AIT guideline (GUIMIT 2019) searching for compromises between both schools. METHODS: Using ADAPTE methodology for transculturizing guidelines and AGREE-II for evaluating guideline quality, GUIMIT selected 3 high-quality Main Reference Guidelines (MRGs): the European Academy of Allergy, Asthma and Immunology (EAACI) guideines, the S2k guideline of various German-speaking medical societies (2014), and the US Practice Parameters on Allergen Immunotherapy 2011. We formulated clinical questions and based responses on the fused evidence available in the MRGs, combined with local possibilities, patient's preference, and costs. We came across several issues on which the MRGs disagreed. These are presented here along with arguments of GUIMIT members to resolve them. GUIMIT (for a complete English version, Supplementary data) concluded the following. RESULTS: Related to the diagnosis of IgE-mediated respiratory allergy, apart from skin prick testing complementary tests (challenges, in vitro testing and molecular such as species-specific allergens) might be useful in selected cases to inform AIT composition. AIT is indicated in allergic rhinitis and suggested in allergic asthma (once controlled) and IgE-mediated atopic dermatitis. Concerning the correct subcutaneous AIT dose for compounding vials according to the US school: dosing tables and formula are given; up to 4 non-related allergens can be mixed, refraining from mixing high with low protease extracts. When using European extracts: the manufacturer's indications should be followed; in multi-allergic patients 2 simultaneous injections can be given (100% consensus); mixing is discouraged. In Mexico only allergoid tablets are available; based on doses used in all sublingual immunotherapy (SLIT) publications referenced in MRGs, GUIMIT suggests a probable effective dose related to subcutaneous immunotherapy (SCIT) might be: 50-200% of the monthly SCIT dose given daily, maximum mixing 4 allergens. Also, a table with practical suggestions on non-evidence-existing issues, developed with a simplified Delphi method, is added. Finally, dissemination and implementation of guidelines is briefly discussed, explaining how we used online tools for this in Mexico. CONCLUSIONS: Countries where European and American AIT extracts are available should adjust AIT according to which school is followed.

C3435T polymorphism of the ABCB1 gene is associated with poor clopidogrel responsiveness in a Mexican population undergoing percutaneous coronary intervention.

BACKGROUND: Clopidogrel is a pro-drug and its intestinal absorption is limited by the P-glycoprotein encoded by the ABCB1 gene. It is metabolized hepatically by cytochrome P450 enzymes encoded by CYP genes to produce an active metabolite that antagonizes the P2Y12 platelet receptor. Some patients exhibit poor clopidogrel responsiveness due to polymorphisms, resulting in thrombotic events. The aim of this study was to determine the relationship between poor clopidogrel responsiveness and the ABCB1, CYP and P2RY12 gene polymorphisms among patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Two hundred seventy-six patients who underwent PCI were included in this study. Clopidogrel responsiveness was determined via optical aggregometry in platelet-rich plasma using 10 µM ADP. Patients exhibiting a platelet aggregation response higher than 70% were classified as poor responders. The genetic polymorphisms were analyzed via real-time PCR. Poor responsiveness to clopidogrel was noted in 22.1% of the patients. The TT genotype of the C3435T polymorphism of the ABCB1 gene and omeprazole usage were each associated with poor clopidogrel responsiveness (Exp (ß) 2.73, p=0.009 and Exp (ß) 3.86, p=0.04, respectively). CONCLUSION: Poor clopidogrel responsiveness is associated with the TT genotype of the C3435T polymorphism of the ABCB1 gene.

Estatinas en adultos mayores, una población creciente / Statins used in the elderly, a growing population

El riesgo cardiovascular es responsable de un cuarto de las muertes por enfermedad coronaria, y dentro de estos pacientes el 75% son mayores de 65 años de edad, población a la que nos enfocaremos en esta revisión. Por ello es de suma importancia considerar tanto los beneficios clínicos como económicos de una terapia preventiva en este grupo poblacional. La prescripción en los ancianos se ha convertido en la actualidad en una cuestión compleja que tiende a incrementar el uso irracional de los fármacos, los errores de medicación, los efectos adversos, así como la subutilización o sobreutilización de los mismos. Las estatinas (inhibidores de la HMG-CoA reductasa), son consideradas como el tratamiento hipolipemiante de primera elección para la disminución del riesgo cardiovascular y a pesar de no haber publicaciones enfocadas en el uso exclusivo de estatinas en la población de adultos mayores así como de múltiples controversias, se pueden encontrar beneficios similares a los percibidos en poblaciones más jóvenes, pero con un enfoque en prevención primaria en la población de edad avanzada.

The cardiovascular risk is responsible for a quarter splits of deaths by coronary illness and inside these patients, three quarter splits are greater than 65 years old. Because of it, it's very important to consider the clinical and economic benefits of a preventive therapy in this population group. The statins (inhibiting of the HMG-CoA reductasa), are considered as the greater hypolipemic therapy election for decrease the cardiovascular risk and in spite of not there to be publications focused in the exclusive use of statins in the population of older adults, besides multiple controversies, similar benefits to them can be found perceived in younger populations, but with a focus in primary prevention in the population of advanced age.

Molecular characterization of an EWSR1-POU5F1 fusion associated with a t(6;22) in an undifferentiated soft tissue sarcoma.

We report a soft tissue sarcoma from the thigh with morphologic features resembling Ewing sarcoma, clear cell sarcoma, and myoepithelial tumor of soft tissue. In addition, the genetic and immunohistochemical findings do not correspond to any established pattern, so the tumor does not clearly fit into any one classification. The karyotype analysis revealed a rare chromosomal rearrangement, t(6;22)(p22;q12), that previously has been reported in bone and epithelial tumors. Molecular studies confirmed the presence of an EWSR1-POU5F1 fusion creating a chimeric gene with the N-terminal transcriptional activation domain of EWSR1 and the C-terminal POU DNA binding domain of POU5F1. This report is novel in that to our knowledge, it is the first complete molecular characterization of an EWSR1-POU5F1 fusion in a soft tissue sarcoma. Evaluation of existing data on the known EWSR1-POU5F1 tumors suggests that the fusion gene functions in a wide variety of cell types and may modify the differentiation state of cells, resulting in susceptibility to tumorigenesis.

Immediate effects of anticancer drugs on mitochondrial oxygen consumption.

The evolving role of mitochondria as a target for many anticancer drugs (e.g. platinum-based compounds, alkylating agents and anthracyclines) prompted us to investigate their immediate effects on the mitochondrial respiratory chain. For this purpose, we used a phosphorescence analyzer that measures [O(2)] in solution. The [O(2)] of solutions containing an appropriate substrate and various cell lines, tumors from patients or beef heart submitochondrial particles (SMPs) declined almost linearly (r>0.99) as a function of time, indicating that the kinetics of cellular oxygen consumption were zero order. Rotenone inhibited respiration, confirming that oxygen was consumed by the respiratory chain. Exposure to a clinically relevant concentration of cisplatin (5 microM at 37 degrees for 1-3 hr) had no effect on the respiration in cells or in SMP. Higher cisplatin concentrations (10-99 microM at 37 degrees for 1-3 hr) produced <25% inhibition. Incubations with 4-hydroperoxycyclophosphamide (50-100 microM at 37 degrees for 1 hr) inhibited oxygen consumption in SMP ( approximately 70% inhibition at 50 microM) and in cells ( approximately 30% inhibition at 50 microM). Incubations (37 degrees for 1 hr) of SMP with doxorubicin (25-100 microM) and daunorubicin (25-100 microM) had no inhibitory effect on the respiration. By contrast, incubations (37 degrees for 1 hr) of cells with doxorubicin (5-20 microM) and daunorubicin (2-20 microM) produced significant inhibition. We conclude that cisplatin does not directly damage the energy converting mechanism of mitochondria. On the other hand, comparable exposures to alkylating agents and anthracyclines produce immediate and dose-dependent impairment of cellular respiration.