Comparative genomic analysis of Halomonas campaniensis wild-type and ultraviolet radiation-mutated strains reveal genomic differences associated with increased ectoine production / El análisis genómico comparativo de cepas mutadas por radiación ultravioleta y de tipo salvaje de Halomonas campaniensis revela diferencias genómicas asociadas con una mayor producción de ectoína

Ectoine is a natural amino acid derivative and one of the most widely used compatible solutes produced by Halomonas species that affects both cellular growth and osmotic equilibrium. The positive effects of UV mutagenesis on both biomass and ectoine content production in ectoine-producing strains have yet to be reported. In this study, the wild-type H. campaniensis strain XH26 (CCTCCM2019776) was subjected to UV mutagenesis to increase ectoine production. Eight rounds of mutagenesis were used to generate mutated XH26 strains with different UV-irradiation exposure times. Ectoine extract concentrations were then evaluated among all strains using high-performance liquid chromatography analysis, alongside whole genome sequencing with the PacBio RS II platform and comparison of the wild-type strain XH26 and the mutant strain G8-52 genomes. The mutant strain G8-52 (CCTCCM2019777) exhibited the highest cell growth rate and ectoine yields among mutated strains in comparison with strain XH26. Further, ectoine levels in the aforementioned strain significantly increased to 1.51 ± 0.01 g L−1 (0.65 g g−1 of cell dry weight), representing a twofold increase compared to wild-type cells (0.51 ± 0.01 g L−1) when grown in culture medium for ectoine accumulation. Concomitantly, electron microscopy revealed that mutated strain G8-52 cells were obviously shorter than wild-type strain XH26 cells. Moreover, strain G8-52 produced a relatively stable ectoine yield (1.50 g L−1) after 40 days of continuous subculture. Comparative genomics analysis suggested that strain XH26 harbored 24 mutations, including 10 nucleotide insertions, 10 nucleotide deletions, and unique single nucleotide polymorphisms. Notably, the genes orf00723 and orf02403 (lipA) of the wild-type strain mutated to davT and gabD in strain G8-52 that encoded for 4-aminobutyrate-2-oxoglutarate transaminase and NAD-dependent succinate-semialdehyde dehydrogenase, respectively. Consequently, these genes may be involved in increased ectoine yields. These results suggest that continuous multiple rounds of UV mutation represent a successful strategy for increasing ectoine production, and that the mutant strain G8-52 is suitable for large-scale fermentation applications.(AU)

Inmunonutrición, evidencias y experiencias / Immunonutrition, evidence and experiences

La inmunonutrición es una ciencia que engloba aspectos relacionados con la nutrición, la inmunidad, la infección, la inflamación y el daño tisular. Las fórmulas inmunomoduladoras han demostrado beneficios en una amplia variedad de situaciones clínicas. El objetivo de este trabajo es revisar la evidencia disponible en inmunonutrición (IN). Para ello, se ha realizado una búsqueda bibliográfica con las palabras clave: inmunonutrición, arginina, glutamina, nucleótidos, ácidos grasos omega-3, ERAS, fast-track. Se han incluido ensayos clínicos, revisiones y guías de práctica clínica. La IN ha demostrado reducir las fístulas en el postoperatorio en pacientes con cáncer de cabeza y cuello. En pacientes con cáncer gástrico y cáncer de esófago, la IN se asocia a una disminución de las complicaciones infecciosas y la estancia hospitalaria. Otras situaciones clínicas que se benefician del uso de la IN son la cirugía del cáncer de páncreas, la cirugía del cáncer colorrectal y los grandes quemados. Son necesarios más estudios controlados, prospectivos y aleatorizados para confirmar los potenciales beneficios de la IN en otras situaciones clínicas como la cirugía torácica no esofágica, el cáncer vesical, la cirugía ginecológica, la fractura de cadera, la patología hepática y la COVID-19, entre otros. (AU)

Immunonutrition is a science that encompasses aspects related to nutrition, immunity, infection, inflammation and tissue damage. Immunomodulatory formulas have shown benefits in a wide variety of clinical situations.The objective of this work was to review the available evidence in immunonutrition (IN). For this, a bibliographic search has been carried outwith the keywords: immunonutrition, arginine, glutamine, nucleotides, omega-3 fatty acids, ERAS, fast-track. Clinical trials, reviews and clinicalpractice guidelines have been included.IN has been shown to reduce postoperative fistulae in head and neck cancer patients and in gastric and esophageal cancer patients, infectiouscomplications and hospital stay. Other clinical situations that benefit from the use of IN are pancreatic cancer surgery, colorectal cancer surgeryand major burns. More controlled, prospective, and randomized studies are necessary to confirm the potential benefits of IN in other clinical situations such as non-esophageal thoracic surgery, bladder cancer, gynecological surgery, hip fracture, liver pathology and COVID-19, among others. (AU)

The integrated comprehension of lncRNA HOXA-AS3 implication on human diseases

Long non-coding RNA (lncRNA) is a non-protein-coding RNA with a length of more than 200 nucleotides. Studies have shown that lncRNAs have vital impacts on various pathological processes and participate in the development of human diseases, usually through acting as competing endogenous RNAs to modulate miRNA expression and biological functions. lncRNA HOXA Cluster Antisense RNA 3 (HOXA-AS3) was a newly discovered lncRNA and has been demonstrated to be abnormally expressed in many diseases. Moreover, HOXA-AS3 expression was closely correlated with the clinicopathologic characteristics in cancer patients. In addition, HOXA-AS3 exhibited significant properties in regulating several biological processes, including cell proliferation, invasion, and migration. Furthermore, HOXA-AS3 has provided promising values in the diagnosis, prognosis, and therapeutic strategies of several diseases such as liver cancer, glioma, lung cancer, oral cancer, gastric cancer, and even atherosclerosis. In this review, we discuss the abnormal expression of HOXA-AS3 in several human disorders and some pathobiological processes and its clinical characteristics, followed by a summary of HOXA-AS3 functions, regulatory mechanisms, and clinical application potential (AU)

Inmunonutrición, cirugía y oncología: un modelo de atenciónnutricional basado en la evidencia / Immunonutrition, surgery and oncology: an evidence-based model of nutritional care

Introducción: La presente revisión de literatura permiteproponer un modelo de acción para identificar oportunamentelos pacientes que requieren cirugía mayor y que puedan be-neficiarse de intervenciones nutricionales como la inmunonu-trición a partir de la evidencia científica. Objetivo: El propósito de esta revisión y síntesis es pro-poner un modelo intervención nutricional en el manejo nutri-cional de los pacientes en el perioperatorio.Material y métodos: Se realizó una revisión rápida de laliteratura, a partir de la consulta en las siguientes fuentes dedatos,EMBASE, MEDLINE (Pubmed), Cochrane Database ofSystematic Reviews (Wiley), LILACS (BVS, interfaz iAHx) y elmotor de búsqueda Google Académico. Resultados: Se identificaron 40 artículos, que cumplieroncon los parámetros establecidos para la revisión sistemática ylos criterios de calidad, que permitieron establecer cuatro fa-ses para la propuesta de intervención nutricional en el manejonutricional perioperatorio, tamización nutricional de rutina enconsulta externa, suplementación preoperatoria con dosis te-rapéutica de inmunonutrición, intervención nutricional intra-hospitalaria y seguimiento nutricional postoperatorio.(AU)

Background: The present literature review allows us topropose a model of action for the timely identification of pa-tients who require major surgery and who may benefit fromnutritional interventions such as immunonutrition based onscientific evidence. Objective: The purpose of this review and synthesis is topropose a nutritional intervention model in the nutritionalmanagement of perioperative patients. Material and methods: A quick review of the literaturewas carried out, based on consultation of the following datasources, EMBASE, MEDLINE (Pubmed), Cochrane Database ofSystematic Reviews (Wiley), LILACS (BVS, iAHx interface) andthe Google Scholar search engine. Results: As a result, 40 articles were identified, which metthe parameters established for the systematic review and the quality criteria, which allowed establishing four phases for theproposal of nutritional intervention 360 in perioperative nutri-tional management, routine nutritional screening in outpa-tient clinic, preoperative supplementation with therapeuticdoses of immunonutrition, in-hospital nutritional interventionand postoperative nutritional follow-up. Conclusion: A nutritional intervention model that includesa nutritional contribution with a formula of amino acids (argi-nine and/or glutamine), polyunsaturated fatty acids (omega-3fatty acid) and a mixture of nucleotides or RNA, is a cost-ef-fective strategy in elective surgery patients for gastrointestinalcancer (stomach and colon cancer), head and neck surgery,patients over 18 years of age.(AU)

Remdesivir y reducción de mortalidad en pacientes con COVID-19: análisis sistematizado de subgrupos de los ensayos clínicos / Remdesivir and mortality reduction in COVID-19 patients: a systematized subgroup analysis of clinical trials

OBJETIVO: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno -no de alto flujo-. La difusión de resultados del estudio SOLIDARITY se acompañó de un metaanálisis que combinó resultados de mortalidad por subgrupos de los ensayos clínicos aleatorizados. El objetivo del presente estudio es analizar metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con COVID-19. MÉTODO: Se usó una herramienta validada para valorar los hallazgos de los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por subgrupos sin condiciones mínimas relevantes, y un cuestionario específico. Este último considera determinados criterios: asociación estadística, incluyendo p de interacción, preespecificación de subgrupos, tamaño muestral, número de factores valorados y resultado global del estudio; plausibilidad biológica de las diferencias observadas; y consistencia entre resultados de estudios similares. Se asignó una puntuación a cada criterio y la herramienta relacionó el sumatorio global con una recomendación sobre la aplicabilidad de los resultados de los subgrupos en la toma de decisiones clínicas. RESULTADOS: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo valoración "nula" (-3 puntos), con p de interacción dudosa (p = 0,0650) y resultado de mortalidad no significativo en población global, restando fiabilidad al análisis de subgrupos. La plausibilidad biológica fue considerada "probable" (+3 puntos), ya que el antiviral pudiera tener mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La consistencia se valoró "posible" (+2 puntos) por compatibilidad de resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de aplicación del análisis por subgrupos según el riesgo de los pacientes fue "nula". CONCLUSIONES: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la mortalidad en pacientes con COVID-19 grave que precisan oxígeno -no de alto flujo- presenta demasiada incertidumbre, y es probable que sea un hallazgo casual. Por tanto, es imprescindible la realización de un ensayo clínico aleatorizado sobre mortalidad en pacientes con oxígeno -no de alto flujo-

OBJECTIVE: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non-high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets from randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. METHOD: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis attached to SOLIDARITY study. It is structured in preliminary questions to reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size, number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of similar studies. A score was assigned to each criterion and the tool related global summation to a recommendation on the applicability of subset results in clinical decision making. RESULTS: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained "null" assessment (-3 points), including a "doubtful" p of interaction (p = 0.0650) among subgroups and mortality reached no statistical significance for global population. These findings reduced the reliability of subset analysis. Biological plausibility was considered "probable" (+3 points) because antiviral could have a greater effect before the inflammatory process and clinical worsening. Consistency between results of similar studies was evaluated as "possible" (+2 points) analysis for compatibility of ACTT-1 and SOLIDARITY study results. The recommendation about application of subset analysis results according to the risk of patients was "null". CONCLUSIONS: This structured interpretation of subgroup analysis suggested too much uncertainty in hypothesis about remdesivir could reduce mortality in patients with severe COVID-19 who required non-high-flow oxygen. It was probably a random finding. Therefore, a randomized clinical trial about effect of remdesivir in mortality in patients with COVID-19 and non-high-flow oxygen is essential

Associations between single-nucleotide polymorphisms and inflammatory bowel disease-associated colorectal cancers in inflammatory bowel disease patients: a meta-analysis

Purpose. To assess the correlation between single-nucleotide polymorphisms (SNPs) and inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) in IBD patients. Methods. A systematic search of PubMed, EmBase, and Cochrane databases was performed. Five genetic models (allelic, dominant, recessive, heterozygous and homozygous models) were used to analyze the associations, and trial sequential analysis was used to analyze the robustness of the results. Results. We collected and analyzed the results of seven trials including a total of 2287 patients in our meta-analysis. A total of 8 SNPs were tested in IBD patients. For rs1800629 of TNF-α, the allelic model showed that polymorphism at this locus significantly increased the risk of IBD-associated CRC in IBD patients (OR 4.45, 95% CI 3.18-6.21, P < 0.001). The results also showed a significant association between rs1800629 and an IBD-associated CRC population (heterozygous model: OR 4.335, 95% CI 2.329-8.069, P < 0.001; homozygous model: OR 11.5, 95% CI 2.498-52.592, P = 0.002; dominant model: OR 4.986, 95% CI 2.754-9.026, P < 0.001; recessive model: OR 7.208, 95% CI 1.588-32.72, P = 0.01). Other studies have found that mutation of rs1143627 of IL1B (allelic model: OR 2.97; 95% CI 1.74-5.05, P < 0.001) and rs1050152 of OCTN1 (allelic model: OR 1.637, 95% CI 1.078-2.485, P = 0.021) increased the proportion of IBD-associated CRC in the population. Moreover, there were significant associations between IBD-associated CRC and ITLN rs2274910, gene desert rs1551398 and rs4871611, FCGR2A rs1801274, and S100-Z rs7712957 in the allelic model. Conclusion. Associations between SNPs and the proportion of IBD-associated CRC in IBD patients were examined, and further investigation of additional SNPs and their association with the risk of morbidity is needed (AU)

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Retrospective analysis of second-line chemotherapy outcomes with paclitaxel or docetaxel in correlation with STMN1 polymorphism in advanced non-small cell lung cancer patients

Purpose. Second-line chemotherapy of advanced non-small cell lung cancer (NSCLC) with docetaxel or pemetrexed allows to achieve objective response rate only in 5-10 % of patients. Recent studies have shown that single nucleotide polymorphisms (SNPs) in genes encoding proteins which regulate dynamics of microtubules may be considered as predictive factors of response to taxane-based chemotherapy. STMN1 gene encodes stathmin 1, which plays role in cell division by regulation of microtubules epolarisation, and this process may be associated with taxanes’ effectiveness. Materials and methods. Using HRM-PCR technique, we evaluated the −2166C>T SNP of STMN1 gene in DNA from peripheral blood leucocytes of 54 advanced NSCLC patients treated in second-line monotherapy with docetaxel or paclitaxel. Results. Patients with TT genotype of STMN1 gene demonstrated significantly longer progression-free survival (PFS) and the lower risk of early disease progression after second-line treatment compared to patients with other STMN1 genotypes (median PFS: 7 and 2 months; p = 0.0154; HR = 0.371; 95 % CI 0.184-0.743). Early disease progression during second-line chemotherapy was significantly more frequently observed in patients with CC genotype of STMN1 in contrast to patients with presence of T allele (median PFS: 2 and 4 months; p = 0.0385; HR = 1.776; 95 % CI 0.905-3.445). Conclusion. Only selected NSCLC patients could benefit from second-line chemotherapy. Therefore, investigations of novel predictive molecular factors for proper qualification of patients to second-line taxane-based chemotherapy are justified. Studied SNP of STMN1 gene may have potential predictive role in such therapy (AU)

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A Kluyveromyces marxianus 2-deoxyglucoseresistant mutant with enhanced activity of xylose utilization

Thermotolerant ethanologenic yeast Kluyveromyces marxianus is capable of fermenting various sugars including xylose but glucose represses to hamper the utilization of other sugars. To acquire glucose repression-defective strains, 33 isolates as 2-deoxyglucose (2-DOG)-resistant mutants were acquired from about 100 colonies grown on plates containing 2-DOG, which were derived from an efficient strain DMKU 3-1042. According to the characteristics of sugar consumption abilities and cell growth and ethanol accumulation along with cultivation time, they were classified into three groups. The first group (3 isolates) utilized glucose and xylose in similar patterns along with cultivation to those of the parental strain, presumably due to reduction of the uptake of 2-DOG or enhancement of its export. The second group (29 isolates) showed greatly delayed utilization of glucose, presumably by reduction of the uptake or initial catabolism of glucose. The last group, only one isolate, showed enhanced utilization ability of xylose in the presence of glucose. Further analysis revealed that the isolate had a single nucleotide mutation to cause amino acid substitution (G270S) in RAG5 encoding hexokinase and exhibited very low activity of the enzyme. The possible mechanism of defectiveness of glucose repression in the mutant is discussed in this paper (AU)

No disponible

Functional characterization of P2Y1 and P2X4 receptors in human neuroblastoma SK-N-MC cells / Caracterización funcional de receptores P2Y1 y P2X4 en células SK-N-MC de neuroblastoma humano

Nucleotides are important signalling molecules in both the peripheral and central nervous system. However, the in vitro study of their receptors can be hampered by the heterogeneity of primary neuronal cultures. The use of clonal neuroblastoma cell lines allows to circumvent this difficulty, so these lines are often used as a model to analyze the properties, regulation and physiological role of nucleotide receptors in neural tissues. Expression studies indicated the presence of P2Y1, P2Y6, P2Y11, P2Y13, P2X1, P2X4, P2X5, P2X6 and P2X7 proteins in SK-N-MC cells. Functional analyses showed transient [Ca2+]i increases upon application of ADP, 2-MeSADP or ADPβS. Responses to these agonists seem to be mediated by a P2Y1 receptor, as demonstrated by the almost complete blockade exerted by the P2Y1-selective antagonist MRS2179. ATP was also able to induce [Ca2+]i increases in SK-N-MC cells. Responses to ATP were partially blocked by MRS2179 and the P2X antagonist TNP-ATP, thus suggesting that ATP can interact with two different P2 receptors: a P2Y1 receptor, inhibited by MRS2179, and a TNP-ATP sensitive P2X receptor. To characterize the P2X receptor responsible for the MRS2179-resistant component of the ATP response, we analyze the effect of several P2X agonists on [Ca2+]i. Cells did not show responses to either α,β-meATP or BzATP, although [Ca2+]i increases could be observed when cells were challenged with CTP. Both the response to CTP and the MRS2179-resistant component of ATP response were potentiated by ivermectin. Such pharmacological profile is consistent with the presence of a functional P2X4 receptor in SK-N-MC cell line

Los nucleótidos son importantes moléculas señalizadoras en el sistema nervioso. El estudio in vitro de sus receptores puede verse obstaculizado por la heterogeneidad de los cultivos neuronales. El uso de líneas celulares de neuroblastoma permite eludir esta dificultad y dichas líneas se utilizan frecuentemente como un modelo con el que analizar las propiedades, regulación y función de los receptores de nucleótidos en tejidos neurales. Estudios de expresión indicaron la presencia de proteínas P2Y1, P2Y6, P2Y11, P2Y13, P2X1, P2X4, P2X5, P2X6 y P2X7 en las células SK-N-MC. Análisis funcionales mostraron incrementos transitorios de [Ca2+]i tras la aplicación de ADP, 2- MeSADP o ADPβS, respuestas que parecen estar mediadas a través un receptor P2Y1, como se pone de manifiesto por el bloqueo casi total ejercido por el antagonista selectivo P2Y1, MRS2179. El ATP también indujo incrementos de [Ca2+]i en las células SK-N-MC, siendo su respuesta parcialmente bloqueada por MRS2179 y por el antagonista P2X TNP-ATP, lo que sugiere que el ATP puede interactuar con dos receptores P2 diferentes: un receptor P2Y1, inhibido por MRS2179, y un receptor P2X sensible a TNP-ATP. Se caracterizó el receptor P2X analizando el efecto de varios agonistas en la [Ca2+]i. Ninguna célula mostró respuestas a α,β- meATP o BzATP, aunque se observaron incrementos de [Ca2+]i cuando las células fueron estimuladas con CTP. Tanto la respuesta a CTP como el componente de la respuesta a ATP resistente a MRS2179, se potenciaron en presencia de ivermectina. Todos estos datos sugieren la presencia de un receptor P2X4 funcional en las células SK-N-MC

Farmaconutrición en el paciente grave / Pharmaconutrition in severely ill patient

El término farmaconutriente se aplica a aquellos compuestos que poseen un efecto añadido al meramente nutricional y que se utilizan como terapia coadyuvante en pacientes con patologías graves que incluyen sepsis, traumatismos, grandes quemados y enfermos quirúrgicos. En general, con su enriquecimiento en las fórmulas enterales o parenterales se pretende modular positivamente la respuesta inflamatoria, la infección y el control del medio interno, valorables a través de mortalidad, tiempo de estancia en hospital y en UCI, días de ventilación mecánica y otros parámetros que permiten dimensionar los efectos de su utilización. Arginina, glutamina, nucleótidos, ácidos grasos omega-3 y micronutrientes antioxidantes constituyen el núcleo de los farmaconutrientes utilizados con la finalidad antedicha, habitualmente en forma de mezclas. En la presente revisión se analiza la evidencia actual acerca de sus efectos, indicaciones, limitaciones, cantidades a aportar, peligros potenciales e incluso contraindicacione (AU)

'Pharmaconutrient' is a term applicable to those compounds which. in addition to their nutritional function, play a role as aids in the treatment of patients with severe pathologies, including sepsis, trauma, burns and major surgery, In general, enrichment of enteral an parenteral formulas with pharmaconutrients contribute to positively modulate the inflammatory response, infection and controlling the internal milieu, which in turn can be evaluated through lower mortality, hospital and intensive care units stay, days of mechanical ventilation and other parameters allowing to asses their effects. Arginine, glutamine, nucleotides, omega-3 fatty acids and antioxidant micronutrients, make up the nucleus of pharmaconutrients used with that aim, usually as mixtures of them. In the present review current evidence about the effects, indications, limitations, doses, potential adverse risks and even counter-indications is analysed (AU)

Alterations in the extracellular catabolism of nucleotides and platelet aggregation induced by high-fat diet in rats: effects of alpha-tocopherol

The aim of this study was to assess whether alfa-tocopherol administration prevented alterations in the ectonucleotidase activities and platelet aggregation induced by high-fat diet in rats. Thus, we examined four groups of male rats which received standard diet, high-fat diet (HFD), α-tocopherol (α-Toc), and high-fat diet plus α-tocopherol. HFD was administered ad libitum and α-Toc by gavage using a dose of 50 mg/kg. After 3 months of treatment, animals were submitted to euthanasia, and blood samples were collected for biochemical assays. Results demonstrate that NTPDase, ectonucleotide pyrophosphatase/phosphodiesterase, and 5'-nucleotidase activities were significantly decreased in platelets of HFD group, while that adenosine deaminase (ADA) activity was significantly increased in this group in comparison to the other groups (P < 0.05). When rats that received HFD were treated with α-Toc, the activities of these enzymes were similar to the control, but ADA activity was significantly increased in relation to the control and α-Toc group (P < 0.05). HFD group showed an increased in platelet aggregation in comparison to the other groups, and treatment with α-Toc significantly reduced platelet aggregation in this group. These findings demonstrated that HFD alters platelet aggregation and purinergic signaling in the platelets and that treatment with α-Toc was capable of modulating the adenine nucleotide hydrolysis in this experimental condition

No disponible

Nuevos ingredientes en las fórmulas para lactantes nacidos a término (II): nucleótidos, poliaminas, lactoferrina bovina, gangliósidos, Beta-palmitato y ácidos grasos poliinsaturados de cadena larga / New additions in infant formulas for full-term infants (II): nucleotides, polyamines, bovine lactoferrin, gangliosides, Beta-palmitate, and long-chain polyunsaturated fatty acids

La leche humana proporciona todos los nutrientes necesarios para el crecimiento del recién nacido a término. Además de los nutrientes universalmente reconocidos, la leche humana contiene un número de componentes no nutritivos que probablemente desempeñan un papel en el crecimiento del lactante. En los últimos años, debido a sus beneficios probados o potenciales para el lactante, distintos fabricantes de fórmulas lácteas han llevado a cabo la adición a éstas de nuevos componentes no nutritivos o de nutrientes semiesenciales. Las adiciones de nucleótidos y ácidos grasos poliinsaturados de cadena larga a las fórmulas lácteas han sido las más relevantes, y han sido aprobadas por diversos organismos internacionales. Se está estudiando si en un futuro no muy lejano podrían añadirse otros nutrientes a las fórmulas lácteas, como los gangliósidos, las poliaminas, la lactoferrina bovina y los triglicéridos con el ácido palmítico predominantemente esterificado en la posición sn-2 (posición β). El objetivo de esta revisión es analizar las bases científicas para la adición de estos compuestos a las fórmulas lácteas (AU)

Human milk provides all necessary nutrients for growth of the term infant. Furthermore, in addition to universally recognized nutrients, human milk contains a number of nonnutritive components that are likely top play a role in supporting infant growth. In the last years, owing to their potential or proven benefits in infancy, new additions of nonnutritive components and semiessential nutrients to infant formulas have been implemented by a number of milk formula manufacturers. Nucleotides and long-chain polyunsaturated fatty acids are the most relevant recent additions to infants formulas, and these have been aproved by a number of internacional agencies. Other nutrients, namely gangliosides, polyamines, bovine lactoferrin, and palmitic acid predominantly esterified in the sn-2 position (β-position) of the triglycerides, are under consideration to be added in the near future. The aim of this review is to analyze the scientific basis for the addition of these compounds to milk formulas (AU)

Bone scintigraphy and secondary osteomalacia due to nephrotoxicity in a chronic hepatitis B patient treated with tenofovir / Gammagrafía ósea y oseteomalacia secundaria a nefrotoxicidad en una paciente con hepatitis B tratada con tenofovir

Tenofovir is a nucleotide analogue used for the treatment of chronic hepatitis B and HIV infection. The safety of tenofovir is high but it has been described that tenofovir produces tubular toxicity and Fanconi's syndrome in some HIV-infected patients. To our knowledge this is the first documented case of bone involvement in Fanconi's syndrome in a patient treated with tenofovir for chronic hepatitis B without HIV coinfection. Bone scintigraphy has proven to be very useful for the diagnosis of secondary osteomalacia. Normalization of the bone scan after the withdrawal of the drug and the decline in alkaline phosphatase and phosphate serum levels reinforce the cause-effect relationship (AU)

El tenofovir es un análogo de nucleótido que se utiliza para el tratamiento de la hepatitis B y de la infección por VIH. La seguridad del fármaco es muy alta, pero se ha descrito que en algunos pacientes VIH produce toxicidad tubular y síndrome de Fanconi. En nuestro conocimiento este es el primer caso en el que se documenta afectación ósea en síndrome de Fanconi en una paciente tratada con tenofovir por hepatitis B. En este contexto la gammagrafía ósea ha resultado ser de gran utilidad para el diagnóstico de osteomalacia secundaria. La normalización de la gammagrafía ósea y de los valores séricos de fosfato y fosfatasa alcalina tras la retirada del fármaco refuerza la relación causa-efecto (AU)

Estudio sobre susceptibilidad de cáncer de vejiga y polimorfismos genéticos de XPC, XPG y CYP en fumadores y no fumadores / Study on Bladder Cancer Susceptibility and Genetic Polymorphisms of XPC, XPG, and CYP in Smokers and Non-Smokers

Objetivo: Investigar la susceptibilidad del gen de cáncer de vejiga y la relación potencial con el tabaquismo. Material y métodos: Se realizó un análisis de los SNP entre los genes de reparación del ADN de XPC, XPG, XRCC1 y 6 miembros del gen de la enzima metabólica CYP 450 por reacción en cadena de la polimerasa basada en sonda TaqMan. Un total de 130 pacientes con cáncer de vejiga y 304 controles sanos estuvieron involucrados. Resultados: Los polimorfismos del gen XPC se relacionaron con el cáncer de vejiga. También se relacionaron con el hábito de fumar en pacientes con cáncer de vejiga, así como con el estadio del tumor, el sexo masculino y la edad avanzada. El polimorfismo del gen XPG también se relacionó con el cáncer de vejiga, sin embargo, era frecuente en mujeres no fumadoras. No se encontró asociación para el gen XRCC1. La combinación de más de 2 polimorfismos en genes de reparación del ADN se asoció con el cáncer de vejiga. No se obtuvo ninguna asociación en ningún gen de la enzima metabólica de CYP450 con cáncer de vejiga o hábito de fumar. Conclusión: Los genes de reparación del ADN XPC y XPG podrían estar relacionados con la carcinogénesis y la progresión del tumor de cáncer de vejiga. Se garantizó confirmación dentro de una población más grande (AU)

Objective: To investigate the gene susceptibility of bladder cancer and potential relation with smoking. Material and methods: An analysis of SNPs were conducted among DNA repair genes of XPC,XPG, XRCC1, and six members of metabolic enzyme gene CYP 450 via TaqMan Probe-based polymerase chain reaction. A total of 130 patients with bladder cancer and 304 healthy controls were involved. Results: Polymorphisms of XPC gene was related to bladder cancer. It was also related to smoking status in bladder cancer patients, as well as to tumour stage, male gender and older age. The XPG gene polymorphism was also related to bladder cancer yet it was prevalent in female non-smokers. No association was acquired for XRCC1 gene. The combination of more than2 polymorphisms in DNA repair genes was associated with bladder cancer. No association was obtained in any of the metabolic enzyme gene of CYP450 with either bladder cancer or smoking status. Conclusion: DNA repair genes XPC and XPG could be related to carcinogenesis and tumour progression of bladder cancer. Confirmation within larger population was warranted (AU)

Prebióticos y nucleótidos en alimentación infantil; revisión de la evidencia / Prebiotics and nucleotides in infant nutrition; review of the evidence

Introducción: Una gran mayoría de preparados infantiles de inicio y continuación comercializados en España presentan en su formulación prebióticos y/o nucleótidos, con objeto de lograr efectos beneficiosos en la prevención de diferentes patologías y protección inmunológica, similares a los de la leche materna. No obstante, atendiendo a la reglamentación vigente, su adición es opcional, ya que no existe suficiente evidencia científica que certifique la obligatoriedad de su inclusión. Objetivo: Revisar sistemáticamente la evidencia científica proveniente de estudios clínicos aleatorizados con grupo control que permita determinar el papel beneficioso para la salud de los lactantes derivada de la adición de prebióticos y/o nucleótidos en preparados infantiles. Metodología: Se buscaron y seleccionaron tanto artículos originales como revisiones en inglés y español de estudios clínicos aleatorizados con grupo control, publicados en las bases de datos de MEDLINE/PubMed, Scielo, Science Direct y Scopus, hasta octubre de 2011. Resultados: Se encontraron 43 ensayos clínicos aleatorizados que cumplieron con los criterios de inclusión. Conclusiones: Son necesarios más estudios a largo plazo, con mayor número de individuos y aleatorizados, así como estandarización de las cantidades suplementadas y demás condiciones experimentales, para poder establecer declaraciones saludables con mayor base científica respecto a la adición de la mezcla de prebióticos (GOS/FOS) y/o nucleótidos en preparados infantiles. La tendencia actual a su inclusión en preparados infantiles puede justificarse en base a las evidencias científicas disponibles hasta el momento, así como a su seguridad y a su presencia en la leche materna (AU)

Introduction: Most of the initiation and maintenance pediatric formulas commercialized in Spain contain prebiotics and/or nucleotides aiming at achieving beneficial effects on prevention of different pathologies and immune protection, similar to human breast milk. However, according to the current legislation, its inclusion is optional since sufficient scientific evidences supporting its mandatory inclusion is lacking. Objective: To systematically review the scientific evidence from randomized clinical studies with a control group allowing determining the beneficial role for infant health derived from the inclusion of prebiotics and/or nucleotides in pediatric formulas. Methodology: We looked for and selected both original papers and reviews in Spanish and English language of placebo controlled randomized clinical studies published in the databases MEDLINE/PubMed, Scielo, Science Direct, and Scopus, until October of 2011. Results: We found 43 randomized clinical trials meeting the inclusion criteria. Conclusions: More long-term randomized studies with higher number of patients, and standardized supplemental amounts and experimental conditions are needed to establish healthy statements with stronger scientific support regarding the addition of a mixture of prebiotics (GOS/FOS) and/or nucleotides in pediatric formulas. The current trend to include them in pediatric formulas may be justified based on the currently available evidence, as well as their safety and their presence in human breast milk (AU)

Interacción entre receptores de glutamato y receptores de nucleótidos en neuronas granulares de cerebelo en cultivo / Cross-talk between glutamate and nucleotide receptors in cerebellar granule neurons in culture

ATP elicits Ca2+ transients in cultured cerebellar granule neuronsacting through specific ionotropic (P2X) and metabotropic (P2Y)purinergic receptors. In these neurons, application of L-Glutamate(L-Glu) immediately before ATP induced a prolonged reductionof ATP-mediated responses that remains at least 5 minutes afterL-Glu wash out. alpha-amino-3-hydro-5-methyl-4-isoxazolpropionicacid (AMPA), N-methyl-D-aspartate (NMDA) and 3,5-dihydroxyphenyl-glycine (DHPG), selective agonists of ionotropic non-NMDA,NMDA and Group I metabotropic glutamate receptors respectively,mimicked Glu-induced attenuating effects. The activity of calciumcalmodulindependent protein kinase II (CaMKII) seems to beinvolved, at least at long term, because inhibitors of CaMKII, 1-[N,Obis(5-isoquinolinesulfonyl)-N-methyl-L-(KN-62) and N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxybenzenesulfonamide(KN-93), abolished the inhibitory effect of L-Glu on ATP-mediatedresponses. However, it is likely that other protein kinases could beinvolved in the cross-talk process between both groups of receptorsat short term. Therefore, these results demonstrate that the activationof glutamate receptors is able to modulate nucleotide responses incerebellar granule neurons(AU)

Interacción entre receptores de glutamato y receptores denucleótidos en neuronas granulares de cerebelo en cultivoEl ATP induce un incremento de Ca2+ en neuronas granulares decerebelo en cultivo actuando a través de receptores purinérgicos específicosionótropicos (P2X) y metabotrópicos (P2Y). En estas neuronas,la aplicación de L-Glutamato (L-Glu) inmediatamente antes del ATPinduce una prolongada disminución de las respuestas mediadas porATP que se mantiene al menos durante cinco minutos tras el lavadodel L-Glu. Los agonistas selectivos de los receptores ionotrópicosde glutamato no-NMDA, NMDA y del Grupo I, el ácido alfa-amino-3-hidro-5-metil-4-isoxazolpropiónico (AMPA), el N-metil-D-aspartato(NMDA) y el 3,5-dihidroxifenil-glicina (DHPG), respectivamente, mimetizanlos efectos atenuantes inducidos por el glutamato. La actividadde la proteína calcio-calmodulina quinasa II (CaMKII) pareceestar implicada en este proceso, al menos a largo plazo, puesto quelos inhibidores de la CaMKII, 1-[N,O-bis(5-isoquinolinesulfonil)-Nmetil-L-tirosil]-4fenilpiperazine (KN-62) y N-[2-[[[3-(4'-clorofenil)-2-propenil]metilamino]metil]fenil]-N-(2-hidroxietil)-4'-metoxibenzenosulfonamida(KN-93), revierten el efecto inhibitorio del L-Glu sobrelas respuestas mediadas por ATP. Sin embargo, es probable que puedanestar implicadas otras proteín quinasas en los procesos de interacciónentre ambos grupos de receptores a corto plazo. Por lo tanto,estos resultados demuestran que la activación de los receptores deglutamato son capaces de modular las respuestas a nucleótidos enneuronas granulares de cerebelo(AU)

Función de los nucleotides de la dieta en la infancia / Function of nucleotides in the infant´s diet

Los nucleótidos (NT) libres se aislaron de la leche humana hace más de 30 años. Desde entonces se han identificado cerca del 20 NT diferentes, entre los que predominan los derivados de la citosina y de la uridina; la leche de vaca y de otros rumiantes contiene cantidades elevadas de orotato, un precursor de nucleótidos pririmidínicos, pero carece prácticamente de los nucleótidos presentes en leche de vaca en la leche humana los NT representan hasta un total del 20% del nitrógeno no proteico y el contenido de NT potencialmente disponibles para el lactante (TPAN) es de 72 mg/l aproximadamente. La Unión Europea reguló en 1996 el uso de nucleótidos en fórmulas infantiles, basándose exclusivamente en los datos disponibles sobre el contenido de nucleótidos libre de la leche humana. Sin embargo, no se han tenido en cuenta los nucleótidos derivados de ARN y ADN. Ésta es la razón por la que las fórmulas norteamericanas y las de numerosos países asiáticos contiene más cantidad de nucleótidos que las fórmulas europeas (AU)

Free nucleotides (NT) were isolated in human milk over 30 years ago. Since then, approximately 20 different NTs have been identified. The derivatives of cytosine and uridine predominate among them. Cow´s milk and that of other ruminants contain elevated amounts of orotato, a precursor of pyrmidinic nucleotides, but there is practically no nucleotide in cow´s milk. The NTs in human milk account for up to 2% of the non-protein nitrogen and the potentially available (TPAN) content for the infant is approximately 72 mg/l. The European Union regulated the use for nucleotides in infant formulae in 1996, exclusively based on the data available on the content of free nucleotides of human milk. However, it did not take RNA and NA derived nucleotides into account. That is why the North American formulae and those of many Asiatic countries have a larger amount of nucleotides than the European formulae (AU)

Tenofovir: farmacología e interacciones / Tenofovir: pharmacology and interactions

Tenofovir es un análogo de los nucleótidos y, por ello, presenta un mecanismo de acción diferente al de los análogos a los nucleósidos. Se administra por vía oral en forma de éster disoproxil, que es desesterificado para alcanzar una biodisponibilidad, que supera el 20%, y que aumenta ligeramente si el fármaco se ingiere con grasas. Presenta una distribución tisular amplia, facilitada por el pequeño tamaño de la molécula y su escasa fijación a proteínas, y se elimina en su práctica totalidad en forma activa por la orina, a través de filtración glomerular y secreción tubular activa. Esta circunstancia obliga a realizar un ajuste de la dosis cuando hay insuficiencia renal. De forma característica, presenta una semivida intracelular que supera en más de 10 veces a la plasmática. Su perfil farmacocinético le configura como un fármaco con poco potencial de producir o de presentar interacciones con otros fármacos. Así, dentro de los antirretrovirales se ha descrito un aumento de la biodisponibilidad de didanosina que conlleva la recomendación de utilizarlo en dosis inferior a la habitual, mientras que puede utilizarse sin ajustes con otros inhibidores análogos y no análogos. Tampoco parece alterar la farmacocinética de los fármacos inhibidores de la proteasa, aunque éstos pueden producir un aumento ligero de la biodisponibilidad de tenofovir que parece tener escasa trascendencia clínica. Se ha señalado la ausencia de interacciones con otros fármacos no antirretrovirales(AU)

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported(AU)

Datos clínicos I. Experiencia clínica de tenofoviren combinaciones con inhibidores no análogos de la transcriptasa inversa / Clinical data I. Clinical experience with tenofovir in combination with nonnucleoside analogue transcriptase inhibitors

La aparición del tratamiento antirretroviral de granactividad ha supuesto una drástica mejora en elpronóstico de los pacientes infectados por el virus deinmunodeficiencia humana. La gran eficacia de lostratamientos antirretrovirales ha desplazado el interéshacia nuevos aspectos de la terapéutica, como ladosificación 1 vez al día de los antirretrovirales, el uso ydiseño de nuevas combinaciones de dosis fijas defármaco y el perfil de seguridad de los fármacos. Eltenofovir disoproxil fumarato (TDF) es un análogo denucleótido inhibidor de la transcriptasa inversa que seadministra 1 vez al día y que en combinación es uno delos fármacos recomendados en pautas de inicio por lamayoría de las guías de práctica clínica. En la actualidad,se dispone de una experiencia de más de 5 años queconfirma que el TDF en combinación con los inhibidoresno análogos de la transcriptasa inversa es un fármacocómodo, seguro, altamente eficaz y adecuado pararegímenes una vez al día con escaso número de comprimidos(AU)

Highly active antirretroviral therapy has transformed theprognosis of patient infected with humanimmunodeficiency virus. The efficacy of these drugs hasshifted the clinicians` attention to other therapeuticaspects like QD regimens, fixed dose combinations andclinical safety. Tenofovir disoproxil fumarate(TDF) is anucleoside monophosphate (nucleotide) analogue that inhibits reverse trascriptase enzyme. It’s administered ina q.d. regimen and it’s recommended by most of theclinical guidelines as a start regimen in combination withtwo other drugs. Currently more than 5 years of clinicalexperience is accumulated and confirmed that acombination of tenofovir and a nonnucleoside analoguetranscriptase inhibitor is a comfortable, safe, highlyeffective and low pill burden regimen(AU)

Datos clínicos II. Experiencia clínica de tenofovir en combinaciones con inhibidores de proteasa / Clinical data II. Clinical experience of tenofovir DF in combination with protease inhibitors

Tenofovir (TDF) es uno de los fármacos de elección en las combinaciones de tratamiento antirretroviral de primera línea. La mayor parte de la información acerca de su eficacia y seguridad en este escenario se originó inicialmente en ensayos clínicos en los que se combinaba con no análogos de nucleósidos. Este hecho, así como la posible interacción de TDF con algunos inhibidores de proteasa (IP) y la sospecha de que esta combinación pudiera incrementar el riesgo de nefrotoxicidad, hace imprescindible analizar la experiencia clínica disponible de la combinación de TDF (asociado a emtricitabina u otro análogo de nucleósido) con un IP. En esta revisión se presentan los datos de eficacia y seguridad procedentes en su mayoría de ensayos clínicos. Tomados en su conjunto, estos estudios aportan suficiente información para poder afirmar que la combinación de TDF con IP es eficaz y segura, lo que justifica su elección en el tratamiento de primera línea o en el rescate tras el fracaso virológico(AU)

Tenofovir is one of the drugs of choice in first-line combinations of antiretroviral therapy. Most data on safety and efficacy in this scenario initially came from clinical trials in which tenofovir was combined with non-nucleoside reverse transcriptase inhibitors. Because of this, as well as the possible interaction of tenofovir with some protease inhibitors and the suspicion that this combination could increase the risk of nephrotoxicity, analysis of the clinical experience available on the combination of tenofovir (associated with emtricitabine or another nucleoside analogue) with a protease inhibitor is essential. The present review reports data on efficacy and safety, mainly from clinical trials. Taken together, these studies provide sufficient information to indicate that the combination of tenofovir and protease inhibitors is safe and effective, justifying its selection in first-line therapy or rescue therapy after virological failure(AU)