Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

Rapid decrease in titer and breadth of neutralizing anti-HCV antibodies in HIV/HCV-coinfected patients who achieved SVR

The main targets for neutralizing anti-hepatitis C virus (HCV) antibodies (HCV-nAbs) are the E1 and E2 envelope glycoproteins. We have studied the characteristics of HCV-nAbs through a retrospective study involving 29 HIV/HCV-coinfected patients who achieved sustained virological response (SVR) with pegIFNα+ribavirin anti-HCV therapy. Plasma samples at baseline and week 24 after SVR were used to perform neutralization assays against fve JFH1-based HCV recombinant viruses coding for E1 and E2 from genotypes 1a (H77), 1b (J4), 2a (JFH1), 3a (S52) and 4a (ED43). At baseline, the majority of plasma samples neutralized 1a, 1b, 2a, and 4a, but not 3a, genotypes. Twenty-four weeks following SVR, most neutralizing titers declined substantially. Furthermore, titers against 3a and 2a were not detected in many patients. Plasma samples with high HCV-nAb titers neutralized all genotypes, and the highest titers at the starting point correlated with the highest titers at week 24 after SVR. In conclusion, high titers of broad-spectrum HCV-nAbs were detected in HIV/HCV-coinfected individuals, however, those titers declined soon after SVRThis study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant numbers PI14/01094 and PI17/00657 to JB, PI17/00903 to JGG, PI14CIII/00011 and PI17CIII/00003 to SR) and Ministerio de Sanidad, Servicios Sociales e Igualdad (grant number EC11-241). Te study was also funded by the RD16CIII/0002/0002, RD16/0025/0018, and RD16/0025/0017 projects as part of the Plan Nacional R+D+I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER

Synergic effect of corneal hysteresis and central corneal thickness in the risk of early‑stage primary open‑angle glaucoma progression

Received: 2 September 2020. Revised: 9 March 2021. Accepted: 19 April 2021. Published online: 7 May 2021.Purpose: To evaluate corneal hysteresis (CH), acquired with ocular response analyzer (ORA), as a risk factor for glaucoma progression in early-stage primary open-angle glaucoma (POAG). Methods: In a historical cohort study, patients diagnosed in 2011 with early-stage POAG according to the Hodapp, Parrish and Anderson classification modified for Octopus perimetry and followed up until glaucomatous progression development; otherwise, observations were censored in October 2018. Cox regression was used to obtain hazard ratios (HR) to evaluate baseline variables (CH, central corneal thickness, gender, age IOP and glaucoma family history) as risk factors for perimetric glaucoma progression. A likelihood ratio test for interaction was performed in order to assess the effect of the combination of CH and CCT on the risk of progression. Results: Of the cohort of 1573 patients, 11.38% developed early-stage POAG progression during the follow-up. The mean follow-up time was 3.28 ± 1.92 years. Patients without progression had a higher CH (11.35 ± 1.43 vs 9.07 ± 1.69 mmHg; p < 0.001) and CCT (570.75 ± 17.71 vs 554.51 ± 23.20; p < 0.001). In the multivariate analysis, each 1 mmHg of lower CH was associated with an increase of 2.13 times in the HR of progression (95% CI: 1.92–2.32; p < 0.001). CH hazard ratio was modified by CCT, with higher values of CCT and CH resulting in a higher HR of early glaucoma progression (p < 0.001). Conclusions: CH can be considered as a risk factor of progression in early-stage POAG. The risk associated with CH changed depending on CCT values, acting synergistically slowing the risk of glaucoma progression with higher values.Depto. de Inmunología, Oftalmología y ORLUnidad Docente de Inmunología, Oftalmología y ORLFac. de PsicologíaFac. de MedicinaFac. de Óptica y OptometríaTRUEinpres

PREVALENCE OF UNKNOWN DIABETES AND IMPAIRED GLUCOSE TOLERANCE IN PATIENTS WITH IMPAIRED FASTING GLUCOSE

There are many community-based studies on the prevalence of diabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). However, studies on the prevalence of IGT and diabetes unknown in patients with IFG, by 75-g oral glucose tolerance test (OGTT), are few and small.CIBEROBN is an Instituto de Salud Carlos III initiative. This work has been co-financied by CIBEROBN, Research Grants of the Ministerio de Economía y Competitividad of Spain (Instituto de Salud Carlos III: PI10/00913), and Consejería de Salud de la Junta de Andalucía of Spain (PI-0037/2008 and PI-0112-2013).Peer Reviewe

NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast

22 páginas, 8 figuras.The activity and expression of plasma membrane NADH coenzyme Q reductase is increased by calorie restriction (CR) in rodents. Although this effect is well-established and is necessary for CR's ability to delay aging, the mechanism is unknown. Here we show that the Saccharomyces cerevisiae homolog, NADH-Coenzyme Q reductase 1 (NQR1), resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We show that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism. Chronological lifespan extension, in contrast, occurs via an SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals.The work was supported by the Spanish Ministerio de Ciencia y Tecnología, Grant BFU2005-03017/BMC, by APP2E04053 Grant of the Universidad Pablo de Olavide, and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health

Chemical factors controlling the steady-state distribution of mixed carbonate-siliciclastic sediments in Bayona Bay (northwest Spain)

The relative space distributions of single mineral constituents in mixed terrigenous-carbonated sediments of the Bayona Bay have been analysed. In order to determine the existence of different mixing mechanisms, a study comparing the general sedimentary trends resulting from the average patterns and the single mineral behaviour, reflected in the single-mineral mapping, was carried out. The relative abundance of all mineral phases in surface sediment samples was first determined by quantitative X-ray powder diffraction data, using the Rietveld method. This procedure enabled us to create specific maps for both the minerals forming the terrigenous fraction and the different calcium carbonate polymorphs involved in the carbonatic component. A cross-linked behaviour between the carbonate facies and the terrigenous minerals involved in the calcium carbonate generation was found, suggesting the existence of a chemical control mechanism which, through dissolution-crystallization processes, constrains the mixed environment's long-term evolution. In the general framework of the region studied, these relations operate for the relative amount of plagioclase to calcium carbonate. The existence of dissolution and growth between both minerals, favoured by the high rate of removal, is proposed, yielding a final crossed pattern, representative of the steady-state. Furthermore, a specific analysis, restricted to the region of low rate of material removal and maximum amount of intermixed sediments, clearly shows an anisotropic distribution for every calcium carbonate polymorph (calcite and aragonite). These correlate with the biotite distribution, and can be connected to local variations in seawater Mg/Ca ratio, induced by biotite weathering.En este trabajo se analiza de forma específica la distribución espacial de cada uno de los minerales involucrados en sedimentos mixtos terrígenos-carbonatados de la bahía de Bayona y se compara con la distribución global de sedimentos, tal como resulta de análisis granulométricos, con el fin de determinar la existencia de diferentes mecanismos de mezcla entre los minerales de ambas fracciones. El contenido porcentual en peso de cada fase mineral, en muestras superficiales de sedimento, se determinó a partir de datos cuantitativos de DRX, empleando el método de Rietveld. Este procedimiento nos ha permitido realizar mapas específicos de distribución, tanto para cada mineral de la fracción terrígena como para cada uno de los diferentes polimorfos de carbonato cálcico en la componente carbonatada. Como resultado de este estudio comparativo, se ha encontrado una correlación, en la distribución espacial y granulométrica, de las facies carbonatadas y los minerales terrígenos implicados en la generación de carbonato cálcico. Un posterior análisis de este resultado sugiere la presencia de mecanismos químicos de control que regulan la interacción entre siliciclastos y carbonatos mediante procesos de disolución-cristalización mediados por el agua del mar. El estudio se ha realizado a dos escalas. En el ámbito general de la bahía de Bayona, las relaciones de distribución observadas entre plagioclasas y carbonato cálcico pueden ser explicadas, dentro del balance global del Ca³⁺ disuelto en el agua del mar, mediante la meteorización química de las plagioclasas y la consiguiente generación de carbonatos. En este caso, los patrones de distribución reflejan la aproximación a un estado estacionario mediante sucesivos eventos de mezcla asociados a la alta removilización material en el medio, tanto para la distribución porcentual en peso como para la distribución granulométrica entre ambos minerales. Finalmente, se realiza un análisis particularizado en una región con baja tasa de removilización y donde la interacción entre sedimentos de ambas fracciones es máxima. El resultado muestra claramente una distribución espacial anisótropa para cada uno de las fases de carbonato cálcico (calcita y aragonito). La abundancia relativa de cada uno de los polimorfos, así como el contenido en Mg³⁺ de la calcita, ha sido correlacionado con la distribución de la biotita y explicado a partir de las diferencias de solubilidad en función de la alta relación Mg³⁺ /Ca³⁺ en el agua de mar que resulta, localmente, de la meteorización química de dicho mineral.Instituto Español de Oceanografí

Statins Inhibit HIV-1 Infection by Down-regulating Rho Activity

Human immunodeficiency virus (HIV)-1 infectivity requires actin-dependent clustering of host lipid raft–associated receptors, a process that might be linked to Rho guanosine triphosphatase (GTPase) activation. Rho GTPase activity can be negatively regulated by statins, a family of drugs used to treat hypercholesterolemia in man. Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase. We show that statins decreased viral load and increased CD4+ cell counts in acute infection models and in chronically HIV-1–infected patients. Viral entry and exit was reduced in statin-treated cells, and inhibition was blocked by the addition of l-mevalonate or of geranylgeranylpyrophosphate, but not by cholesterol. Cell treatment with a geranylgeranyl transferase inhibitor, but not a farnesyl transferase inhibitor, specifically inhibited entry of HIV-1–pseudotyped viruses. Statins blocked Rho-A activation induced by HIV-1 binding to target cells, and expression of the dominant negative mutant RhoN19 inhibited HIV-1 envelope fusion with target cell membranes, reducing cell infection rates. We suggest that statins have direct anti–HIV-1 effects by targeting Rho

Métodos cualitativos a dos milenios de su surgimiento. Un acercamiento a las perspectivas educacional y salubrista.

With the general aim of identifying the qualitative methods that would facilitate a closer approach in the praxis to the educative and salubrista perspective, a scrutiny was realized with specialists from the inductive and deductive methods and logical historical. The selected qualitative methods that are analyzed are: observation, phenomenological, ethnographic, action research and biographical method. A comparative summary of the advantages known or not to be explored of each method for the educational field and for the health, from its emergence until the present according to bibliographical references, is presented. It reaffirms the need to go deeper into the use of qualitative methods in the field of health through the exploration and application of its potentialities. Con la finalidad general de identificar los métodos cualitativos que facilitarían un mayor acercamiento en la praxis a la perspectiva educacional y salubrista, se realizó un escrutinio con especialistas a partir de los métodos inductivo y deductivo e histórico lógico. Los métodos cualitativos seleccionados que se analizan son: la observación, el fenomenológico, el etnográfico, la investigación-acción y el método biográfico. Se expone un resumen comparativo de las ventajas conocidas o por explorar de cada método para el ámbito educacional y para la salud, desde su surgimiento hasta el presente según referencias bibliográficas. Se reafirma la necesidad de profundizar más en el uso de los métodos cualitativos en el ámbito de la  salud a través de la exploración y aplicación de sus potencialidades. 

ICES. 2020. Working Group on Acoustic and Egg Surveys for Sardine and Anchovy in ICES areas 7, 8 and 9

he Working Group on Acoustic and Egg Surveys (WGACEGG) coordinates pelagic surveys for a number of stocks and provides monitoring for the two major sardine and anchovy stocks in ICES areas 6, 7, 8, and 9. The group evaluated small pelagic fish biomass indices derived from acoustic and Daily Egg Production Method (DEPM) surveys in ICES areas 6, 7, 8 and 9. These indices have been provided to the ICES Working Group on Southern Horse Mackerel, Anchovy and Sardine (WGHANSA), the Working Group on Widely Distributed Stocks (WGWIDE) and the Herring Assessment Working Group for the Area South of 62ºN (HAWG) stock assessment group, to serve as fishery-independent input for analytical assessment purposes. DEPM and acoustic indices were derived based on data collected using independent methods. Acoustic- and DEPM-derived biomass indices from quasi-synoptic surveys conducted in the Bay of Biscay in spring were compared, to assess the presence of potential bias and to improve the precision of fish stock biomass estimates. The DEPM-based anchovy biomass index was 22% higher than the acoustic index in 2019. Unusual concentrations of anchovy in Eastern Cantabrian Sea, an area not covered by the acoustic survey, and the presence near the sea surface of actively spawning individuals possibly under-sampled by acoustics in central Bay of Bay had been postulated as potential causes of this discrepancy. No significant difference was found between sardine biomass indices derived from DEPM and acoustics in 2019. The group has updated its database of standard gridded maps covering the European Atlantic area. This initiative continues to inform on the spatial dynamics of various parameters collected during the surveys coordinated under the auspices of the group (fish acoustic densities, anchovy and sardine egg abundance, surface temperature and salinity). Results of an analysis of the time series of gridded maps (anchovy and sardine acoustic density, surface salinity and temperature) showed quantitative changes in the spatial and temporal distribution of anchovy and sardine over the last 15 years, and further define their habitats in European Atlantic waters in spring. The timing and spatial coverage of DEPM and acoustic surveys that will be conducted by group members in 2020 were planned to optimise the monitoring of anchovy and sardine populations and their pelagic environment in the European Atlantic area. The synoptic nature of the survey components has been assessed for each target species. A manual describing the protocols used during the DEPM surveys coordinated by the WGACEGG group was reviewed, and writing of a manual of WGACEGG acoustic surveys continued. Both manuals will be available in 2020. The final results of the 2017 sardine DEPM assessment were endorsed by the group