N-nitrosopiperidina y N-nitrosodibutilamina (II): relevancia en la carcinógenesis química y genotoxicidad

La N-nitrosopiperidina (NPIP) y la N-nitrosodibutilamina (NDBA) han sido clasificadas como posibles carcinógenos en humanos. La NPIP causa tumores en esófago, y también en cavidad nasal, hígado y estómago, mientras que la NDBA es carcinógeno de vejiga urinaria. Ambas N-nitrosaminas son consideradas carcinógenos genotóxicos indirectos puesto que necesitan una bioactivación para generar metabolitos que reaccionen con el DNA. La principal lesión al DNA inducida por las N-nitrosaminas es el daño alquilativo. En el caso de la NDBA, la posición de alquilación es en el O6 de la guanina, formando la O6 butilguanina y la O6-4-hidroxibutilguanina. Sin embargo, esta N-nitrosamina alquila preferentemente proteínas. Por otra parte, la bioactivación de la NPIP genera metabolitos que reaccionan con el N2 de la guanina in vitro, aunque se desconocen sus efectos in vivo. Además, durante la activación metabólica pueden también producirse especies reactivas del oxígeno (EROs) y del nitrógeno (ERNs). Las lesiones oxidativas y nitrativas más comunes son la 8- hidroxideoxiguanosina (8 OHdG) y la 8-nitroguanina, respectivamente, que producen mutaciones y conducen a la carcinogénesis.N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA) have been classified as possibly carcinogenic to humans. NPIP causes tumours in oesophagus, and also in nasal cavity, liver and stomach, whereas NDBA is a bladder carcinogen. Both N-nitrosamines are considered indirect genotoxic carcinogens since they need a bioactivation to generate metabolites that react with DNA. The main DNA lesion induced by N nitrosamines is the alkylative damage. In the case of NDBA, the alkylation position is in O6 of guanine, forming O6 butylguanine and O6-4-hydroxybutylguanine. However, this N-nitrosamine alkylates proteins preferably. On the other hand, NPIP bioactivation generates metabolites that react with N2 of guanine in vitro, although its in vivo effects are unknown. Moreover, during metabolic activation reactive oxygen species (ROS) and nitrogen species (RNS) can be also produced. The most common oxidative and nitrative lesions are 8-hydroxydeoxyguanosine (8-OhdG) and 8-nitroguanine, respectively, that produce mutations and lead to carcinogenesis

N-nitrosopiperidina y N-nitrosodibutilamina (I): formación, exposición humana y metabolismo

Los vegetales, el agua de bebida y los productos cárnicos son las principales fuentes de exposición de nitratos en humanos. La toxicidad de estos compuestos es resultado de su conversión en nitritos que actúan como agentes nitrosantes en la formación de las Nnitrosaminas. Las N-nitrosaminas son uno de los grupos de agentes carcinogénicos más estudiados y existe una gran preocupación debido a su presencia en nuestra vida diaria. Sin embargo, son muy escasos los estudios realizados con dos N-nitrosaminas, la Nnitrosopiperidina (NPIP) y la N-nitrosodibutilamina (NDBA). La NPIP se encuentra en productos cárnicos que incluyan especias en la formulación de sus mezclas y la NDBA en productos cárnicos envasados en goma y en chupetes y tetinas para biberones. Además, la NPIP y la NDBA son compuestos genotóxicos indirectos que necesitan una activación metabólica para dañar el DNA y ejercer su efecto carcinogénico. Este proceso es llevado a cabo por el citocromo P450, en concreto, por las isoformas enzimáticas CYP 2A6 y el CYP 1A1, respectivamente.Vegetables, drinking water and meat products are the main sources of exposure to nitrates in humans. The toxicity of these compounds is usually the result of the conversion of nitrates into nitrites, which act as nitrosating agents in the N-nitrosamine formation. N-nitrosamines are one of the most studied carcinogenic group and great concern exists due to its presence in our daily life. However, the performed studies with two N-nitrosamines, N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA), are very limited. NPIP is found in meat products with spices in their formulation and NDBA in meat products packed in rubber nettings and in pacifiers and nipples. Moreover, NPIP and NDBA are indirect genotoxic compounds that need a metabolic activation to damage DNA and exert their carcinogenic effect. This process is carried out by cytochrome P450, in particular, by enzymatic isoforms CYP 2A6 y el CYP 1A1, respectively

Diffusion–dispersion numerical discretization for solute transport in 2D transient shallow flows

The 2D solute transport equation can be incorporated into the 2D shallow water equations in order to solve both flow and solute interactions in a coupled system of equations. In order to solve this system, an explicit finite volume scheme based on Roe’s linearization is proposed. Moreover, it is feasible to decouple the solute transport equation from the hydrodynamic system in a conservative way. In this case, the advection part is solved in essence defining a numerical flux, allowing the use of higher order numerical schemes. However, the discretization of the diffusion–dispersion terms have to be carefully analysed. In particular, time-step restrictions linked to the nature of the solute equation itself as well as the numerical diffusion associated to the numerical scheme used are question of interest in this work. These improvements are tested in an analytical case as well as in a laboratory test case with a passive solute (fluorescein) released from a reservoir. Experimental measurements are compared against the numerical results obtained with the proposed model and a sensitivity analysis is carried out, confirming an agreement with the longitudinal coefficients and an underestimation of the transversal ones, respectively

Subsurface imaging of silicon nanowire circuits and iron oxide nanoparticles with sub-10 nm spatial resolution

Non-destructive subsurface characterization of nanoscale structures and devices is of significant interest in nanolithography and nanomanufacturing. In those areas, the accurate location of the buried structures and their nanomechanical properties are relevant for optimization of the nanofabrication process and the functionality of the system. Here we demonstrate the capabilities of bimodal and trimodal force microscopy for imaging silicon nanowire devices buried under an ultrathin polymer film. We resolve the morphology and periodicities of silicon nanowire pairs. We report a spatial resolution in the sub-10 nm range for nanostructures buried under a 70 nm thick polymer film. By using numerical simulations we explain the role of the excited modes in the subsurface imaging process. Independent of the bimodal or trimodal atomic force microscopy approach, the fundamental mode is the most suitable for tracking the topography while the higher modes modulate the interaction of the tip with the buried nanostructures and provide subsurface contrast.This work was funded by the European Union FP7/2007-2013 under Grant Agreement No. 318804 (SNM), the Ministerio de Economía y Competitividad (Spain) under grants MAT2013-44858-R, CSD2010-00024 and the European Research Council ERC-AdG-340177 (3DNanoMech).Peer reviewe

Use of internal boundary conditions for levees representation: application to river flood management

River floods can be simulated with the 2D shallow water system of equations using finite volume methods, where the terrain is discretized in cells that form the computational mesh. Usually a proper treatment of wet/dry fronts is required. River levees can be modelled as part of the topography by means of sufficiently small cells of higher elevation than the rest of the bed level in locally refined meshes. This procedure is associated with a large computational time since the time step depends directly on the cell size. The alternative proposed in this work includes the levees as internal boundary conditions in the 2D numerical scheme. In particular, levees have been defined by a weir law that, depending on the relative values of water surface levels on both sides, can formulate the discharge for different situations (i.e. free flow and submerged flow). In addition, having identified numerical difficulties in cases of low discharge under free flow conditions, a novel procedure to avoid oscillations has been developed and called volume transport method. The validation and comparison between methods has been carried out with benchmark test cases and, in addition, with a real flood event in the Ebro River (Spain)

Simulation of PID control applied to irrigation channels

Open-channel flow usually includes many hydraulic elements to help with the regulation of water supply in terms of automatic control. On the other hand, the one-dimensional Shallow Water Equations (SWE) are widely used to model and predict the flow dynamics in this kind of configurations. In this work, the unsteady SWE are used to model the water motion and they are solved using a finite volume upwind scheme able to cope with all flow regimes. Furthermore, the regulation of hydraulic structures at channels is frequently based on the PID controller. In this work, the implementation and coupling of the channel flow simulation with hydraulic elements and PID regulation is performed

Implicit 2D surface flow models performance assessment: Shallow Water Equations vs. Zero-Inertia Model

Zero-Inertia (ZI) models are used in overland flow simulation due to their mathematical simplicity, compared to more complex formulations such as Shallow Water (SW) models. The main hypothesis in ZI models is that the flow is driven by water surface and friction gradients, neglecting local accelerations. On the other hand, SW models are a complete dynamical formulation that provide more information at the cost of a higher level of complexity. In realistic problems, the usually huge number of cells required to ensure accurate spatial representation implies a large amount of computing effort and time. This is particularly true in 2D models. Hence, there is an interest in developing efficient numerical methods. In general terms, numerical schemes used to solve time dependent problems can be classified in two groups, attending to the time evaluation of the unknowns: explicit and implicit methods. Explicit schemes offer the possibility to update the solution at every cell from the known values but are restricted by numerical stability reasons. This can lead to very slow simulations in case of using fine meshes. Implicit schemes avoid this restriction at the cost of generating a system of as many equations as computational cells multiplied by the number of variables to solve. In this work, an implicit finite volume numerical scheme has been used to solve the 2D equations in both ZI and SW models. The scheme is formulated so that both quadrilateral and triangular meshes can be used. A conservative linearization is done for the flux terms, leading to a non-structured matrix for unstructured meshes thus requiring iterative methods for solving the system. A comparison between 2D SW and 2D ZI is done in terms of performance, efficiency and mesh requirements, in which both models benefit of an implicit temporal discretization in steady and nearly-steady situations

Implicit finite volume simulation of 2D shallow water flows in flexible meshes

In this work, an implicit method for solving 2D hyperbolic systems of equations is presented, focusing on the application to the 2D shallow water equations. It is based on the first order Roe''s scheme, in the framework of finite volume methods. A conservative linearization is done for the flux terms, leading to a non-structured matrix for unstructured meshes thus requiring iterative methods for solving the system. The validation is done by comparing numerical and exact solutions in both unsteady and steady cases. In order to test the applicability of the implicit scheme to real world situations, a laboratory scale tsunami simulation is carried out and compared to the experimental data. The implicit schemes have the advantage of the unconditional stability, but a quality loss in the transient solution can appear for high CFL numbers. The properties of the scheme are well suited for the simulation of unsteady shallow water flows over irregular topography using all kind of meshes

Chronic Elevation of Liver Enzymes in Acute Intermittent Porphyria Initially Misdiagnosed as Autoimmune Hepatitis

Autoimmune hepatitis is a disease characterized by an elevation of liver enzymes, as well as specific autoantibodies. It is more common in women than men. We describe a 32-year-old woman with elevated transaminases, autoantibodies, and a liver biopsy result suggestive of autoimmune hepatitis. The indicated treatment was administered without showing a satisfactory response. The patient had a family history of acute intermittent porphyria (AIP) so we decided to begin treatment with hematin, achieving a complete remission of the symptoms. Acute intermittent porphyria is a rare condition characterized by neurovisceral symptoms, abdominal pain being the most common of them. The disease has a higher prevalence among young women and certain European countries such as Sweden, Great Britain, and Spain. A correct diagnosis and prompt treatment are essential because patients affected by AIP must have a strict followup due to the fatal outcome of the outbreaks