The profitability of value-added products in dairy farm diversification initiatives

A more open and competitive dairy market has encouraged certain dairy farms to adopt value-adding strategies in order to achieve a higher profitability, which may be important for farms’ survival. This paper investigated the role of some product characteristics in the profitability of value-added products in these farms. For this purpose, we used a unique database of 265 different products commercialized by 49 Spanish dairy farms that offers information on nine attributes of each product. Using hedonic models as a baseline, we examined the influence of these attributes on the margin per liter (ML) of the products. The results of the regression indicated that cheese and yogurt generated 0.688 and 1.518 € more of margin per liter than liquid milk. Similarly, we found a set of attributes that have a positive influence on ML, including possession of a certificate of protected designation of origin (PDO), the milk-type composition (proportion of sheep milk), a longer expiration period, and involvement in direct marketing strategies (DMS). However, other recognized attributes such as organic labeling, maturation period, size of the sales unit and returnable packaging did not have a significant influence on ML. Our findings also showed that firms producing more elaborated products as cheese and yogurt need a lower percentage of their production to cover the fixed costs associated to transformation and commercialization. Overall, our results revealed that the elaboration of value-added dairy products improves the profitability of dairy farms

Pharmacogenomics of prostaglandin and leukotriene receptors

Los antecedentes genéticos individuales junto con los efectos ambientales se cree que están detrás de muchas enfermedades complejas. Una serie de variantes genéticas, principalmente los SNPs (single nucleotide polymorphisms), han demostrado estar asociados con diferentes patologías y afecciones inflamatorias, que representan potenciales dianas terapéuticas. Las prostaglandinas (PTGs) y leucotrienos (LTs) son eicosanoides derivados del ácido araquidónico y relacionados con ácidos grasos poliinsaturados participan tanto en la homeostasis normal y en condiciones inflamatorias. Estos mediadores lípidos bioactivos son sintetizados a través de dos grandes vías enzimáticas multipaso: PTGs por la ciclooxigenasa y la lipooxigenasa DE 5 LTS. Los principales efectos fisiológicos de PTGs incluyen vasodilatación y la fuga vascular (PTGE2); la maduración de los mastocitos, eosinófilos, y reacciones alérgicas (PTGD2); vascular y la contracción del músculo liso de las vías respiratorias (PTGF2), e inhibición de la agregación plaquetaria (PTGI2). LTB4 está principalmente involucrado en el reclutamiento de los neutrófilos, fuga vascular y en la función de la barrera epitelial, mientras que cisteinil LTs (CysLTs) (LTC4, LTD4 y LTE4) inducen la broncoconstricción y extravasación de neutrófilos, y también participar en la fuga vascular. PTGs y LTs ejercen sus funciones biológicas mediante su unión a receptores afines, que pertenecen a las siete transmembranas acopladas a proteínas G, la superfamilia de receptores. Los SNPs en genes que codifican estos receptores pueden influir en su funcionalidad, ya que tienen un papel en la susceptibilidad a las enfermedades y la respuesta al tratamiento de los medicamentos. En esta revisión resumimos los SNPs en PTGs y receptores de LTs y su relevancia en enfermedades humanas. También ofrecemos información sobre la expresión génica. Por último, podemos especular sobre la dirección futura de este tema.Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.Trabajo patrocinado por: Programa Miguel Servet. Ref CP14/00034, para José Antonio Cornejo García Ministerio de Economía y Competitividad y Instituto Nacional de Salud Carlos III y Fondos FEDER. Programa Sara Borrell. Ref. CD14/00242, para James R. Perkins Ministerio de Economía y Competitividad e Instituto Nacional de Salud Carlos III y Fondos FEDER. Becas FISPI12/02247, FISPI13/02598 y FISPI15/00726 Servicio Público de Salud de Andalucía. Beca PI-0279-2012 Junta de Extremadura y Fondos FEDER. Beca GR15026peerReviewe

NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs

Las reacciones de hipersensibilidad inducidas por medicamentos antiinflamatorios no esteroideos (AINE) están clasificadas por la Red Europea de Alergia a los Medicamentos (ENDA) como reacciones cruzadas o selectivas. La primera es el tipo más frecuente e incluye a los pacientes con síntomas exclusivamente respiratorios (AINE - enfermedad respiratoria exacerbada, ENDA) o exclusivamente cutáneos: urticaria/angioedema inducido por AINEs (NIUA); y enfermedad cutánea exacerbada por AINEs (NECD). Sin embargo, aunque no se refleja en el esquema de clasificación actual (ENDA), en la práctica clínica se observa con frecuencia una combinación de síntomas tanto cutáneos como respiratorios o incluso de otros órganos, como los síntomas del tracto gastrointestinal (reacciones mixtas o combinadas). Esta entidad no ha sido suficientemente caracterizada. Nuestro objetivo era caracterizar clínicamente las reacciones mixtas a los AINEs, comparando sus características clínicas con las del NERD y la NIUA. Evaluamos a los pacientes con síntomas que sugerían hipersensibilidad a los AINEs que acudieron a la Unidad de Alergia del Hospital Universitario Regional de Málaga (Málaga, España) entre 2008 y 2015. Se incluyeron 880 pacientes con reacción cruzada confirmada en base a la historia clínica, prueba de provocación nasal positiva con acetilsalicilato de lisina (NPT-LASA) y/o prueba de provocación de drogas positiva (DPT) con ácido acetilsalicílico (ASA), que se clasificaron como mezclados (261; 29,6%), NERD (108; 12,3%) o NIUA (511; 58,1%). Se compararon los síntomas, los medicamentos, las enfermedades subyacentes y los métodos de diagnóstico dentro de los grupos y entre ellos. Entre los pacientes mezclados, el subgrupo más común comprendía aquellos que desarrollaban urticaria/angioedema más rinitis/asma (n = 138), que tenían un mayor porcentaje de rinitis subyacente (p < 0,0001) y asma (p < 0,0001) que los pacientes de NIUA, mostrando similitudes con la NERD. Estas diferencias no se encontraron en el subgrupo de pacientes mezclados que desarrollaron síntomas respiratorios como el edema de la glotis; estos eran más similares a la NIUA. El porcentaje de NPT-LASA positivo fue similar para los grupos de mezcla (77%) y NERD (78,7%). Concluimos que las reacciones mixtas son reacciones de hipersensibilidad a los AINEs que afectan al menos a dos órganos. Además de la clásica afectación cutánea y respiratoria, en nuestra población algunos pacientes también desarrollan síntomas gastrointestinales. Dada la alta tasa de respuestas positivas al NPT-LASA en el NERD así como las reacciones mixtas, sugerimos que todos los pacientes que reporten síntomas respiratorios, independientemente de si tienen otros síntomas asociados, deben ser evaluados inicialmente usando el NPT-LASA, lo cual representa menos riesgo que el DPT.Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross-reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p < 0.0001) and asthma (p < 0.0001) than NIUA patients, showing similarities to NERD. These differences were not found in the sub-group of blended patients who developed such respiratory symptoms as glottis oedema; these were more similar to NIUA. The percentage of positive NPT-LASA was similar for blended (77%) and NERD groups (78.7%). We conclude that blended reactions are hypersensitivity reactions to NSAIDs affecting at least two organs. In addition to classical skin and respiratory involvement, in our population a number of patients also develop gastrointestinal symptoms. Given the high rate of positive responses to NPT-LASA in NERD as well as blended reactions, we suggest that all patients reporting respiratory symptoms, regardless of whether they have other associated symptoms, should be initially evaluated using NPT-LASA, which poses less risk than DPT.• Gobierno de Andalucía. Ayuda PI-0463-2013 • Instituto de Salud Carlos III y Fondo Europeo Regional de Desarrollo. Ayuda RETIC ARADyAL RD16/0006/0001 y PI17/1253 • Sociedad Española de Alergología. Fondo de Investigación de la Fundación de la SEAIC 2016 • Instituto de Salud Carlos III, Ministerio de Economía y Competitividad y Fondo Europeo Social. Contrato de investigación Juan Rodes JR15/00036, para Inmaculada Doña Díaz. Contrato Río Hortega CM16/0067, para Gádor Bogas Herrera. Programa Miguel Servet CP14/00034, para José Antonio Cornejo García. Programa Sara Borrell CD14/00242, para James Richard Perkins.peerReviewe

Asthma and rhinitis induced by selective immediate reactions to paracetamol and non-steroidal anti-inflammatory drugs in aspirin tolerant subjects

En sujetos con anti-inflamatorios no esteroideos (AINES) se agravan las enfermedades respiratorias (ERNE) y los síntomas son desencadenados por el ácido acetilsalicílico (AAS) y otros potentes inhibidores COX-1 y, en algunos casos, por la debilidad de la COX-1 o los inhibidores selectivos de la COX-2. El mecanismo está relacionado con la prostaglandina vía inhibición y la liberación de leucotrienos. Los sujetos que reaccionan a un solo AINES y toleran otros se consideran respondedores selectivos, y a menudo presentan urticaria y/o angioedema y anafilaxia (SNIUAA). Un mecanismo inmunológico está implicado en estas reacciones. Sin embargo, la evidencia anecdótica sugiere que los respondedores selectivos que presentan síntomas de las vías respiratorias también pueden existir en los síntomas respiratorios. Nuestro objetivo fue determinar si los sujetos pueden desarrollar respuestas selectivas a los AINES/paracetamol que se manifiestan como vías respiratorias superiores/inferiores de los síntomas respiratorios. Para ello, estudiamos informes de pacientes con rinitis y/o asma inducida por el paracetamol o un único NSAID que tolera la ASA. Una evaluación alergológica plus reto, controlados con ASA, se llevó a cabo. Si la tolerancia ASA se encuentra, se procede a una provocación oral con el fármaco responsable. La aparición de los síntomas fue supervisada por un cuestionario clínico, midiendo el FEV1 y/o las vías respiratorias nasales y los cambios de volumen pre y post-desafío. De un total de 21 casos iniciales, hemos confirmado la aparición de problemas nasales y/o manifestaciones bronquiales en diez, caracterizados por una disminución significativa en el VEF1% y/o una disminución en el volumen de la cavidad nasal tras la administración del fármaco. Todos los casos tolerados cuentan con ASA. Esto demuestra que los sujetos con tolerante ASA presentan manifestaciones sistémicas de rinitis y/o asma inducida por el paracetamol o un único NSAID sin piel. Se requiere más investigación para saber si estos pacientes representan un nuevo fenotipo clínico para ser incluido dentro de la actual clasificación de las reacciones de hipersensibilidad a AINES.In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation.Trabajo patrocinado por: Programa Miguel Servet. Ref CP14/00034, para José Antonio Cornejo García Ministerio de Economía y Competitividad y Instituto Nacional de Salud Carlos III y Fondos FEDER. Programa Sara Borrell. Ref. CD14/00242, para James R. Perkins Ministerio de Economía y Competitividad e Instituto Nacional de Salud Carlos III y Fondos FEDER. Becas FISPI12/02247, FISPI13/02598, FISPI15/00726 y FIS PI15/00303 Servicio Público de Salud de Andalucía. Becas PI-0279-2012 y PI-0463- 2013 Junta de Extremadura y Fondos FEDER. Beca GR15026peerReviewe

Assessment of the denaturation of collagen protein concentrates using different techniques

The use of collagen and gelatin in the field of regenerative medicine is widely extended. However, most of the studies in this topic are focused on the scaffolds’ properties, but only a few are related to the properties of the raw material used. The raw material analysis not only consists of a study of the composition, but also of the denaturation degree that can influence the processing and properties of the structure of the scaffold. Thus, the denaturation degree analysis of different collagen proteins was performed and assessed by the comparison of four different methods: differential scanning calorimetry (DSC), Fourier transform Infrared Spectroscopy (FTIR) and circular dichroism (CD) spectra and sulfhydryls content analysis. DSC measurements put forward a glass transition between 88°C and 95°C as well as from the FTIR measurements; the characteristic peaks for proteins are evidenced. However, from the sulfur content, only a small proportion of free sulfhydryls are present with respect to their total amount. In addition, CD spectra allow to estimate the secondary structure of the protein by the analysis of the α-helix and β-strand and also quantify the denaturation degree with the ‘positive/negative ratio’ (RPN) from the CD profiles, obtaining values in the range between 25% and 100%.Ministerio de Economía y Competitividad (Spanish Government) / MINECO/FEDER (UE) CTQ2015-71164-

Fluorescent Calixarene-Schiff as a Nanovehicle with Biomedical Purposes

Gene therapy is a technique that is currently under expansion and development. Recent advances in genetic medicine have paved the way for a broader range of therapies and laid the groundwork for next-generation technologies. A terminally substituted difluorene-diester Schiff Base calix[4]arene has been studied in this work as possible nanovector to be used in gene therapy. Changes to luminescent behavior of the calixarene macrocycle are reported in the presence of ct-DNA. The calixarene macrocycle interacts with calf thymus DNA (ct-DNA), generating changes in its conformation. Partial double-strand denaturation is induced at low concentrations of the calixarene, resulting in compaction of the ct-DNA. However, interaction between calixarene molecules themselves takes place at high calixarene concentrations, favoring the decompaction of the polynucleotide. Based on cytotoxicity studies, the calixarene macrocycle investigated has the potential to be used as a nanovehicle and improve the therapeutic efficacy of pharmacological agents against tumors

Metallo-Liposomes of Ruthenium Used as Promising Vectors of Genetic Material

Gene therapy is a therapeutic process consisting of the transport of genetic material into cells. The design and preparation of novel carriers to transport DNA is an important research line in the medical field. Hybrid compounds such as metallo-liposomes, containing a mixture of lipids, were prepared and characterized. Cationic metal lipids derived from the [Ru(bpy)3]2+ complex, RuC11C11 or RuC19C19, both with different hydrophobic/lipophilic ratios, were mixed with the phospholipid DOPE. A relation between the size and the molar fraction α was found and a multidisciplinary study about the interaction between the metallo-liposomes and DNA was performed. The metallo-liposomes/DNA association was quantified and a relationship between Kapp and α was obtained. Techniques such as AFM, SEM, zeta potential, dynamic light scattering and agarose gel electrophoresis demonstrated the formation of lipoplexes and showed the structure of the liposomes. L/D values corresponding to the polynucleotide's condensation were estimated. In vitro assays proved the low cell toxicity of the metallo-liposomes, lower for normal cells than for cancer cell lines, and a good internalization into cells. The latter as well as the transfection measurements carried out with plasmid DNA pEGFP-C1 have demonstrated a good availability of the Ru(II)-based liposomes for being used as non-toxic nanovectors in gene therapy.España Consejería de Educación y Ciencia de la Junta de Andalucía (Proyecto de Excelencia P12-FQM-1105, FQM-206 and FQM-274, and PI-0005-2018)España,, Universidad de Sevilla, VI Plan Propio Universidad de Sevilla (PP2018-10338)España Ministerio de Ciencia, Innovación y Universidades (RTI2018-100692-B-I00

Metallo-Liposomes Derived from the [Ru(bpy)3]2+ Complex as Nanocarriers of Therapeutic Agents

The obtaining of nanocarriers of gene material and small drugs is still an interesting research line. Side-effects produced by the toxicity of several pharmaceutics, the high concentrations needed to get therapeutic effects, or their excessive use by patients have motivated the search for new nanostructures. For these reasons, cationic metallo-liposomes composed by phosphatidylcholine (PC), cholesterol (CHO) and RuC1C19 (a surfactant derived from the metallic complex [Ru(bpy)3]2+) were prepared and characterized by using diverse techniques (zeta potential, dynamic light scattering and electronic transmission microscopy –TEM-). Unimodal or bimodal populations of spherical aggregates with small sizes were obtained depending on the composition of the liposomes. The presence of cholesterol favored the formation of small aggregates. ct-DNA was condensed in the presence of the liposomes investigated. In-vitro assays demonstrated the ability of these nanoaggregates to internalize into different cell lines. A positive gene transfection into human bone osteosarcoma epithelial cells (U2OS) was also observed. The RuC1C19 surfactant was used as sensor to quantify the binding of DNA to the liposomes. Doxorubicin was encapsulated into the metallo-liposomes, demonstrating their ability to be also used as nanocarriers of drugs. A relationship between then encapsulation percentage of the antibiotic and the composition of the aggregates has been established.Junta de Andalucía 2019/FQM-206, 2019/FQM-274Ministerio de Ciencia e Innovación RTI2018-100692-BI00, PI-0005-2018, P18-RT-127

Multivalent Calixarene-Based Liposomes as Platforms for Gene and Drug Delivery

The formation of calixarene-based liposomes was investigated, and the characterization of these nanostructures was carried out using several techniques. Four amphiphilic calixarenes were used. The length of the hydrophobic chains attached to the lower rim as well as the nature of the polar group present in the upper rim of the calixarenes were varied. The lipid bilayer was formed with one calixarene and with the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DOPE. The cytotoxicity of the liposomes for various cell lines was also studied. From the results obtained, the liposomes formed with the least cytotoxic calixarene, (TEAC12)4 , were used as nanocarriers of both nucleic acids and the antineoplastic drug doxorubicin, DOX. Results showed that (TEAC12)4/DOPE/p-EGFP-C1 lipoplexes, of a given composition, can transfect the genetic material, although the transfection efficiency substantially increases in the presence of an additional amount of DOPE as coadjuvant. On the other hand, the (TEAC12)4/DOPE liposomes present a high doxorubicin encapsulation efficiency, and a slow controlled release, which could diminish the side effects of the drugThis work was financed by the Consejería de Conocimiento, Innovación y Universidades de la Junta de Andalucía (FQM-206, FQM-274, and PY20-01234), the VI Plan Propio Universidad de Sevilla (PP2019/00000748), RTI2018-100692-B-100; P18-RT-1271; PI18-0005-2018; VI-PP AY.SUPLEM2019; RYC-2015-18670, The R+D+I grant PID2019-104195G from the Spanish Ministry of Science and Innovation-Agencia Estatal de Investigación/10.13039/501100011033 (P.H.) and the European Union (Feder Funds). The authors thank the University of Seville for the grant VPPI-US. J.A.L. also thanks the Fundación ONCE funded by the Fondo Social Europe

Allergic Reactions to Metamizole: Immediate and Delayed Responses

[EN] Background: Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. Methods: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. Results: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/ anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. Conclusions: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites.The present study has been supported by the Institute of Health ‘Carlos III’ of the Ministry of Economy and Competitiveness [grants cofounded by European Regional Development Fund (ERDF), Red de Reacciones Adversas a Alergenos y Farmacos (RD12/0013/0001 and PI15/01317)] and by Consejeria de Salud de la Junta de Andalucía (PI-0463-2013).Blanca-López, N.; Pérez-Sanchez, N.; Agúndez, JA.; García-Martín, E.; Torres, MJ.; Cornejo-Garcia, JA.; Perkins, JR.... (2016). Allergic Reactions to Metamizole: Immediate and Delayed Responses. International Archives of Allergy and Immunology. 169(4):223-230. https://doi.org/10.1159/000444798S223230169