Validación del modelo SWAT en la cuenca del río Quequén Grande y evaluación de potenciales cambios a nivel de cuenca

El modelo SWAT ha sido recientemente validado para la cuenca del Rio Quequén Grande (935.533 has) en el sudeste bonaerense. Dicho trabajo se realizó en el marco de un proyecto internacional enfocado en la evaluación en los cambios en la productividad del agua frente a futuros potenciales escenarios climáticos. SWAT fue seleccionado como modelo para trabajar a escala de cuenca por constituir una herramienta valiosa para estudiar el impacto de cambios climáticos de uso de tierras, como así también el impacto de cambios en prácticas de manejo y uso de fertilizantes y agroquímicos sobre la calidad y cantidad de fuentes de agua, en cuencas agrícolas. SWAT fue calibrado para escorrentía superficial para el periodo 1996-2000 y validado para el periodo 2001- 2006. En la validación, el modelo presentó una eficiencia de Nash-Sutcliffe de 0,37 y 0,61 para caudales diarios y mensuales respectivamente. El modelo fue exitoso al predecir un cambio significativo en los caudales que aumentaron de 16.6 m3/s, durante el periodo calibración, a 40 m3/s en el periodo de validación. En este trabajo se discuten el impacto de potenciales cambios en el uso de tierras y en las precipitaciones a nivel de cuenca, en base a simulaciones de escenarios posibles.The SWAT model has been recently validated for streamflow at Quequen Grande river watershed (935.533 has), as a part of an international bigger project focused on the evaluation of changes in water productivity against potential future scenarios of climate change. SWAT was chosen as watershed scale model since it constitutes a valuable tool to study the impact of potential climate and land use changes, as well as the impact of management practices and fertilizer and pesticide use on water sources, in agricultural watersheds. SWAT was calibrated for the period 1996-2000 and validated for 2001-2006. Model predictions for daily and monthly streamflow presented Nash Sutcliffe coefficients of 0,37 and 0,61 respectively, for the validation period. Daily predictions for this watershed were acceptable, since there was not a representative network of rain gages to cover the almost one million hectares of the watershed. The model also succeeds on predicting a significant change on average streamflow that increased from 16,6 m3/s in the calibration period to 40 m3/s in the validation period. In this paper, the hydrologic impact of potential changes in the land use change and precipitations are discussed, based on model simulations for plausible scenarios, at watershed level

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy

Ultrasound settings significantly alter arterial lumen and wall thickness measurements

Background. Flow-mediated dilation (FMD) and carotid intima-medial thickness (CIMT), measured by ultrasound, are widely used to test the efficacy of cardioprotective interventions. Although assessment methods vary, automated edge-detecting image analysis software is routinely used to measure changes in FMD and CIMT. We aimed to quantify the effect that commonly adjusted ultrasound settings have on arterial lumen and wall thickness measurements made with CIMT measurement software. Methods. We constructed phantom arteries from a tissue-mimicking agar compound and scanned them in a water bath with a 10 MHz multi-frequency linear-array probe attached to a high-resolution ultrasound machine. B-mode images of the phantoms were recorded with dynamic range (DR) and gain set at five decibel (dB) increments from 40 dB to 60 dB and -10 dB to +10 dB respectively. Lumen diameter and wall-thickness were measured off-line using CIMT measurement software. Results. Lumen measurements: there was a strong linear relationship between DR and gain and measured lumen diameter. For a given gain level, a 5 dB increase in DR reduced the measured lumen diameter by 0.02 ± 0.004 mm (p \u3c 0.001). For a given DR level, a 5 dB increase in gain reduced measured lumen diameter by 0.04 ± 0.004 mm (p \u3c 0.001). A 5 mm increase in distance between the ultrasound probe and the artery reduced measured lumen diameter by 0.04 ± 0.03 mm (p \u3c 0.001). CIMT measurements: For a fixed gain level, a 5 dB increase in DR increased measured wall thickness by 0.003 ± 0.002 mm (p \u3c 0.001). The effects of increasing gain were not consistent and appeared to vary depending on the distance between the artery and the ultrasound probe and the thickness of the artery wall. Conclusion. DR, gain and probe distance significantly alter lumen diameter and CIMT measurements made using image analysis software. When CIMT and FMD are used to test the efficacy of cardioprotective interventions, the DR, gain and probe position used to record baseline scans should be documented and replicated in post-treatment scans in individual trial subjects. If more than one sonographer or imaging centre is used to collect data, the study protocol should document specific DR and gain settings to be used in all subjects

Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins). IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents

Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil

As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enables identification of ~2,000 previously undescribed mobile element insertions without previous description, nearly 5 Mb of genomic segments absent from the human genome reference, and over 140 alleles from HLA genes absent from public resources. We reclassify and curate pathogenicity assertions for nearly four hundred variants in genes associated with dominantly-inherited Mendelian disorders and calculate the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observe that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS

Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG. © 2013 The American Society of Human Genetics.Funding for UK10K was provided by the Wellcome Trust under award WT091310