The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model.

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.

Constraints on the permeability structure of alluvial aquifers from the poro-elastic inversion of multi-frequency P-wave velocity logs

We have explored the possibility of obtaining first-order permeability estimates for saturated alluvial sediments based on the poro-elastic interpretation of the P-wave velocity dispersion inferred from sonic logs. Modern sonic logging tools designed for environmental and engineering applications allow one for P-wave velocity measurements at multiple emitter frequencies over a bandwidth covering 5 to 10 octaves. Methodological considerations indicate that, for saturated unconsolidated sediments in the silt to sand range and typical emitter frequencies ranging from approximately 1 to 30 kHz, the observable velocity dispersion should be sufficiently pronounced to allow one for reliable first-order estimations of the permeability structure. The corresponding predictions have been tested on and verified for a borehole penetrating a typical surficial alluvial aquifer. In addition to multifrequency sonic logs, a comprehensive suite of nuclear and electrical logs, an S-wave log, a litholog, and a limited number laboratory measurements of the permeability from retrieved core material were also available. This complementary information was found to be essential for parameterizing the poro-elastic inversion procedure and for assessing the uncertainty and internal consistency of corresponding permeability estimates. Our results indicate that the thus obtained permeability estimates are largely consistent with those expected based on the corresponding granulometric characteristics, as well as with the available evidence form laboratory measurements. These findings are also consistent with evidence from ocean acoustics, which indicate that, over a frequency range of several orders-of-magnitude, the classical theory of poro-elasticity is generally capable of explaining the observed P-wave velocity dispersion in medium- to fine-grained seabed sediments

The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution.

IMPORTANCE OF THE FIELD: The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs. AREAS COVERED IN THIS REVIEW: A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution. WHAT THE READER WILL GAIN: Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure-activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier. TAKE HOME MESSAGE: The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.

Evaluation of Asphalt Mix Permeability, MLR-90-2, 1992

Efforts to eliminate rutting on the Interstate system have resulted in 3/4 in. aggregate mixes, with 75 blow Marshall, 85% crushed aggregate mix designs. On a few of these projects paved in 1988-1989, water has appeared on the surfaces. Some conclusions have been reached by visual on-sight investigations that the water is coming from surface water, rain and melting snow gaining entry into the surface asphalt mixture, then coming back out in selected areas. Cores were taken from several Interstate projects and tested for permeability to investigate the surface water theory that supposedly happens with only the 3/4 in. mixtures. All cores were of asphalt overlays over portland cement concrete, except for the Clarke County project which is full depth AC. The testing consisted of densities, permeabilities, voids by high pressure airmeter (HPAM), extraction, gradations, AC content, and film thicknesses. Resilient modulus, indirect tensile and retained strengths after freeze/thaw were also done. All of the test results are about as expected. Permeabilities, the main reason for testing, ranged from 0.00 to 2.67 ft per day and averages less than 1/2 ft per day if the following two tests are disregarded. One test on each binder course came out to 15.24 ft/day, and a surface course at 13.78 ft/day but these are not out of supposedly problem projects.

Permeability of Granular Subbase Materials, MLR-90-4, 1991

The purpose of this research was to evaluate the materials Iowa uses as a granular subbase and to determine if it provides adequate drainage. Numerous laboratory and in-situ tests were conducted on the materials currently being used in Iowa. The follow conclusions can be made based on the test results: 1. The crushed concrete that is used as a subbase material has a relatively low permeability compared to many other materials used by other states. 2. Further research and tests are needed to find the necessary parameters for crushed concrete to make sure it is providing its optimum drainage and preventing premature damage of the pavement. 3. We have definitely made improvements in drainage in the past few months, but there are many areas that we can improve on that will increase the permeability of this material and insure that the pavement system is safe from premature damage due to water. The current gradation specification for granular subbase material at the start of this study was: Sieve # % Passing 1” 100 #8 10-35 #50 0-15 #200 0-6

Diseño de un protocolo para el cambio de prolongador en Diálisis Peritoneal

El cambio de prolongador del equipo de Diálisis Peritoneal es una intervención competencia de la enfermería que debe ser cumplimentada siguiendo un protocolo que minimice el riesgo de contaminación y por tanto de la aparición de peritonitis. No existen recomendaciones claras y unánimes sobre cómo desinfectar las conexiones, ya que esto va a depender fundamentalmente de si el conector del catéter es de titanio o no y de cómo debe cebarse el nuevo prolongador. Objetivo: Conocer como se realiza el cambio de prolongador en las diferentes unidades nefrológicas del Estado con el fin de consensuar el procedimiento más adecuado. Material y método: Estudio descriptivo transversal realizado en febrero de 2008 a partir de un cuestionario estructurado y autocumplimentado de diseño propio del que garantizó su validez y fiabilidad. En la encuesta se recogió la experiencia de la persona encuestada en el campo de la DP, el sistema utilizado, y el cumplimiento de los ítems que se consideraron fundamentales para una buena praxis en el procedimiento del cambio de prolongador, basados en la literatura consultada y el las recomendaciones de los proveedores de los productos para DP. Resultados: Se obtuvieron 53 encuestas de enfermeras que manifestaron tener experiencia en DP entre 3 meses y 32 años. El grado de cumplimiento de las acciones necesarias para cambiar el prolongador (lavado de manos, preparación campo estéril, lavado del conector) fue entre un 95 y un 100%, mientras que los ítems desinfección de la conexión y drenaje de líquido peritoneal tras el cambio obtuvieron grados de cumplimentación entre un 28 y un 83%. Conclusiones: Nuestro estudio presenta limitaciones, ya que se trataba de hacer una prospección inicial sobre el tema, se debe profundizar en él y consensuar un protocolo válido de cambio de prolongador para cualquiera de los sistemas que ofrece la industria y definir muy claramente el proceso de desinfección del conector y la conveniencia o no de realizar un recambio peritoneal completo tras el cambio.

Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability.

Light toxicity is suspected to enhance certain retinal degenerative processes such as age-related macular degeneration. Death of photoreceptors can be induced by their exposure to the visible light, and although cellular processes within photoreceptors have been characterized extensively, the role of the retinal pigment epithelium (RPE) in this model is less well understood. We demonstrate that exposition to intense light causes the immediate breakdown of the outer blood-retinal barrier (BRB). In a molecular level, we observed the slackening of adherens junctions tying up the RPE and massive leakage of albumin into the neural retina. Retinal pigment epithelial cells normally secrete vascular endothelial growth factor (VEGF) at their basolateral side; light damage in contrast leads to VEGF increase on the apical side - that is, in the neuroretina. Blocking VEGF, by means of lentiviral gene transfer to express an anti-VEGF antibody in RPE cells, inhibits outer BRB breakdown and retinal degeneration, as illustrated by functional, behavioral and morphometric analysis. Our data show that exposure to high levels of visible light induces hyperpermeability of the RPE, likely involving VEGF signaling. The resulting retinal edema contributes to irreversible damage to photoreceptors. These data suggest that anti-VEGF compounds are of therapeutic interest when the outer BRB is altered by retinal stresses.

Low Permeability of Concrete for Bridge Deck Overlay, MLR-89-1, 1993

The penetration of chloride ions from deicing salts into the portland cement concrete of bridge decks can cause corrosion and serious damage to the reinforcing steel. Concrete properties which prevent chloride penetration into the bridge deck and provide a good structural and economic wearing surface are desirable. A variety of mix designs have been tried in the past in search of improved performance and lower costs for bridge deck overlay concrete. A group of mixes with various designs have been tested in this project and results are being compared to determine which concrete mix appears to be the most cost effective and resistant to chloride penetration for bridge deck overlay use.

The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells.

Cilengitide is a high-affinity cyclic pentapeptdic alphaV integrin antagonist previously reported to suppress angiogenesis by inducing anoikis of endothelial cells adhering through alphaVbeta3/alphaVbeta5 integrins. Angiogenic endothelial cells express multiple integrins, in particular those of the beta1 family, and little is known on the effect of cilengitide on endothelial cells expressing alphaVbeta3 but adhering through beta1 integrins. Through morphological, biochemical, pharmacological and functional approaches we investigated the effect of cilengitide on alphaVbeta3-expressing human umbilical vein endothelial cells (HUVEC) cultured on the beta1 ligands fibronectin and collagen I. We show that cilengitide activated cell surface alphaVbeta3, stimulated phosphorylation of FAK (Y(397) and Y(576/577)), Src (S(418)) and VE-cadherin (Y(658) and Y(731)), redistributed alphaVbeta3 at the cell periphery, caused disappearance of VE-cadherin from cellular junctions, increased the permeability of HUVEC monolayers and detached HUVEC adhering on low-density beta1 integrin ligands. Pharmacological inhibition of Src kinase activity fully prevented cilengitide-induced phosphorylation of Src, FAK and VE-cadherin, and redistribution of alphaVbeta3 and VE-cadherin and partially prevented increased permeability, but did not prevent HUVEC detachment from low-density matrices. Taken together, these observations reveal a previously unreported effect of cilengitide on endothelial cells namely its ability to elicit signaling events disrupting VE-cadherin localization at cellular contacts and to increase endothelial monolayer permeability. These effects are potentially relevant to the clinical use of cilengitide as anticancer agent.

Evaluation of Rapid Determination of the Chloride Permeability of Portland Cement Concrete by AASHTO T277-83, MLR-86-11, 1987

An Iowa D.O.T. Laboratory built machine was constructed for the chloride permeability testing of concrete by measuring electric current through a specimen between a salt solution and a base solution. This study had two purposes. The first was to evaluate the machine's performance. To do this, three concrete mixes were made consisting of different cement factors and water/cement ratios. Each mix was tested for chloride ion content by the 90- day salt ponding method and for chloride permeability at a 28-day cure by the permeability machine. The results from each test were evaluated to see if there was correlation between chloride ion content and the chloride permeability. It was determined that there was a correlation and that the permeability machine was satisfactory for determining chloride permeability in concrete. The second purpose of this study was to examine the effects that pozzolans have on the chloride permeability of concrete. Four mixes were made: one without any pozzolans as a control, one with class C fly ash, one with class F fly ash, and one with silica fume. Specimens from each mix were evaluated for chloride ion content by the 90-day salt ponding test and by the laboratory built machine for chloride permeability after curing 28 days. Specimens from these mixes were also taken from the salt ponding slabs after completion of the ponding test to examine the effect chloride ion content has on the operation of the chloride permeability machine. Specimens containing pozzolans were also examined for chloride permeability after a cure of 180 days. It was determined that the addition of pozzolans to concrete lowers the chloride permeability as measured by the permeability machine. Class F fly ash and silica fume in the concrete had a major effect in lowering the chloride permeability in concrete as measured by the permeability machine.

Peritoneal carcinomatosis due to ovarian cancer: comparison between MDCT, MRI and 18F-FDG PET/CT

Purpose: To compare MDCT, MRI and 18F-FDG PET/CT for the detection of peritoneal carcinomatosis due to ovarian cancerMethods and Materials: Fifteen women (mean age 65±) with clinical suspicion of ovarian cancer and peritoneal carcinomatosis underwent MDCT, MRI and 18F-FDG PET/CT, simultaneously and shortly performed before surgery (delay 8.1± days). According to the peritoneal cancer index nine abdominopelvic regions were defined. We applied four scores of lesion size on MDCT and MR images, while the maximal standard uptake value (SUVmax) was measured on 18F-FDG PET/CT. Three sites of lymphadenopathy and posterobasal pleural carcinomatosis were also analyzed. First, one radiologist blindly and separately read MDCT and MR images, while one nuclear physician blindly read PET/CT images grading each lesion according to four diagnostic certitudes. Secondly, all the images were reviewed jointly and compared with histopathology. Receiver operating characteristics (ROC) analysis was performed.Results: Peritoneal implants were proven in ten women (75%). Altogether, 228 abdominopelvic sites were compared. Sensitivity and specificity for MDCT was 90.2% and 90.6%, for MRI 93.5% and 86.3%, and for 18F-FDG PET/CT 92.7% and 95.7%, respectively. ROC area under the curve were 0.93 for MDCT and MRI, and 0.96 for 18F-FDG PET/CT respectively. No significant differences (p=0.11) were found between the three modalities.Conclusion: Although MRI revealed to be the most sensitive and 18F-FDG PET/CT the most specific modality, no significant differences were shown between the three techniques.

Concrete Pavement Mixture Design and Analysis (MDA): Evaluation of the Fresh and Hardened Properties of Concrete Mixtures Containing Permeability-Reducing Admixtures to Develop Standard Test Protocol, 2014

Concrete durability may be considered as the ability to maintain serviceability over the design life without significant deterioration, and is generally a direct function of the mixture permeability. Therefore, reducing permeability will improve the potential durability of a given mixture and, in turn, improve the serviceability and longevity of the structure. Given the importance of this property, engineers often look for methods that can decrease permeability. One approach is to add chemical compounds known as integral waterproofing admixtures or permeability-reducing admixtures, which help fill and block capillary pores in the paste. Currently, there are no standard approaches to evaluate the effectiveness of permeability-reducing admixtures or to compare different products in the US. A review of manufacturers’ data sheets shows that a wide range of test methods have been used, and rarely are the same tests used on more than one product. This study investigated the fresh and hardened properties of mixtures containing commercially available hydrophilic and hydrophobic types of permeability-reducing admixtures. The aim was to develop a standard test protocol that would help owners, engineers, and specifiers compare different products and to evaluate their effects on concrete mixtures that may be exposed to hydrostatic or non-hydrostatic pressure. In this experimental program, 11 concrete mixtures were prepared with a fixed water-to-cement ratio and cement content. One plain mixture was prepared as a reference, 5 mixtures were prepared using the recommended dosage of the different permeability-reducing admixtures, and 5 mixtures were prepared using double the recommended dosage. Slump, air content, setting time, compressive and flexural strength, shrinkage, and durability indicating tests including electrical resistivity, rapid chloride penetration, air permeability, permeable voids, and sorptivity tests were conducted at various ages. The data are presented and recommendations for a testing protocol are provided.

Air Content and Permeability of PCC Pavements: 1909 to 2006, MLR-05-02, 2007

Portland cement concrete pavements have given excellent service history for Iowa. Many of these pavements placed during the 1920’s and 1930’s are still in service today. Many factors go in to achieve a long term durable concrete pavement. Probably the most important is the durability of the aggregate. Until the 1930’s, pit run gravel was the most predominant aggregate used. Many of these gravels provided long term performance and their durability is dependent upon the carbonate fraction of the gravel. Later, limestone (calcium carbonate) and dolomite (calcium, magnesium carbonate) sources were mined across Iowa. The durability of these carbonate aggregates is largely dependent upon the pore system which can cause freeze thaw problems known as D-cracking, which was a problem with some sources during the 1960’s. Also, some of these carbonate aggregates are also susceptible to deterioration from deicing salts. Geologists have identified the major components that affect the durability of these carbonate aggregates and sources are tested to ensure long term performance in Portland cement concrete. Air entrainment was originally put in concrete to improve scaling resistance. It is well known that air entrainment is required to provide freeze thaw protection in concrete pavements today. In Iowa, air entrainment was not introduced in concrete pavements until 1952. This research investigates properties that made older concrete pavements durable without air entrainment.

Gut permeability and food allergies.

Intestinal permeability is a critical feature of the gastrointestinal epithelium as it must allow an efficient passage of nutrients and restrict the entry of larger molecules, such as protein antigen, in order to facilitate appropriate immune responses towards food antigens. The proper regulation of the epithelial barrier relies on multiple, intricate physiological and immunologic mechanisms, in terms of which recent progresses regarding the cellular and molecular components have been unravelled. In genetically predisposed individuals, breakdown of oral tolerance can occur, leading to the inadequate production of allergen-specific IgE and the recruitment of mast cells in the gastrointestinal mucosa. Under such conditions, the intestinal permeability towards allergen is altered via different mechanisms, with IgE-CD23-mediated transport across the mucosa playing an important amplification role. Additionally, during the effector phase of the allergic reaction, when mast cells degranulate, a series of inflammatory mediators, such as proteases and cytokines, are released and further affects intestinal permeability. This leads to an increase in the passage of allergens and hence contributes to perpetuate the inflammatory reaction. In this review, we describe the importance of properly balanced intestinal permeability in oral tolerance induction and address the processes involved in damaging the intestinal barrier in the sensitized epithelium and during allergic reactions. We conclude by speculating on the effect of increased intestinal permeability on the onset of sensitization towards dietary antigens.