Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of abdominal ultrasound in inflammatory bowel disease. / Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el empleo de la ecografía abdominal en la enfermedad inflamatoria intestinal.

Ultrasound has an excellent diagnostic performance when Crohn's disease is suspected, when performing an activity assessment, or determining the extension and location of Crohn's disease, very similar to other examinations such as MRI or CT. It has a good correlation with endoscopic lesions and allows the detection of complications such as strictures, fistulas or abscesses. It complements colonoscopy in the diagnosis and, given its tolerance, cost and immediacy, it can be considered as a good tool for disease monitoring. In ulcerative colitis, its role is less relevant, being limited to assessing the extent and activity when it is not possible with other diagnostic techniques or if there are doubts with these. Despite its advantages, its use in inflammatory bowel disease (IBD) is not widespread in Spain. For this reason, this document reviews the advantages and disadvantages of the technique to promote knowledge about it and implementation of it in IBD Units.

Urinary bladder lipoma: an illustrative case.

Urinary bladder lipomas are rare neoplasms. Therefore, very few of them have been reported in the literature. We present a case that illustrates the typical features that allow radiologists to diagnose this entity: a solid lesion that arises from the urinary bladder wall, showing an endophytic growth and homogeneous hypoattenuation. After its surgical resection, the diagnosis was confirmed by anatomo-pathological analysis. In the discussion we describe other neoplasms that should also be considered when a submucosal bladder neoplasm is detected on computed tomography or other imaging techniques.

Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors.

Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.

Repetitive patterns in rapid optical variations in the nearby black-hole binary V404 Cygni.

How black holes accrete surrounding matter is a fundamental yet unsolved question in astrophysics. It is generally believed that matter is absorbed into black holes via accretion disks, the state of which depends primarily on the mass-accretion rate. When this rate approaches the critical rate (the Eddington limit), thermal instability is supposed to occur in the inner disk, causing repetitive patterns of large-amplitude X-ray variability (oscillations) on timescales of minutes to hours. In fact, such oscillations have been observed only in sources with a high mass-accretion rate, such as GRS 1915+105 (refs 2, 3). These large-amplitude, relatively slow timescale, phenomena are thought to have physical origins distinct from those of X-ray or optical variations with small amplitudes and fast timescales (less than about 10 seconds) often observed in other black-hole binaries-for example, XTE J1118+480 (ref. 4) and GX 339-4 (ref. 5). Here we report an extensive multi-colour optical photometric data set of V404 Cygni, an X-ray transient source containing a black hole of nine solar masses (and a companion star) at a distance of 2.4 kiloparsecs (ref. 8). Our data show that optical oscillations on timescales of 100 seconds to 2.5 hours can occur at mass-accretion rates more than ten times lower than previously thought. This suggests that the accretion rate is not the critical parameter for inducing inner-disk instabilities. Instead, we propose that a long orbital period is a key condition for these large-amplitude oscillations, because the outer part of the large disk in binaries with long orbital periods will have surface densities too low to maintain sustained mass accretion to the inner part of the disk. The lack of sustained accretion--not the actual rate--would then be the critical factor causing large-amplitude oscillations in long-period systems.

Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study.

The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors.

Growth hormone upregulates intestinal trefoil factor expression in the ileum of rats after γ-radiation.

Growth hormone (GH) and intestinal trefoil factor (ITF) have been involved in intestinal protection and repair. This study investigates the effects of GH administration on ITF expression and histological changes associated with tissue injury in an intestinal rat model of radiation. Adult male rats were divided into four groups: control, GH, radiation and radiation + GH (GHyRAD). Ileum samples were obtained at 2 or 72 h after radiation and processed to determine ITF levels (mRNA and protein) by quantitative polymerase chain reaction, Western blot and immunohistochemistry. In addition, goblet ITF-positive cells were identified by immunohistochemistry at 72 h. Our results showed an upregulation of mRNA and protein production of ITF in ileum samples after GH and radiation + GH compared with control and irradiated samples. Irradiation alone affected ITF protein expression. However, irradiation after GH pretreatment produced the highest ITF mRNA and protein levels at both the tested time points. ITF-producing goblet cells were identified in intestinal villi (apical location). GH treatment increased the number of ITF-producing goblet cells, and radiation after GH treatment displayed further increase in the number of ITF-positive goblet cells. GH upregulates ITF in normal intestinal tissue. This upregulation is higher when radiation is given after GH treatment. Nevertheless, the mechanism by which GH regulates ITF expression remains unclear and is still under investigation. These results could open up new avenues in the therapeutic reparative and protective effects of GH during radiotherapy and chemotherapy.

Effects of mannoprotein E1 in liquid diet on inflammatory response and TLR5 expression in the gut of rats infected by Salmonella typhimurium.

BACKGROUND: Mannoproteins are yeast cell wall componend, and rich in mannose. The use of foods rich in mannose as carbohydrate, could have a bioprotective effect against entrobacteria intestinal infection. Nothing is known about mannoproteins' activity in inflammatory bowel processes induced by entrobacteria.This study investigates the effects of mannoprotein administration via a liquid diet on inflammatory response and TLR5 expression during intestinal tissue injury in a rat model of infection with Salmonella typhimurium. METHODS: Adult Wistar male rats were divided into three groups: control, and mannoprotein E1 at 10 or 15%. Animals were fed with a liquid diet supplemented or not with mannoprotein E1. Groups were infected by intragastrical administration of S. typhimurium. 24 h post-inoculation samples of spleen, ileum and liver were collected for microbiological studies. Gut samples were processed to determine levels of proinflammatory cytokines (mRNA) and TLR5 (mRNA and protein) by quantitative PCR and Western-blot, and the number of proliferative and apoptotic cells determined by immunohistochemistry. RESULTS: Ininfected levels of proinflammatory cytokines and TLR5 were higher in untreated controls than in the animals receiving mannoprotein. Proliferation was similar in both groups, whereas apoptosis was higher in controls. Curiosly, the mannoprotein effect was dose dependent. CONCLUSIONS: Mannoprotein administration in a liquid diet seems to protect intestinal tissue against S. typhimurium infection. This protection seems to expressed as a lower pro-inflammatory response and TLR5 downregulation in gut epithelium, as well as by an inhibition of apoptosis. Nevertheless, the molecular mechanism by which mannoprotein is able to regulate these responses remain unclear. These results could open up new avenues in the use of mannoproteins as prebiotics in the therapeutic strategy for treatment of inflammatory gut processes induced by microbia.

Exogenous ghrelin regulates proliferation and apoptosis in the hypotrophic gut mucosa of the rat.

Ghrelin is the natural endogenous ligand for growth hormone secretagogue receptors. This peptide regulates energy homeostasis and expenditure and is a potential link between gut absorptive function and growth. We hypothesized that ghrelin may induce a proliferative and antiapoptotic action promoting the recovery of the hypotrophic gut mucosa. Therefore, the aim of the study was to determine the action of exogenous ghrelin following gut mucosal hypotrophia in rats fed an elemental diet. An elemental diet provides readily absorbable simple nutrients and is usually given to patients with absorptive dysfunction. Male Wistar rats (n = 48) were fed the elemental diet for one week to induce mucosal hypotrophy and then treated for another week with systemic ghrelin and pair-fed with either a normoproteic or hyperproteic isocaloric liquid diet. Another group received a standard diet instead of the elemental diet and served as control (normotrophy). The elemental diet induced intestinal hypotrophia characterized by decreased proliferation in the ileum and increased apoptosis in jejunum and ileum. Ghrelin administration restored normal levels of proliferation in the ileum and apoptosis in the jejunum, with partial apoptosis restoration in the ileum. Ghrelin levels in plasma and fundus were increased in all groups, although the highest levels were found in rats treated with exogenous ghrelin. Ghrelin administration has a positive effect in the hypotrophic gut, regulating both proliferation and apoptosis towards a physiological balance counteracting the negative changes induced by an elemental diet in the intestines.

Communications: Evidence for the role of fluctuations in the thermodynamics of nanoscale drops and the implications in computations of the surface tension.

Test-area deformations are used to analyze vapor-liquid interfaces of Lennard-Jones particles by molecular dynamics simulation. For planar vapor-liquid interfaces the change in free energy is captured by the average of the corresponding change in energy, the leading-order contribution. This is consistent with the commonly used mechanical (pressure-tensor) route for the surface tension. By contrast for liquid drops, one finds a large second-order contribution associated with fluctuations in energy. Both the first- and second-order terms make comparable contributions, invalidating the mechanical relation for the surface tension of small drops. The latter is seen to increase above the planar value for drop radii of approximately 8 particle diameters, followed by an apparent weak maximum and slow decay to the planar limit, consistent with a small negative Tolman length.

Vapor-liquid interfacial properties of fully flexible Lennard-Jones chains.

We consider the computation of the interfacial properties of molecular chains from direct simulation of the vapor-liquid interface. The molecules are modeled as fully flexible chains formed from tangentially bonded monomers with truncated Lennard-Jones interactions. Four different model systems comprising of 4, 8, 12, and 16 monomers per molecule are considered. The simulations are performed in the canonical ensemble, and the vapor-liquid interfacial tension is evaluated using the test area and the wandering interface methods. In addition to the surface tension, we also obtain density profiles, coexistence densities, critical temperature and density, and interfacial thickness as functions of temperature, paying particular attention to the effect of the chain length on these properties. According to our results, the main effect of increasing the chain length (at fixed temperature) is to sharpen the vapor-liquid interface and to increase the width of the biphasic coexistence region. As a result, the interfacial thickness decreases and the surface tension increases as the molecular chains get longer. The interfacial thickness and surface tension appear to exhibit an asymptotic limiting behavior for long chains. A similar behavior is also observed for the coexistence densities and critical properties. Our simulation results indicate that the asymptotic regime is reached for Lennard-Jones chains formed from eight monomer segments. We also include a preliminary study on the effect of the cutoff distance on the interfacial properties. Our results indicate that all of the properties exhibit a dependence with the distance at which the interactions are truncated, though the relative effect varies from one property to the other. The interfacial thickness and, more particularly, the interfacial tension are found to be strongly dependent on the particular choice of cutoff, whereas the density profiles and coexistence densities are, in general, less sensitive to the truncation.

Estimating errors in free energy calculations from thermodynamic integration using fitted data.

A procedure to estimate the statistical uncertainties associated with free energies computed from thermodynamic integration using fitted data is described. The method involves generating synthetic data sets from the actual simulation data and performing an analysis of the resulting distribution of free energy values. These values follow a Gaussian distribution, and the corresponding standard deviation is associated with the error in the computed value of the free energy. The impact of these uncertainties on the coexistence pressure is examined for first-order transitions. The approach is demonstrated with an examination of finite-size effects at the freezing transition of hard spheres.

Determination of the melting point of hard spheres from direct coexistence simulation methods.

We consider the computation of the coexistence pressure of the liquid-solid transition of a system of hard spheres from direct simulation of the inhomogeneous system formed from liquid and solid phases separated by an interface. Monte Carlo simulations of the interfacial system are performed in three different ensembles. In a first approach, a series of simulations is carried out in the isothermal-isobaric ensemble, where the solid is allowed to relax to its equilibrium crystalline structure, thus avoiding the appearance of artificial stress in the system. Here, the total volume of the system fluctuates due to changes in the three dimensions of the simulation box. In a second approach, we consider simulations of the inhomogeneous system in an isothermal-isobaric ensemble where the normal pressure, as well as the area of the (planar) fluid-solid interface, are kept constant. Now, the total volume of the system fluctuates due to changes in the longitudinal dimension of the simulation box. In both approaches, the coexistence pressure is estimated by monitoring the evolution of the density along several simulations carried out at different pressures. Both routes are seen to provide consistent values of the fluid-solid coexistence pressure, p=11.54(4)k(B)T/sigma(3), which indicates that the error introduced by the use of the standard constant-pressure ensemble for this particular problem is small, provided the systems are sufficiently large. An additional simulation of the interfacial system is conducted in a canonical ensemble where the dimensions of the simulation box are allowed to change subject to the constraint that the total volume is kept fixed. In this approach, the coexistence pressure corresponds to the normal component of the pressure tensor, which can be computed as an appropriate ensemble average in a single simulation. This route yields a value of p=11.54(4)k(B)T/sigma(3). We conclude that the results obtained for the coexistence pressure from direct simulations of the liquid and solid phases in coexistence using different ensembles are mutually consistent and are in excellent agreement with the values obtained from free energy calculations.

Computation of surface tensions using expanded ensemble simulations.

A method for the direct simulation of the surface tension is examined. The technique is based on the thermodynamic route to the interfacial tension and makes use of the expanded ensemble simulation method for the calculation of the free energy difference between two inhomogeneous systems with the same number of particles, temperature, and volume, but different interfacial area. The method is completely general and suitable for systems with either continuous or discontinuous interactions. The adequacy of the expanded ensemble method is assessed by computing the interfacial tension of the planar vapor-liquid interface of Lennard-Jones, Lennard-Jones dimers, Gay-Berne, and square-well model fluids; in the latter, the interactions are discontinuous and the present method does not exhibit the asymmetry of other related methods, such as the test area. The expanded ensemble simulation results are compared with simulation data obtained from other techniques (mechanical and test area) with overall good agreement.

Right-atrial floating thrombus attached to the interatrial septum with massive pulmonary embolism diagnosed by echocardiography.

The presence of a right-atrium thrombus is considered as an unusual form of thromboembolic disease, with a prevalence of 10-18%. Most of them are located in the right-atria. Its mortality is about 45%. Echocardiography is very important to detect them and to control the effectiveness of the treatment, which can be either conservative or surgical. We present a case of a man to show the importance of echocardiography in this pathological diagnosis, what is essential for a right-treatment.

System-size dependence of the free energy of crystalline solids.

We investigate the system-size dependence of the Helmholtz free energy of crystalline solids from computer simulation. We employ a standard thermodynamic integration technique along a reversible path that links the crystalline solid with a noninteracting Einstein crystal with the same structure. The key contribution to the free energy is computed by using the so-called expanded-ensemble technique and the results are compared with those obtained from conventional integration of the derivative of the free energy along the path using Gaussian-Legendre quadrature. We find that both methods yield fully consistent results. The free energy is found to exhibit a strong dependence with system size, in agreement with the behavior found by Polson et al. [J. Chem. Phys. 112, 5339 (2000)] but at variance with the dependence reported more recently by Chang and Sandler [J. Chem. Phys. 118, 8390 (2003)]. This has been tested for the face-centered cubic (fcc) and hexagonal close-packed phases of a crystal of hard spheres at a density close to the melting point. We also investigate any possible dependence of the free energy of the solid phase with the shape of the simulation box. We find that this contribution may not be as important as previous investigations suggest. The present results seem to indicate that there is a non-negligible contribution to the free energy arising from the orientation of the closed-packed crystal layers with respect to the simulation cell. This contribution is particularly noticeable for small system sizes and is believed to be an effect of the periodic boundary conditions used in the simulations. The results presented here corroborate the stability of the fcc phase of the hard-sphere solid close to melting.

The nature of the calculation of the pressure in molecular simulations of continuous models from volume perturbations.

We consider some fundamental aspects of the calculation of the pressure from simulations by performing volume perturbations. The method, initially proposed for hard-core potentials by Eppenga and Frenkel [Mol. Phys.52, 1303 (1984)] and then extended to continuous potentials by Harismiadis et al. [J. Chem. Phys. 105, 8469 (1996)], is based on the numerical estimate of the change in Helmholtz free energy associated with the perturbation which, in turn, can be expressed as an ensemble average of the corresponding Boltzmann factor. The approach can be easily generalized to the calculation of components of the pressure tensor and also to ensembles other than the canonical ensemble. The accuracy of the method is assessed by comparing simulation results obtained from the volume-perturbation route with those obtained from the usual virial expression for several prototype fluid models. Monte Carlo simulation data are reported for bulk fluids and for inhomogeneous systems containing a vapor-liquid interface.

Density functional theory and simulation of the columnar phase of a system of parallel hard ellipsoids with attractive interactions.

A simple molecular model consisting of parallel hard oblate ellipsoids with superimposed square-well attractive interactions of variable range is considered for the study of the phase behavior of thermotropic discotic molecules. A density functional theory appropriate for nonuniform fluids is formulated in which the hard-core contributions to the free energy are treated within a nonlocal weighted-density approximation (WDA) while the attractive contributions are treated at a mean-field level. It is shown that the columnar phase becomes stable relative to the nematic phase at fluid densities for a range of values of the range of the attractive well. In these cases, the region of stability of the columnar phase is bounded at high temperatures by a nematic-columnar-solid triple point. The calculations show that if the attractions are made too long ranged (lambda/D> or approximately =0.84 for particles of aspect ratio of L/D=0.1, where lambda/D is the range of the attractive interaction in units of the molecular diameter D), columnar ordering becomes unstable and the nematic phase dominates at all fluid densities. It is shown that columnar ordering is also predicted when the density functional theory is supplemented with the smoothed-density approximation (SDA). Computer simulations have also been carried out for a particular choice of model parameters; our simulation data confirm the stabilization of the hexagonal columnar phase between the solid and nematic phases. A comparison with simulation data allows us to conclude that the WDA provides a fairly good description of the columnar phase and very good agreement for the nematic-columnar transition properties. On the other hand, our calculations show that the SDA largely underestimates the transition pressure and predicts a too-strongly first-order nematic-columnar transition

Computer simulation of nematic reentrance in a simple molecular model.

We report a computer simulation study of a system of parallel hard ellipsoids with attractive interactions represented by a spherically symmetric square well of range lamba. For suitable values of the results are consistent with the sequence of phases nematic (N), smectic-A (SmA), reentrant nematic (N(re)), and crystal (Cr) under pressure. Both the N-SmA and the SmA-N(re) transitions are found to be first order or continuous depending on temperature. Moreover, we show that a generalized van der Waals-type theory provides a qualitative description of the observed phase behavior.

Test-area simulation method for the direct determination of the interfacial tension of systems with continuous or discontinuous potentials.

A novel test-area (TA) technique for the direct simulation of the interfacial tension of systems interacting through arbitrary intermolecular potentials is presented in this paper. The most commonly used method invokes the mechanical relation for the interfacial tension in terms of the tangential and normal components of the pressure tensor relative to the interface (the relation of Kirkwood and Buff [J. Chem. Phys. 17, 338 (1949)]). For particles interacting through discontinuous intermolecular potentials (e.g., hard-core fluids) this involves the determination of delta functions which are impractical to evaluate, particularly in the case of nonspherical molecules. By contrast we employ a thermodynamic route to determine the surface tension from a free-energy perturbation due to a test change in the surface area. There are important distinctions between our test-area approach and the computation of a free-energy difference of two (or more) systems with different interfacial areas (the method of Bennett [J. Comput. Phys. 22, 245 (1976)]), which can also be used to determine the surface tension. In order to demonstrate the adequacy of the method, the surface tension computed from test-area Monte Carlo (TAMC) simulations are compared with the data obtained with other techniques (e.g., mechanical and free-energy differences) for the vapor-liquid interface of Lennard-Jones and square-well fluids; the latter corresponds to a discontinuous potential which is difficult to treat with standard methods. Our thermodynamic test-area approach offers advantages over existing techniques of computational efficiency, ease of implementation, and generality. The TA method can easily be implemented within either Monte Carlo (TAMC) or molecular-dynamics (TAMD) algorithms for different types of interfaces (vapor-liquid, liquid-liquid, fluid-solid, etc.) of pure systems and mixtures consisting of complex polyatomic molecules.