Endocrine, immune and renal toxicity in male largemouth bass after chronic exposure to glyphosate and Rodeo®.

Glyphosate is the most used herbicide worldwide, with no historical comparison. It is used for genetically modified crops, and particularly in Florida, it is used as a sugar cane ripener. An aquatic formulation (Rodeo®) is used to treat aquatic weeds in waterbodies and drainage canals. Because of its extended use, glyphosate can run off or be sprayed directly into waterbodies, and chronically expose aquatic wildlife. Exposure in animal models has been associated with kidney and liver damage and glyphosate has been suggested as an endocrine disruptor. We exposed adult male largemouth bass for 21 days to two doses of glyphosate and Rodeo® (chemically equivalent concentration of glyphosate) at 0.5 mg L-1 and 10 mg L-1 and to a clean water control (n=4 fish/tank in quadruplicate). Concentrations during the experiment were corroborated with UHPLC-MS/MS. Total RNA was isolated from the trunk kidney and head kidney. RNA-seq was performed for the high doses compared to controls. Transcripts were analyzed with fish and mammalian pathway analyses software. Transcripts mapped to Zebrafish metabolic pathways using PaintOmics showed steroid hormone biosynthesis in the trunk kidney as the most significantly enriched pathway. Steroid hormones were measured in plasma by UHPLC-MS/MS. Total androgens were significantly reduced at 0.5 mg L-1 of glyphosate and at equivalent concentrations in Rodeo® compared to controls. 11-ketotestosterone and estrone concentrations were significantly reduced in all doses. A gene involved in the conversion of testosterone to 11-ketotestosterone was down-regulated by glyphosate. Using the mammalian pathway analysis algorithm, cellular processes associated with T-cell activation/development and intracellular pH were significantly enriched in the trunk kidney by glyphosate and Rodeo® exposure. Endocrine disruption was corroborated at the hormone and gene expression levels. Rodeo® and glyphosate share gene expression pathways, however, Rodeo® had more pronounced effects in largemouth bass.

A new genome allows the identification of genes associated with natural variation in aluminium tolerance in Brachiaria grasses.

Toxic concentrations of aluminium cations and low phosphorus availability are the main yield-limiting factors in acidic soils, which represent half of the potentially available arable land. Brachiaria grasses, which are commonly sown as forage in the tropics because of their resilience and low demand for nutrients, show greater tolerance to high concentrations of aluminium cations (Al3+) than most other grass crops. In this work, we explored the natural variation in tolerance to Al3+ between high and low tolerant Brachiaria species and characterized their transcriptional differences during stress. We identified three QTLs (quantitative trait loci) associated with root vigour during Al3+ stress in their hybrid progeny. By integrating these results with a new Brachiaria reference genome, we identified 30 genes putatively responsible for Al3+ tolerance in Brachiaria. We observed differential expression during stress of genes involved in RNA translation, response signalling, cell wall composition, and vesicle location homologous to aluminium-induced proteins involved in limiting uptake or localizing the toxin. However, there was limited regulation of malate transporters in Brachiaria, which suggests that exudation of organic acids and other external tolerance mechanisms, common in other grasses, might not be relevant in Brachiaria. The contrasting regulation of RNA translation and response signalling suggests that response timing is critical in high Al3+-tolerant Brachiaria.

Translocation of a parthenogenesis gene candidate to an alternate carrier chromosome in apomictic Brachiaria humidicola.

BACKGROUND: The apomictic reproductive mode of Brachiaria (syn. Urochloa) forage species allows breeders to faithfully propagate heterozygous genotypes through seed over multiple generations. In Brachiaria, reproductive mode segregates as single dominant locus, the apospory-specific genomic region (ASGR). The AGSR has been mapped to an area of reduced recombination on Brachiaria decumbens chromosome 5. A primer pair designed within ASGR-BABY BOOM-like (BBML), the candidate gene for the parthenogenesis component of apomixis in Pennisetum squamulatum, was diagnostic for reproductive mode in the closely related species B. ruziziensis, B. brizantha, and B. decumbens. In this study, we used a mapping population of the distantly related commercial species B. humidicola to map the ASGR and test for conservation of ASGR-BBML sequences across Brachiaria species. RESULTS: Dense genetic maps were constructed for the maternal and paternal genomes of a hexaploid (2n = 6x = 36) B. humidicola F1 mapping population (n = 102) using genotyping-by-sequencing, simple sequence repeat, amplified fragment length polymorphism, and transcriptome derived single nucleotide polymorphism markers. Comparative genomics with Setaria italica provided confirmation for x = 6 as the base chromosome number of B. humidicola. High resolution molecular karyotyping indicated that the six homologous chromosomes of the sexual female parent paired at random, whereas preferential pairing of subgenomes was observed in the apomictic male parent. Furthermore, evidence for compensated aneuploidy was found in the apomictic parent, with only five homologous linkage groups identified for chromosome 5 and seven homologous linkage groups of chromosome 6. The ASGR mapped to B. humidicola chromosome 1, a region syntenic with chromosomes 1 and 7 of S. italica. The ASGR-BBML specific PCR product cosegregated with the ASGR in the F1 mapping population, despite its location on a different carrier chromosome than B. decumbens. CONCLUSIONS: The first dense molecular maps of B. humidicola provide strong support for cytogenetic evidence indicating a base chromosome number of six in this species. Furthermore, these results show conservation of the ASGR across the Paniceae in different chromosomal backgrounds and support postulation of the ASGR-BBML as candidate genes for the parthenogenesis component of apomixis.

A Parthenogenesis Gene Candidate and Evidence for Segmental Allopolyploidy in Apomictic Brachiaria decumbens.

Apomixis, asexual reproduction through seed, enables breeders to identify and faithfully propagate superior heterozygous genotypes by seed without the disadvantages of vegetative propagation or the expense and complexity of hybrid seed production. The availability of new tools such as genotyping by sequencing and bioinformatics pipelines for species lacking reference genomes now makes the construction of dense maps possible in apomictic species, despite complications including polyploidy, multisomic inheritance, self-incompatibility, and high levels of heterozygosity. In this study, we developed saturated linkage maps for the maternal and paternal genomes of an interspecific Brachiaria ruziziensis (R. Germ. and C. M. Evrard) × B. decumbens Stapf. F1 mapping population in order to identify markers linked to apomixis. High-resolution molecular karyotyping and comparative genomics with Setaria italica (L.) P. Beauv provided conclusive evidence for segmental allopolyploidy in B. decumbens, with strong preferential pairing of homologs across the genome and multisomic segregation relatively more common in chromosome 8. The apospory-specific genomic region (ASGR) was mapped to a region of reduced recombination on B. decumbens chromosome 5. The Pennisetum squamulatum (L.) R.Br. PsASGR-BABY BOOM-like (psASGR-BBML)-specific primer pair p779/p780 was in perfect linkage with the ASGR in the F1 mapping population and diagnostic for reproductive mode in a diversity panel of known sexual and apomict Brachiaria (Trin.) Griseb. and P. maximum Jacq. germplasm accessions and cultivars. These findings indicate that ASGR-BBML gene sequences are highly conserved across the Paniceae and add further support for the postulation of the ASGR-BBML as candidate genes for the apomictic function of parthenogenesis.

Evaluación de eficacia y seguridad de Dabigatran y Rivaroxaban, comparados con Warfarina y otros anticoagulantes orales, en pacientes con fibrilación auricular / Efficacy and safety assessment of Dabigatran and Rivaroxaban compared to warfarin and other oral anticoagulants in patients with atrial fibrillation

Introducción: el uso de los nuevos anticoagulantes orales como Dabigatran, Ribaroxaban y Apixaban en pacientes con FA no valvular ha sido evaluado en los estudios RELY, ROCKET-AF y ARISTOTELE, respectivamente. En ellos se demuestra su eficacia en la prevención de embolia, con un perfil de seguridad similar o incluso mejor que la terapia estándar con Warfarina. En los últimos tres años es significativo el número de estudios (revisiones sistemáticas, más que ECA) que se han publicado con estos nuevos anticoagulantes orales. Dada su relativa recién aparición e indicación por las Guías de Práctica Clínica, se hace necesario adelantar una revisión de literatura que permita sintetizar todos estos nuevos conocimientos y poder generar una o varias recomendaciones aplicables a la población colombiana. Objetivos: sintetizar y evaluar la eficacia y seguridad de Rivaroxaban y Dabigatran en adultos con fibrilación auricular no valvular. Métodos: revisión sistemática de literatura. Se incluyeron estudios de pacientes con fibrilación auricular no valvular en quienes se interviniera con Warfarina o alguno de los nuevos anticoagulantes aprobados en Colombia (Dabigatran, Rivaroxaban, Apixaban). El Apixaban solo se tuvo en cuenta como medicamento comparador. Serealizó una búsqueda en los principales recursos bibliográficos (Cochrane, Medline, Embase, LILACS) para revisiones sistemáticas con meta-análisis y meta-análisis en red. Adicionalmente se realizó una búsqueda de ECA y estudios observacionales para meta-analizar y reportar las medidas de efecto que no fueran descritas por las revisiones sistemáticas elegidas, según los desenlaces propuestos por el grupo desarrollador. Resultados: se seleccionaron 15 estudios de un total de 1840. Se encontraron comparaciones directas entre Rivaroxaban y Dabigatran con Warfarina, así como comparaciones indirectas entre los nuevos anticoagulantes orales para la mayoría de desenlaces propuestos. Para el desenlace primario (ACV isquémico) se encontró beneficio con Dabigatran 150mg en comparación con Warfarina y con Dabigatran 110mg (OR=0,76 (0,58-0,98) y 0,67 (0,53-0,86) respectivamente). Ninguna comparación indirecta fue estadísticamente significativa para eficacia. Tanto Dabigatran (150mg y 110mg) como Rivaroxaban son más seguros que Warfarina para la prevención de hemorragias intracraneales (OR=0,42 (0,28-0,61); 0,30 (0,19-0,46) y 0,64 (0,46-0,88) respectivamente). Conclusiones: Dabigatran (150 mg) es más eficaz que Warfarina para la prevención de ACV isquémico. Rivaroxaban es más eficaz que Warfarina para la prevención de embolismos sistémicos. El uso de Dabigatran (150 o 110 mg) o de Rivaroxaban es más seguro que Warfarina para la prevención de hemorragias intracraneanas. Debido a la falta de comparaciones directas, no es posible afirmar que la eficacia de uno de los NACOS aprobados para su uso en Colombia sea más eficaz que otro. Sin embargo, Dabigatran parece brindar un mayor beneficio clínico neto que Rivaroxaban para esta indicación terapéutica.(AU)

Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection.

BACKGROUND: Prevention of chronic chagasic cardiomyopathy (CCC) by treating infected populations with trypanocidal therapy (TT) remains a challenge. Despite a renewed enthusiasm for TT, uncertainty regarding its efficacy, concerns about its safety and limited availability remain barriers for a wider use of conventional drugs. We have updated a previous version of this review. OBJECTIVES: To systematically search, appraise, identify and extract data from eligible studies comparing the outcome of cohorts of seropositive individuals to Trypanosoma cruzi exposed to TT versus placebo or no treatment. SEARCH METHODS: We sought eligible studies in electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), Issue 1, 2014); MEDLINE (Ovid, 1946 to January week 5 2014); EMBASE (Ovid, 1980 to 2014 week 6) and LILACS (up to 6 May 2010)) by combining terms related with the disease and the treatment. The search also included a Google search, handsearch for references in review or selected articles, and search of expert files. We applied no language restrictions. SELECTION CRITERIA: Review authors screened the retrieved references for eligibility (those dealing with human participants treated with TT) and then assessed the pre-selected studies in full for inclusion. We included randomised controlled trials (RCTs) and observational studies that provided data on either mortality or clinical progression of CCC after at least four years of follow-up. DATA COLLECTION AND ANALYSIS: Teams of two review authors independently carried out the study selection, data extraction and risk of bias assessment, with a referee resolving disagreement within the pairs. Data collection included study design, characteristics of the population and interventions or exposures and outcome measures. We defined categories of outcome data as parasite-related (positive serology, xenodiagnosis or polymerase chain reaction (PCR) after TT) and participant-related (including efficacy outcomes such as progression towards CCC, all-cause mortality and side effects of TT). We reported pooled outcome data as Mantel-Haenszel odds ratios (OR) or standardised mean differences (SMD) along with 95% confidence intervals (CI), using a random-effects model. I(2) statistics provided an estimate of heterogeneity across studies. We conducted an exploratory meta-regression analysis of the relationship between positive-serology and progression of CCC or mortality. MAIN RESULTS: We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela.TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I(2) = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I(2) = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I(2) = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I(2) = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I(2) = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I(2) = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). AUTHORS' CONCLUSIONS: Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.

Leishmaniasis tegumentaria americana en el valle de Aroa / American cutaneous leishmaniasis in the Aroa zone

Se realizó un estudio retrospectivo desde el punto de vista clínico-epidemiológico, de 180 casos de Leishmaniasis Cutánea Americana, diagnósticados en el Hospital "José Elias Landínez" de Aroa, Estado Yaracuy, entre 1987 y 1992, para determinar si tenían características diferentes a las reportadas en otras áreas activas de Leishmaniasis del país. Se valoraron los siguientes parámetros: procedencia geográfica de los casos, sexo, edad, tipo de Leishmaniasis Cutánea Americana, número de lesiones por paciente, ubicación corporal de las lesiones, tamaño de las lesiones, tiempo de evolución y curación. Se encontraron características clínicas similares a las reportadas en otras series en donde el agente causal fue LEISHMANIA brasiliensis