A NOVEL PROCESS TO USE SALT CAVERNS TO RECEIVE SHIP BORNE LNG

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michael M. McCall; William M. Bishop; Marcus Krekel

2005-05-31

This cooperative research project validates use of man made salt caverns to receive and store the cargoes of LNG ships in lieu of large liquid LNG tanks. Salt caverns will not tolerate direct injection of LNG because it is a cryogenic liquid, too cold for contact with salt. This research confirmed the technical processes and the economic benefits of pressuring the LNG up to dense phase, warming it to salt compatible temperatures and then directly injecting the dense phase gas into salt caverns for storage. The use of salt caverns to store natural gas sourced from LNG imports, particularly whenmore » located offshore, provides a highly secure, large scale and lower cost import facility as an alternative to tank based LNG import terminals. This design can unload a ship in the same time as unloading at a tank based terminal. The Strategic Petroleum Reserve uses man made salt caverns to securely store large quantities of crude oil. Similarly, this project describes a novel application of salt cavern gas storage technologies used for the first time in conjunction with LNG receiving. The energy industry uses man made salt caverns to store an array of gases and liquids but has never used man made salt caverns directly in the importation of LNG. This project has adapted and expanded the field of salt cavern storage technology and combined it with novel equipment and processes to accommodate LNG importation. The salt cavern based LNG receiving terminal described in the project can be located onshore or offshore, but the focus of the design and cost estimates has been on an offshore location, away from congested channels and ports. The salt cavern based terminal can provide large volumes of gas storage, high deliverability from storage, and is simplified in operation compared to tank based LNG terminals. Phase I of this project included mathematical modeling that proved a salt cavern based receiving terminal could be built at lower capital cost, and would have significantly higher delivery capacity, shorter construction time, and be much more secure than a conventional liquid tank based terminal. Operating costs of a salt cavern terminal are lower than tank based terminals because ''boil off'' is eliminated and maintenance costs of caverns are lower than LNG tanks. Phase II included the development of offshore mooring designs, wave tank tests, high pressure LNG pump field tests, heat exchanger field tests, and development of a model offshore LNG facility and cavern design. Engineers designed a model facility, prepared equipment lists, and confirmed capital and operating costs. In addition, vendors quoted fabrication and installation costs, confirming that an offshore salt cavern based LNG terminal would have lower capital and operating costs than a similarly sized offshore tank based terminal. Salt cavern storage is infinitely more secure than surface storage tanks, far less susceptible to accidents or purposeful damage, and much more acceptable to the community. More than thirty industry participants provided cost sharing, technical expertise, and guidance in the conduct and evaluation of the field tests, facility design and operating and cost estimates. Their close participation has accelerated the industry's acceptance of the conclusions of this research. The industry participants also developed and submitted several alternative designs for offshore mooring and for high pressure LNG heat exchangers in addition to those that were field tested in this project. HNG Storage, a developer, owner, and operator of natural gas storage facilities, and a participant in the DOE research has announced they will lead the development of the first offshore salt cavern based LNG import facility. Which will be called the Freedom LNG Terminal. It will be located offshore Louisiana, and is expected to be jointly developed with other members of the research group yet to be named. An offshore port license application is scheduled to be filed by fourth quarter 2005 and the terminal could be operational by 2009. This terminal allows the large volume importation of LNG without disrupting coastal port operations by being offshore, out of sight of land.« less

Sonar atlas of caverns comprising the U.S. Strategic Petroleum Reserve. Volume 4, West Hackberry site, Louisiana.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rautman, Christopher Arthur; Lord, Anna Snider

2007-09-01

Downhole sonar surveys from the four active U.S. Strategic Petroleum Reserve sites have been modeled and used to generate a four-volume sonar atlas, showing the three-dimensional geometry of each cavern. This volume 4 focuses on the West Hackberry SPR site, located in southwestern Louisiana. Volumes 1, 2, and 3, respectively, present images for the Bayou Choctaw SPR site, Louisiana, the Big Hill SPR site, Texas, and the Bryan Mound SPR site, Texas. The atlas uses a consistent presentation format throughout. The basic geometric measurements provided by the down-cavern surveys have also been used to generate a number of geometric attributes,more » the values of which have been mapped onto the geometric form of each cavern using a color-shading scheme. The intent of the various geometrical attributes is to highlight deviations of the cavern shape from the idealized cylindrical form of a carefully leached underground storage cavern in salt. The atlas format does not allow interpretation of such geometric deviations and anomalies. However, significant geometric anomalies, not directly related to the leaching history of the cavern, may provide insight into the internal structure of the relevant salt dome.« less

Sonar atlas of caverns comprising the U.S. Strategic Petroleum Reserve. Volume 2, Big Hill Site, Texas.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rautman, Christopher Arthur; Lord, Anna Snider

2007-08-01

Downhole sonar surveys from the four active U.S. Strategic Petroleum Reserve sites have been modeled and used to generate a four-volume sonar atlas, showing the three-dimensional geometry of each cavern. This volume 2 focuses on the Big Hill SPR site, located in southeastern Texas. Volumes 1, 3, and 4, respectively, present images for the Bayou Choctaw SPR site, Louisiana, the Bryan Mound SPR site, Texas, and the West Hackberry SPR site, Louisiana. The atlas uses a consistent presentation format throughout. The basic geometric measurements provided by the down-cavern surveys have also been used to generate a number of geometric attributes,more » the values of which have been mapped onto the geometric form of each cavern using a color-shading scheme. The intent of the various geometrical attributes is to highlight deviations of the cavern shape from the idealized cylindrical form of a carefully leached underground storage cavern in salt. The atlas format does not allow interpretation of such geometric deviations and anomalies. However, significant geometric anomalies, not directly related to the leaching history of the cavern, may provide insight into the internal structure of the relevant salt dome.« less

Sonar atlas of caverns comprising the U.S. Strategic Petroleum Reserve. Volume 1, Bayou Choctaw site, Louisiana.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rautman, Christopher Arthur; Lord, Anna Snider

2007-10-01

Downhole sonar surveys from the four active U.S. Strategic Petroleum Reserve sites have been modeled and used to generate a four-volume sonar atlas, showing the three-dimensional geometry of each cavern. This volume 1 focuses on the Bayou Choctaw SPR site, located in southern Louisiana. Volumes 2, 3, and 4, respectively, present images for the Big Hill SPR site, Texas, the Bryan Mound SPR site, Texas, and the West Hackberry SPR site, Louisiana. The atlas uses a consistent presentation format throughout. The basic geometric measurements provided by the down-cavern surveys have also been used to generate a number of geometric attributes,more » the values of which have been mapped onto the geometric form of each cavern using a color-shading scheme. The intent of the various geometrical attributes is to highlight deviations of the cavern shape from the idealized cylindrical form of a carefully leached underground storage cavern in salt. The atlas format does not allow interpretation of such geometric deviations and anomalies. However, significant geometric anomalies, not directly related to the leaching history of the cavern, may provide insight into the internal structure of the relevant salt dome.« less

Characterizing Excavation Damaged Zone and Stability of Pressurized Lined Rock Caverns for Underground Compressed Air Energy Storage

NASA Astrophysics Data System (ADS)

Kim, Hyung-Mok; Rutqvist, Jonny; Jeong, Ju-Hwan; Choi, Byung-Hee; Ryu, Dong-Woo; Song, Won-Kyong

2013-09-01

In this paper, we investigate the influence of the excavation damaged zone (EDZ) on the geomechanical performance of compressed air energy storage (CAES) in lined rock caverns. We conducted a detailed characterization of the EDZ in rock caverns that have been excavated for a Korean pilot test program on CAES in (concrete) lined rock caverns at shallow depth. The EDZ was characterized by measurements of P- and S-wave velocities and permeability across the EDZ and into undisturbed host rock. Moreover, we constructed an in situ concrete lining model and conducted permeability measurements in boreholes penetrating the concrete, through the EDZ and into the undisturbed host rock. Using the site-specific conditions and the results of the EDZ characterization, we carried out a model simulation to investigate the influence of the EDZ on the CAES performance, in particular related to geomechanical responses and stability. We used a modeling approach including coupled thermodynamic multiphase flow and geomechanics, which was proven to be useful in previous generic CAES studies. Our modeling results showed that the potential for inducing tensile fractures and air leakage through the concrete lining could be substantially reduced if the EDZ around the cavern could be minimized. Moreover, the results showed that the most favorable design for reducing the potential for tensile failure in the lining would be a relatively compliant concrete lining with a tight inner seal, and a relatively stiff (uncompliant) host rock with a minimized EDZ. Because EDZ compliance depends on its compressibility (or modulus) and thickness, care should be taken during drill and blast operations to minimize the damage to the cavern walls.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rautman, Christopher Arthur; Lord, Anna Snider

Downhole sonar surveys from the four active U.S. Strategic Petroleum Reserve sites have been modeled and used to generate a four-volume sonar atlas, showing the three-dimensional geometry of each cavern. This volume 3 focuses on the Bryan Mound SPR site, located in southeastern Texas. Volumes 1, 2, and 4, respectively, present images for the Bayou Choctaw SPR site, Louisiana, the Big Hill SPR site, Texas, and the West Hackberry SPR site, Louisiana. The atlas uses a consistent presentation format throughout. The basic geometric measurements provided by the down-cavern surveys have also been used to generate a number of geometric attributes,more » the values of which have been mapped onto the geometric form of each cavern using a color-shading scheme. The intent of the various geometrical attributes is to highlight deviations of the cavern shape from the idealized cylindrical form of a carefully leached underground storage cavern in salt. The atlas format does not allow interpretation of such geometric deviations and anomalies. However, significant geometric anomalies, not directly related to the leaching history of the cavern, may provide insight into the internal structure of the relevant salt dome.« less

Coupled thermal-hydrological-mechanical behavior of rock mass surrounding a high-temperature thermal energy storage cavern at shallow depth

DOE PAGES

Park, Jung-Wook; Rutqvist, Jonny; Ryu, Dongwoo; ...

2016-01-15

The present study is aimed at numerically examining the thermal-hydrological-mechanical (THM) processes within the rock mass surrounding a cavern used for thermal energy storage (TES). We considered a cylindrical rock cavern with a height of 50 m and a radius of 10 m storing thermal energy of 350ºC as a conceptual TES model and simulated its operation for 30 years using THM coupled numerical modeling. At first, the insulator performance was not considered for the purpose of investigating the possible coupled THM behavior of the surrounding rock mass; then, the effects of an insulator were examined for different insulator thicknesses.more » The key concerns were focused on the hydro-thermal multiphase flow and heat transport in the rock mass around the thermal storage cavern, the effect of evaporation of rock mass, thermal impact on near the ground surface and the mechanical behavior of the surrounding rock mass. It is shown that the rock temperature around the cavern rapidly increased in the early stage and, consequently, evaporation of groundwater occurred, raising the fluid pressure. However, evaporation and multiphase flow did not have a significant effect on the heat transfer and mechanical behavior in spite of the high-temperature (350ºC) heat source. The simulations showed that large-scale heat flow around a cavern was expected to be conductiondominated for a reasonable value of rock mass permeability. Thermal expansion as a result of the heating of the rock mass from the storage cavern led to a ground surface uplift on the order of a few centimeters and to the development of tensile stress above the storage cavern, increasing the potentials for shear and tensile failures after a few years of the operation. Finally, the analysis showed that high tangential stress in proximity of the storage cavern can some shear failure and local damage, although large rock wall failure could likely be controlled with appropriate insulators and reinforcement.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jung-Wook; Rutqvist, Jonny; Ryu, Dongwoo

The present study is aimed at numerically examining the thermal-hydrological-mechanical (THM) processes within the rock mass surrounding a cavern used for thermal energy storage (TES). We considered a cylindrical rock cavern with a height of 50 m and a radius of 10 m storing thermal energy of 350ºC as a conceptual TES model and simulated its operation for 30 years using THM coupled numerical modeling. At first, the insulator performance was not considered for the purpose of investigating the possible coupled THM behavior of the surrounding rock mass; then, the effects of an insulator were examined for different insulator thicknesses.more » The key concerns were focused on the hydro-thermal multiphase flow and heat transport in the rock mass around the thermal storage cavern, the effect of evaporation of rock mass, thermal impact on near the ground surface and the mechanical behavior of the surrounding rock mass. It is shown that the rock temperature around the cavern rapidly increased in the early stage and, consequently, evaporation of groundwater occurred, raising the fluid pressure. However, evaporation and multiphase flow did not have a significant effect on the heat transfer and mechanical behavior in spite of the high-temperature (350ºC) heat source. The simulations showed that large-scale heat flow around a cavern was expected to be conductiondominated for a reasonable value of rock mass permeability. Thermal expansion as a result of the heating of the rock mass from the storage cavern led to a ground surface uplift on the order of a few centimeters and to the development of tensile stress above the storage cavern, increasing the potentials for shear and tensile failures after a few years of the operation. Finally, the analysis showed that high tangential stress in proximity of the storage cavern can some shear failure and local damage, although large rock wall failure could likely be controlled with appropriate insulators and reinforcement.« less

Assessment of the Available Drawdowns for Oil Storage Caverns at the West Hackberry SPR Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sobolik, Steven R.

The Department of Energy, in response to requests from the U.S. Congress, wishes to maintain an up-to-date table documenting the number of available full drawdowns of each of the caverns owned by the Strategic Petroleum Reserve. This information is important for assessing the SPR’s ability to deliver oil to domestic oil companies expeditiously if national or world events dictate a rapid sale and deployment of the oil reserves. What factors go into assessing available drawdowns? The evaluation of drawdown risks require the consideration of several factors regarding cavern and wellbore integrity and stability, including stress states caused by cavern geometrymore » and operations, salt damage caused by dilatant and tensile stresses, the effect on enhanced creep on wellbore integrity, the sympathetic stress effect of operations on neighboring caverns. Based on the work over the past several months, a consensus has been built regarding the assessment of drawdown capabilities and risks for the SPR caverns. This paper draws upon the recently West Hackberry model upgrade and analyses to reevaluate and update the available drawdowns for each of those caverns. Similar papers for the Bryan Mound, Big Hill, and Bayou Choctaw papers will be developed as the upgrades to those analyses are completed. The rationale and documentation of the methodology is described in the remainder of this report, as are the updated estimates of available drawdowns for the West Hackberry caverns.« less

Hexahedral Finite Element Mesh Capturing Realistic Geometries of Bayou Choctaw Strategic Petroleum Reserve

NASA Astrophysics Data System (ADS)

Park, B. Y.; Roberts, B. L.; Sobolik, S. R.

2016-12-01

The U.S. Strategic Petroleum Reserve (SPR) stores crude oil in 60 caverns located at four sites located along the Gulf Coast. As a matter of normal operation of caverns in a salt dome, the continuous mechanical creep of salt, along with the change in internal cavern and casing pressure due to cavern closure and fluid exchanges, impose several mechanical conditions on the skin, well, and casing of a cavern that could potentially create damage. Sandia, on behalf of DOE, is evaluating the structural integrity of the salt surrounding existing caverns in the Bayou Choctaw (BC) salt dome in Louisiana. In reality, the geometry, spacing, and depths of the caverns are irregular. It is not easy to realize the naturally and artificially formed cavern and salt dome for numerical analysis. It is harder to convert the geometries into the meshed mass consisting of only hexahedral finite elements. A three-dimensional (3D) finite element mesh capturing realistic geometries of the Bayou Choctaw site has been constructed using the seismic and sonar survey data obtained from the field (see Figures below). The mesh consists of hexahedral elements because the salt constitutive model is coded using hexahedral elements. Techniques to reduce the number of elements as much as possible to save on computer run time while maintaining computational accuracy are also developed. These methodologies could also be applied to construct computational meshes for the Big Hill, Bryan Mound, and West Hackberry SPR sites. The methodology could be applied to the complicated shape masses for not only various civil and geological structures but also biological applications such as artificial limbs. The newly developed mesh is expected to provide more accurate solutions of geotechnical concerns that arise due to the close proximity of the caverns to each other or to the edge of salt. Also, there are nine abandoned caverns, one of which is believed to be in a quasi-stable condition. Stability issues for these abandoned caverns must be evaluated and, if necessary, addressed to prevent potential cavern collapse. The integrity of wellbores at the interbed between the caprock and salt is another concern because oil leaks could occur due to the horizontal and downward movements of the salt top relative to the caprock.

Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats.

PubMed

Martínez-Salamanca, Juan I; Zurita, Mercedes; Costa, Carla; Martínez-Salamanca, Eduardo; Fernández, Argentina; Castela, Angela; Vaquero, Jesús; Carballido, Joaquín; Angulo, Javier

2016-01-01

Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI). To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI. Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC. In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue. BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups. A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Simulation of Cavern Formation and Karst Development Using Salt

ERIC Educational Resources Information Center

Kent, Douglas C.; Ross, Alex R.

1975-01-01

A salt model was developed as a teaching tool to demonstrate the development of caverns and karst topography. Salt slabs are placed in a watertight box to represent fractured limestone. Erosion resulting from water flow can be photographed in time-lapse sequence or demonstrated in the laboratory. (Author/CP)

SANSMIC design document.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Paula D.; Rudeen, David Keith

2015-07-01

The United States Strategic Petroleum Reserve (SPR) maintains an underground storage system consisting of caverns that were leached or solution mined in four salt domes located near the Gulf of Mexico in Texas and Louisiana. The SPR comprises more than 60 active caverns containing approximately 700 million barrels of crude oil. Sandia National Labo- ratories (SNL) is the geotechnical advisor to the SPR. As the most pressing need at the inception of the SPR was to create and fill storage volume with oil, the decision was made to leach the caverns and fill them simultaneously (leach-fill). Therefore, A.J. Russo developedmore » SANSMIC in the early 1980s which allows for a transient oil-brine interface (OBI) making it possible to model leach-fill and withdrawal operations. As the majority of caverns are currently filled to storage capacity, the primary uses of SANSMIC at this time are related to the effects of small and large withdrawals, expansion of existing caverns, and projecting future pillar to diameter ratios. SANSMIC was identified by SNL as a priority candidate for qualification. This report continues the quality assurance (QA) process by documenting the "as built" mathematical and numerical models that comprise this document. The pro- gram flow is outlined and the models are discussed in detail. Code features that were added later or were not documented previously have been expounded. No changes in the code's physics have occurred since the original documentation (Russo, 1981, 1983) although recent experiments may yield improvements to the temperature and plume methods in the future.« less

Micro-Macro Analysis and Phenomenological Modelling of Salt Viscous Damage and Application to Salt Caverns

NASA Astrophysics Data System (ADS)

Zhu, Cheng; Pouya, Ahmad; Arson, Chloé

2015-11-01

This paper aims to gain fundamental understanding of the microscopic mechanisms that control the transition between secondary and tertiary creep around salt caverns in typical geological storage conditions. We use a self-consistent inclusion-matrix model to homogenize the viscoplastic deformation of halite polycrystals and predict the number of broken grains in a Representative Elementary Volume of salt. We use this micro-macro modeling framework to simulate creep tests under various axial stresses, which gives us the critical viscoplastic strain at which grain breakage (i.e., tertiary creep) is expected to occur. The comparison of simulation results for short-term and long-term creep indicates that the initiation of tertiary creep depends on the stress and the viscoplastic strain. We use the critical viscoplastic deformation as a yield criterion to control the transition between secondary and tertiary creep in a phenomenological viscoplastic model, which we implement into the Finite Element Method program POROFIS. We model a 850-m-deep salt cavern of irregular shape, in axis-symmetric conditions. Simulations of cavern depressurization indicate that a strain-dependent damage evolution law is more suitable than a stress-dependent damage evolution law, because it avoids high damage concentrations and allows capturing the formation of a damaged zone around the cavity. The modeling framework explained in this paper is expected to provide new insights to link grain breakage to phenomenological damage variables used in Continuum Damage Mechanics.

Dilatancy Criteria for Salt Cavern Design: A Comparison Between Stress- and Strain-Based Approaches

NASA Astrophysics Data System (ADS)

Labaune, P.; Rouabhi, A.; Tijani, M.; Blanco-Martín, L.; You, T.

2018-02-01

This paper presents a new approach for salt cavern design, based on the use of the onset of dilatancy as a design threshold. In the proposed approach, a rheological model that includes dilatancy at the constitutive level is developed, and a strain-based dilatancy criterion is defined. As compared to classical design methods that consist in simulating cavern behavior through creep laws (fitted on long-term tests) and then using a criterion (derived from short-terms tests or experience) to determine the stability of the excavation, the proposed approach is consistent both with short- and long-term conditions. The new strain-based dilatancy criterion is compared to a stress-based dilatancy criterion through numerical simulations of salt caverns under cyclic loading conditions. The dilatancy zones predicted by the strain-based criterion are larger than the ones predicted by the stress-based criteria, which is conservative yet constructive for design purposes.

Threat of a sinkhole: A reevaluation of Cavern 4, Bayou Choctaw salt dome, Louisiana

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neal, J.T.; Todd, J.L.; Linn, J.K.

1993-09-01

Cavern Lake at Bayou Choctaw salt dome resulted from the failure of Cavern 7 in 1954. Uncontrolled solutioning of this cavern through the thin caprock had set the stage for overburden to collapse into the cavern below. A similar situation developed with nearby Cavern 4, but with less dissolutioning of the caprock. Because pressure loss was already a problem and because another 800 ft diameter lake would have endangered surface operations, solutioning of Cavern 4 was stopped and the cavern abandoned in 1957 in order to protect the already-small site. In 1978 the Strategic Petroleum Reserve (SPR) acquired a numbermore » of caverns at Bayou Choctaw, including Cavern 4, and the possible repeat of the Cavern 7 failure and formation of another lake thus became an issue. The cavern dimensions were re-sonared in 1980 for comparison with 1963 and 1977 surveys. Annual surface leveling between 1982--1992 showed less subsidence occurring than the site average, and a cavern monitoring system, installed in 1984, has revealed no anomalous motion. Repeat sonar surveys in 1992 showed very little, if any, change occurred since 1980 although a small amount of uncertainty exists as a result of changing sonar techniques. We conclude that significant additional solutioning or erosion of the caprock has not occurred and that there is no increased threat to SPR operations.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinkebein, Thomas E.

The intrusion of gas into oils stored within the SPR has been examined. When oil is stored in domal salts, gases intrude into the stored oil from the surrounding salt. Aspects of the mechanism of gas intrusion have been examined. In all cases, this gas intrusion results in increases in the oil vapor pressure. Data that have been gathered from 1993 to August 2002 are presented to show the resultant increases in bubble-point pressure on a cavern-by-cavern as well as on a stream basis. The measurement techniques are presented with particular emphasis on the TVP 95. Data analysis methods aremore » presented to show the methods required to obtain recombined cavern oil compositions. Gas-oil ratios are also computed from the data and are presented on a cavern-by-cavern and stream basis. The observed increases in bubble-point pressure and gas-oil ratio are further statistically analyzed to allow data interpretation. Emissions plume modeling is used to determine adherence to state air regulations. Gas intrusion is observed to be variable among the sites and within each dome. Gas intrusions at Bryan Mound and Big Hill have resulted in the largest increases in bubble-point pressure for the Strategic Petroleum Reserve (SPR). The streams at Bayou Choctaw and West Hackberry show minimal bubble-point pressure increases. Emissions plume modeling, using the state mandated ISCST code, of oil storage tanks showed that virtually no gas may be released when H2S standards are considered. DOE plans to scavenge H2S to comply with the very tight standards on this gas. With the assumption of scavenging, benzene releases become the next most controlling factor. Model results show that a GOR of 0.6 SCF/BBL may be emissions that are within standards. Employing the benzene gas release standard will significantly improve oil deliverability. New plume modeling using the computational fluid dynamics code, FLUENT, is addressing limitations of the state mandated ISCST model.« less

Instability risk analysis and risk assessment system establishment of underground storage caverns in bedded salt rock

NASA Astrophysics Data System (ADS)

Jing, Wenjun; Zhao, Yan

2018-02-01

Stability is an important part of geotechnical engineering research. The operating experiences of underground storage caverns in salt rock all around the world show that the stability of the caverns is the key problem of safe operation. Currently, the combination of theoretical analysis and numerical simulation are the mainly adopts method of reserve stability analysis. This paper introduces the concept of risk into the stability analysis of underground geotechnical structure, and studies the instability of underground storage cavern in salt rock from the perspective of risk analysis. Firstly, the definition and classification of cavern instability risk is proposed, and the damage mechanism is analyzed from the mechanical angle. Then the main stability evaluating indicators of cavern instability risk are proposed, and an evaluation method of cavern instability risk is put forward. Finally, the established cavern instability risk assessment system is applied to the analysis and prediction of cavern instability risk after 30 years of operation in a proposed storage cavern group in the Huai’an salt mine. This research can provide a useful theoretical base for the safe operation and management of underground storage caverns in salt rock.

SU-E-I-91: Quantitative Assessment of Early Hepatocellular Carcinoma and Cavernous Hemangioma of Live Using In-Line Phase-Contrast X-Ray Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, J

Purpose: To investigate the potential utility of in-line phase-contrast imaging (ILPCI) technique with synchrotron radiation in detecting early hepatocellular carcinoma and cavernous hemangioma of live using in vitro model system. Methods: Without contrast agents, three typical early hepatocellular carcinoma specimens and three typical cavernous hemangioma of live specimens were imaged using ILPCI. To quantitatively discriminate early hepatocellular carcinoma tissues and cavernous hemangioma tissues, the projection images texture feature based on gray level co-occurrence matrix (GLCM) were extracted. The texture parameters of energy, inertia, entropy, correlation, sum average, sum entropy, difference average, difference entropy and inverse difference moment, were obtained respectively.more » Results: In the ILPCI planar images of early hepatocellular carcinoma specimens, vessel trees were clearly visualized on the micrometer scale. Obvious distortion deformation was presented, and the vessel mostly appeared as a ‘dry stick’. Liver textures appeared not regularly. In the ILPCI planar images of cavernous hemangioma of live specimens, typical vessels had not been found compared with the early hepatocellular carcinoma planar images. The planar images of cavernous hemangioma of live specimens clearly displayed the dilated hepatic sinusoids with the diameter of less than 100 microns, but all of them were overlapped with each other. The texture parameters of energy, inertia, entropy, correlation, sum average, sum entropy, and difference average, showed a statistically significant between the two types specimens image (P<0.01), except the texture parameters of difference entropy and inverse difference moment(P>0.01). Conclusion: The results indicate that there are obvious changes in morphological levels including vessel structures and liver textures. The study proves that this imaging technique has a potential value in evaluating early hepatocellular carcinoma and cavernous hemangioma of live.« less

Efficacy of transsphenoidal surgery in achieving biochemical cure of growth hormone-secreting pituitary adenomas among patients with cavernous sinus invasion: a systematic review and meta-analysis.

PubMed

Briceno, Vanessa; Zaidi, Hasan A; Doucette, Joanne A; Onomichi, Kaho B; Alreshidi, Amer; Mekary, Rania A; Smith, Timothy R

2017-05-01

Growth hormone-secreting pituitary adenomas in adults can result in severe craniofacial disfigurement and potentially fatal medical complications. Surgical resection leading to remission of the disease is dependent on complete surgical resection of the tumor. Lesions that invade the cavernous sinus may not be safely accessible via an endonasal transsphenoidal surgery (TSS), and the rates of biochemical remission of patients with residual disease vary widely in the literature. We conducted a meta-analysis to examine the prevalence of biochemical remission after TSS among patients with growth hormone-secreting pituitary adenomas with and without cavernous sinus invasion. Embase, PubMed, and Cochrane Library databases were searched for relevant publications. Fourteen studies with 972 patients with biochemically confirmed growth hormone-secreting pituitary adenomas were included in the meta-analysis. The overall remission prevalence under a fixed-effect model was 47.6% (95% CI = 40.8-54.4%) for patients with invasive macroadenomas (I 2  = 74.6%, p < 0.01); 76.4% (95% CI = 72.2-80.1%) for patients with non-invasive macroadenomas (I 2  = 59.6%, p = 0.03); and 74.2% (95% CI = 66.3-80.7%) for patients with non-invasive microadenomas (I 2  = 36.4, p = 0.10). The significant difference among the three groups resulted from the difference between patients with or without cavernous sinus invasion (p = 0.01) and not from the size of adenomas among those without cavernous sinus invasion (p = 0.66). The prevalence of biochemical remission in patients with cavernous sinus invasion was lower than in patients without cavernous sinus invasion after TSS for acromegaly.

BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells promote erectile function in a rat model of cavernous nerve electrocautery injury.

PubMed

Song, Lujie; Zhu, Jianqiang; Zhang, Xiong; Cui, Zhiqiang; Fu, Qiang; Huang, Jianwen; Lu, Hongkai

2016-01-01

Erectile dysfunction (ED) continues to be a significant problem for men following radical prostatectomy. We hypothesize that intracavernous injection of BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) can ameliorate ED in a rat model of cavernous nerve electrocautery injury (CNEI). Forty-two male Sprague-Dawley rats were randomly divided into four groups: sham + PBS (n = 6), CNEI + PBS (n = 12), CNEI + hUCB-MSCs (n = 12) and CNEI + BDNF-hUCB-MSCs (n = 12). At day 28 post-surgery, erectile function was examined and specimens were harvested for histology. Immunofluorescence staining, Masson's trichrome staining and transmission electron microscopy were performed to determine the structural changes in corpus cavernosum. Cells that are injected into penis were labeled by BrdU and tracked by immunofluorescence staining. Three days post-surgery, the concentration of BDNF protein in penile tissues was measured by Western blotting. Rats intracavernosally injected with BDNF-hUCB-MSCs showed the most significant improvement in the ratio of maximal ICP to MAP (ICP/MAP). Histological examinations showed moderate recovery of nNOS-positive nerve fibers, ratio of smooth muscle to collagen and smooth muscle content in the CNEI + hUCB-MSCs group and remarkable recovery in the CNEI + BDNF-hUCB-MSCs group compared to the CNEI + PBS group. By TEM examination, atrophy of myelinated and non-myelinated nerve fibers was noted in CNEI + PBS group and significant recovery was observed in two treated groups. There were more BrdU-positive cells in the BDNF-hUCB-MSCs group than in the hUCB-MSCs group both in the penis and in the MPG. Three days post-surgery, the concentration of BDNF protein in penile tissues in BDNF-hUCB-MSCs group was much higher than in other groups. Intracavernous injection of BDNF-hypersecreting hUCB-MSCs can enhance the recovery of erectile function, promote the CNs regeneration and inhibit corpus cavernosum fibrosis after CNEI in a rat model.

Crater Formation Above Salt Caverns: Piston vs Hour-glass

NASA Astrophysics Data System (ADS)

Berest, P.

2016-12-01

Conditions leading to crater formation above salt caverns are discussed. In most cases, at the end of leaching, the cavern roof had reached the top of the salt formation, allowing direct contact between brine and marl (or argillite) layers that compose the overburden of the salt formation. These layers are prone to weathering when in contact with saturated brine. Stoping takes place, and the cavern roof rises through the overburden. This process may be several years or dozens of years long. In Lorraine salt formations, stoping stops when the rising cavern top reaches a competent layer, the Beaumont Dolomite. Operators then lower cavern-brine pressure to trigger collapse. A rigid cylinder of rock (a "piston") drops into the cavern, and a crater whose initial edges are vertical is created. Cavern drop is more abrupt when the cavern top is filled partly with air. The contour of the piston is circular, as a circle is the shape such that the ratio between perimeter and area is minimal. In other cases, for instance in Kansas, the cavern rises until the uppermost keystone in the bedrock at shallow depth is breached, permitting loose materials to flow into the cavern through a relatively narrow hole at the bottom of the sink hole, as in an hour glass.

Limestone Caverns

ERIC Educational Resources Information Center

Powell, Richard L.

1970-01-01

Describes the origin of limestone caverns, using Mammoth Cave as an example, with particular reference to the importance of groundwater information of caverns, the present condition of groundwater, and how caverns develop within fluctuating groundwater zones. (BR)

Historical Cavern Floor Rise for All SPR Sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moriarty, Dylan Michael

2016-09-01

The Strategic Petroleum Reserve (SPR) contains the largest supply is the largest stockpile of government-owned emergency crude oil in the world. The oil is stored in multiple salt caverns spread over four sites in Louisiana and Texas. Cavern infrastructure near the bottom of the cavern can be damaged from vertical floor movement. This report presents a comprehensive history of floor movements in each cavern. Most of the cavern floor rise rates ranged from 0.5-3.5 ft/yr, however, there were several caverns with much higher rise rates. BH103, BM106, and BH105 had the three highest rise rates. Information from this report willmore » be used to better predict future vertical floor movements and optimally place cavern infrastructure. The reasons for floor rise are not entirely understood and should be investigated.« less

Manufactured caverns in carbonate rock

DOEpatents

Bruce, David A.; Falta, Ronald W.; Castle, James W.; Murdoch, Lawrence C.

2007-01-02

Disclosed is a process for manufacturing underground caverns suitable in one embodiment for storage of large volumes of gaseous or liquid materials. The method is an acid dissolution process that can be utilized to form caverns in carbonate rock formations. The caverns can be used to store large quantities of materials near transportation facilities or destination markets. The caverns can be used for storage of materials including fossil fuels, such as natural gas, refined products formed from fossil fuels, or waste materials, such as hazardous waste materials. The caverns can also be utilized for applications involving human access such as recreation or research. The method can also be utilized to form calcium chloride as a by-product of the cavern formation process.

Expansion analyses of strategic petroleum reserve in Bayou Choctaw : revised locations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ehgartner, Brian L.; Park, Byoung Yoon

2010-11-01

This report summarizes a series of three-dimensional simulations for the Bayou Choctaw Strategic Petroleum Reserve. The U.S. Department of Energy plans to leach two new caverns and convert one of the existing caverns within the Bayou Choctaw salt dome to expand its petroleum reserve storage capacity. An existing finite element mesh from previous analyses is modified by changing the locations of two caverns. The structural integrity of the three expansion caverns and the interaction between all the caverns in the dome are investigated. The impacts of the expansion on underground creep closure, surface subsidence, infrastructure, and well integrity are quantified.more » Two scenarios were used for the duration and timing of workover conditions where wellhead pressures are temporarily reduced to atmospheric pressure. The three expansion caverns are predicted to be structurally stable against tensile failure for both scenarios. Dilatant failure is not expected within the vicinity of the expansion caverns. Damage to surface structures is not predicted and there is not a marked increase in surface strains due to the presence of the three expansion caverns. The wells into the caverns should not undergo yield. The results show that from a structural viewpoint, the locations of the two newly proposed expansion caverns are acceptable, and all three expansion caverns can be safely constructed and operated.« less

Cavernous antioxidant effect of green tea, epigallocatechin-3-gallate with/without sildenafil citrate intake in aged diabetic rats.

PubMed

Mostafa, T; Sabry, D; Abdelaal, A M; Mostafa, I; Taymour, M

2013-08-01

This study aimed to assess the cavernous antioxidant effect of green tea (GT), epigallocatechin-3-gallate (EGCG) with/without sildenafil citrate intake in aged diabetic rats. One hundred and four aged male white albino rat were divided into controls that received ordinary chow, streptozotocin (STZ)-induced aged diabetic rats, STZ-induced diabetic rats on infused green tea, induced diabetic rats on epigallocatechin-3-gallate and STZ-induced diabetic rats on sildenafil citrate added to EGCG. After 8 weeks, dissected cavernous tissues were assessed for gene expression of eNOS, cavernous malondialdehyde (MDA), glutathione peroxidase (GPx), cyclic guanosine monophosphate (cGMP), and serum testosterone (T). STZ-induced diabetic rats on GT demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats. Diabetic rats on EGCG demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats or diabetic rats on GT. Diabetic rats on EGCG added to sildenafil showed significant increase in cavernous eNOS, cGMP and significant decrease in cavernous MDA compared with other groups. Serum T demonstrated nonsignificant difference between the investigated groups. It is concluded that GT and EGCG have significant cavernous antioxidant effects that are increased if sildenafil is added. © 2012 Blackwell Verlag GmbH.

Visualization of hydraulic connections using Borehole Array around LPG Underground Storage Cavern

NASA Astrophysics Data System (ADS)

Shimo, M.; Mashimo, H.; Maejima, T.; Aoki, K.

2006-12-01

This paper presents a systematic approach to visualize the hydraulic connections within the fractured rock mass around the underground LPG storage caverns using array of water injection boreholes. By taking advantage that water injection boreholes are located so as to cover the storage caverns, a complete sketch of hydraulic conditions around the caverns, such as locations of water conducting fractures, hydraulic conductivity and groundwater pressure can be obtained. Applicability of the proposed techniques have been tested in an on-going construction project operated by JOGMEC, Japan Oil, Gas and Metals National Corporation, at Namikata, Western part of Japan. Three 26m x 30m x 485m caverns, located at 150 - 200 m below the ground surface in a granitic rock, are under construction. By systematically monitoring the pressure responses between the neighboring boreholes during drilling of total 387 boreholes around the two propane caverns, a spatial profile of the hydraulic connections and hydraulic conductivity around the caverns has been successfully obtained. Locations of localized depressurized zones created during an arch excavation have been detected by monitoring pressure in each borehole after stopping water supply to that borehole temporarily. Measurement has been conducted using each one of the 302 boreholes, one at a time. Observation shows that there is a clear correlation between total pressure drop and pressure gradient versus time curve on semi-logarithmic plot, dH/log10t, as expected by the numerical prediction. Regions where dH/log10t is larger than a certain criteria, determined by a numerical simulation for flow around a cavern in a rock with uniform hydraulic conductivity, have been evaluated as a depressurized zone caused by insufficient water supply, possibly due to existence of the high permeable zones. Separate pore pressure measurement around the caverns also supports this interpretation that a low pressure is prevailing near the borehole where a large value of dH/log10t is obtained. As a countermeasure to avoid further depressurization, installation of additional water injection hole was conducted. The same observation was then repeated. It is recognized that dH/log10t has recovered above the criteria, showing that the local water balance has been improved. Finally it is concluded that the proposed rather simple but space encompassing observation is applicable to groundwater management during construction and also provides useful information for creating a hydrogeological model, considering a fracture network system, that will be used for the evaluation of the cavern performance as a storage tank.

Sonar surveys used in gas-storage cavern analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crossley, N.G.

1998-05-04

Natural-gas storage cavern internal configuration, inspection information, and cavern integrity data can be obtained during high-pressure operations with specialized gas-sonar survey logging techniques. TransGas Ltd., Regina, Sask., has successfully performed these operations on several of its deepest and highest pressurized caverns. The data can determine gas-in-place inventory and assess changes in spatial volumes. These changes can result from cavern creep, shrinkage, or closure or from various downhole abnormalities such as fluid infill or collapse of the sidewall or roof. The paper discusses conventional surveys with sonar, running surveys in pressurized caverns, accuracy of the sonar survey, initial development of Cavernmore » 5, a roof fall, Cavern 4 development, and a damaged string.« less

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

2016-04-01

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. © 2015 Blackwell Verlag GmbH.

Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats

PubMed Central

Shan, Hai-Tao; Zhang, Hai-Bo; Chen, Wen-Tao; Chen, Feng-Zhi; Wang, Tao; Luo, Jin-Tai; Yue, Min; Lin, Ji-Hong; Wei, An-Yang

2017-01-01

Stem cell transplantation and low-energy shock-wave therapy (LESWT) have emerged as potential and effective treatment protocols for diabetic erectile dysfunction. During the tracking of transplanted stem cells in diabetic erectile dysfunction models, the number of visible stem cells was rather low and decreased quickly. LESWT could recruit endogenous stem cells to the cavernous body and improve the microenvironment in diabetic cavernous tissue. Thus, we deduced that LESWT might benefit transplanted stem cell survival and improve the effects of stem cell transplantation. In this research, 42 streptozotocin-induced diabetic rats were randomized into four groups: the diabetic group (n = 6), the LESWT group (n = 6), the bone marrow-derived mesenchymal stem cell (BMSC) transplantation group (n = 15), and the combination of LESWT and BMSC transplantation group (n = 15). One and three days after BMSC transplantation, three rats were randomly chosen to observe the survival numbers of BMSCs in the cavernous body. Four weeks after BMSC transplantation, the following parameters were assessed: the surviving number of transplanted BMSCs in the cavernous tissue, erectile function, real-time polymerase chain reaction, and penile immunohistochemical assessment. Our research found that LESWT favored the survival of transplanted BMSCs in the cavernous body, which might be related to increased stromal cell-derived factor-1 expression and the enhancement of angiogenesis in the diabetic cavernous tissue. The combination of LESWT and BMSC transplantation could improve the erectile function of diabetic erectile function rats more effectively than LESWT or BMSC transplantation performed alone. PMID:27427555

Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats.

PubMed

Shan, Hai-Tao; Zhang, Hai-Bo; Chen, Wen-Tao; Chen, Feng-Zhi; Wang, Tao; Luo, Jin-Tai; Yue, Min; Lin, Ji-Hong; Wei, An-Yang

2017-01-01

Stem cell transplantation and low-energy shock-wave therapy (LESWT) have emerged as potential and effective treatment protocols for diabetic erectile dysfunction. During the tracking of transplanted stem cells in diabetic erectile dysfunction models, the number of visible stem cells was rather low and decreased quickly. LESWT could recruit endogenous stem cells to the cavernous body and improve the microenvironment in diabetic cavernous tissue. Thus, we deduced that LESWT might benefit transplanted stem cell survival and improve the effects of stem cell transplantation. In this research, 42 streptozotocin-induced diabetic rats were randomized into four groups: the diabetic group (n = 6), the LESWT group (n = 6), the bone marrow-derived mesenchymal stem cell (BMSC) transplantation group (n = 15), and the combination of LESWT and BMSC transplantation group (n = 15). One and three days after BMSC transplantation, three rats were randomly chosen to observe the survival numbers of BMSCs in the cavernous body. Four weeks after BMSC transplantation, the following parameters were assessed: the surviving number of transplanted BMSCs in the cavernous tissue, erectile function, real-time polymerase chain reaction, and penile immunohistochemical assessment. Our research found that LESWT favored the survival of transplanted BMSCs in the cavernous body, which might be related to increased stromal cell-derived factor-1 expression and the enhancement of angiogenesis in the diabetic cavernous tissue. The combination of LESWT and BMSC transplantation could improve the erectile function of diabetic erectile function rats more effectively than LESWT or BMSC transplantation performed alone.

The association of carotid cavernous fistula with Graves’ ophthalmopathy

PubMed Central

Celik, Ozlem; Buyuktas, Deram; Islak, Civan; Sarici, A Murat; Gundogdu, A Sadi

2013-01-01

Graves’ ophthalmopathy (GO) is one of the frequent manifestations of the disorder which is an inflammatory process due to fibroblast infiltration, fibroblast proliferation and accumulation of glycosaminoglycans. Eye irritation, dryness, excessive tearing, visual blurring, diplopia, pain, visual loss, retroorbital discomfort are the symptoms and they can mimic carotid cavernous fistulas. Carotid cavernous fistulas are abnormal communications between the carotid arterial system and the cavernous sinus. The clinical manifestations of GO can mimic the signs of carotid cavernous fistulas. Carotid cavernous fistulas should be considered in the differential diagnosis of the GO patients especially who are not responding to the standard treatment and when there is a unilateral or asymmetric eye involvement. Here we report the second case report with concurrent occurrence of GO and carotid cavernous fistula in the literature. PMID:23571267

Directable weathering of concave rock using curvature estimation.

PubMed

Jones, Michael D; Farley, McKay; Butler, Joseph; Beardall, Matthew

2010-01-01

We address the problem of directable weathering of exposed concave rock for use in computer-generated animation or games. Previous weathering models that admit concave surfaces are computationally inefficient and difficult to control. In nature, the spheroidal and cavernous weathering rates depend on the surface curvature. Spheroidal weathering is fastest in areas with large positive mean curvature and cavernous weathering is fastest in areas with large negative mean curvature. We simulate both processes using an approximation of mean curvature on a voxel grid. Both weathering rates are also influenced by rock durability. The user controls rock durability by editing a durability graph before and during weathering simulation. Simulations of rockfall and colluvium deposition further improve realism. The profile of the final weathered rock matches the shape of the durability graph up to the effects of weathering and colluvium deposition. We demonstrate the top-down directability and visual plausibility of the resulting model through a series of screenshots and rendered images. The results include the weathering of a cube into a sphere and of a sheltered inside corner into a cavern as predicted by the underlying geomorphological models.

Bilateral Cavernous Nerve Crush Injury in the Rat Model: A Comparative Review of Pharmacologic Interventions.

PubMed

Haney, Nora M; Nguyen, Hoang M T; Honda, Matthew; Abdel-Mageed, Asim B; Hellstrom, Wayne J G

2018-04-01

It is common for men to develop erectile dysfunction after radical prostatectomy. The anatomy of the rat allows the cavernous nerve (CN) to be identified, dissected, and injured in a controlled fashion. Therefore, bilateral CN injury (BCNI) in the rat model is routinely used to study post-prostatectomy erectile dysfunction. To compare and contrast the available literature on pharmacologic intervention after BCNI in the rat. A literature search was performed on PubMed for cavernous nerve and injury and erectile dysfunction and rat. Only articles with BCNI and pharmacologic intervention that could be grouped into categories of immune modulation, growth factor therapy, receptor kinase inhibition, phosphodiesterase type 5 inhibition, and anti-inflammatory and antifibrotic interventions were included. To assess outcomes of pharmaceutical intervention on erectile function recovery after BCNI in the rat model. The ratio of maximum intracavernous pressure to mean arterial pressure was the main outcome measure chosen for this analysis. All interventions improved erectile function recovery after BCNI based on the ratio of maximum intracavernous pressure to mean arterial pressure results. Additional end-point analysis examined the corpus cavernosa and/or the major pelvic ganglion and CN. There was extreme heterogeneity within the literature, making accurate comparisons between crush injury and therapeutic interventions difficult. BCNI in the rat is the accepted animal model used to study nerve-sparing post-prostatectomy erectile dysfunction. However, an important limitation is extreme variability. Efforts should be made to decrease this variability and increase the translational utility toward clinical trials in humans. Haney NM, Nguyen HMT, Honda M, et al. Bilateral Cavernous Nerve Crush Injury in the Rat Model: A Comparative Review of Pharmacologic Interventions. Sex Med Rev 2018;6:234-241. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Systematic Evaluation of Salt Cavern Well Integrity

NASA Astrophysics Data System (ADS)

Roberts, B. L.; Lord, D. L.; Lord, A. S.; Bettin, G.; Sobolik, S. R.; Park, B. Y.

2017-12-01

The U.S. Strategic Petroleum Reserve (SPR) holds a reserve of crude oil ( 700 million barrels) to help ease any interruptions in oil import to the United States. The oil is stored in a set of 63 underground caverns distributed across four sites along the U.S. Gulf Coast. The caverns were solution mined into salt domes at each of the four sites. The plastic nature of the salt is beneficial for the storage of crude oil as it heals any fractures that may occur in the salt. The SPR is responsible for operating and maintaining the nearly 120 wells used to access the storage caverns over operational lifetimes spanning decades. Salt creep can induce deformation of the well casing which must be remediated to insure cavern and well integrity. This is particularly true at the interface between the plastic salt and the rigid caprock. The Department of Energy, the SPR Management and Operations contractor, and Sandia National Laboratories has developed a multidimensional well-grading system for the salt cavern access wells. This system is designed to assign numeric grades to each well indicating its risk of losing integrity and remediation priority. The system consists of several main components which themselves may consist of sub-components. The main components consider such things as salt cavern pressure history, results from geomechanical simulations modeling salt deformation, and measurements of well casing deformation due to salt creep. In addition, the geology of the salt domes and their overlying caprock is also included in the grading. These multiple factors are combined into summary values giving the monitoring and remediation priority for each well. Sandia National Laboratories is a multimission laboratory managed and operated by National Technology and Engineering Solutions of Sandia LLC, a wholly owned subsidiary of Honeywell International Inc. for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-NA0003525.

[Fracture of the penis].

PubMed

Kogan, M I; Obeĭd, M T; Siziakin, D V

2007-01-01

Rupture of the cavernous bodies is a serious penile trauma which may result in severe long-term consequences. Standard suturing of the cavernous body is accompanied with posttraumatic complications: erectile dysfunction and distortion of the penis. The results of examination and treatment of 38 patients with rupture of the tunica albuginea of the penile cavernous bodies are presented. The technique of the cavernous body wound suturing was perfected. Long-term sequences of fracture of the penis in conservative policy and different methods of cavernous body wound suturing are compared.

Beta electron fluxes inside a magnetic plasma cavern: Calculation and comparison with experiment

NASA Astrophysics Data System (ADS)

Stupitskii, E. L.; Smirnov, E. V.; Kulikova, N. A.

2010-12-01

We study the possibility of electrostatic blanking of beta electrons in the expanding spherical blob of a radioactive plasma in a rarefied ionosphere. From numerical studies on the dynamics of beta electrons departing a cavern, we obtain the form of a function that determines the portion of departing electrons and calculate the flux density of beta electrons inside the cavern in relation to the Starfish Prime nuclear blast. We show that the flux density of electrons in geomagnetic flux tubes and inside the cavern depend on a correct allowance for the quantity of beta electrons returning to the cavern. On the basis of a physical analysis, we determine the approximate criterion for the return of electrons from a geomagnetic flux tube to the cavern. We compare calculation results in terms of the flux density of beta electrons inside the cavern with the recently published experimental results from operation Starfish Prime.

Cavernous sinus thrombosis caused by contralateral sphenoid sinusitis: a case report

PubMed Central

2013-01-01

Objective To report a rare case of unilateral cavernous sinus thrombosis caused by contralateral sphenoid sinusitis. Case report A 33-year-old female visited our hospital for severe, right-sided, temporal headache, chemosis, periorbital edema, and proptosis. These signs were associated with congested erythematous nasal mucosa with purulent discharge from the right superior nasal meatus. Contrast enhanced CT showed dilated left superior ophthalmic vein, suggestive of thrombosis, contrast enhancement of the left cavernous sinuses, and dilation of cavernous sinus, indicating cavernous sinus inflammation. The right maxillary, ethmoid and sphenoid sinuses showed mucosal thickening and retention of purulent material. She was diagnosed with cavernous sinus thrombosis caused by contralateral sphenoid sinusitis. All clinical symptoms and signs improved after endoscopic sphenoidotomy and appropriate medical treatment. Conclusions Sphenoiditis can cause contralateral cavernous sinus thrombosis. Early surgical sphenoidotomy and aggressive medical treatment are the cornerstones of successful management of this life-threatening complication. PMID:23497466

[Endovascular treatment of carotid-cavernous fistula type A with platinium coils].

PubMed

Culafić, Slobodan; Juszkat, Robert; Rusović, Sinisa; Stefanović, Dara; Minić, Ljubodrag; Spaić, Milan

2008-12-01

Carotid-cavernous fistulas are abnormal communications between carotid arteries or their branches and the cavernous system caused mostly by trauma. Posttraumatic fistulas represent 70% of all carotid-cavernous fistulas and they are mostly high-flow shunts (type A). This type gives characteristic eye symptoms. This paper presents a 44-year old male patient with carotid-cavernous fistula as a result of penetrating head injury. In clinical presentation the patient had exophthalmos, conjunctival chemosis and weakening of vision on the right eye, headache and diplopia. Digital subtracted angiography showed high-flow carotid-cavernous fistula, which was vascularised from the left carotid artery and from vertebrobasilar artery. Endovascular embolization with platinum coils was performed through the transarterial route (endoarterial approach). Check angiogram confirmed that the fistula was closed and that no new communications developed. Embolization of complex carotid-cavernous fistula type A was successfully performed with platinum coils by endovascular approach.

Antifibrogenic role of valproic acid in streptozotocin induced diabetic rat penis.

PubMed

Kutlu, O; Karaguzel, E; Gurgen, S G; Okatan, A E; Kutlu, S; Bayraktar, C; Kazaz, I O; Eren, H

2016-05-01

We investigated the therapeutic effects of valproic acid (VPA) on erectile dysfunction and reducing penile fibrosis in streptozocin (STZ)-induced diabetic rats. Eighteen male rats were divided into three experimental groups (Control, STZ-DM, STZ-DM plus VPA) and diabetes was induced by transperitoneal single dose STZ. Eight weeks after, VPA and placebo treatments were given according to groups for 15 days. All rats were anesthetised for the measurement of in vivo erectile response to cavernous nerve stimulation. Afterward penes were evaluated histologically in terms of immune labelling scores of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Slides were also evaluated in terms of collagen/smooth muscle ratio and penile apoptosis. After the treatment with VPA, erectile responses were found as improved when compared with STZ-DM rats but not statistically meaningful. eNOS and VEGF immune expressions diminished in penile corpora of STZ-DM rats and improved with VPA treatment. VPA led to decrease in TGF-β1 expression and collagen content of diabetic rats' penes. Penile apoptosis was not diminished with VPA. In conclusion, VPA treatment seems to be effective for reducing penile fibrosis in diabetic rats and more prolonged treatment period may enhance erectile functions. © 2015 Blackwell Verlag GmbH.

Structural Stability Monitoring of a Physical Model Test on an Underground Cavern Group during Deep Excavations Using FBG Sensors.

PubMed

Li, Yong; Wang, Hanpeng; Zhu, Weishen; Li, Shucai; Liu, Jian

2015-08-31

Fiber Bragg Grating (FBG) sensors are comprehensively recognized as a structural stability monitoring device for all kinds of geo-materials by either embedding into or bonding onto the structural entities. The physical model in geotechnical engineering, which could accurately simulate the construction processes and the effects on the stability of underground caverns on the basis of satisfying the similarity principles, is an actual physical entity. Using a physical model test of underground caverns in Shuangjiangkou Hydropower Station, FBG sensors were used to determine how to model the small displacements of some key monitoring points in the large-scale physical model during excavation. In the process of building the test specimen, it is most successful to embed FBG sensors in the physical model through making an opening and adding some quick-set silicon. The experimental results show that the FBG sensor has higher measuring accuracy than other conventional sensors like electrical resistance strain gages and extensometers. The experimental results are also in good agreement with the numerical simulation results. In conclusion, FBG sensors could effectively measure small displacements of monitoring points in the whole process of the physical model test. The experimental results reveal the deformation and failure characteristics of the surrounding rock mass and make some guidance for the in situ engineering construction.

Structural Stability Monitoring of a Physical Model Test on an Underground Cavern Group during Deep Excavations Using FBG Sensors

PubMed Central

Li, Yong; Wang, Hanpeng; Zhu, Weishen; Li, Shucai; Liu, Jian

2015-01-01

Fiber Bragg Grating (FBG) sensors are comprehensively recognized as a structural stability monitoring device for all kinds of geo-materials by either embedding into or bonding onto the structural entities. The physical model in geotechnical engineering, which could accurately simulate the construction processes and the effects on the stability of underground caverns on the basis of satisfying the similarity principles, is an actual physical entity. Using a physical model test of underground caverns in Shuangjiangkou Hydropower Station, FBG sensors were used to determine how to model the small displacements of some key monitoring points in the large-scale physical model during excavation. In the process of building the test specimen, it is most successful to embed FBG sensors in the physical model through making an opening and adding some quick-set silicon. The experimental results show that the FBG sensor has higher measuring accuracy than other conventional sensors like electrical resistance strain gages and extensometers. The experimental results are also in good agreement with the numerical simulation results. In conclusion, FBG sensors could effectively measure small displacements of monitoring points in the whole process of the physical model test. The experimental results reveal the deformation and failure characteristics of the surrounding rock mass and make some guidance for the in situ engineering construction. PMID:26404287

A Comparison of Simplified Two-dimensional Flow Models Exemplified by Water Flow in a Cavern

NASA Astrophysics Data System (ADS)

Prybytak, Dzmitry; Zima, Piotr

2017-12-01

The paper shows the results of a comparison of simplified models describing a two-dimensional water flow in the example of a water flow through a straight channel sector with a cavern. The following models were tested: the two-dimensional potential flow model, the Stokes model and the Navier-Stokes model. In order to solve the first two, the boundary element method was employed, whereas to solve the Navier-Stokes equations, the open-source code library OpenFOAM was applied. The results of numerical solutions were compared with the results of measurements carried out on a test stand in a hydraulic laboratory. The measurements were taken with an ADV probe (Acoustic Doppler Velocimeter). Finally, differences between the results obtained from the mathematical models and the results of laboratory measurements were analysed.

Japan's exploration of vertical holes and subsurface caverns on the Moon and Mars

NASA Astrophysics Data System (ADS)

Haruyama, J.; Kawano, I.; Kubota, T.; Yoshida, K.; Kawakatsu, Y.; Kato, H.; Otsuki, M.; Watanabe, K.; Nishibori, T.; Yamamoto, Y.; Iwata, T.; Ishigami, G.; Yamada, T. T.

2013-12-01

Recently, gigantic vertical holes exceeding several tens of meters in diameter and depth were discovered on the Moon and Mars. Based on high-resolution image data, lunar holes and some Martian pits (called 'holes' hereafter) are probably skylights of subsurface caverns such as lava tubes or magma chambers. We are starting preparations for exploring the caverns through the vertical holes. The holes and subsurface caverns have high potential as resources for scientific studies. Various important geological and mineralogical processes could be uniquely and effectively observed inside these holes and subsurface caverns. The exposed fresh lava layers on the vertical walls of the lunar and Martian holes would provide information on volcanic eruption histories. The lava layers may also provide information on past magnetic fields of the celestial bodies. The regolith layers may be sandwiched between lava layers and may preserve volatile elements including solar wind protons that could be a clue to understanding past solar activities. Water molecules from solar winds or cometary/meteorite impacts may be stored inside the caverns because of mild temperatures there. The fresh lava materials forming the walls and floors of caverns might trap endogenic volatiles from magma eruptions that will be key materials for revealing the formation and early evolution of the Moon and Mars. Furthermore, the Martian subsurface caverns are highly expected to be life cradles where the temperatures are probably stable and that are free from ultra-violet and other cosmic rays that break chemical bonds, thus avoiding polymerization of molecules. Discovering extraterrestrial life and its varieties is one of our ultimate scientific purposes for exploring the lunar and Martian subsurface caverns. In addition to scientific interests, lunar and Martian subsurface caverns are excellent candidates for future lunar bases. We expect such caverns to have high potential due to stable temperatures; absence of ultra-violet rays, cosmic rays, and meteorite impacts; spacious volumes based on analogues of terrestrial lava tubes; tight walls and floors possibly glass-coated by rapid cooling inside the caverns; and so on. Exploration of subsurface caverns of the Moon and Mars would provide answers to various basic and applied scientific questions fundamental to understanding the nature of the Moon, Mars, and life. Furthermore, it could provide knowledge to enable constructing lunar and Martian bases for robotic and/or manned activities there. However, Japan does not have the technology for soft-landing on gravitational celestial bodies. First, we should acquire that technology. Next, we should acquire the technology for approaching and descending into holes that could be skylights of caverns. We should also develop the technology to move on the floors where there are many boulders and/or a mound of dusts. We should also consider how to investigate the dark inside of the caverns. There are many engineering challenges for exploring the lunar and Martian subsurface caverns, but our team is prepared to meet them.

"Tepid" Geysers above salt caverns

NASA Astrophysics Data System (ADS)

Bérest, Pierre; Brouard, Benoît; Zakharov, Vassily

2018-06-01

The formation of a brine geyser erupting from the wellhead of a large underground salt cavern is described. In most cases, the brine outflow from an opened cavern is slow; it results from the cavern creep closure and the thermal expansion of the cavern brine. These two processes are smooth; however, the brine outflow often is bumpy, as it is modulated by atmospheric pressure variations that generate an elastic increase (or decrease) of both cavern and brine volumes. In addition, when the flow is fast enough, the brine thermodynamic behavior in the wellbore is adiabatic. The cold brine expelled from the cavern wellhead is substituted with warm brine entering the borehole bottom, resulting in a lighter brine column. The brine outflow increases. In some cases, the flow becomes so fast that inertia terms must be taken into account. A geyser forms, coming to an end when the pressure in the cavern has dropped sufficiently. A better picture is obtained when head losses are considered. A closed-form solution can be reached. This proves that two cases must be distinguished, depending on whether the cold brine initially contained in the wellbore is expelled fully or not. It can also be shown that geyser formation is a rare event, as it requires both that the wellbore be narrow and that the cavern be very compressible. This study stemmed from an actual example in which a geyser was observed. However, scarce information is available, making any definite interpretation difficult. xml:lang="fr"

CaveMan Enterprise version 1.0 Software Validation and Verification.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hart, David

The U.S. Department of Energy Strategic Petroleum Reserve stores crude oil in caverns solution-mined in salt domes along the Gulf Coast of Louisiana and Texas. The CaveMan software program has been used since the late 1990s as one tool to analyze pressure mea- surements monitored at each cavern. The purpose of this monitoring is to catch potential cavern integrity issues as soon as possible. The CaveMan software was written in Microsoft Visual Basic, and embedded in a Microsoft Excel workbook; this method of running the CaveMan software is no longer sustainable. As such, a new version called CaveMan Enter- prisemore » has been developed. CaveMan Enterprise version 1.0 does not have any changes to the CaveMan numerical models. CaveMan Enterprise represents, instead, a change from desktop-managed work- books to an enterprise framework, moving data management into coordinated databases and porting the numerical modeling codes into the Python programming language. This document provides a report of the code validation and verification testing.« less

Electrocautery-induced cavernous nerve injury in rats that mimics radical prostatectomy in humans.

PubMed

Song, Lu-Jie; Zhu, Jian-Qiang; Xie, Min-Kai; Wang, Yong-Chuan; Li, Hong-Bin; Cui, Zhi-Qiang; Lu, Hong-Kai; Xu, Yue-Min

2014-07-01

To investigate the early and delayed effects of cavernous nerve electrocautery injury (CNEI) in a rat model, with the expectation that this model could be used to test rehabilitation therapies for erectile dysfunction (ED) after radical prostatectomy (RP). In all, 30 male Sprague-Dawley rats were randomly divided equally into two groups (15 per group). The control group received CNs exposure surgery only and the experimental group received bilateral CNEI. At 1, 4 and 16 weeks after surgery (five rats at each time point), the ratio of maximal intracavernosal pressure (ICP) to mean arterial pressure (MAP) was measured in the two groups. Neurofilament expression in the dorsal penile nerves was assessed by immunofluorescent staining and Masson's trichrome staining was used to assess the smooth muscle to collagen ratio in both groups. At the 1-week follow-up, the mean ICP/MAP was significantly lower in the CNEI group compared with the control group, at 9.94% vs 70.06% (P < 0.05). The mean ICP/MAP in the CNEI group was substantially increased at the 4- (35.97%) and 16-week (37.11%) follow-ups compared with the 1-week follow-up (P < 0.05). At all three follow-up time points, the CNEI group had significantly decreased neurofilament staining compared with the control group (P < 0.05). Also, neurofilament expressions in the CNEI group at both 4 and 16 weeks were significantly higher than that at 1 week (P < 0.05), but there was no difference between 4 and 16 weeks (P > 0.05). The smooth muscle to collagen ratio in the CNEI group was significantly lower than in the control group at the 4- and 16-week follow-ups (P < 0.05), and the ratio at 16 weeks was further reduced compared with that at 4 weeks (P < 0.05). In the CNEI rat model, we found the damaging effects of CNEI were accompanied by a decline in ICP, reduced numbers of nerve fibres in the dorsal penile nerve, and exacerbated fibrosis in the corpus cavernosum. This may provide a basis for studying potential preventative measures or treatment strategies to ameliorate ED caused by CNEI during RP. © 2013 The Authors. BJU International © 2013 BJU International.

Interactive evolution concept for analyzing a rock salt cavern under cyclic thermo-mechanical loading

NASA Astrophysics Data System (ADS)

König, Diethard; Mahmoudi, Elham; Khaledi, Kavan; von Blumenthal, Achim; Schanz, Tom

2016-04-01

The excess electricity produced by renewable energy sources available during off-peak periods of consumption can be used e.g. to produce and compress hydrogen or to compress air. Afterwards the pressurized gas is stored in the rock salt cavities. During this process, thermo-mechanical cyclic loading is applied to the rock salt surrounding the cavern. Compared to the operation of conventional storage caverns in rock salt the frequencies of filling and discharging cycles and therefore the thermo-mechanical loading cycles are much higher, e.g. daily or weekly compared to seasonally or yearly. The stress strain behavior of rock salt as well as the deformation behavior and the stability of caverns in rock salt under such loading conditions are unknown. To overcome this, existing experimental studies have to be supplemented by exploring the behavior of rock salt under combined thermo-mechanical cyclic loading. Existing constitutive relations have to be extended to cover degradation of rock salt under thermo-mechanical cyclic loading. At least the complex system of a cavern in rock salt under these loading conditions has to be analyzed by numerical modeling taking into account the uncertainties due to limited access in large depth to investigate material composition and properties. An interactive evolution concept is presented to link the different components of such a study - experimental modeling, constitutive modeling and numerical modeling. A triaxial experimental setup is designed to characterize the cyclic thermo-mechanical behavior of rock salt. The imposed boundary conditions in the experimental setup are assumed to be similar to the stress state obtained from a full-scale numerical simulation. The computational model relies primarily on the governing constitutive model for predicting the behavior of rock salt cavity. Hence, a sophisticated elasto-viscoplastic creep constitutive model is developed to take into account the dilatancy and damage progress, as well as the temperature effects. The contributed input parameters in the constitutive model are calibrated using the experimental measurements. In the following, the initial numerical simulation is modified based on the introduced constitutive model implemented in a finite element code. However, because of the significant levels of uncertainties involved in the design procedure of such structures, a reliable design can be achieved by employing probabilistic approaches. Therefore, the numerical calculation is extended by statistical tools such as sensitivity analysis, probabilistic analysis and robust reliability-based design. Uncertainties e.g. due to limited site investigation, which is always fragmentary within these depths, can be compensated by using data sets of field measurements for back calculation of input parameters with the developed numerical model. Monitoring concepts can be optimized by identifying sensor localizations e.g. using sensitivity analyses.

Expression of the apelin-APJ pathway and effects on erectile function in a mouse model of vasculogenic erectile dysfunction.

PubMed

Kwon, Mi-Hye; Tuvshintur, Buyankhuu; Kim, Woo Jean; Jin, Hai-Rong; Yin, Guo Nan; Song, Kang-Moon; Choi, Min Ji; Kwon, Ki-Dong; Batbold, Dulguun; Ryu, Ji-Kan; Suh, Jun-Kyu

2013-12-01

Much attention has recently been focused on therapeutic angiogenesis as a treatment for erectile dysfunction (ED). The apelin and apelin receptor (APJ) system is known to cause endothelium-dependent vasodilatation and to be involved in angiogenesis. To examine the differential expression of apelin and APJ in animal models of vasculogenic ED and to determine whether and how enhancement of apelin-APJ signaling restores erectile function in hypercholesterolemic mice. Acute cavernous ischemia was induced in C57BL/6J mice by bilateral occlusion of internal iliac arteries, and chronic vasculogenic ED was induced by feeding a high-cholesterol diet or by intraperitoneal injection of streptozotocin. Messenger RNA (mRNA) levels of apelin and APJ were determined in cavernous tissue of each vasculogenic ED model by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We evaluated erectile function by electrical stimulation of the cavernous nerve in hypercholesterolemic mice 1, 3, 7, and 14 days after a single intracavernous injection of apelin protein (5 μg/20 μL). The penis was harvested for histologic examinations and Western blot analysis. The cavernous mRNA expression of apelin and APJ was up-regulated in acute ischemia model and down-regulated in chronic vasculogenic ED models. A significant restoration of erectile function was noted 1 day after injection of apelin protein into the penis of hypercholesterolemic mice; however, erectile function returned to baseline values thereafter. The beneficial effects of apelin on erectile function resulted mainly from an activation of endothelial nitric oxide synthase and increase in nitric oxide bioavailability through reduction in reactive oxygen species-mediated endothelial apoptosis rather than through direct endothelial cell proliferation. These findings suggest that apelin-APJ signaling is a potential therapeutic target in the treatment of vasculogenic ED. Further studies are needed to develop a potent agonist for APJ and to determine the role of repeated dosing of apelin on long-term recovery of erectile function. © 2013 International Society for Sexual Medicine.

Brainstem and cerebellar cavernous malformations.

PubMed

Atwal, Gursant S; Sarris, Christina E; Spetzler, Robert F

2017-01-01

Cavernous malformations are vascular lesions that occur throughout the central nervous system, most commonly in the supratentorial location, with brainstem and cerebellar cavernous malformations occurring more rarely. Cavernous malformations are associated with developmental venous anomalies that occur sporadically or in familial form. Patients with a cavernous malformation can present with headaches, seizures, sensorimotor disturbances, or focal neurologic deficits based on the anatomic location of the lesion. Patients with infratentorial lesions present more commonly with a focal neurologic deficit. Cavernous malformations are increasingly discovered incidentally due to the increasing use of magnetic resonance imaging. Understanding the natural history of these lesions is essential to their management. Observation and surgical resection are both reasonable options in the treatment of patients with these lesions. The clinical presentation of the patient, the location of the lesion, and the surgical risk assessment all play critical roles in management decision-making. © 2017 Elsevier B.V. All rights reserved.

Deep Fracturing of the Hard Rock Surrounding a Large Underground Cavern Subjected to High Geostress: In Situ Observation and Mechanism Analysis

NASA Astrophysics Data System (ADS)

Feng, Xia-Ting; Pei, Shu-Feng; Jiang, Quan; Zhou, Yang-Yi; Li, Shao-Jun; Yao, Zhi-Bin

2017-08-01

Rocks that are far removed from caverns or tunnels peripheries and subjected to high geostress may undergo `deep fracturing'. Deep fracturing of hard rock can cause serious hazards that cause delays and increase the cost of construction of underground caverns with high sidewalls and large spans (especially when subjected to high geostress). To extensively investigate the mechanism responsible for deep fracturing, and the relationship between fracturing and the excavation & support of caverns, this paper presents a basic procedure for making in situ observations on the deep fracturing process in hard rock. The basic procedure involves predicting the stress concentration zones in the surrounding rocks of caverns induced by excavation using geomechanical techniques. Boreholes are then drilled through these stress concentration zones from pre-existing tunnels (such as auxiliary galleries) toward the caverns before its excavation. Continuous observations of the fracturing of the surrounding rocks are performed during excavation using a borehole camera in the boreholes in order to analyze the evolution of the fracturing process. The deep fracturing observed in a large underground cavern (high sidewalls and large span) in southwest China excavated in basalt under high geostress is also discussed. By continuously observing the hard rock surrounding the arch on the upstream side of the cavern during the excavation of the first three layers, it was observed that the fracturing developed into the surrounding rocks with downward excavation of the cavern. Fracturing was found at distances up to 8-9 m from the cavern periphery during the excavation of Layer III. Also, the cracks propagated along pre-existing joints or at the interfaces between quartz porphyry and the rock matrix. The relationship between deep fracturing of the surrounding rocks and the advance of the cavern working faces was analyzed during excavation of Layer Ib. The results indicate that the extent of the stress relief zone is about 7 m if footage of 3 m is adopted for the rate of advance of the cavern faces. An analysis of the effects of the initial geostress and evolving stress concentration on deep fracturing was also made. It could be concluded that the deep fracturing of the rocks in the upstream side of the cavern is caused by the combined effect of the high initial geostress, the transfer of the stress concentration zone toward the deep surrounding rocks, and the occurrence of discontinuities.

An interesting case of angiogenesis in cavernous hemangioma.

PubMed

Das, Dipankar; Bhattacharjee, Kasturi; Deka, Panna; Bhattacharjee, Harsha; Misra, Diva Kant; Koul, Akanksha; Kapoor, Deepika; Deka, Apurba

2016-10-01

Cavernous hemangioma is the most common orbital tumor in adult. There is lot of literatures for clinicopathological features of this tumor. These tumors had been studied for the model of angiogenesis in many of the experimental setups. We present a case of 34-year-old male with this tumor in the left eye with computerized tomography evidence. Postsurgical laboratory findings gave interesting evidence of tumor angiogenesis with tumor endothelial cells and sprouting of the small vessels endothelial cells. Podosome rosette could be conceptualized from the characteristic patterns seen in the tumor.

Simultaneous and sequential hemorrhage of multiple cerebral cavernous malformations: a case report.

PubMed

Louis, Nundia; Marsh, Robert

2016-02-09

The etiology of cerebral cavernous malformation hemorrhage is not well understood. Causative physiologic parameters preceding hemorrhagic cavernous malformation events are often not reported. We present a case of an individual with sequential simultaneous hemorrhages in multiple cerebral cavernous malformations with a new onset diagnosis of hypertension. A 42-year-old white man was admitted to our facility with worsening headache, left facial and tongue numbness, dizziness, diplopia, and elevated blood pressure. His past medical history was significant for new onset diagnosis of hypertension and chronic seasonal allergies. Serial imaging over the ensuing 8 days revealed sequential hemorrhagic lesions. He underwent suboccipital craniotomy for resection of the lesions located in the fourth ventricle and right cerebellum. One month after surgery, he had near complete resolution of his symptoms with mild residual vertigo but symptomatic chronic hypertension. Many studies have focused on genetic and inflammatory mechanisms contributing to cerebral cavernous malformation rupture, but few have reported on the potential of hemodynamic changes contributing to cerebral cavernous malformation rupture. Systemic blood pressure changes clearly have an effect on angioma pressures. When considering the histopathological features of cerebral cavernous malformation architecture, changes in arterial pressure could cause meaningful alterations in hemorrhage propensity and patterns.

Successful Transarterial Embolization of a Posttraumatic Fistula Between a Posterior Communicating Artery Aneurysm and the Cavernous Sinus: A Case Report.

PubMed

Jinbo, Yin; Jun, Liu; Kejie, Mou; Zheng, Zhou

2015-01-01

Posterior communicating artery (PCoA) aneurysm-cavernous sinus fistulae are an extremely rare complication of head injury . The treatment of PCoA aneurysm-cavernous sinus fistulae has not been well described. A 27-year-old man was admitted with a retroocular bruit and blurred vision of the left eye seven months after a severe head injury. We report the angiographic appearance of a posterior communicating artery (PCoA) aneurysm with a fistula to the cavernous sinus. This injury had been previously misinterpreted to be a PCoA aneurysm by computerized tomographic angiography (CTA). The patient was successfully treated with coils and Onyx of a fistula between the PCoA aneurysm and cavernous sinus.

Derivation and application of an analytical rock displacement solution on rectangular cavern wall using the inverse mapping method.

PubMed

Gao, Mingzhong; Yu, Bin; Qiu, Zhiqiang; Yin, Xiangang; Li, Shengwei; Liu, Qiang

2017-01-01

Rectangular caverns are increasingly used in underground engineering projects, the failure mechanism of rectangular cavern wall rock is significantly different as a result of the cross-sectional shape and variations in wall stress distributions. However, the conventional computational method always results in a long-winded computational process and multiple displacement solutions of internal rectangular wall rock. This paper uses a Laurent series complex method to obtain a mapping function expression based on complex variable function theory and conformal transformation. This method is combined with the Schwarz-Christoffel method to calculate the mapping function coefficient and to determine the rectangular cavern wall rock deformation. With regard to the inverse mapping concept, the mapping relation between the polar coordinate system within plane ς and a corresponding unique plane coordinate point inside the cavern wall rock is discussed. The disadvantage of multiple solutions when mapping from the plane to the polar coordinate system is addressed. This theoretical formula is used to calculate wall rock boundary deformation and displacement field nephograms inside the wall rock for a given cavern height and width. A comparison with ANSYS numerical software results suggests that the theoretical solution and numerical solution exhibit identical trends, thereby demonstrating the method's validity. This method greatly improves the computing accuracy and reduces the difficulty in solving for cavern boundary and internal wall rock displacements. The proposed method provides a theoretical guide for controlling cavern wall rock deformation failure.

Derivation and application of an analytical rock displacement solution on rectangular cavern wall using the inverse mapping method

PubMed Central

Gao, Mingzhong; Qiu, Zhiqiang; Yin, Xiangang; Li, Shengwei; Liu, Qiang

2017-01-01

Rectangular caverns are increasingly used in underground engineering projects, the failure mechanism of rectangular cavern wall rock is significantly different as a result of the cross-sectional shape and variations in wall stress distributions. However, the conventional computational method always results in a long-winded computational process and multiple displacement solutions of internal rectangular wall rock. This paper uses a Laurent series complex method to obtain a mapping function expression based on complex variable function theory and conformal transformation. This method is combined with the Schwarz-Christoffel method to calculate the mapping function coefficient and to determine the rectangular cavern wall rock deformation. With regard to the inverse mapping concept, the mapping relation between the polar coordinate system within plane ς and a corresponding unique plane coordinate point inside the cavern wall rock is discussed. The disadvantage of multiple solutions when mapping from the plane to the polar coordinate system is addressed. This theoretical formula is used to calculate wall rock boundary deformation and displacement field nephograms inside the wall rock for a given cavern height and width. A comparison with ANSYS numerical software results suggests that the theoretical solution and numerical solution exhibit identical trends, thereby demonstrating the method’s validity. This method greatly improves the computing accuracy and reduces the difficulty in solving for cavern boundary and internal wall rock displacements. The proposed method provides a theoretical guide for controlling cavern wall rock deformation failure. PMID:29155892

Comparison of mathematical models of fibrosis. Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by M. Ben Amar and C. Bianca

NASA Astrophysics Data System (ADS)

Kachapova, Farida

2016-07-01

Mathematical and computational models in biology and medicine help to improve diagnostics and medical treatments. Modeling of pathological fibrosis is reviewed by M. Ben Amar and C. Bianca in [4]. Pathological fibrosis is the process when excessive fibrous tissue is deposited on an organ or tissue during a wound healing and can obliterate their normal function. In [4] the phenomena of fibrosis are briefly explained including the causes, mechanism and management; research models of pathological fibrosis are described, compared and critically analyzed. Different models are suitable at different levels: molecular, cellular and tissue. The main goal of mathematical modeling of fibrosis is to predict long term behavior of the system depending on bifurcation parameters; there are two main trends: inhibition of fibrosis due to an active immune system and swelling of fibrosis because of a weak immune system.

Modeling the mechanical properties of liver fibrosis in rats.

PubMed

Zhu, Ying; Chen, Xin; Zhang, Xinyu; Chen, Siping; Shen, Yuanyuan; Song, Liang

2016-06-14

The progression of liver fibrosis changes the biomechanical properties of liver tissue. This study characterized and compared different liver fibrosis stages in rats in terms of viscoelasticity. Three viscoelastic models, the Voigt, Maxwell, and Zener models, were applied to experimental data from rheometer tests and then the elasticity and viscosity were estimated for each fibrosis stage. The study found that both elasticity and viscosity are correlated with the various stages of liver fibrosis. The study revealed that the Zener model is the optimal model for describing the mechanical properties of each fibrosis stage, but there is no significant difference between the Zener and Voigt models in their performance on liver fibrosis staging. Therefore the Voigt model can still be effectively used for liver fibrosis grading. Copyright © 2016 Elsevier Ltd. All rights reserved.

nNOS-positive minor-branches of the dorsal penile nerves is associated with erectile function in the bilateral cavernous injury model of rats.

PubMed

Chen, Yen-Lin; Chao, Ting-Ting; Wu, Yi-No; Chen, Meng-Chuan; Lin, Ying-Hung; Liao, Chun-Hou; Wu, Chien-Chih; Chen, Kuo-Chiang; Chou, Shang-Shing P; Chiang, Han-Sun

2018-01-17

The changes in neuronal nitric oxide synthases (nNOS) in the dorsal penile nerves (DPNs) are consistent with cavernous nerve (CN) injury in rat models. However, the anatomical relationship and morphological changes between the minor branches of the DPNs and the CNs after injury have never been clearly explored. There were forty 12 week old male Sprague-Dawley rats receiving bilateral cavernous nerve injury (BCNI). Erectile function of intracavernous pressure and mean arterial pressure were measured. The histology and ultrastructure with H&E stain, Masson's trichrome stain and immunohistochemical stains were applied on the examination of CNs and DPNs. We demonstrated communicating nerve branches between the DPNs and the CNs in rats. The greatest damage and lowest erectile function were seen in the 14 th day and partially recovered in the 28 th day after BCNI. The nNOS positive DPN minor branches' number was significantly correlated with erectile function. The sub-analysis of the number of nNOS positive DPN minor branches also matched with the time course of the erectile function after BCNI. We suggest the regeneration of the DPNs minor branches would ameliorate the erectile function in BCNI rats.

New animal models of cystic fibrosis: what are they teaching us?

PubMed Central

Keiser, Nicholas W.; Engelhardt, John F.

2013-01-01

Purpose of review Cystic fibrosis is the first human genetic disease to benefit from the directed engineering of three different species of animal models (mice, pigs, and ferrets). Recent studies on the cystic fibrosis pig and ferret models are providing new information about the pathophysiology of cystic fibrosis in various organ systems. Additionally, new conditional cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice are teaching unexpected lessons about CFTR function in surprising cellular locations. Comparisons between these animal models and the human condition are key to dissecting the complexities of disease pathophysiology in cystic fibrosis. Recent findings Cystic fibrosis pigs and ferrets have provided new models to study the spontaneous development of disease in the lung and pancreas, two organs that are largely spared overt spontaneous disease in cystic fibrosis mice. New cystic fibrosis mouse models are now interrogating CFTR functions involved in growth and inflammation at an organ-based level using conditional knockout technology. Together, these models are providing new insights on the human condition. Summary Basic and clinical cystic fibrosis research will benefit greatly from the comparative pathophysiology of cystic fibrosis mice, pigs, and ferrets. Both similarities and differences between these three cystic fibrosis models will inform pathophysiologically important mechanisms of CFTR function in humans and aid in the development of both organ-specific and general therapies for cystic fibrosis. PMID:21857224

36 CFR 7.47 - Carlsbad Caverns National Park.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Carlsbad Caverns National Park. 7.47 Section 7.47 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR SPECIAL REGULATIONS, AREAS OF THE NATIONAL PARK SYSTEM § 7.47 Carlsbad Caverns National Park. (a...

36 CFR 7.47 - Carlsbad Caverns National Park.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Carlsbad Caverns National Park. 7.47 Section 7.47 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR SPECIAL REGULATIONS, AREAS OF THE NATIONAL PARK SYSTEM § 7.47 Carlsbad Caverns National Park. (a...

36 CFR 7.47 - Carlsbad Caverns National Park.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Carlsbad Caverns National Park. 7.47 Section 7.47 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR SPECIAL REGULATIONS, AREAS OF THE NATIONAL PARK SYSTEM § 7.47 Carlsbad Caverns National Park. (a...

36 CFR 7.47 - Carlsbad Caverns National Park.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Carlsbad Caverns National Park. 7.47 Section 7.47 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR SPECIAL REGULATIONS, AREAS OF THE NATIONAL PARK SYSTEM § 7.47 Carlsbad Caverns National Park. (a...

36 CFR 7.47 - Carlsbad Caverns National Park.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Carlsbad Caverns National Park. 7.47 Section 7.47 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR SPECIAL REGULATIONS, AREAS OF THE NATIONAL PARK SYSTEM § 7.47 Carlsbad Caverns National Park. (a...

Direct carotid cavernous fistula after submucous resection of the nasal septum.

PubMed

Bizri, A R; al-Ajam, M; Zaytoun, G; al-Kutoubi, A

2000-01-01

A carotid cavernous fistula (CCF) is an abnormal arteriovenous anastomosis between the carotid artery and the cavernous sinus. Etiologies of this condition reported in the literature so far include facial trauma, rupture of an intracavernous aneurysm of the carotid artery, Ehler-Danlos syndrome and fibromuscular dysplasia of the cerebral arteries. Such fistulae were reported as complications of rhinoplasty, transsphenoidal surgery, embolization of cavernous sinus meningioma, and rhinocerebral mucormycosis. CCF may also occur spontaneously in children or as a congenital malformation. However, to our knowledge, submucous resection of the nasal septum has not been reported before to cause direct carotid-cavernous fistula. CT and angiographic findings are presented and a review of the literature for reported causes of CCF is made as well as a brief discussion of the possible pathophysiology.

Construction of the bridge in the cavern in the Vrata tunnel (Croatia)

NASA Astrophysics Data System (ADS)

Garasic, Mladen; Sasa Kovacevic, Meho; Juric-Kacunic, Danijela

2010-05-01

In the Dinaric karst system in Croatia some 11500 speleological objects have been explored so far, more than 1000 of which were discovered during construction works. Such speleological objects without natural entrance on the terrain surface (which are called "caverns") have been discovered on the construction sites of the highways. Over the past twenty years they have been systematically investigated and treated. A special kind of remediation was conducted in the cavern's large hall of the "Vrata" tunnel on the Zagreb - Rijeka highway. Due to size, shape, cavern's position and hydrogeological parameters (fissured and karstified aquifers) within the karst system it was necessary to design and construct a 58 m bridge over the cavern. In addition, the cavern's vault had to be reinforced and stabilized, as the overburden was very thin. The beam-and -stringer grid with special anchors was used. The cavern's rehabilitation in the "Vrata" tunnel was a unique undertaking, and the bridge (without piers) is the cavern's longest bridge in the world. A speleological object of large dimensions was discovered in the "Vrata"tunnel's right tube on the Rijeka-Zagreb highway. Speleological, geotechnical, engineering geological and hydrogeological investigation works were carried out for the purpose of preservation the speleological object (cavern). On the basis of classification results of rock masses and conducted numerical analyses the support system for the cavern's vault stabilization was selected. The support system's elements include the beam-and-stringer grid constructed on the terrain's surface above the cavern, tendons and geotechnical anchors. To ensure stability of the speleological object, and to conduct the backward numerical analyses the measurement of vertical deformations from the terrain's surface along the rock's mass by means of sliding micrometers was undertaken. Backward numerical analyses combined with geotechnical measurements enable safer and more rational approach to design and construction of underground structures. They contribute to the knowledge on rock mass performance and to determination of its physical and mechanical parameters connecting them with rock classification results. The analyses are a great help in verification or modification of elements' features of primary support system. Tunnel and bridge in tunnel "Vrata" were opened for traffic in November 2008. Keywords: speleology, cave, Dinaric karst, Croatia, tunnel, karst phenomena, geotechnical engineering.

Spontaneous subarachnoid hemorrhage due to ruptured cavernous internal carotid artery aneurysm after medical prolactinoma treatment.

PubMed

Khalsa, Siri Sahib; Hollon, Todd C; Shastri, Ravi; Trobe, Jonathan D; Gemmete, Joseph J; Pandey, Aditya S

2017-03-01

Aneurysms of the cavernous segment of the internal carotid artery (ICA) are believed to have a low risk of subarachnoid haemorrhage (SAH), given the confines of the dural rings and the anterior clinoid process. The risk may be greater when the bony and dural protection has been eroded. We report a case of spontaneous SAH from rupture of a cavernous ICA aneurysm in a patient whose large prolactinoma had markedly decreased in size as the result of cabergoline treatment. After passing a balloon test occlusion, the patient underwent successful endovascular vessel deconstruction. This case suggests that an eroding skull base lesion may distort normal anterior cranial base anatomy and allow communication between the cavernous ICA and subarachnoid space. The potential for SAH due to cavernous ICA aneurysm rupture should be recognised in patients with previous pituitary or other skull base lesions adjacent to the cavernous sinus. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Frontal Lobe Cavernous Malformations in Pediatric Patients: Clinical Features and Surgical Outcomes.

PubMed

Wang, Chengjun; Zhao, Meng; Wang, Jia; Wang, Shuo; Jiang, Zhongli; Zhao, Jizong

2018-01-01

The purpose of this study is to investigate the clinical manifestations, surgical treatment, and neurologic outcomes of frontal lobe cavernous malformations in children. A retrospective analysis of 23 pediatric frontal lobe cavernous malformation patients who underwent surgical treatment in Beijing Tiantan Hospital was performed. The case series included 16 boys and 7 girls. Gross total removal without surgical mortality was achieved in all patients. The mean follow-up period after surgery was 33.1 months. Two patients who left hospital with motor deficits gradually recovered after rehabilitative treatment, and other patients were considered to be in excellent clinical condition. For symptomatic frontal lobe cavernous malformations, neurosurgical management should be the treatment of choice. Conservative treatment may be warranted in asymptomatic frontal lobe cavernous malformations, especially the deep-seated or eloquently located cases.

Hazard assessment of the stability of a cavern roof along the coastline

NASA Astrophysics Data System (ADS)

Reina, A.; Lollino, P.

2009-04-01

This work concerns the hazard assessment about the stability of a large shallow depth cavern, located along the coastline rocky sector of Polignano town (Apulia, Southern Italy) under an intensely urbanised area. This cavern, which lies at the sea level, has been created by a prolonged process of sea erosion within a rock mass formed of a lower stratified limestone mass and an upper Gravina Calcarenite mass. The thickness of the cavern roof, which has a dome shape, is less than 10 metres in the centre. Important buildings, as hotels and private houses, are located just above the top of the roof. Erosion processes have been observed to be still active along the whole cavern due to climate factors and, in particular, to sea salt weathering and sea spray effects. In 2007 a large calcarenite block, 3 m large, fell down from the cavern roof and consequently a field investigation campaign was carried out for a rational stabilization plan in order to understand the current stability conditions of the roof and the potential failure mechanism. Therefore, a thorough geo-structural survey has firstly been carried out, together with laboratory and in-situ testing for measuring the physical and mechanical properties of the calcarenite rock and of the corresponding joints. A monitoring system has also been planned and installed in order to measure the erosional rate and the block displacements in the cavern.

Biology of vascular malformations of the brain.

PubMed

Leblanc, Gabrielle G; Golanov, Eugene; Awad, Issam A; Young, William L

2009-12-01

This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review- The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.

Cavernous carotid aneurysms in the era of flow diversion: a need to revisit treatment paradigms.

PubMed

Tanweer, O; Raz, E; Brunswick, A; Zumofen, D; Shapiro, M; Riina, H A; Fouladvand, M; Becske, T; Nelson, P K

2014-12-01

Recent techniques of endoluminal reconstruction with flow-diverting stents have not been incorporated into treatment algorithms for cavernous carotid aneurysms. This study examines the authors' institutional experience and a systematic review of the literature for outcomes and complications using the Pipeline Embolization Device in unruptured cavernous carotid aneurysms. A retrospective search for cavernous carotid aneurysms from a prospectively collected data base of aneurysms treated with the Pipeline Embolization Device at our institution was performed. Baseline demographic, clinical, and laboratory values; intrainterventional data; and data at all follow-up visits were collected. A systematic review of the literature for complication data was performed with inquiries sent when clarification of data was needed. Forty-three cavernous carotid aneurysms were included in the study. Our mean radiographic follow-up was 2.05 years. On last follow-up, 88.4% of the aneurysms treated had complete or near-complete occlusion. Aneurysm complete or near-complete occlusion rates at 6 months, 12 months, and 36 months were 81.4%, 89.7%, and 100%, respectively. Of patients with neuro-ophthalmologic deficits on presentation, 84.2% had improvement in their visual symptoms. Overall, we had a 0% mortality rate and a 2.3% major neurologic complication rate. Our systematic review of the literature yielded 227 cavernous carotid aneurysms treated with the Pipeline Embolization Device with mortality and morbidity rates of 0.4% and 3.1%, respectively. Endoluminal reconstruction with flow diversion for large unruptured cavernous carotid aneurysms can yield high efficacy with low complications. Further long-term data will be helpful in assessing the durability of the cure; however, we advocate a revisiting of current management paradigms for cavernous carotid aneurysms. © 2014 by American Journal of Neuroradiology.

A rare case of important and recurrent abnormal uterine bleeding in a post partum woman caused by cavernous hemangioma: a case report and review of literature.

PubMed

Aka, Kacou Edele; Apollinaire Horo, Gninlgninrin; Fomba, Minata; Kouyate, Salif; Koffi, Abdoul Koffi; Konan, Seni; Fanny, Mohamed; Effi, Benjamin; Kone, Mamourou

2017-01-01

The cavernous hemangioma is a rare benign vascular tumor. About 50 cases of this disease were found in the literature over the last century and only 9 cases of cavernous hemangioma on the pregnant uterus were published it comes into cavernous or capillary form. The symptomatology is not unequivocal and when it occurs during pregnancy or postpartum, it causes life-threatening cataclysmic hemorrhage. Antenatal diagnosis is difficult and requires a multidisciplinary approach with pathologists, radiologists and gynecologists to avoid these complications or unnecessary hysterectomies. The diagnosis is histological. Hysterectomy is possible after failure of conservative treatment means. We report a rare case, a novel mixed cavernous hemangioma of the body associated with a capillary hemangioma of the cervix in a patient of 28 years 5th visors with recurrent genital bleeding in the postpartum period leading to a hysterectomy.

OCT image segmentation of the prostate nerves

NASA Astrophysics Data System (ADS)

Chitchian, Shahab; Weldon, Thomas P.; Fried, Nathaniel M.

2009-08-01

The cavernous nerves course along the surface of the prostate and are responsible for erectile function. Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery may improve nerve preservation and postoperative sexual potency. In this study, 2-D OCT images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. Three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The features were segmented using a nearestneighbor classifier. N-ary morphological post-processing was used to remove small voids. The cavernous nerves were differentiated from the prostate gland with a segmentation error rate of only 0.058 +/- 0.019.

A singular case of cavernous internal carotid artery aneurysm in patient with cavernous sinus syndrome and bacterial meningitis.

PubMed

Sacchetti, Federico; Stagni, Silvia; Spinardi, Luca; Raumer, Luigi; Dentale, Nicola; Cirillo, Luigi

2016-09-01

We report the uncommon case of an acute cavernous sinus syndrome in a patient who was consequently discovered to have both a cavernous internal carotid artery aneurysm and bacterial meningitis. Which came first, the chicken or the egg? Which of the two, the aneurysm or the meningitis, gave rise to the patient's symptoms? We briefly reviewed the literature of similar cases and tried to analyze the possible pathophysiological relationship between these findings. Moreover, this case highlights the importance of a multidisciplinary management of these patients to better decide between a medical and a surgical and/or endovascular treatment.

Designed angiopoietin-1 variant, COMP-angiopoietin-1, rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse

PubMed Central

Ryu, Ji-Kan; Kim, Woo Jean; Koh, Young Jun; Piao, Shuguang; Jin, Hai-Rong; Lee, Sae-Won; Choi, Min Ji; Shin, Hwa-Yean; Kwon, Mi-Hye; Jung, Keehoon; Koh, Gou Young; Suh, Jun-Kyu

2015-01-01

Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3-/- mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED. PMID:25783805

Induced Seismicity Monitoring of an Underground Salt Cavern Prone to Collapse

NASA Astrophysics Data System (ADS)

Mercerat, E. D.; Driad-Lebeau, L.; Bernard, P.

2010-02-01

Within the framework of a large research project launched to assess the feasibility of microseismic monitoring of growing underground caverns, this specific work focuses on the analysis of the induced seismicity recorded in a salt mine environment. A local seismic network has been installed over an underground salt cavern located in the Lorraine basin (Northeast of France). The microseismic network includes four 3-components and three single component geophones deployed at depths between 30 and 125 m in cemented boreholes drilled in the vicinity of the study area. The underground cavern under monitoring is located within a salt layer at 180 m depth and it presents a rather irregular shape that can be approximated by a cylindrical volume of 50 m height and 180 m diameter. Presently, the cavern is full of saturated brine inducing a significant pressure on its walls (~2.0 MPa) to keep the overburden mechanically stable. Nevertheless some small microseismic events were recorded by the network and analyzed (approximately 2,000 events in 2 years of recording). In October 2005 and April 2007, two controlled pressure transient experiments were carried out in the cavern, in order to analyze the mechanical response of the overburden by tracking the induced microseismicity. The recorded events were mainly grouped in clusters of 3-30 s of signal duration with emergent first arrivals and rather low frequency content (between 20 and 120 Hz). Some of these events have been spatially located by travel-time picking close to the actual cavern and its immediate roof. Preliminary spectral analysis of isolated microearthquakes suggests sources with non-negligible tensile components possibly related to fluid-filled cracks. Rock-debris falling into the cavern from delamination of clay marls in the immediate roof is probably another source of seismic excitation. This was later confirmed when the most important seismic swarms occurred at the site during May 2007, accompanied by the detachment of more than 8 × 104 m3 of marly material on top of the cavern roof. In any case, no clear evidence of classical brittle ruptures in the most competent layers of the overburden has been observed during the analyzed period. Current work is focused on the discrimination of all these possible mechanisms to better understand the damage processes in the cavern overburden and to assess its final collapse hazard.

A new model of cavern diameter based on a validated CFD study on stirring of a highly shear-thinning fluid.

PubMed

Story, Anna; Jaworski, Zdzisław

2017-01-01

Results of numerical simulations of momentum transfer for a highly shear-thinning fluid (0.2% Carbopol) in a stirred tank equipped with a Prochem Maxflo T type impeller are presented. The simulation results were validated using LDA data and both tangential and axial force measurements in the laminar and early transitional flow range. A good agreement between the predicted and experimental results of the local fluid velocity components was found. From the predicted and experimental values of both tangential and axial forces, the power number, Po , and thrust number, Th , were also calculated. Values of the absolute relative deviations were below 4.0 and 10.5%, respectively, for Po and Th , which confirms a satisfactory agreement with experiments. An intensive mixing zone, known as cavern, was observed near the impeller. In this zone, the local values of fluid velocity, strain rate, Metzner-Otto coefficient, shear stress and intensity of energy dissipation were all characterized by strong variability. Based on the results of experimental study a new model using non-dimensional impeller force number was proposed to predict the cavern diameter. Comparative numerical simulations were also carried out for a Newtonian fluid (water) and their results were similarly well verified using LDA measurements, as well as experimental power number values.

Modified three-dimensional skull base model with artificial dura mater, cranial nerves, and venous sinuses for training in skull base surgery: technical note.

PubMed

Mori, Kentaro; Yamamoto, Takuji; Oyama, Kazutaka; Ueno, Hideaki; Nakao, Yasuaki; Honma, Keiichirou

2008-12-01

Experience with dissection of the cavernous sinus and the temporal bone is essential for training in skull base surgery, but the opportunities for cadaver dissection are very limited. A modification of a commercially available prototype three-dimensional (3D) skull base model, made by a selective laser sintering method and incorporating surface details and inner bony structures such as the inner ear structures and air cells, is proposed to include artificial dura mater, cranial nerves, venous sinuses, and the internal carotid artery for such surgical training. The transpetrosal approach and epidural cavernous sinus surgery (Dolenc's technique) were performed on this modified model using a high speed drill or ultrasonic bone curette under an operating microscope. The model could be dissected in almost the same way as a real cadaver. The modified 3D skull base model provides a good educational tool for training in skull base surgery.

Submarine groundwater discharge into the coast revealed by water chemistry of man-made undersea liquefied petroleum gas cavern

NASA Astrophysics Data System (ADS)

Lee, Jin-Yong; Cho, Byung Wook

2008-10-01

SummaryThe occurrence of submarine groundwater discharge (SGD) as well as its supply of many nutrients and metals to coastal seawaters is now generally known. However, previous studies have focused on the chemical and radiological analysis of groundwater, surface seawater, shallow marine sediments and their pore waters, as well as the measurement of upward flow through the marine sediments, as end members of the discharge process. In this study, chemical and isotopic analysis results of marine subsurface waters are reported. These were obtained from deep boreholes of an undersea liquefied petroleum gas (LPG) storage cavern, located about 8 km off the western coast of Korea. The cavern is about 130-150 m below the sea bottom, which is covered by a 4.8-19.5 m silty clay stratum. An isotopic composition (δ 2H and δ 18O) of the marine subsurface waters falls on a mixing line between terrestrial groundwater and seawater. Vertical EC profiling at the cavern boreholes revealed the existence of a fresh water zone. An increase in the contents of ferrous iron and manganese and a decrease in levels of nitrate, bicarbonate and cavern seepage were recorded in August 2006, indicating a decreased submarine groundwater flux originating from land, mainly caused by an elevated cavern gas pressure. It is suggested in this study that the main source of fresh waters in the man-made undersea cavern is the submarine groundwater discharge mainly originating from the land.

Phase II Study to Assess the Efficacy of Hypofractionated Stereotactic Radiotherapy in Patients With Large Cavernous Sinus Hemangiomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Xin; Liu Xiaoxia; Mei Guanghai

Purpose: Cavernous sinus hemangioma is a rare vascular tumor. The direct microsurgical approach usually results in massive hemorrhage. Although radiosurgery plays an important role in managing cavernous sinus hemangiomas as a treatment alternative to microsurgery, the potential for increased toxicity with single-session treatment of large tumors is a concern. The purpose of this study was to assess the efficacy of hypofractionated stereotactic radiotherapy in patients with large cavernous sinus hemangiomas. Methods: Fourteen patients with large (volume >20 cm{sup 3}) cavernous sinus hemangiomas were enrolled in a prospective Phase II study between December 2007 and December 2010. The hypofractionated stereotactic radiotherapymore » dose was 21 Gy delivered in 3 fractions. Results: After a mean follow-up of 15 months (range, 6-36 months), the magnetic resonance images showed a mean of 77% tumor volume reduction (range, 44-99%). Among the 6 patients with cranial nerve impairments before hypofractionated stereotactic radiotherapy, 1 achieved symptomatic complete resolution and 5 had improvement. No radiotherapy-related complications were observed during follow-up. Conclusion: Our current experience, though preliminary, substantiates the role of hypofractionated stereotactic radiotherapy for large cavernous sinus hemangiomas. Although a longer and more extensive follow-up is needed, hypofractionated stereotactic radiotherapy of 21 Gy delivered in 3 fractions is effective in reducing the tumor volume without causing any new deficits and can be considered as a treatment modality for large cavernous sinus hemangiomas.« less

Surgical Outcomes of Cavernous Sinus Syndrome in Pituitary Adenomas.

PubMed

Fu, Weilun; Duan, Lian; Geng, Sumin

2017-11-01

The type of pituitary adenoma with a manifestation that includes cavernous sinus syndrome is rare. Based on the clinical data of 70 patients, this study investigated the pathogenesis, imaging characteristics, and prognostic factors of pituitary adenoma with cavernous sinus syndrome. We conducted a retrospective analysis of the characteristics of patients with pituitary adenoma with cavernous sinus syndrome who received surgical treatment. The patients were classified into different prognosis groups according to the time required for them to recover from the cavernous sinus syndrome. Univariate analyses were conducted for the correlations between the prognosis and factors. Of the 3598 cases of pituitary adenomas, 70 (1.95%) presented cavernous sinus syndrome. Of the patients, 55.7% recovered within 2 weeks of surgery, 24.3% recovered from 2 weeks to 1 year after surgery, and 20% had not returned to normal after more than 1 year after surgery. Univariate analyses showed that shorter disease duration (P < 0.001), lower Knosp grade (P = 0.045), a transsphenoidal approach (P < 0.001), and associated pituitary apoplexy (P = 0.012) were predictive factors of early postoperative recovery. The prognosis of cavernous sinus syndrome differs depending on the mechanism of the syndrome. There was no significant difference in the prognosis between patients with total pituitary adenoma resection and subtotal resection. Timely surgery within 100 days of symptom occurrence, Knosp grade 0-2, and associated pituitary apoplexy are predictive factors of good prognosis. Copyright © 2017 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Paula D.; Flores, Karen A.; Lord, David L.

Bryan Mound 5 ( BM5 ) and West Hackberry 9 ( WH9 ) have the potential to create a significant amount of new storage space should the caverns be deemed "leach - ready". This study discusses the original drilling history of the caverns, surrounding geology, current stability, and, based on this culmination of data, makes a preliminary assessment of the leach potential for the cavern. The risks associated with leaching BM5 present substantial problems for the SPR . The odd shape and large amount of insoluble material make it difficult to de termine whether a targeted leach would have themore » desired effect and create useable ullage or further distort the shape with preferential leaching . T he likelihood of salt falls and damaged or severed casing string is significant . In addition, a targeted le ach would require the relocation of approximately 27 MMB of oil . Due to the abundance of unknown factors associated with this cavern, a targeted leach of BM5 is not recommended. A targeted leaching of the neck of WH 9 could potentially eliminate or diminis h the mid - cavern ledge result ing in a more stable cavern with a more favorable shape. A better understanding of the composition of the surrounding salt and a less complicated leaching history yields more confidence in the ability to successfully leach this region. A targeted leach of WH9 can be recommended upon the completion of a full leach plan with consideration of the impacts upon nearby caverns .« less

Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease.

PubMed

Siddiqui, Mohammad S; Patidar, Kavish R; Boyett, Sherry; Luketic, Velimir A; Puri, Puneet; Sanyal, Arun J

2016-04-01

In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a sensitivity of 60.2% for F ≥ 1 and 70.6% for F ≥ 3 fibrosis. These non-invasive models of fibrosis can predict varying degrees of fibrosis from routinely collected clinical information in non-alcoholic fatty liver disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The diagnostic value of a globulin/platelet model for evaluating liver fibrosis in chronic hepatitis B patients.

PubMed

Coskun, Banu Demet; Altinkaya, Engin; Sevinc, Eylem; Ozen, Mustafa; Karaman, Hatice; Karaman, Ahmet; Poyrazoglu, Orhan

2015-12-01

Liver biopsy, which is considered the best method for evaluating hepatic fibrosis, has important adverse events. Therefore, non-invasive tests have been developed to determine the degree of hepatic fibrosis in patients with chronic hepatitis B. To verify the usefulness of a new fibrosis index the globulin/platelet model in patients with chronic hepatitis B and to compare it with other noninvasive tests for predicting significant fibrosis. This study was the second to evaluate the globulin/platelet model in HBV patients. We retrospectively investigated 228 patients with chronic hepatitis B who performed liver biopsy from 2013 to 2014. The globulin/platelet model, APGA [AST/Platelet/Gamma-glutamyl transpeptidase/Alfa-fetoprotein], FIB4, fibrosis index, cirrhosis discriminate score, and Fibro-quotient were calculated, and the diagnostic accuracies of all of the fibrosis indices were compared between the F0-2 (no-mild fibrosis) and F3-6 (significant fibrosis) groups. All of the noninvasive markers were significantly correlated with the stage of liver fibrosis (p < 0,001). To predict significant fibrosis (F ≥ 3), the area under the curve (95% CI) was found to be greatest for APGA (0.83 [0.74-0.86]), followed by FIB-4 (0.75[0.69-0.80]), the globulin/platelet model (0.74 [0.68-0.79]), fibrosis index (0.72 [0.6-0.78], cirrhosis discriminate score (0.71 [0.64-0.76]) and Fibro-quotient (0.62 [0.55-0.7]). The area under the receiver operating characteristic curves of APGA was significantly higher than that of the other noninvasive fibrosis markers (p < 0.05). While the APGA index was found to be the most valuable test for the prediction significant fibrosis in patients with chronic hepatitis B, GP model was the thirth valuable test. Therefore, we recommended that APGA could be used instead of the GP model for prediction liver fibrosis.

Extraosseous, epidural cavernous hemangioma with back pain.

PubMed

Ozkal, Birol; Yaldiz, Can; Yaman, Onur; Ozdemır, Nail; Dalbayrak, Sedat

2015-01-01

Cavernous malformations are characterized by enlarged vascular structures located in benign neural tissues within the cerebellum and spinal cord of the central nervous system. Cavernous hemangiomas (CHs) account for 5% to 12% of all spinal vascular malformations. We removed a hemorrhagic thoracic mass in a 40-year-old male patient who presented with progressive neurological deficits. We found it appropriate to present this case due to its rarity.

SPR Hydrostatic Column Model Verification and Validation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bettin, Giorgia; Lord, David; Rudeen, David Keith

2015-10-01

A Hydrostatic Column Model (HCM) was developed to help differentiate between normal "tight" well behavior and small-leak behavior under nitrogen for testing the pressure integrity of crude oil storage wells at the U.S. Strategic Petroleum Reserve. This effort was motivated by steady, yet distinct, pressure behavior of a series of Big Hill caverns that have been placed under nitrogen for extended period of time. This report describes the HCM model, its functional requirements, the model structure and the verification and validation process. Different modes of operation are also described, which illustrate how the software can be used to model extendedmore » nitrogen monitoring and Mechanical Integrity Tests by predicting wellhead pressures along with nitrogen interface movements. Model verification has shown that the program runs correctly and it is implemented as intended. The cavern BH101 long term nitrogen test was used to validate the model which showed very good agreement with measured data. This supports the claim that the model is, in fact, capturing the relevant physical phenomena and can be used to make accurate predictions of both wellhead pressure and interface movements.« less

Seneca Compressed Air Energy Storage (CAES) Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

None, None

2012-11-30

Compressed Air Energy Storage (CAES) is a hybrid energy storage and generation concept that has many potential benefits especially in a location with increasing percentages of intermittent wind energy generation. The objectives of the NYSEG Seneca CAES Project included: for Phase 1, development of a Front End Engineering Design for a 130MW to 210 MW utility-owned facility including capital costs; project financials based on the engineering design and forecasts of energy market revenues; design of the salt cavern to be used for air storage; draft environmental permit filings; and draft NYISO interconnection filing; for Phase 2, objectives included plant constructionmore » with a target in-service date of mid-2016; and for Phase 3, objectives included commercial demonstration, testing, and two-years of performance reporting. This Final Report is presented now at the end of Phase 1 because NYSEG has concluded that the economics of the project are not favorable for development in the current economic environment in New York State. The proposed site is located in NYSEG’s service territory in the Town of Reading, New York, at the southern end of Seneca Lake, in New York State’s Finger Lakes region. The landowner of the proposed site is Inergy, a company that owns the salt solution mining facility at this property. Inergy would have developed a new air storage cavern facility to be designed for NYSEG specifically for the Seneca CAES project. A large volume, natural gas storage facility owned and operated by Inergy is also located near this site and would have provided a source of high pressure pipeline quality natural gas for use in the CAES plant. The site has an electrical take-away capability of 210 MW via two NYSEG 115 kV circuits located approximately one half mile from the plant site. Cooling tower make-up water would have been supplied from Seneca Lake. NYSEG’s engineering consultant WorleyParsons Group thoroughly evaluated three CAES designs and concluded that any of the designs would perform acceptably. Their general scope of work included development of detailed project construction schedules, capital cost and cash flow estimates for both CAES cycles, and development of detailed operational data, including fuel and compression energy requirements, to support dispatch modeling for the CAES cycles. The Dispatch Modeling Consultant selected for this project was Customized Energy Solutions (CES). Their general scope of work included development of wholesale electric and gas market price forecasts and development of a dispatch model specific to CAES technologies. Parsons Brinkerhoff Energy Storage Services (PBESS) was retained to develop an air storage cavern and well system design for the CAES project. Their general scope of work included development of a cavern design, solution mining plan, and air production well design, cost, and schedule estimates for the project. Detailed Front End Engineering Design (FEED) during Phase 1 of the project determined that CAES plant capital equipment costs were much greater than the $125.6- million originally estimated by EPRI for the project. The initial air storage cavern Design Basis was increased from a single five million cubic foot capacity cavern to three, five million cubic foot caverns with associated air production wells and piping. The result of this change in storage cavern Design Basis increased project capital costs significantly. In addition, the development time required to complete the three cavern system was estimated at approximately six years. This meant that the CAES plant would initially go into service with only one third of the required storage capacity and would not achieve full capability until after approximately five years of commercial operation. The market price forecasting and dispatch modeling completed by CES indicated that the CAES technologies would operate at only 10 to 20% capacity factors and the resulting overall project economics were not favorable for further development. As a result of all of these factors, the Phase 1 FEED developed an installed CAES plant cost estimate of approximately $2,300/KW for the 210MW CAES 1A and 2 cycles. The capital cost for the 136 MW CAES 1 cycle was even higher due to the lower generating capacity of the cycle. Notably, the large equipment could have generated additional capacity (up to 270MW) which would have improved the cost per KW; however, the output was limited by the night time transmission system capability. The research herein, therefore, is particular to the site-specific factors that influenced the design and the current and forecasted generation mix and energy prices in Upstate New York and may not necessarily indicate that CAES plants cannot be economically constructed in other places in New York State or the world.« less

Carotid-cavernous fistula after functional endoscopic sinus surgery.

PubMed

Karaman, Emin; Isildak, Huseyin; Haciyev, Yusuf; Kaytaz, Asim; Enver, Ozgun

2009-03-01

Carotid-cavernous fistulas (CCFs) are anomalous communications between the carotid arterial system and the venous cavernous sinus. They can arise because of spontaneous or trauma causes. Most caroticocavernous fistulas are of spontaneous origin and unknown etiology. Spontaneous CCF may also be associated with cavernous sinus pathology such as arteriosclerotic changes of the arterial wall, fibromuscular dysplasia, or Ehler-Danlos syndrome. Traumatic CCFs may occur after either blunt or penetrating head trauma. Their clinical presentation is related to their size and to the type of venous drainage, which can lead to a variety of symptoms, such as visual loss, proptosis, bruit, chemosis, cranial nerve impairment, intracranial hemorrhage (rare), and so on. Treatment by endovascular transarterial embolization with electrolytically detachable coils is a very effective method for CCF with good outcomes. Carotid-cavernous fistulas have been rarely reported after craniofacial surgery and are uncommon pathologies in otolaryngology practice. In this study, we report a 40-year-old woman with CCF secondary to blunt trauma of functional endoscopic sinus surgery.

Analysis of SPR salt cavern remedial leach program 2013.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Paula D.; Gutierrez, Karen A.; Lord, David L.

The storage caverns of the US Strategic Petroleum Reserve (SPR) exhibit creep behavior resulting in reduction of storage capacity over time. Maintenance of oil storage capacity requires periodic controlled leaching named remedial leach. The 30 MMB sale in summer 2011 provided space available to facilitate leaching operations. The objective of this report is to present the results and analyses of remedial leach activity at the SPR following the 2011 sale until mid-January 2013. This report focuses on caverns BH101, BH104, WH105 and WH106. Three of the four hanging strings were damaged resulting in deviations from normal leach patterns; however, themore » deviations did not affect the immediate geomechanical stability of the caverns. Significant leaching occurred in the toes of the caverns likely decreasing the number of available drawdowns until P/D ratio criteria are met. SANSMIC shows good agreement with sonar data and reasonably predicted the location and size of the enhanced leaching region resulting from string breakage.« less

Endoscope-assisted resection of cavernous angioma at the foramen of Monro: a case report.

PubMed

Matsumoto, Yuji; Kurozumi, Kazuhiko; Shimazu, Yousuke; Ichikawa, Tomotsugu; Date, Isao

2016-01-01

Intraventricular cavernous angiomas are rare pathological entities, and those located at the foramen of Monro are even rarer. We herein present a case of cavernous angioma at the foramen of Monro that was successfully treated by neuroendoscope-assisted surgical removal, and review the relevant literature. A 65-year-old woman had experienced headache and vomiting for 10 days before admission to another hospital. Magnetic resonance imaging (MRI) showed a mass at the foramen of Monro, and obstructive hydrocephalus of both lateral ventricles. The patient was then referred to our hospital. Neurological examination on admission to our hospital showed memory disturbance (Mini-Mental State Examination 20/30) and wide-based gait. A cavernous angioma at the foramen of Monro was diagnosed based on the typical popcorn-like appearance of the lesion on MRI. The lesion was completely removed by neuroendoscope-assisted transcortical surgery with the Viewsite Brain Access System (Vycor Medical Inc., Boca Raton, FL), leading to a reduction in the size of the ventricles. The resected mass was histologically confirmed to be cavernous angioma. The patient's symptoms resolved immediately and there were no postoperative complications. Minimally invasive neuroendoscope-assisted surgery was used to successfully treat a cavernous angioma at the foramen of Monro.

Borehole geophysical and flowmeter data for eight boreholes in the vicinity of Jim Woodruff Lock and Dam, Lake Seminole, Jackson County, Florida

USGS Publications Warehouse

Clarke, John S.; Hamrick, Michael D.; Holloway, O. Gary

2011-01-01

Borehole geophysical logs and flowmeter data were collected in April 2011 from eight boreholes to identify the depth and orientation of cavernous zones within the Miocene Tampa Limestone in the vicinity of Jim Woodruff Lock and Dam in Jackson County, Florida. These data are used to assess leakage near the dam. Each of the eight boreholes was terminated in limestone at depths ranging from 84 to 104 feet. Large cavernous zones were encountered in most of the borings, with several exceeding 20-inches in diameter. The cavernous zones generally were between 1 and 5 feet in height, but a cavern in one of the borings reached a height of about 6 feet. The resistivity of limestone layers penetrated by the boreholes generally was less than 1,000 ohm-meters. Formation resistivity near the cavernous zones did not show an appreciable contrast from surrounding bedrock, probably because the bedrock is saturated, owing to its primary permeability. Measured flow rates in the eight boreholes determined using an electromagnetic flowmeter were all less than ±0.1 liter per second. These low flow rates suggest that vertical hydraulic gradients in the boreholes are negligible and that hydraulic head in the various cavernous zones shows only minor, if any, variation.

Short Hairpin Ribonucleic Acid Constructs Targeting Insulin-like Growth Factor Binding Protein-3 Reversed Decreased Testosterone Concentrations in Diabetic Rats

PubMed Central

Zhou, Zhang-Yan; Fei-Li; Cheng, Shao-Ping; Huang, Hui; Peng, Bi-Wen; Wang, Jing; Liu, Chang-Mao; Xing, Cheng; Sun, Ya-Ling; Bsoul, Najeeb; Pan, Hui; Yi, Cun-Jian; Liu, Rong-Hua; Zhong, Guang-Jun

2015-01-01

Background The aim of this study was to determine if shRNA constructs targeting insulin-like growth factor binding protein-3 can rehabilitate decreased serum testosterone concentrations in streptozotocin-induced diabetic rats. Material/Methods After 12 weeks of intracavernous administration of IGFBP-3 shRNA, intracavernous pressure responses to electrical stimulation of cavernous nerves were evaluated. The expression of IGFBP-3 at mRNA and protein levels was detected by quantitative real-time PCR analysis and Western blot, respectively. The concentrations of serum testosterone and cavernous cyclic guanosine monophosphate were detected by enzyme-linked immunosorbent assay. Results After 12 weeks of intracavernous administration of IGFBP-3 shRNA, the cavernosal pressure was significantly increased in response to the cavernous nerves stimulation compared to the diabetic control group (p<0.01). Cavernous IGFBP-3 expression at both mRNA and protein levels was significantly inhibited. Both serum testosterone and cavernous cyclic guanosine monophosphate concentrations were significantly increased in the IGFBP-3 shRNA treatment group compared to the diabetic control group (p<0.01). Conclusions These results suggest that IGFBP-3 shRNA may rehabilitate erectile function via increases of concentrations of serum testosterone and cavernous cyclic guanosine monophosphate in streptozotocin-induced diabetic rats. PMID:25582342

Hypertrophic olivary degeneration following surgical resection or gamma knife radiosurgery of brainstem cavernous malformations: an 11-case series and a review of literature.

PubMed

Yun, Jung-Ho; Ahn, Jae Sung; Park, Jung Cheol; Kwon, Do Hoon; Kwun, Byung Duk; Kim, Chang Jin

2013-03-01

We describe 11 patients with hypertrophic olivary degeneration (HOD) after surgical resection or gamma knife radiosurgery for brainstem cavernous malformations. In addition, we statistically analyzed the predicting factors associated with the development of HOD. From January 2001 to May 2011, a total of 73 patients (30 in the surgical group and 43 in the radiosurgery group) with brainstem cavernous malformations were treated in our institute. Of them, 11 patients (incidence: 15 %) developed HOD with high signal intensity on T2-weighted MRI during follow-up. The predicting factors (location, size, age, and treatment method) associated with the development of HOD were statistically analyzed. Among the 11 HOD patients, seven patients received surgical resection and four patients received gamma knife radiosurgery. Six patients had bilateral HOD and the remaining five patients had unilateral HOD. Overall HOD-associated symptoms presented in four patients, including three palatal tremors and one ataxia. In all four patients with symptoms, these symptoms disappeared incompletely within the clinical follow-up period. The size of the cavernous malformation, age of patient, and treatment methods were not significantly correlated with the development of HOD. A significantly higher incidence of HOD was associated with midbrain cavernous malformations than with pontine or medulla cavernous malformations. HOD should be recognized as a non-infrequent complication of surgical resection or gamma knife radiosurgery within the brainstem, especially for midbrain cavernous malformations. In addition, to the best of our knowledge, this is the first report on HOD development after radiosurgery.

Novel Evidence-Based Classification of Cavernous Venous Occlusive Disease.

PubMed

Pathak, Ram A; Rawal, Bhupendra; Li, Zhuo; Broderick, Gregory A

2016-10-01

The primary aim of our study was to determine whether an evidence-based rationale could categorize cavernous venous occlusive disease into mild, moderate and severe erectile dysfunction. A total of 863 patients underwent color duplex Doppler ultrasound from January 2010 to June 2013 performed by a single urologist. We identified a cohort of 75 patients (8.7%) with a diagnosis of cavernous venous occlusive disease based on a unilateral resistive index less than 0.9, and right and left peak systolic velocity 35 cm per second or less after visual sexual stimulation. At a median followup of 13 months patients were evaluated for treatment efficacy. A total of 75 patients with a median age of 60 years (range 19 to 83) and a mean body mass index of 26.3 kg/m(2) (range 19.0 to 39.3) satisfied the criteria of cavernous venous occlusive disease. When substratified into tertiles, resistive index cutoffs were obtained, including mild cavernous venous occlusive disease-81.6 to 94.0, moderate disease-72.6 to 81.5 and severe disease-59.5 to 72.5. Using these 3 groups the phosphodiesterase type 5-inhibitor failure rate (p = 0.017) and SHIM (Sexual Health Inventory for Men) score categories (1 to 10 vs 11 to 20, p = 0.030) were statistically significantly different for mild, moderate and severe cavernous venous occlusive disease. Treatment satisfaction was also statistically significantly different. Penile prosthetic placement was a more common outcome among patients with erectile dysfunction and more severe cavernous venous occlusive disease. Our retrospective analysis supports a correlation between the phosphodiesterase type 5 inhibitor failure rate, SHIM score and the rate of surgical intervention using resistive index values. Our data further suggest that an evidence-based classification of cavernous venous occlusive disease by color Doppler ultrasound is possible and can triage patients to penile prosthetic placement. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Analysis of the evolution of the instability process of a coastal cavern

NASA Astrophysics Data System (ADS)

Lollino, P.; Reina, A.

2012-04-01

This work concerns the study performed for the interpretation of the potential failure mechanism of a large natural cavern, which is located along the rocky cliffs of Polignano a Mare town (Apulia, Southern Italy) under an intensely urbanised area. This cavern, which is located at the sea level, was formed due to an intense process of salt and wave erosion, mainly acting during sea storms, within a rock mass formed of a lower stratified limestone mass and an upper soft calcarenite mass. Therefore, the influence of the climatic factors and of the upward erosion process within the cavern has been specifically investigated. At present, the thickness of the cave roof, which has a dome shape, is less than 10 metres in the centre and several buildings are founded on the ground surface above. In 2006 a large calcarenite block, of about 1.5 m diameter, fell down from the roof of the cavern and afterwards field and laboratory investigations as well as both simple analytical methods and elasto-plastic numerical modelling were carried out in order to assess the current state of the roof and to interpret the effects of the potential evolution of the inner erosion and of the local failure processes of the cave. As such, a detailed geo-structural survey has firstly been carried out, together with laboratory and in-situ testing for the geomechanical characterisation of the rock materials and of the corresponding joints. An analysis of the sea storms occurred within the observation period has also been performed by considering daily rainfall and wind data. The rate of erosion has been measured by means of special nets installed at the sea level to collect the material falling down from the roof and the corresponding measurements, which lasted for about one year, indicate an erosion rate of at least 0.005 m3/month. A structural monitoring system, including extensometers and joint-meters, was also installed in several points of the cave in order to measure eventual block displacements within the cavern and the results show some correlations of the logged data with the occurrence of sea storms and in general with the weather factors. The results of both simplified analytical methods and numerical analysis show that the cave is at present stable. Also, numerical modelling was aimed at defining the conditions under which general failure of the cave might occur. In particular, sensitivity analyses have been carried out to assess the influence of specific factors, as the progressive reduction of the roof thickness due to erosion or the gradual reduction of the strength properties of the calcarenite due to weathering processes.

Muon-Induced Neutrons Do Not Explain the DAMA Data

NASA Astrophysics Data System (ADS)

Klinger, J.; Kudryavtsev, V. A.

2015-04-01

We present an accurate model of the muon-induced background in the DAMA/LIBRA experiment. Our work challenges proposed mechanisms which seek to explain the observed DAMA signal modulation with muon-induced backgrounds. Muon generation and transport are performed using the MUSIC /MUSUN code, and subsequent interactions in the vicinity of the DAMA detector cavern are simulated with Geant4. We estimate the total muon-induced neutron flux in the detector cavern to be Φnν=1.0 ×10-9 cm-2 s-1 . We predict 3.49 ×10-5 counts /day /kg /keV , which accounts for less than 0.3% of the DAMA signal modulation amplitude.

Flow diversion in the treatment of carotid injury and carotid-cavernous fistula after transsphenoidal surgery

PubMed Central

Lum, Cheemum; Ahmed, Muhammad E; Glikstein, Rafael; dos Santos, Marlise P; Lesiuk, Howard; Labib, Mohamed; Kassam, Amin B

2015-01-01

We describe a case of iatrogenic carotid injury with secondary carotid-cavernous fistula (CCF) treated with a silk flow diverter stent placed within the injured internal carotid artery and coils placed within the cavernous sinus. Flow diverters may offer a simple and potentially safe vessel-sparing option in this rare complication of transsphenoidal surgery. The management options are discussed and the relevant literature is reviewed. PMID:26015526

Transvenous embolization in spontaneous direct carotid-cavernous fistula in childhood

PubMed Central

Mercado, Glenna B.; Irie, Keiko; Negoro, Makoto; Moriya, Shigeta; Tanaka, Teppei; Ohmura, Masahiro; Sadato, Akiyo; Hayakawa, Motuharu; Sano, Hirotoshi

2011-01-01

Carotid cavernous fistula (CCF) is an abnormal arteriovenous communication in the cavernous sinus. Direct CCF results from a tear in the intracavernous carotid artery. Typically, it has a high flow and usually presents with oculo-orbital venous congestive features such as exophthalmos, chemosis, and sometimes oculomotor or abducens cranial nerve palsy. Indirect CCF generally occurs spontaneously with subtle signs. We report a rare case of spontaneous direct CCF in childhood who did not have the usual history of craniofacial trauma or connective tissue disorder but presented with progressive chemosis and exophthalmos of the right eye. This report aims also to describe the safety and success of transvenous embolization with coils of the superior ophthalmic vein and cavernous sinus through the inferior petrosal sinus. PMID:22059104

Characterization of Gas Transport Properties of Fractured Rocks By Borehole and Chamber Tests.

NASA Astrophysics Data System (ADS)

Shimo, M.; Shimaya, S.; Maejima, T.

2014-12-01

Gas transport characteristics of fractured rocks is a great concern to variety of engineering applications such as underground storage of LPG, nuclear waste disposal, CCS and gas flooding in the oil field. Besides absolute permeability, relative permeability and capillary pressure as a function of water saturation have direct influences to the results of two phase flow simulation. However, number of the reported gas flow tests for fractured rocks are limited, therefore, the applicability of the conventional two-phase flow functions used for porous media, such as Mualem-van Genuchten model, to prediction of the gas transport in the fractured rock mass are not well understood. The authors conducted the two types of in-situ tests, with different scales, a borehole gas-injection test and a chamber gas-injection test in fractured granitic rock. These tests were conducted in the Cretaceous granitic rocks at the Namikata underground LPG storage cavern construction site in Ehime Prefecture in Japan, preceding to the cavern scale gas-tightness test. A borehole injection test was conducted using vertical and sub-vertical boreholes drilled from the water injection tunnel nearly at the depth of the top of the cavern, EL-150m. A new type downhole gas injection equipment that is capable to create a small 'cavern' within a borehole was developed. After performing a series of preliminary tests to investigate the hydraulic conductivity and gas-tightness, i.e. threshold pressure, gas injection tests were conducted under different gas pressure. Fig.1 shows an example of the test results From a chamber test using a air pressurizing chamber with volume of approximately166m3, the gas-tightness was confirmed within the uncertainty of 22Pa under the storage pressure of 0.7MPa, however, significant air leakage occurred possibly through an open fracture intersecting the chamber just after cavern pressure exceeds the initial hydrostatic pressure at the ceiling level of the chamber. Anomalies were detected in the data of the pore pressure as well as AE monitoring around the chamber. Results from the above two tests were simulated using a multi-phase transport simulator, TOUGH2, developed at Lawrence Berkeley National Laboratory. Fig.2 shows the model and an example of the simulation.

A servo controlled gradient loading triaxial model test system for deep-buried cavern.

PubMed

Chen, Xu-guang; Zhang, Qiang-yong; Li, Shu-cai

2015-10-01

A servo controlled gradient loading model test system is developed to simulate the gradient geostress in deep-buried cavern. This system consists of the gradient loading apparatus, the digital servo control device, and the measurement system. Among them, the gradient loading apparatus is the main component which is used for exerting load onto the model. This loading apparatus is placed inside the counterforce wall/beam and is divided to several different loading zones, with each loading zone independently controlled. This design enables the gradient loading. Hence, the "real" geostress field surrounding the deep-buried cavern can be simulated. The loading or unloading process can be controlled by the human-computer interaction machines, i.e., the digital servo control system. It realizes the automation and visualization of model loading/unloading. In addition, this digital servo could control and regulate hydraulic loading instantaneously, which stabilizes the geostress onto the model over a long term. During the loading procedure, the collision between two adjacent loading platens is also eliminated by developing a guide frame. This collision phenomenon is induced by the volume shrinkage of the model when compressed in true 3D state. In addition, several accurate measurements, including the optical and grating-based method, are adopted to monitor the small deformation of the model. Hence, the distortion of the model could be accurately measured. In order to validate the performance of this innovative model test system, a 3D geomechanical test was conducted on a simulated deep-buried underground reservoir. The result shows that the radial convergence increases rapidly with the release of the stress in the reservoir. Moreover, the deformation increases with the increase of the gas production rate. This observation is consistence with field observation in petroleum engineering. The system is therefore capable of testing deep-buried engineering structures.

Numerical simulation for the coupled thermo-mechanical performance of a lined rock cavern for underground compressed air energy storage

NASA Astrophysics Data System (ADS)

Zhou, Shu-Wei; Xia, Cai-Chu; Zhao, Hai-Bin; Mei, Song-Hua; Zhou, Yu

2017-12-01

Compressed air energy storage (CAES) is a technology that uses compressed air to store surplus electricity generated from low power consumption time for use at peak times. This paper presents a thermo-mechanical modeling for the thermodynamic and mechanical responses of a lined rock cavern used for CAES. The simulation was accomplished in COMSOL Multiphysics and comparisons of the numerical simulation and some analytical solutions validated the thermo-mechanical modeling. Air pressure and temperatures in the sealing layer and concrete lining exhibited a similar trend of ‘up-down-down-up’ in one cycle. Significant temperature fluctuation occurred only in the concrete lining and sealing layer, and no strong fluctuation was observed in the host rock. In the case of steel sealing, principal stresses in the sealing layer were larger than those in the concrete and host rock. The maximum compressive stresses of the three layers and the displacement on the cavern surface increased with the increase of cycle number. However, the maximum tensile stresses exhibited the opposite trend. Polymer sealing achieved a relatively larger air temperature and pressure compared with steel and air-tight concrete sealing. For concrete layer thicknesses of 0 and 0.1 m and an initial air pressure of 4.5 MPa, the maximum rock temperature could reach 135 °C and 123 °C respectively in a 30 day simulation.

Geomechanical analysis to predict the oil leak at the wellbores in Big Hill Strategic Petroleum Reserve

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Byoung Yoon

2014-02-01

Oil leaks were found in wellbores of Caverns 105 and 109 at the Big Hill Strategic Petroleum Reserve site. According to the field observations, two instances of casing damage occurred at the depth of the interbed between the caprock bottom and salt top. A three dimensional finite element model, which contains wellbore element blocks and allows each cavern to be configured individually, is constructed to investigate the wellbore damage mechanism. The model also contains element blocks to represent interface between each lithology and a shear zone to examine the interbed behavior in a realistic manner. The causes of the damagedmore » casing segments are a result of vertical and horizontal movements of the interbed between the caprock and salt dome. The salt top subsides because the volume of caverns below the salt top decrease with time due to salt creep closure, while the caprock subsides at a slower rate because the caprock is thick and stiffer. This discrepancy yields a deformation of the well. The deformed wellbore may fail at some time. An oil leak occurs when the wellbore fails. A possible oil leak date of each well is determined using the equivalent plastic strain failure criterion. A well grading system for a remediation plan is developed based on the predicted leak dates of each wellbore.« less

Geomechanical Simulation to Predict the Oil Leak at the Wellbores in Big Hill Strategic Petroleum Reserve.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Byoung; Herrick, Courtney G.

2015-02-01

Oil leaks were found in wellbores of Caverns 105 and 109 at the Big Hill Strategic Petroleum Reserve site. According to the field observations, two instances of casing damage occurred at the depth of the interbed between the caprock bottom and salt top. A three dimensional finite element model, which contains wellbore element blocks and allows each cavern to be configured individually, is constructed to investigate the wellbore damage mechanism. The model also contains element blocks to represent interface between each lithology and a shear zone to examine the interbed behavior in a realistic manner. The causes of the damagedmore » casing segments are a result of vertical and horizontal movements of the interbed between the caprock and salt dome. The salt top subsides because the volume of caverns below the salt top decrease with time due to salt creep closure, while the caprock subsides at a slower rate because the caprock is thick and stiffer. This discrepancy produces a deformation of the well. The deformed wellbore may fail at some time. An oil leak occurs when the wellbore fails. A possible oil leak date of each well is determined using an equivalent plastic strain failure criterion. A well grading system for a remediation plan is developed based on the predicted leak dates of each wellbore.« less

Losartan, an Angiotensin type I receptor, restores erectile function by downregulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats.

PubMed

Yang, Rong; Yang, Bin; Wen, Yanting; Fang, Feng; Cui, Souxi; Lin, Guiting; Sun, Zeyu; Wang, Run; Dai, Yutian

2009-03-01

The high incidence of erectile dysfunction (ED) in diabetes highlights the need for good treatment strategies. Recent evidence indicates that blockade of the angiotensin type I receptor (AT1) may reverse ED from various diseases. To explore the role of cavernous renin-angiotensin system (RAS) in the pathogenesis of diabetic ED and the role of losartan in the treatment of diabetic ED. The AT1 blocker (ARB) losartan (30 mg/kg/d) was administered to rats with streptozocin (65 mg/kg)-induced diabetes. Erectile function, cavernous structure, and tissue gene and protein expression of RAS in the corpora cavernosa were studied. We sought to determine the changes of cavernous RAS in the condition of diabetes and after treatment with losartan. RAS components (angiotensinogen, [pro]renin receptor, angiotensin-converting enzyme [ACE], and AT1) were expressed in cavernosal tissue. In diabetic rats, RAS components were upregulated, resulting in the increased concentration of angiotensin II (Ang II) in the corpora. A positive feedback loop for Ang II formation in cavernosum was also identified, which could contribute to overactivity of cavernous RAS in diabetic rats. Administration of losartan blocked the effect of Ang II, downregulated the expression of AT1 and Ang II generated locally, and partially restored erectile function (losartan-treated group revealed an improved intracavernous pressure/mean systemic arterial pressure ratio as compared with the diabetic group (0.480 +/- 0.031 vs. 0.329 +/- 0.020, P < 0.01). However, losartan could not elevate the reduced smooth muscle/collagen ratio in diabetic rats. The cavernous RAS plays a role in modulating erectile function in corpora cavernosa and is involved in the pathogenesis of diabetic ED. ARB can restore diabetic ED through downregulating cavernous RAS.

The cavernous sinus in cluster headache - a quantitative structural magnetic resonance imaging study.

PubMed

Arkink, Enrico B; Schoonman, Guus G; van Vliet, Jorine A; Bakels, Hannah S; Sneeboer, Marjolein Am; Haan, Joost; van Buchem, Mark A; Ferrari, Michel D; Kruit, Mark C

2017-03-01

Background It has been hypothesized that a constitutionally narrow cavernous sinus might predispose individuals to cluster headache. Cavernous sinus dimensions, however, have never been assessed. Methods In this case-control study, we measured the dimensions of the cavernous sinus, skull base, internal carotid and pituitary gland with high-resolution T2-weighted magnetic resonance imaging in 25 episodic, 24 chronic and 13 probable cluster headache patients, 8 chronic paroxysmal hemicrania patients and 22 headache-free controls. Dimensions were compared between groups, correcting for age, sex and transcranial diameter. Results On qualitative inspection, no relevant pathology or anatomic variants that were previously associated with cluster headache or chronic paroxysmal hemicranias were observed in the cavernous sinus or paracavernous structures. The left-to-right transcranial diameter at the temporal fossa level (mean ± SD) was larger in the headache groups (episodic cluster headache: 147.5 ± 7.3 mm, p = 0.044; chronic cluster headache: 150.2 ± 7.3 mm, p < 0.001; probable cluster headache: 146.0 ± 5.3 mm, p = 0.012; and chronic paroxysmal hemicrania: 145.2 ± 9.4 mm, p = 0.044) compared with controls (140.2 ± 8.0 mm). After adjusting for transcranial diameter and correcting for multiple comparisons, there were no differences in the dimensions of the cavernous sinus and surrounding structures between headache patients and controls. Conclusion Patients with cluster headache or chronic paroxysmal hemicrania had wider skulls than headache-free controls, but the proportional dimensions of the cavernous sinus were similar.

Brainstem cavernous malformations: anatomical, clinical, and surgical considerations.

PubMed

Giliberto, Giuliano; Lanzino, Desiree J; Diehn, Felix E; Factor, David; Flemming, Kelly D; Lanzino, Giuseppe

2010-09-01

Symptomatic brainstem cavernous malformations carry a high risk of permanent neurological deficit related to recurrent hemorrhage, which justifies aggressive management. Detailed knowledge of the microscopic and surface anatomy is important for understanding the clinical presentation, predicting possible surgical complications, and formulating an adequate surgical plan. In this article the authors review and illustrate the surgical and microscopic anatomy of the brainstem, provide anatomoclinical correlations, and illustrate a few clinical cases of cavernous malformations in the most common brainstem areas.

Spinal Epidural Haemangioma Associated with Extensive Gastrointestinal Haemangiomas

PubMed Central

Cheng, L.T.E.; Lim, W.E.H.

2005-01-01

Summary A case of spinal epidural cavernous haemangioma associated with gastrointestinal haemangiomas is discussed. The patient was a young Chinese female presenting with chronic lower back pain. She had a history of extensive gastric and small bowel haemangiomas. Lumbar spine MRI showed a heterogeneously enhancing epidural mass infiltrating the paravertebral muscles. Open biopsy confirmed an epidural cavernous haemangioma. To our knowledge, an association between spinal epidural cavernous haemangiomas and gastrointestinal haemangiomas has not been reported. PMID:20584496

Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target.

PubMed

Brooks, Danielle; Zimmer, Alexandra; Wakefield, Lalage; Lyle, L Tiffany; Difilippantonio, Simone; Tucci, Fabio C; Illiano, Stephane; Annunziata, Christina M; Steeg, Patricia S

2018-05-04

The lysophosphatidic acid receptor 1 (LPAR1) is mechanistically implicated in both tumor metastasis and tissue fibrosis. Previously, metastasis was increased when fulminant fibrosis was first induced in mice, suggesting a direct connection between these processes. The current report examined the extent of metastasis-induced fibrosis in breast cancer model systems, and tested the metastasis preventive efficacy and fibrosis attenuation of antagonists for LPAR1 and Idiopathic Pulmonary Fibrosis (IPF) in breast and ovarian cancer models. Staining analysis demonstrated only focal, low-moderate levels of fibrosis in lungs from eleven metastasis model systems. Two orally available LPAR1 antagonists, SAR100842 and EPGN9878, significantly inhibited breast cancer motility to LPA in vitro . Both compounds were negative for metastasis prevention and failed to reduce fibrosis in the experimental MDA-MB-231T and spontaneous murine 4T1 in vivo breast cancer metastasis models. SAR100842 demonstrated only occasional reductions in invasive metastases in the SKOV3 and OVCAR5 ovarian cancer experimental metastasis models. Two approved drugs for IPF, nintedanib and pirfenidone, were investigated. Both were ineffective at preventing MDA-MB-231T metastasis, with no attenuation of fibrosis. In summary, metastasis-induced fibrosis is only a minor component of metastasis in untreated progressive breast cancer. LPAR1 antagonists, despite in vitro evidence of specificity and efficacy, were ineffective in vivo as oral agents, as were approved IPF drugs. The data argue against LPAR1 and fibrosis as monotherapy targets for metastasis prevention in triple-negative breast cancer and ovarian cancer.

Calvarial bone cavernous hemangioma with intradural invasion: An unusual aggressive course-Case report and literature review.

PubMed

Nasi, Davide; Somma, Lucia di; Iacoangeli, Maurizio; Liverotti, Valentina; Zizzi, Antonio; Dobran, Mauro; Gladi, Maurizio; Scerrati, Massimo

2016-01-01

Cavernous hemangioma of the skull is a rare pathological diagnosis, accounting for 0.2% of bone tumors and 7% of skull tumors. Usually calvarial bone cavernous hemangioma are associated with a benign clinical course and, despite their enlargement and subsequent erosion of the surrounding bone, the inner table of the skull remains intact and the lesion is completely extracranial. The authors present the unique case of a huge left frontal bone cavernous malformation with intradural extension and brain compression determining a right hemiparesis. Calvarial cavernous hemangiomas are benign tumors. They arise from vessels in the diploic space and tend to involve the outer table of the skull with relative sparing of the inner table. More extensive involvement of the inner table and extradural space is very unusual and few cases are reported in literature. To the best of our knowledge, intradural invasion of calvarial hemangioma has not been previously reported. Our case highlights the possibility of an aggressive course of this rare benign pathology. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Calvarial bone cavernous hemangioma with intradural invasion: An unusual aggressive course—Case report and literature review

PubMed Central

Nasi, Davide; Somma, Lucia di; Iacoangeli, Maurizio; Liverotti, Valentina; Zizzi, Antonio; Dobran, Mauro; Gladi, Maurizio; Scerrati, Massimo

2016-01-01

Introduction Cavernous hemangioma of the skull is a rare pathological diagnosis, accounting for 0.2% of bone tumors and 7% of skull tumors. Usually calvarial bone cavernous hemangioma are associated with a benign clinical course and, despite their enlargement and subsequent erosion of the surrounding bone, the inner table of the skull remains intact and the lesion is completely extracranial. Presentation of a case The authors present the unique case of a huge left frontal bone cavernous malformation with intradural extension and brain compression determining a right hemiparesis. Discussion Calvarial cavernous hemangiomas are benign tumors. They arise from vessels in the diploic space and tend to involve the outer table of the skull with relative sparing of the inner table. More extensive involvement of the inner table and extradural space is very unusual and few cases are reported in literature. To the best of our knowledge, intradural invasion of calvarial hemangioma has not been previously reported. Conclusion Our case highlights the possibility of an aggressive course of this rare benign pathology. PMID:27061482

Strains and stresses in the rock around and unlined hot water cavern

NASA Astrophysics Data System (ADS)

Rehbinder, Göran

1984-07-01

Hot water stored in an unlined rock cavern is an efficient energy storage. A research program has been carried out with a test plant at the city of Avesta, Sweden. The plant consists of a rock cavern, the volume of which is 15000 m3, which serves as an energy buffer in the district heating system of the city. The water is heated from a garbage incinerator located close to the cavern. During the first test period the temperature of the stored water has varied between 40°C and 95°C. The heating of the rock causes strains and stresses in the rock. The measurements show that the state in the rock does mainly respond to the average temperature and not to the fluctuations. The maximum thermal stress is 9 MPa occurring at the wall of the cavern. The heave of the ground is less than 5 mm. The development of stress and strain will continue after the first test period since thermal equilibrium was not reached during this period.

Hypophysopexy technique for radiosurgical treatment of cavernous sinus pituitary adenoma.

PubMed

Couldwell, William T; Rosenow, Joshua M; Rovit, Richard L; Benzil, Deborah L

2002-01-01

Stereotactic radiosurgery is being used with increased frequency in the treatment of residual or recurrent pituitary adenomas. The major risk associated with radiosurgical treatment of residual or recurrent pituitary tumor adjacent to normal functional pituitary gland is radiation of the pituitary, which frequently leads to the development of hypopituitarism. The authors describe a technique of pituitary transposition to reduce the radiation dose to the normal pituitary gland in cases of planned radiosurgical treatment of residual pituitary adenoma within the cavernous sinus. A sellar exploration for tumor resection is performed, the pituitary gland is transposed from the region of the cavernous sinus, and a fat and fascia graft is interposed between the normal pituitary gland and the residual tumor in the cavernous sinus. The residual tumor may then be treated with stereotactic radiosurgery. The increased distance between the normal pituitary gland and the residual tumor facilitates treatment of the tumor with radiosurgery and reduces the radiation to the normal pituitary gland. An illustrative case of a young female with recurrent acromegaly and a pituitary adenoma invading the cavernous sinus is described.

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

PubMed Central

Rieder, Florian; Kessler, Sean; Sans, Miquel

2012-01-01

Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies. PMID:22878121

The effect of different antihypertensive drugs on cavernous tissue in experimental chronic renal insufficiency.

PubMed

Toblli, Jorge E; Stella, Inés; Mazza, Osvaldo N; Ferder, León; Inserra, Felipe

2006-01-01

Male erectile dysfunction increases in prevalence in patients with severe chronic renal failure. Since arterial hypertension induces significant damage in cavernous tissue (CT), and considering that hypertension is extremely common in patients with end-stage renal disease (ESRD), the aim of this study was to evaluate the effect of the most conventionally employed antihypertensive drugs on CT in a rat model of renal insufficiency. Five groups of male rats with subtotal nephrectomy (STNx) and 1 with sham operations were studied over 6 months: STNx without treatment, STNx with benazepril (BZ), STNx with losartan (LS), STNx with amlodipine (AML) and STNx with atenolol (AT) plus the sham group. All rats were sacrificed at 6 months after STNx, and penises processed for LM and immunohistochemical studies. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries and the amount of collagen type III were evaluated. All groups with antihypertensive drugs showed similar control in blood pressure throughout the study. Un-treated STNx, STNx with AML and STNx with AT presented significant (p<0.01) hypertrophy in both VSM and CSM, together with an increased amount of collagen type III in CT. Conversely, STNx with either BZ or LS showed a substantial (p<0.01) reduction in all of these variables, with values not different from the sham group. There was a significant (p<0.01) negative correlation between creatinine clearance and the amount of VSM, CSM and collagen type III deposition in CT in untreated STNx, STNx with AML and STNx with AT, but not in STNx with BZ, STNx with LS and sham. These results suggest that the interactions against the renin-angiotensin system (RAS) either by ACE inhibitors or angiotensin AT1 receptor blockers produce considerable benefits regarding structural abnormalities in CT in this animal model of renal insufficiency beyond blood pressure control.

Brainstem Cavernous Angioma

MedlinePlus

... echo” (as opposed to spin-echo or proton beam) imaging. Gradient-echo MRI is most efficient at ... radiosurgery for cavernous malformations: Kjellberg's experience with proton beam therapy in 98 cases at the Harvard Cyclotron. ...

Spontaneous dural cavernous fistula in infancy.

PubMed

Johnson, Paul B; Lelli, Gary J; Khorsandi, Azita; Dellarocca, David A

2010-01-01

A 4-month-old boy presented with the sudden onset of proptosis and dilated episcleral veins. CT revealed an enlarged superior ophthalmic vein and diffusely thickened extraocular muscles. MRI and angiography confirmed a dural middle meningeal--cavernous sinus fistula. Embolization was performed leading to successful resolution of the patient's signs and symptoms. Spontaneous atraumatic arteriovenous cavernous fistulae in infancy are extremely rare, but should be included in the differential diagnosis of infants with orbital congestion. Appropriate treatment leads to prevention of amblyopia, glaucoma, and anisometropia.

Inactivated Orf virus (Parapoxvirus ovis) elicits antifibrotic activity in models of liver fibrosis.

PubMed

Nowatzky, Janina; Knorr, Andreas; Hirth-Dietrich, Claudia; Siegling, Angela; Volk, Hans-Dieter; Limmer, Andreas; Knolle, Percy; Weber, Olaf

2013-05-01

Inactivated Orf virus (ORFV, Parapoxvirus ovis) demonstrates strong antiviral activity in animal models including a human hepatitis B virus (HBV)-transgenic mouse. In addition, expression of interferon (IFN)-γ and interleukin-10 (IL-10) was induced after administration of inactivated ORFV in these mice. IFN-γ and IL-10 are known to elicit antifibrotic activity. We therefore aimed to study antifibrotic activity of inactivated ORFV in models of liver fibrosis. We characterized ORFV-induced hepatic cytokine expression in rats. We then studied ORFV in two models of liver fibrosis in rats, pig serum-induced liver fibrosis and carbon tetrachloride (CCL4 )-induced liver fibrosis. ORFV induced hepatic expression of IFN-γ and IL-10 in rats. ORFV mediated antifibrotic activity when administrated concomitantly with the fibrosis-inducing agents in both models of liver fibrosis. Importantly, when CCL4 -induced liver fibrosis was already established, ORFV application still showed significant antifibrotic activity. In addition, we were able to demonstrate a direct antifibrotic effect of ORFV on stellate cells. These results establish a potential novel antifibrotic therapeutic approach that not only prevents but also resolves established liver fibrosis. Further studies are required to unravel the details of the mechanisms involved. © 2012 The Japan Society of Hepatology.

The transport of drug in fibrosis. Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca

NASA Astrophysics Data System (ADS)

Ivancevic, Vladimir

2016-07-01

The topic of the review article [1] is the derivation of a multiscale paradigm for the modeling of fibrosis. Firstly, the biological process of the physiological and pathological fibrosis including therapeutical actions is reviewed. Fibrosis can be a consequence of tissue damage, infections and autoimmune diseases, foreign material, tumors. Some questions regarding the pathogenesis, progression and possible regression of fibrosis are lacking. At each scale of observation, different theoretical tools coming from computational, mathematical and physical biology have been proposed. However a complete framework that takes into account the different mechanisms occurring at different scales is still missing. Therefore with the main aim to define a multiscale approach for the modeling of fibrosis, the authors of [1] have presented different top-down and bottom-up approaches that have been developed in the literature. Specifically, their description refers to models for fibrosis diseases based on ordinary and partial differential equation, agents [2], thermostatted kinetic theory [3-5], coarse-grained structures [6-8] and constitutive laws for fibrous collagen networks [9]. A critical analysis has been addressed for all frameworks discussed in the paper. Open problems and future research directions referring to both biological and modeling insight of fibrosis are presented. The paper concludes with the ambitious aim of a multiscale model.

PD-1/PD-L1 Pathway Mediates the Alleviation of Pulmonary Fibrosis by Human Mesenchymal Stem Cells in Humanized Mice.

PubMed

Ni, Ke; Liu, Ming; Zheng, Jian; Wen, Liyan; Chen, Qingyun; Xiang, Zheng; Lam, Kowk-Tai; Liu, Yinping; Chan, Godfrey Chi-Fung; Lau, Yu-Lung; Tu, Wenwei

2018-06-01

Pulmonary fibrosis is a chronic progressive lung disease with few treatments. Human mesenchymal stem cells (MSCs) have been shown to be beneficial in pulmonary fibrosis because they have immunomodulatory capacity. However, there is no reliable model to test the therapeutic effect of human MSCs in vivo. To mimic pulmonary fibrosis in humans, we established a novel bleomycin-induced pulmonary fibrosis model in humanized mice. With this model, the benefit of human MSCs in pulmonary fibrosis and the underlying mechanisms were investigated. In addition, the relevant parameters in patients with pulmonary fibrosis were examined. We demonstrate that human CD8 + T cells were critical for the induction of pulmonary fibrosis in humanized mice. Human MSCs could alleviate pulmonary fibrosis and improve lung function by suppressing bleomycin-induced human T-cell infiltration and proinflammatory cytokine production in the lungs of humanized mice. Importantly, alleviation of pulmonary fibrosis by human MSCs was mediated by the PD-1/programmed death-ligand 1 pathway. Moreover, abnormal PD-1 expression was found in circulating T cells and lung tissues of patients with pulmonary fibrosis. Our study supports the potential benefit of targeting the PD-1/programmed death-ligand 1 pathway in the treatment of pulmonary fibrosis.

Analogue of Caldera Dynamics: the Controlled Salt Cavern Collapse

NASA Astrophysics Data System (ADS)

Jousset, P. G.; Rohmer, J.

2012-12-01

Caldera collapse (or pit-crater) dynamics are inferred from geological observations and laboratory experiments. Here, we present an analogue of caldera collapse at field scale and possible analogy with large scale caldera dynamics. Through an original exploitation technique in sedimentary environment, a salt layer is emptied, leaving a brine-filled cavern, which eventually collapses after overburden falls into the cavern. Such a collapse was monitored in East France by many instruments (including GPS, extensometers, geophones, broadband seismological sensors, tiltmeter, gravity meter, … ), which allowed us to describe mechanisms of the collapse. Micro-seismicity is a good indicator of spatio-temporal evolution of physical properties of rocks prior to catastrophic events like volcanic eruptions or landslides and may be triggered by a number of causes including dynamic characteristics of processes in play or/and external forces. We show evidence of triggered micro-seismicity observed in the vicinity of this underground salt cavern prone to collapse by a remote M~7.2 earthquake, which occurred ~12000 kilometres away. High-dynamic broadband records reveal the strong time-correlation between a dramatic change in the rate of local high-frequency micro-seismicity and the passage of low-frequency seismic waves, including body, Love and Rayleigh surface waves. Pressure was lowered in the cavern by pumping operations of brine out of the cavern. We demonstrate the near critical state of the cavern before the collapse by means of 2D axisymmetric elastic finite-element simulations. Stress oscillations due to the seismic waves may have exceeded the strength required for the rupture of the complex media made of brine and rock triggering micro-earthquakes and leading to damage of the overburden and eventually collapse of the salt cavern. The increment of stress necessary for the failure of a Dolomite layer is of the same order or magnitude as the maximum dynamic stress magnitude observed during the passage of the earthquakes waves. On this basis, we discuss the possible contribution of the Love and Rayleigh low-frequency surfaces waves. This experiment may help us understand mechanisms of caldera formation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirby, Carolyn L; Lord, Anna C. Snider

The Bryan Mound caprock was subjected to extens ive sulphur mining prior to the development of the Strategic Petroleum Reserve. Undoubtedl y, the mining has modified the caprock integrity. Cavern wells at Bryan Mound have been subject to a host of well integr ity concerns with many likely compromised by the cavernous capro ck, surrounding corrosive environment (H 2 SO 4 ), and associated elevated residual temperatures al l of which are a product of the mining activities. The intent of this study was to understand the sulphur mining process and how the mining has affected the stability of themore » caprock and how the compromised caprock has influenced the integrity of the cavern wells. After an extensiv e search to collect pert inent information through state agencies, literature sear ches, and the Sandia SPR librar y, a better understanding of the caprock can be inferred from the knowledge gaine d. Specifically, the discovery of the original ore reserve map goes a long way towards modeling caprock stability. In addition the gained knowledge of sulphur mining - subs idence, superheated corrosive wa ters, and caprock collapse - helps to better predict the post mi ning effects on wellbore integrity. This page intentionally left blank« less

Preoperatively staging liver fibrosis using noninvasive method in Hepatitis B virus-infected hepatocellular carcinoma patients

PubMed Central

Gao, Hengyi; Zhu, Feng; Wang, Min; Zhang, Hang; Ye, Dawei; Yang, Jiayin; Jiang, Li; Liu, Chang; Qin, Renyi; Yan, Lunan; Xiao, Guangqin

2017-01-01

Background Advanced liver fibrosis can result in serious complications (even patient’s death) after partial hepatectomy. Preoperatively percutaneous liver biopsy is an invasive and expensive method to assess liver fibrosis. We aim to establish a noninvasive model, on the basis of preoperative biomarkers, to predict liver fibrosis in hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection. Methods The HBV-infected liver cancer patients who had received hepatectomy were retrospectively and prospectively enrolled in this study. Univariate analysis was used to compare the variables of the patients with mild to moderate liver fibrosis and with severe liver fibrosis. The significant factors were selected into binary logistic regression analysis. Factors determined to be significant were used to establish a noninvasive model. Then the diagnostic accuracy of this novel model was examined based on sensitivity, specificity and area under the receiver-operating characteristic curve (AUC). Results This study included 2,176 HBV-infected HCC patients who had undergone partial hepatectomy (1,682 retrospective subjects and 494 prospective subjects). Regression analysis indicated that total bilirubin and prothrombin time had positive correlation with liver fibrosis. It also demonstrated that blood platelet count and fibrinogen had negative correlation with liver fibrosis. The AUC values of the model based on these four factors for predicting significant fibrosis, advanced fibrosis and cirrhosis were 0.79-0.83, 0.83-0.85 and 0.85-0.88, respectively. Conclusion The results showed that this novel preoperative model was an excellent noninvasive method for assessing liver fibrosis in HBV-infected HCC patients. PMID:28008144

A time for multi-scale modeling of anti-fibrotic therapies. Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca

NASA Astrophysics Data System (ADS)

Wu, Min

2016-07-01

The development of anti-fibrotic therapies in diversities of diseases becomes more and more urgent recently, such as in pulmonary, renal and liver fibrosis [1,2], as well as in malignant tumor growths [3]. As reviewed by Ben Amar and Bianca [4], various theoretical, experimental and in-silico models have been developed to understand the fibrosis process, where the implication on therapeutic strategies has also been frequently demonstrated (e.g., [5-7]). In [4], these models are analyzed and sorted according to their approaches, and in the end of [4], a unified multi-scale approach was proposed to understand fibrosis. While one of the major purposes of extensive modeling of fibrosis is to shed light on therapeutic strategies, the theoretical, experimental and in-silico studies of anti-fibrosis therapies should be conducted more intensively.

Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate

PubMed Central

Lee, Sang Jin; Park, Jong-Hwan; Lee, Jun-Young; Jeong, Yu-Jin; Song, Jeong Ah; Lee, Kyuhong; Kim, Dong-Jae

2016-01-01

Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-β production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice. PMID:27182113

Speckle reduction during all-fiber common-path optical coherence tomography of the cavernous nerves

NASA Astrophysics Data System (ADS)

Chitchian, Shahab; Fiddy, Michael; Fried, Nathaniel M.

2009-02-01

Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery, which are responsible for erectile function, may improve nerve preservation and postoperative sexual potency. In this study, we use a rat prostate, ex vivo, to evaluate the feasibility of optical coherence tomography (OCT) as a diagnostic tool for real-time imaging and identification of the cavernous nerves. A novel OCT system based on an all single-mode fiber common-path interferometer-based scanning system is used for this purpose. A wavelet shrinkage denoising technique using Stein's unbiased risk estimator (SURE) algorithm to calculate a data-adaptive threshold is implemented for speckle noise reduction in the OCT image. The signal-to-noise ratio (SNR) was improved by 9 dB and the image quality metrics of the cavernous nerves also improved significantly.

Optical Coherence Tomography Angiography of Retinal Cavernous Hemangioma.

PubMed

Pierro, Luisa; Marchese, Alessandro; Gagliardi, Marco; Bandello, Francesco

2017-08-01

Retinal cavernous hemangioma is a rare, benign, retinal tumor characterized by angiomatous proliferation of vessels within the inner retina or the optic disc.1 Here we report a case of retinal cavernous hemangioma on the margin of the optic disc in the right eye of a 61-year-old asymptomatic female. The lesion was studied with multimodal imaging which included structural optical coherence tomography, fluorescein angiography, blue fundus auto-fluorescence, optical coherence tomography angiography (OCTA) (DRI OCT Triton; Topcon, Tokyo, Japan) and visual field examination. Blood circulation inside retinal cavernous hemangioma lesion is typically low-stagnant.2 However, OCTA demonstrated blood flow inside the lesion, illustrating its vascular circulation.3 Visual field was within the normal limits, except from a slight enlargement of the blind spot. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:684-685.]. Copyright 2017, SLACK Incorporated.

Monitoring and/or Detection of Wellbore Leakage In Energy Storage Wells

NASA Astrophysics Data System (ADS)

Ratigan, J.

2017-12-01

Energy (compressed natural gas, crude oil, NGL, and LPG) storage wells in solution-mined caverns in salt formations are required to be tested for integrity every five years. Rules promulgated for such testing typically assume the cavern interval in the salt formation is inherently impermeable, even though some experience demonstrates that this is not always the case. A protocol for testing the cavern impermeable hypothesis should be developed. The description for the integrity test of the "well" component of the well and cavern storage system was developed more than 30 years ago. However, some of the implicit assumptions inherent to the decades-old well test protocol are no longer applicable to the large diameter, high flow rate wells commonly constructed today. More detailed test protocols are necessary for the more contemporary energy storage wells.

Focal dystonia secondary to cavernous angioma of the basal ganglia: case report and review of the literature.

PubMed

Lorenzana, L; Cabezudo, J M; Porras, L F; Polaina, M; Rodriguez-Sanchez, J A; Garcia-Yagüe, L M

1992-12-01

The case of a young woman with focal dystonia of the hand due to a cavernous angioma of the basal ganglia is presented. The lesion involved the anterior third of the lentiform nucleus and a large portion of white matter anterior to this nucleus and lateral to the head of the caudate, as shown by magnetic resonance imaging; it was completely removed through a computed tomography-assisted stereotactic craniotomy by microsurgical technique, resulting in the cure of the patient. These facts support the pathophysiological hypothesis of a disruption of the striatopallidothalamic projection to the premotor cortex as the cause of symptomatic dystonia. A review of the reported cases of cavernous angiomas of the deep cerebral gray nuclei shows that this is the first case of cavernous angioma associated with movement disorder.

Cavernous hemangioma of the orbit: an unusual acute presentation

PubMed Central

Louisraj, Sophia; Ponnudurai, Thendral; Rodriguez, Dominic; Thomas, Philip A; Nelson Jesudasan, Christadoss Arul

2017-01-01

We report an unusual presentation of an orbital cavernous hemangioma in a 26-year-old female, who noted sudden redness and swelling of the left eye (LE) on waking up. At presentation, upper eyelid edema with periorbital ecchymosis and subconjunctival hemorrhage were noted in the LE. Although there was transient symptomatic relief with topical medications, blurring of vision developed in the LE. When seen 10 days later, the patient’s LE showed axial proptosis. Magnetic resonance imaging revealed an intraconal soft tissue mass in the superomedial quadrant of the left orbit. Superior orbitotomy with mass excision was done; histopathological examination of the excised mass revealed a cavernous hemangioma. The patient had complete visual recovery following surgery. To our knowledge, an acute presentation of an orbital cavernous hemangioma with subconjunctival hemorrhage and periorbital ecchymosis has not previously been reported. PMID:28769595

Effects of hyperglycemia on rat cavernous nerve axons: a functional and ultrastructural study.

PubMed

Zotova, Elena G; Schaumburg, Herbert H; Raine, Cedric S; Cannella, Barbara; Tar, Moses; Melman, Arnold; Arezzo, Joseph C

2008-10-01

The present study explored parallel changes in the physiology and structure of myelinated (Adelta) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (< 2.5 m/s). Even with prolonged hyperglycemia (> 4 months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy.

EFFECTS OF HYPERGLYCEMIA ON RAT CAVERNOUS NERVE AXONS: A FUNCTIONAL AND ULTRASTRUCTURAL STUDY

PubMed Central

Zotova, Elena G.; Schaumburg, Herbert H.; Raine, Cedric S.; Cannella, Barbara; Tar, Moses; Melman, Arnold; Arezzo, Joseph C.

2008-01-01

The present study explored parallel changes in the physiology and structure of myelinated (Aδ) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (<2.5 m/sec). Even with prolonged hyperglycemia (> 4 months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy. PMID:18687329

Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report

PubMed Central

2011-01-01

Introduction Poland syndrome is a congenital disorder related to chest and hand anomalies on one side of the body. Its etiology remains unclear, with an ipsilateral vascular alteration (of unknown origin) to the subclavian artery in early embryogenesis being the currently accepted theory. Cavernous malformations are vascular hamartomas, which have been linked to a genetic etiology, particularly in familial cases, which commonly present with multiple lesions. Our case report is the first to describe multiple cavernous malformations associated with Poland syndrome, further supporting the vascular etiology theory, but pointing to a genetic rather than a mechanistic factor disrupting blood flow in the corresponding vessels. Case presentation A 41-year-old Caucasian man with Poland syndrome on the right side of his body presented to our hospital with a secondary generalized seizure and was found to have multiple cavernous malformations distributed in his brain, cerebellum, and brain stem, with a predominance of lesions in the left hemisphere. Conclusion The distribution of cavernous malformations in the left hemisphere and the right-sided Poland syndrome in our patient could not be explained by a mechanistic disruption of one of the subclavian arteries. A genetic alteration, as in familial cavernous malformations, would be a more appropriate etiologic diagnosis of Poland syndrome in our patient. Further genetic and pathological studies of the involved blood vessels in patients with Poland syndrome could lead to a better understanding of the disease. PMID:21933407

MFAP4: a candidate biomarker for hepatic and pulmonary fibrosis?

PubMed

Mölleken, Christian; Poschmann, Gereon; Bonella, Francesco; Costabel, Ulrich; Sitek, Barbara; Stühler, Kai; Meyer, Helmut E; Schmiegel, Wolff H; Marcussen, Niels; Helmer, Michael; Nielsen, Ole; Hansen, Søren; Schlosser, Anders; Holmskov, Uffe; Sorensen, Grith Lykke

2016-03-29

Several comparable mechanisms have been identified for hepatic and pulmonary fibrosis. The human microfibrillar associated glycoprotein 4 (MFAP4), produced by activated myofibroblasts, is a ubiquitous protein playing a potential role in extracellular matrix (ECM) turnover and was recently identified as biomarker for hepatic fibrosis in hepatitis C patients. The current study aimed to evaluate serum levels of MFAP4 in patients with pulmonary fibrosis in order to test its potential as biomarker in clinical practice. A further aim was to determine whether MFAP4 deficiency in mice affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age were studied. Serum levels of MFAP4 were measured by ELISA in patients and in mice. Surfactant protein D (SP-D) and LDH were measured as comparison biomarkers in patients with pulmonary fibrosis. Morphometric assessment and the Sircol kit were used to determine the amount of collagen in the lung tissue in the mouse model. Serum levels of MFAP4 were not elevated in lung fibrosis - neither in the patients with IPF or HP nor in the animal model. Furthermore no significant correlations with pulmonary function tests of IPF patients could be found for MFAP4. MFAP4 levels were increased in BAL of bleomycin treated mice with pulmonary fibrosis. MFAP4 is not elevated in sera of patients with pulmonary fibrosis or bleomycin treated mice with pulmonary fibrosis. This may be due to different pathogenic mechanisms of liver and lung fibrogenesis. MFAP4 seems to be useful as serum biomarker for hepatic but not for lung fibrosis.

Segmentation of optical coherence tomography images for differentiation of the cavernous nerves from the prostate gland

NASA Astrophysics Data System (ADS)

Chitchian, Shahab; Weldon, Thomas P.; Fried, Nathaniel M.

2009-07-01

The cavernous nerves course along the surface of the prostate and are responsible for erectile function. Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery may improve nerve preservation and postoperative sexual potency. Two-dimensional (2-D) optical coherence tomography (OCT) images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. To detect these nerves, three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The Gabor feature was applied with different standard deviations in the x and y directions. In the Daubechies wavelet feature, an 8-tap Daubechies orthonormal wavelet was implemented, and the low-pass sub-band was chosen as the filtered image. Last, Laws feature extraction was applied to the images. The features were segmented using a nearest-neighbor classifier. N-ary morphological postprocessing was used to remove small voids. The cavernous nerves were differentiated from the prostate gland with a segmentation error rate of only 0.058+/-0.019. This algorithm may be useful for implementation in clinical endoscopic OCT systems currently being studied for potential intraoperative diagnostic use in laparoscopic and robotic nerve-sparing prostate cancer surgery.

Horizontal natural gas storage caverns and methods for producing same

DOEpatents

Russo, Anthony

1995-01-01

The invention provides caverns and methods for producing caverns in bedded salt deposits for the storage of materials that are not solvents for salt. The contemplated salt deposits are of the bedded, non-domed variety, more particularly salt found in layered formations that are sufficiently thick to enable the production of commercially usefully sized caverns completely encompassed by walls of salt of the formation. In a preferred method, a first bore hole is drilled into the salt formation and a cavity for receiving insolubles is leached from the salt formation. Thereafter, at a predetermined distance away from the first bore hole, a second bore hole is drilled towards the salt formation. As this drill approaches the salt, the drill assumes a slant approach and enters the salt and drills through it in a horizontal direction until it intersects the cavity for receiving insolubles. This produces a substantially horizontal conduit from which solvent is controlledly supplied to the surrounding salt formation, leaching the salt and producing a concentrated brine which is removed through the first bore hole. Insolubles are collected in the cavity for receiving insolubles. By controlledly supplying solvent, a horizontal cavern is produced with two bore holes extending therefrom.

Segmentation of optical coherence tomography images for differentiation of the cavernous nerves from the prostate gland.

PubMed

Chitchian, Shahab; Weldon, Thomas P; Fried, Nathaniel M

2009-01-01

The cavernous nerves course along the surface of the prostate and are responsible for erectile function. Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery may improve nerve preservation and postoperative sexual potency. Two-dimensional (2-D) optical coherence tomography (OCT) images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. To detect these nerves, three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The Gabor feature was applied with different standard deviations in the x and y directions. In the Daubechies wavelet feature, an 8-tap Daubechies orthonormal wavelet was implemented, and the low-pass sub-band was chosen as the filtered image. Last, Laws feature extraction was applied to the images. The features were segmented using a nearest-neighbor classifier. N-ary morphological postprocessing was used to remove small voids. The cavernous nerves were differentiated from the prostate gland with a segmentation error rate of only 0.058+/-0.019. This algorithm may be useful for implementation in clinical endoscopic OCT systems currently being studied for potential intraoperative diagnostic use in laparoscopic and robotic nerve-sparing prostate cancer surgery.

The role of magnetic resonance diffusion-weighted imaging and three-dimensional arterial spin labelling perfusion imaging in the differentiation of parasellar meningioma and cavernous haemangioma.

PubMed

Xiao, Hua-Feng; Lou, Xin; Liu, Meng-Yu; Wang, Yu-Lin; Wang, Yan; Chen, Zhi-Ye; Shi, Kai-Ning; Ma, Lin

2014-08-01

To evaluate the diagnostic value of magnetic resonance diffusion-weighted imaging (DWI) and three-dimensional arterial spin labelling perfusion imaging (3D-ASL) in distinguishing cavernous haemangioma from parasellar meningioma, using histological data as a reference standard. Patients with parasellar meningioma or parasellar cavernous haemangioma underwent conventional T1- and T2-weighted magnetic resonance imaging (MRI) followed by DWI and 3D-ASL using a 3.0 Tesla MRI. The minimum apparent diffusion coefficient (minADC) from DWI and the maximal normalized cerebral blood flow (nCBF) from 3D-ASL were measured in each tumour. Diagnosis was confirmed by histology. MinADC was significantly lower and nCBF significantly higher in meningioma (n = 19) than cavernous haemangioma (n = 15). There was a significant negative correlation between minADC and nCBF (r = -0.605). DWI and 3D-ASL are useful in differentiating cavernous haemangiomas from parasellar meningiomas, particularly in situations when the appearance on conventional MRI sequences is otherwise ambiguous. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Assessment of Hepatic Fibrosis with the Stiffness of Liver and the Dynamic of Blood in Liver

NASA Astrophysics Data System (ADS)

Chen, Hao; Ye, Lihong; Li, Zhenyan; Jiang, Yi

Cirrhosis affects liver functions, and is a significant public health problem. Early stages of liver fibrosis are difficult to diagnose. The mechanism of fibrosis changing the mechanical properties of the liver tissue and altering the dynamic of blood flow is still unclear. In collaboration with clinicians specialized in hepatic fibrosis, we have developed a mechanical model to integrate our empirical understanding of fibrosis development and connect the fibrosis stage to mechanical properties of tissue and the consequential blood flow pattern changes. We modeled toxin distribution in the liver that leads to tissue damage and collagen deposition. We showed that the excessive collagen forms polygonal patterns, resembling those found in pathology images. Treating the collagen bundles as elastic spring networks, we also showed a nonlinear relationship between liver stiffness and fibrosis stage, which is consistent with experimental observations. We further modeled the stiffness affecting the mechanical properties of the portal veins, resulting in altered blood flow pattern. These results are supported by ultrasound Doppler measurements from hepatic fibrosis patients. These results promise a new noninvasive diagnostic tool for early fibrosis.

[Value of non-invasive models of liver fibrosis in judgment of treatment timing in chronic hepatitis B patients with ALT < 2×upper limit of normal].

PubMed

Zhou, Q Q; Hu, Y B; Zhou, K; Zhang, W W; Li, M H; Dong, P; Di, J G; Hong, L; Du, Q W; Xie, Y; Sun, Q F

2016-09-20

Objective: To investigate the value of non-invasive liver fibrosis models, FIB-4, S index, aspartate aminotransferase to platelet ratio index(APRI), globulin-platelet(GP)model, aspartate aminotransferase/platelet/gamma-glutamyl transpeptidase/alpha-fetoprotein(APGA), and platelet/age/phosphatase/alpha-fetoprotein/aspartate aminotransferase(PAPAS), in the diagnosis of marked liver fibrosis in chronic hepatitis B(CHB)patients with ALT < 2×upper limit of normal(ULN), as well as treatment timing for this population. Methods: A total of 389 CHB patients with ALT < 2×ULN who were admitted to Beijing Ditan Hospital and whose treatment timing was difficult to judge were enrolled. Transdermal liver biopsy was performed to obtain pathological results, and routine serological tests were performed, including routine blood test, serum biochemical parameters, hepatitis B virus(HBV)markers, and HBV DNA. According to liver pathology, the patients were divided into non-marked liver fibrosis group(S < 2)with 324 patients and marked liver fibrosis group(S≥2)with 65 patients. The non-invasive models for predicting liver fibrosis was established with reference to original articles. SPSS 19.0 software was used for statistical analysis, and the receiver operating characteristic(ROC)curve was used to compare the value of different non-invasive models in predicting marked liver fibrosis in this population. Results: All the non-invasive models had a certain diagnostic value for liver fibrosis degree in these patients, and the areas under the ROC curve for APRI, FIB-4, APGA, S index, PAPAS, and GP model were 0.718, 0.691, 0.758, 0.729, 0.673, and 0.691, respectively. APGA had the largest area under the ROC curve(0.758, 95% CI 0.673-0.844), and gamma-glutamyl transpeptidase was significantly positively correlated with liver fibrosis degree. Conclusion: The non-invasive models of liver fibrosis can identify marked liver fibrosis in CHB patients with ALT < 2×ULN in whom it is difficult to judge treatment timing and help to determine treatment timing for them. APGA model has the highest value and can reduce the need for liver biopsy to the certain degree.

Ten Triangles around Cavernous Sinus for Surgical Approach, Described by Schematic Diagram and Three Dimensional Models with the Sectioned Images.

PubMed

Chung, Beom Sun; Ahn, Young Hwan; Park, Jin Seo

2016-09-01

For the surgical approach to lesions around the cavernous sinus (CS), triangular spaces around CS have been devised. However, educational materials for learning the triangles were insufficient. The purpose of this study is to present educational materials about the triangles, consisting of a schematic diagram and 3-dimensional (3D) models with sectioned images. To achieve the purposes, other studies were analyzed to establish new definitions and names of the triangular spaces. Learning materials including schematic diagrams and 3D models with cadaver's sectioned images were manufactured. Our new definition was attested by observing the sectioned images and 3D models. The triangles and the four representative surgical approaches were stereoscopically indicated on the 3D models. All materials of this study were put into Portable Document Format file and were distributed freely at our homepage (anatomy.dongguk.ac.kr/triangles). By using our schematic diagram and the 3D models with sectioned images, ten triangles and the related structures could be understood and observed accurately. We expect that our data will contribute to anatomy education, surgery training, and radiologic understanding of the triangles and related structures.

Beneficial Effects of Scutellaria baicalensis on Penile Erection in Streptozotocin-Induced Diabetic Rats.

PubMed

Li, Xiang; Lee, Yun Jung; Kim, Hye Yoom; Tan, Rui; Park, Min Cheol; Kang, Dae Gill; Lee, Ho Sub

2016-01-01

We have reported that ethanol extracts of the root from Scutellaria baicalensis Georgi (ESB) relax cavernous smooth muscles via the NO/cGMP system and Ca[Formula: see text]-sensitive K[Formula: see text] channels in the rabbit corpus cavernosum. In the present study, erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve. The ICP/MAP ratio was dose-dependently increased by the treatment of ESB in normal SD rats ([Formula: see text]). To investigate the beneficial effect of ESB on erectile dysfunction in a diabetic animal model, male SD rats were injected with streptozotocin (60[Formula: see text]mg/kg) and then 300[Formula: see text]mg/kg/day ESB was administered daily for eight weeks. In our in vivo study, administration of ESB in STZ rats significantly increased the ICP, ICP/MAP ratio, area under the curve (AUC), as well as the cavernous cGMP levels. Morphometric analyses showed that ESB administration increased both smooth muscle volume and the regular arrangement of collagen fibers compared to the STZ group. The protein expression levels of endothelial nitric oxide synthase (eNOS) and SM [Formula: see text]-actin from penile tissues were also significantly increased in the ESB-treated rats. Taken together, these results suggest that ESB ameliorates penile erectile dysfunction via the activation of the NO/cGMP pathways of the penile corpus cavernosum in a streptozotocin-induced diabetic rat model.

Tolerance of cranial nerves of the cavernous sinus to radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tishler, R.B.; Loeffler, J.S.; Alexander, E. III

1993-09-20

Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. The authors examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (Universitymore » of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy. 21 refs., 4 tabs.« less

Cavernous sinus involvement is not a risk factor for the primary tumor site treatment outcome of Sinonasal adenoid cystic carcinoma.

PubMed

Lee, Yi-Chan; Lee, Ta-Jen; Tsang, Ngan-Ming; Huang, Yenlin; Hsu, Cheng-Lung; Hsin, Li-Jen; Lee, Yi-Hsuan; Chang, Kai-Ping

2018-02-05

Sinonasal adenoid cystic carcinoma is a rare malignancy of the head and neck. Cavernous sinus invasion from sinonasal adenoid cystic carcinoma and its related management have rarely been investigated. This study evaluated the relationship between treatment outcome and cavernous sinus involvement in addition to other parameters. A retrospective case series study was conducted at a tertiary referral center. The medical records of 47 patients diagnosed with primary sinonasal adenoid cystic carcinoma between 1984 and 2015 were retrospectively reviewed. The survival impact of the primary treatment modalities and the anatomic sites of tumor involvement were analyzed. Cavernous sinus invasion was observed in 8 patients (17%), of whom 7 had ACC tumors originating from the maxillary sinus. The results of univariate analysis revealed that tumor stage, primary surgery, and the absence of skull-base and infratemporal fossa invasion were associated with better overall survival (P = 0.033, P = 0.012, P = 0.011, and P = 0.040, respectively) and better disease-free survival (P = 0.019, P = 0.001, P = 0.017, and P = 0.029, respectively). Multivariate analysis identified primary surgery as the only independent prognostic factor for disease-free survival (P = 0.026). Cavernous sinus invasion by sinonasal adenoid cystic carcinoma was not associated with worse overall survival or disease-free survival (P = 0.200 and P = 0.198, respectively). Because maxillary adenoid cystic carcinoma is associated with a higher rate of cavernous sinus invasion, such cases warrant caution during preoperative planning. Primary surgery as the initial therapy provides better locoregional control and survival for patients with sinonasal adenoid cystic carcinoma. Cavernous sinus invasion did not significantly impact survival; thus, it should not be regarded as a contraindication for curative treatment.

Salinization of groundwater around underground LPG storage caverns, Korea : statistical interpretation

NASA Astrophysics Data System (ADS)

Lee, J.; Chang, H.

2001-12-01

In this research, we investigate the reciprocal influence between groundwater flow and its salinization occurred in two underground cavern sites, using major ion chemistry, PCA for chemical analysis data, and cross-correlation for various hydraulic data. The study areas are two underground LPG storage facilities constructed in South Sea coast, Yosu, and West Sea coastal regions, Pyeongtaek, Korea. Considerably high concentration of major cations and anions of groundwaters at both sites showed brackish or saline water types. In Yosu site, some great chemical difference of groundwater samples between rainy and dry season was caused by temporal intrusion of high-saline water into propane and butane cavern zone, but not in Pyeongtaek site. Cl/Br ratios and δ 18O- δ D distribution for tracing of salinization source water in both sites revealed that two kind of saline water (seawater and halite-dissolved solution) could influence the groundwater salinization in Yosu site, whereas only seawater intrusion could affect the groundwater chemistry of the observation wells in Pyeongtaek site. PCA performed by 8 and 10 chemical ions as statistical variables in both sites showed that intensive intrusion of seawater through butane cavern was occurred at Yosu site while seawater-groundwater mixing was observed at some observation wells located in the marginal part of Pyeongtaek site. Cross-correlation results revealed that the positive relationship between hydraulic head and cavern operating pressure was far more conspicuous at propane cavern zone in both sites (65 ~90% of correlation coefficients). According to the cross-correlation results of Yosu site, small change of head could provoke massive influx of halite-dissolved solution from surface through vertically developed fracture networks. However in Pyeongtaek site, the pressure-sensitive observation wells are not completely consistent with seawater-mixed wells, and the hydraulic change of heads at these wells related to the operating pressure is highly associated with horizontal fault developed along the east-west line of propane cavern zone.

A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

PubMed

Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

2011-04-01

Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

Modeling Groundwater Flow and Infiltration at Potential Low-Level Radioactive Waste Disposal Sites in Taiwan

NASA Astrophysics Data System (ADS)

Arnold, B. W.; Lee, C.; Ma, C.; Knowlton, R. G.

2006-12-01

Taiwan is evaluating representative sites for the potential disposal of low-level radioactive waste (LLW), including consideration of shallow land burial and cavern disposal concepts. A representative site for shallow land burial is on a small island in the Taiwan Strait with basalt bedrock. The shallow land burial concept includes an engineered cover to limit infiltration into the waste disposal cell. A representative site for cavern disposal is located on the southeast coast of Taiwan. The tunnel system for this disposal concept would be several hundred meters below the mountainous land surface in argillite bedrock. The LLW will consist of about 966,000 drums, primarily from the operation and decommissioning of four nuclear power plants. Sandia National Laboratories and the Institute of Nuclear Energy Research have collaborated to develop performance assessment models to evaluate the long-term safety of LLW disposal at these representative sites. Important components of the system models are sub-models of groundwater flow in the natural system and infiltration through the engineered cover for the shallow land burial concept. The FEHM software code was used to simulate groundwater flow in three-dimensional models at both sites. In addition, a higher-resolution two-dimensional model was developed to simulate flow through the engineered tunnel system at the cavern site. The HELP software was used to simulate infiltration through the cover at the island site. The primary objective of these preliminary models is to provide a modeling framework, given the lack of site-specific data and detailed engineering design specifications. The steady-state groundwater flow model at the island site uses a specified recharge boundary at the land surface and specified head at the island shoreline. Simulated groundwater flow vectors are extracted from the FEHM model along a cross section through one of the LLW disposal cells for utilization in radionuclide transport simulations in the performance assessment model with the BLT-MS software. Infiltration through the engineered cover is simulated to be about 3 mm/yr and 49 mm/yr, with and without a geomembrane layer, respectively. For the cavern LLW disposal site, the FEHM basin-scale flow model uses specified recharge flux, constant head at the ocean shoreline, and head-dependent flux boundaries along flowing streams. Groundwater flow vectors are extracted along a cross section for use in radionuclide transport simulations. Transport simulations indicate that a significant fraction of contaminants may ultimately discharge to nearby streams. FEHM flow simulations with the drift-scale model indicate that the flow rates within the backfilled tunnels may be more than two orders of magnitude lower than in the host rock. Sandia National Laboratories is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy under Contract DE-AC04-94AL85000.

Navigated transcranial magnetic stimulation in preoperative planning for the treatment of motor area cavernous angiomas

PubMed Central

Paiva, Wellingson Silva; Fonoff, Erich Talamoni; Marcolin, Marco Antonio; Bor-Seng-Shu, Edson; Figueiredo, Eberval Gadelha; Teixeira, Manoel Jacobsen

2013-01-01

Since the introduction of microscopic techniques, radical surgery for cavernous angiomas has become a recommended treatment option. However, the treatment of motor area cavernous angioma represents a great challenge for the surgical team. Here, we describe an approach guided by frameless neuronavigation and preoperative functional mapping with transcranial magnetic stimulation (TMS), for surgical planning. We used TMS to map the motor cortex and its relationship with the angioma. We achieved complete resection of the lesions in the surgeries, while avoiding areas of motor response identified during the preoperative mapping. We verified the complete control of seizures (Engel class 1A) in the patients with previous refractory epilepsy. Postsurgery, one patient was seizure-free without medication, and two patients required only one medication for seizure control. Thus, navigated TMS appears to be a useful tool, in preoperative planning for cavernous angiomas of the motor area. PMID:24353424

Simpler score of routine laboratory tests predicts liver fibrosis in patients with chronic hepatitis B.

PubMed

Zhou, Kun; Gao, Chun-Fang; Zhao, Yun-Peng; Liu, Hai-Lin; Zheng, Rui-Dan; Xian, Jian-Chun; Xu, Hong-Tao; Mao, Yi-Min; Zeng, Min-De; Lu, Lun-Gen

2010-09-01

In recent years, a great interest has been dedicated to the development of noninvasive predictive models to substitute liver biopsy for fibrosis assessment and follow-up. Our aim was to provide a simpler model consisting of routine laboratory markers for predicting liver fibrosis in patients chronically infected with hepatitis B virus (HBV) in order to optimize their clinical management. Liver fibrosis was staged in 386 chronic HBV carriers who underwent liver biopsy and routine laboratory testing. Correlations between routine laboratory markers and fibrosis stage were statistically assessed. After logistic regression analysis, a novel predictive model was constructed. This S index was validated in an independent cohort of 146 chronic HBV carriers in comparison to the SLFG model, Fibrometer, Hepascore, Hui model, Forns score and APRI using receiver operating characteristic (ROC) curves. The diagnostic values of each marker panels were better than single routine laboratory markers. The S index consisting of gamma-glutamyltransferase (GGT), platelets (PLT) and albumin (ALB) (S-index: 1000 x GGT/(PLT x ALB(2))) had a higher diagnostic accuracy in predicting degree of fibrosis than any other mathematical model tested. The areas under the ROC curves (AUROC) were 0.812 and 0.890 for predicting significant fibrosis and cirrhosis in the validation cohort, respectively. The S index, a simpler mathematical model consisting of routine laboratory markers predicts significant fibrosis and cirrhosis in patients with chronic HBV infection with a high degree of accuracy, potentially decreasing the need for liver biopsy.

Optimized Mouse Models for Liver Fibrosis.

PubMed

Kim, Yong Ook; Popov, Yury; Schuppan, Detlef

2017-01-01

Fibrosis is the excessive accumulation of extracellular matrix components due to chronic injury, with collagens as predominant structural components. Liver fibrosis can progress to cirrhosis, which is characterized by a severe distortion of the delicate hepatic vascular architecture, the shunting of the blood supply away from hepatocytes and the resultant functional liver failure. Cirrhosis is associated with a highly increased morbidity and mortality and represents the major hard endpoint in clinical studies of chronic liver diseases. Moreover, cirrhosis is a strong cofactor of primary liver cancer. In vivo models are indispensable tools to study the cellular and molecular mechanisms of liver fibrosis and to develop specific antifibrotic therapies towards clinical translation. Here, we provide a detailed description of select optimized mouse models of liver fibrosis and state-of-the-art fibrosis readouts.

Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

PubMed

Black, Sylvester M; Woodley, Frederick W; Tumin, Dmitry; Mumtaz, Khalid; Whitson, Bryan A; Tobias, Joseph D; Hayes, Don

2016-04-01

Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

Myometrial cavernous hemangioma with pulmonary thromboembolism in a post-partum woman: a case report and review of the literature.

PubMed

Bhavsar, Tapan; Wurzel, John; Duker, Nahum

2012-11-23

Cavernous hemangiomas of the uterus are rare benign vascular lesions. Nine cases of diffuse cavernous hemangioma of the gravid uterus have been reported, most of which diffusely involved the myometrium. These vascular malformations are clinically significant, and may cause pronounced bleeding resulting in maternal or fetal demise. Thrombosis of cavernous hemangiomas of the uterus has been previously reported. We here report the first case in which a thrombosed cavernous hemangioma of the myometrium resulted in a fatal pulmonary embolism in a post-partum woman. A 25-year-old obese African-American woman who had one pregnancy and was delivered of twins by cesarean section was admitted 1 week after the successful delivery. The 12-day clinical course included ventilator-dependent respiratory failure, systemic hypertension, methicillin-resistant Staphylococcus aureus in the sputum, leukocytosis and asystole. A transabdominal ultrasound examination showed heterogeneous thickened and irregular products in the endometrial canal. The laboratory values were relevant for an increased prothrombin time, activated partial thromboplastin time, ferritin and a decrease in hemoglobin. The clinical cause of death was cited as acute respiratory distress syndrome. At autopsy, a 400g spongy, hemorrhagic uterus with multiple cystic spaces measuring approximately 0.5 × 0.4cm filled with thrombi within the myometrium was identified. Immunohistological examination with a CD31 stain for vascular endothelium associated antigen confirmed several endothelium-lined vessels, some of which contained thrombi. These histological features were consistent with cavernous hemangioma of the myometrium. A histological examination of the lungs revealed multiple fresh thromboemboli in small- and medium-sized pulmonary arteries in the right upper and lower lobes without organization, but with adjacent areas of fresh hemorrhagic infarction. This case underscores the importance of a high index of suspicion in a pregnant or post-partum woman presenting with respiratory symptoms. Thrombosis of the cavernous hemangiomas of the gravid or post-partum uterus is a rare entity. This case is of interest because it indicates that this condition can be fatally complicated by embolization of the thrombi in the cavernous myometrial hemangiomas. Although delivery by conservative methods, as well as cesarean section, is possible without resorting to hysterectomy, occasionally, the consequences could be fatal as in this case.

Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients

PubMed Central

Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

2016-01-01

AIM To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. METHODS A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). RESULTS Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage (P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. CONCLUSION Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy. PMID:27917265

Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients.

PubMed

Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

2016-11-18

To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage ( P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy.

Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models

PubMed Central

Désogère, Pauline; Tapias, Luis F.; Hariri, Lida P.; Rotile, Nicholas J.; Rietz, Tyson A.; Probst, Clemens K.; Blasi, Francesco; Day, Helen; Mino-Kenudson, Mari; Weinreb, Paul; Violette, Shelia M.; Fuchs, Bryan C.; Tager, Andrew M.; Lanuti, Michael; Caravan, Peter

2017-01-01

Pulmonary fibrosis is a scarring of the lungs that can arise from radiation injury, drug toxicity, environmental or genetic causes, and for unknown reasons [idiopathic pulmonary fibrosis (IPF)]. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe a peptide-based PET probe (68Ga-CBP8) that targets collagen type I. We evaluated 68Ga-CBP8 in vivo in the bleomycin-induced mouse model of pulmonary fibrosis. 68Ga-CBP8 showed high specificity for pulmonary fibrosis and high target:background ratios in diseased animals. The lung PET signal and lung 68Ga-CBP8 uptake (quantified ex vivo) correlated linearly (r2=0.80) with the amount of lung collagen in mice with fibrosis. We further demonstrated that the 68Ga-CBP8 probe could be used to monitor response to treatment in a second mouse model of pulmonary fibrosis associated with vascular leak. Ex vivo analysis of lung tissue from patients with IPF supported the animal findings. These studies indicate that 68Ga-CBP8 is a promising candidate for non-invasive imaging of human pulmonary fibrosis. PMID:28381537

Effects of Electrostatic Environment on Charged Particle Transport near Lunar Holes

NASA Astrophysics Data System (ADS)

Miyake, Y.; Nishino, M. N.

2017-12-01

The Moon has neither dense atmosphere nor intrinsic magnetic field, and solar wind interactions with lunar surfaces are one of major plasma processes. The near-surface, dayside electrostatic environment is governed mainly by volume charges of solar wind plasma and photoelectrons as well as charged lunar surfaces. In fact, the electric environment strongly depends on surface topologies, as it will produce a shaded region, the electric environment of which can be very different from that in a sunlit condition. As one of high-profile terrains on the Moon, we have been focusing on the lunar vertical holes (or lunar pits), identified by the KAGUYA satellite and the Lunar Reconnaissance Orbiter. In order to model the distinctive electric and dust environments near the holes, we have started three-dimensional particle simulation analysis. The present study addresses the plasma environment of a lunar hole that is accompanied with a subsurface cavern. Besides the topographical effect of having a cavern, an investigation is focused on the following points. The first point is how deeply the solar wind protons are accessible into the hole and cavern. This point is relevant not only to an electric environment but also to possible existence of volatiles at permanently shaded regions of the hole. In order to examine the possibility, we implemented a proton scattering process at lunar surfaces into the simulation model. The other is the role of some minor current components such as secondary electrons, scattered protons, and charged dust grains at the lunar surface. Such minor currents become important for the charging of shaded surfaces, as major current components (solar wind plasma and photoelectrons) are not accessible there. We address these points based on kinetic model descriptions.

Icariside II Promotes the Differentiation of Adipose Tissue-Derived Stem Cells to Schwann Cells to Preserve Erectile Function after Cavernous Nerve Injury.

PubMed

Zheng, Tao; Zhang, Tian-Biao; Wang, Chao-Liang; Zhang, Wei-Xing; Jia, Dong-Hui; Yang, Fan; Sun, Yang-Yang; Ding, Xiao-Ju; Wang, Rui

2018-06-14

Icariside II (ICA II) is used in erectile dysfunction treatment. Adipose tissue-derived stem cells (ADSCs) are efficient at improving erectile function. This study aimed to explore the action mechanism of ADSCs in improving erectile function. ADSCs were isolated from the adipose tissues of rats. Cell proliferation was determined using the Cell Counting Kit-8 (CCK-8) assay. The expressions of mRNA and protein were determined separately through qRT-PCR and western blot. The endogenous expressions of related genes were regulated using recombinant plasmids and cell transfection. A Dual- Luciferase Reporter Assay was performed to determine the interaction between miR-34a and STAT3. Rat models with bilateral cavernous nerve injuries (BCNIs) were used to assess erectile function through the detection of mean arterial pressure (MAP) and intracavernosal pressure (ICP). ICA II promoted ADSCs' proliferation and differentiation to Schwann cells (SCs) through the inhibition of miR-34a. Suppressed miR-34a promoted the differentiation of ADSCs to SCs by upregulating STAT3. ICA II promoted the differentiation of ADSCs to SCs through the miR-34a/STAT3 pathway. The combination of ICA II and ADSCs preserved the erectile function of the BCNI model rats. ADSCs treated with ICA II markedly preserved the erectile function of the BCNI model rats, which was reversed through miR-34a overexpression. ICA II promotes the differentiation of ADSCs to SCs through the miR- 34a/STAT3 pathway, contributing to erectile function preservation after the occurrence of a cavernous nerve injury.

Comparison and Tensorial Formulation of Inelastic Constitutive Models of Salt Rock Behaviour and Efficient Numerical Implementatio

NASA Astrophysics Data System (ADS)

Nagel, T.; Böttcher, N.; Görke, U. J.; Kolditz, O.

2014-12-01

The design process of geotechnical installations includes the application of numerical simulation tools for safety assessment, dimensioning and long term effectiveness estimations. Underground salt caverns can be used for the storage of natural gas, hydrogen, oil, waste or compressed air. For their design one has to take into account fluctuating internal pressures due to different levels of filling, the stresses imposed by the surrounding rock mass, irregular geometries and possibly heterogeneous material properties [3] in order to estimate long term cavern convergence as well as locally critical wall stresses. Constitutive models applied to rock salt are usually viscoplastic in nature and most often based on a Burgers-type rheological model extended by non-linear viscosity functions and/or plastic friction elements. Besides plastic dilatation, healing and damage are sometimes accounted for as well [2]. The scales of the geotechnical system to be simulated and the laboratory tests from which material parameters are determined are vastly different. The most common material testing modalities to determine material parameters in geoengineering are the uniaxial and the triaxial compression tests. Some constitutive formulations in widespread use are formulated based on equivalent rather than tensorial quantities valid under these specific test conditions and are subsequently applied to heterogeneous underground systems and complex 3D load cases. We show here that this procedure is inappropriate and can lead to erroneous results. We further propose alternative formulations of the constitutive models in question that restore their validity under arbitrary loading conditions. For an efficient numerical simulation, the discussed constitutive models are integrated locally with a Newton-Raphson algorithm that directly provides the algorithmically consistent tangent matrix for the global Newton iteration of the displacement based finite element formulation. Finally, the finite element implementations of the proposed constitutive formulations are employed to simulate an underground salt cavern used for compressed air energy storage with OpenGeoSys [1]. Transient convergence and stress fields are evaluated for typical fluctuating operation pressure regimes.

Unprecedented Zipangu Underworld of the Moon Exploration (UZUME)

NASA Astrophysics Data System (ADS)

Haruyama, J.; Kawano, I.; Kubota, T.; Otsuki, M.; Kato, H.; Nishibori, T.; Iwata, T.; Yamamoto, Y.; Nagamatsu, A.; Shimada, K.; Ishihara, Y.; Hasenaka, T.; Morota, T.; Nishino, M. N.; Hashizume, K.; Saiki, K.; Shirao, M.; Komatsu, G.; Hasebe, N.; Shimizu, H.; Miyamoto, H.; Kobayashi, K.; Yokobori, S.; Michikami, T.; Yamamoto, S.; Yokota, Y.; Arisumi, H.; Ishigami, G.; Furutani, K.; Michikawa, Y.

2014-04-01

On the Moon, three huge vertical holes (several tens to a hundred meters in diameter and depth) were discovered in SELENE (nicknamed Kaguya) Terrain Camera data of 10 m pixel resolution. These holes are probably skylights of underground large caverns such as lava tubes, or magma chambers. The huge holes and their associated subsurface caverns are among the most important future exploration targets from the viewpoint of constructing lunar bases and many scientific aspects. We are now planning to explore the caverns through the skylight holes. We name the project as UZUME (Unprecedented Zipangu (Japan) Underworld of the Moon Exploration).

Bayou Choctaw Well Integrity Grading Component Based on Geomechanical Simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Byoung

2016-09-08

This letter report provides a Bayou Choctaw (BC) Strategic Petroleum Reserve (SPR) well grading system based on the geomechanical simulation. The analyses described in this letter were used to evaluate the caverns’ geomechanical effect on wellbore integrity, which is an important component in the well integrity grading system recently developed by Roberts et al. [2015]. Using these analyses, the wellbores for caverns BC-17 and 20 are expected to be significantly impacted by cavern geomechanics, BC-18 and 19 are expected to be medium impacted; and the other caverns are expected to be less impacted.

Pure Epidural Cavernous Hemangioma of the Cervical Spine that Presented with an Acute Sensory Deficit Caused by Hemorrhage

PubMed Central

Lee, Sang-Ho; Chung, Seung-Eun; Paeng, Sung-Suk; Kim, Hye-Sung; Yoon, Sang-Wook; Yu, Jeong-Sik

2006-01-01

Pure epidural cavernous hemangioma of the spine without vertebral involvement is rare. Due to the slow growth of this lesion, the most common symptoms are chronic pain, myelopathy, and radiculopathy. In our case, the patient complained of an acute onset sensory deficit of the C4 dermatome. An MRI revealed an epidural mass with an acute hematoma. Here, we report a case of a pure epidural cavernous hemangioma that presented with acute neurologic symptoms caused by intralesional hemorrhage and an acute epidural hematoma, which were demonstrated on the patient's MRI. PMID:17191320

Pure epidural cavernous hemangioma of the cervical spine that presented with an acute sensory deficit caused by hemorrhage.

PubMed

Jo, Byung-June; Lee, Sang-Ho; Chung, Seung-Eun; Paeng, Sung-Suk; Kim, Hye-Sung; Yoon, Sang-Wook; Yu, Jeong-Sik

2006-12-31

Pure epidural cavernous hemangioma of the spine without vertebral involvement is rare. Due to the slow growth of this lesion, the most common symptoms are chronic pain, myelopathy, and radiculopathy. In our case, the patient complained of an acute onset sensory deficit of the C4 dermatome. An MRI revealed an epidural mass with an acute hematoma. Here, we report a case of a pure epidural cavernous hemangioma that presented with acute neurologic symptoms caused by intralesional hemorrhage and an acute epidural hematoma, which were demonstrated on the patient's MRI.

A cavernous sinus lesion clinically responsive to steroids.

PubMed

Ruff, M W; Carabenciov, I D; Johnson, D R; Pollock, B E; Parisi, J E; Klaas, J P

2018-04-20

Tolosa Hunt syndrome (THS) is characterized by painful ophthalmoplegia secondary to idiopathic granulomatous inflammation of the cavernous sinus. The characteristic finding on MRI is an enhancing T1 isointense and T2 hypo- or hyperintense cavernous sinus mass lesion, which may result in focal narrowing of the ipsilateral internal carotid artery. Although the incidence is quite rare, it is a common diagnostic consideration in cases that present with multiple cranial neuropathies. However, the differential diagnosis for a unilateral cavernous sinus lesion in adults is broad and includes neoplastic, inflammatory (such as sarcoidosis and immunoglobulin G4-related disease [IgG4-RD]), infectious etiologies (such as syphilis and leprosy), as well as vascular lesions. We describe a patient presenting with neurologic symptoms referable to a persistent unilateral cavernous sinus MRI abnormality, initially thought to be consistent with Tolosa-Hunt syndrome, that was clinically but not radiographically responsive to steroids. Following reevaluation due to the presence of new symptoms, pathology revealed that the abnormality was most consistent with chordoma, a rare skull based tumor. In patients with a presumed diagnosis of Tolosa-Hunt syndrome, close clinical and radiographic follow-up is imperative, with early consideration for biopsy in patients that fail to respond to treatment both clinically and radiographically. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pure Spinal Epidural Cavernous Hemangioma with Intralesional Hemorrhage: A Rare Cause of Thoracic Myelopathy

PubMed Central

Jang, Donghwan; Kim, Choonghyo; Lee, Seung Jin; Ryu, Young-Joon

2014-01-01

Although cavernous hemangiomas occur frequently in the intracranial structures, they are rare in the spine. Most of spinal hemangiomas are vertebral origin and "pure" epidural hemangiomas not originating from the vertebral bone are very rare. Our spinal hemangioma case is extremely rare because of its "pure" epidural involvement and intralesional hemorrhage. A 64-year-old man presented with progressive paraparesis from two months ago. His motor weakness was rated as grade 4/5 in bilateral lower extremities. He also complained of decreased sensation below the T4 sensory dermatome, which continuously progressed to the higher dermatome level. Magnetic resonance imaging demonstrated thoracic spinal tumor at T3-T4 level. The tumor was located epidural space compressing thoracic spinal cord ventrally. The tumor was not involved with the thoracic vertebral bone. We performed T3-5 laminectomy and removed the tumor completely. The tumor was not infiltrating into intradural space or vertebral bone. The histopathologic study confirmed the epidural tumor as cavernous hemangioma. Postoperatively, his weakness improved gradually. Four months later, his paraparesis recovered completely. Here, we present a case of pure spinal epidural cavernous hemangioma, which has intralesional hemorrhage. We believe cavernous hemangioma should be included in the differential diagnosis of the spinal epidural tumors. PMID:25110490

Cavernous Transformation of Portal Vein Secondary to Portal Vein Thrombosis: A Case Report

PubMed Central

Ramos, Radhames; Park, Yoojin; Shazad, Ghulamullah; A.Garcia, Christine; Cohen, Ronny

2012-01-01

There are few reported cases of cavernous transformation of the portal vein (CTPV) in adults. We present a case of a 58 year-old male who was found to have this complication due to portal vein thrombosis (PVT). A 58-year old African American male with chronic alcohol and tobacco use presented with a 25-day history of weakness, generalized malaise, nausea and vomiting associated with progressively worsening anorexia and weight loss. The patient was admitted for severe anemia in conjunction with abnormal liver function tests and electrolyte abnormalities, and to rule out end stage liver disease or hepatic malignancy. The work-up for anemia showed no significant colon abnormalities, cholecystitis, liver cirrhosis, or liver abnormalities but could not rule out malignancy. An esophageogastroduodenoscopy (EGD) was suspicious for a mass compressing the stomach and small bowel. After further work-up, the hepatic mass has been diagnosed as a cavernous transformation of the portal vein (CTPV), a very rare complication of portal vein thrombosis (PVT). Cavernous Transformation of the Portal Vein (CTPV) is a rare and incurable complication of portal vein thrombosis (PVT) that should be considered as one of the differential diagnoses of a hepatic mass. Keywords Cavernous transformation of the portal vein; Portal vein thrombosis; Portal hypertension; Hyperbilirubinemia; Hepatic mass PMID:22383935

Cavernous sinus tuberculoma mimicking a neoplasm: Case report, literature review, and diagnostic and treatment suggestions for tuberculomas in rare locations

PubMed Central

Jaimovich, Sebastián G.; Thea, Victor Castillo; Guevara, Martin; Gardella, Javier L.

2013-01-01

Background: Cavernous sinus tuberculomas are extremely rare, but the increasing incidence worldwide of central nervous system (CNS) tuberculosis, mostly due to human immunodeficiency virus and poor sanitary conditions, and the ability of tuberculomas to mimic a brain neoplasm makes cavernous sinus tuberculomas a suspicious pathologic finding in the differential diagnosis of a brain space-occupying lesion. Case Description: We present an immunocompetent patient with no signs of systemic tuberculosis and an isolated right cavernous sinus space-occupying lesion. A skull base approach was performed and tumor resection achieved. The postoperative course was uneventful. Pathologic findings consisted of a tuberculoma and antituberculous treatment was immediately begun with total tumor regression after a 12-month regimen. After reviewing the literature, we propose suggestions to orient the diagnosis and a treatment algorithm for tuberculomas in rare locations. Conclusion: Tuberculomas in rare locations, as the cavernous sinus, are a challenging pathology as they have the ability to mimic a brain neoplasm. Although first line treatment are antituberculous therapy (4 drugs for at least 12 months) and adjuvant steroids, in inconclusive cases, surgical biopsy or excision is recommended for histopathologic confirmation and to reduce the mass effect, always following with antituberculous therapy and adjuvant steroids. PMID:24381801

Radiotherapy induced dermatitis is a strong predictor for late fibrosis in head and neck cancer. The development of a predictive model for late fibrosis.

PubMed

Nevens, Daan; Duprez, Fréderic; Daisne, Jean Francois; Laenen, Annouschka; De Neve, Wilfried; Nuyts, Sandra

2017-02-01

To determine if the severity of radiodermatitis at the end of radio(chemo)therapy (R(C)T) for head and neck cancer (HNC) is a predictive factor for late fibrosis of the neck and to find a model to predict neck fibrosis grade⩾2 (fibrosis RTOG 2-4 ) at 6months following R(C)T for HNC. 161 patients were prospectively included. We correlated radiodermatitis at the end of RCT, age, sex, T/N stage, tumor site, concomitant chemotherapy, upfront neck dissection, neo-adjuvant chemotherapy, accelerated RT, smoking, alcohol consumption, HPV status and the dose prescribed to the elective neck with fibrosis RTOG 2-4 6months after the end of treatment. Radiodermatitis at the end of R(C)T ⩾grade 3 proved to be associated with the incidence of fibrosis RTOG 2-4 at 6months (p<0.01). Furthermore, upfront neck dissection (p<0.01), increasing N stage (p<0.01) and tumor site (p=0.02) are significantly associated in univariate analysis with fibrosis RTOG 2-4 at 6months of follow-up. Upfront neck dissection and radiodermatitis grade⩾3 at the end of R(C)T were identified by our multivariate model. Additionally, increasing N stage was selected as an independent predictor variable. The AUC for this model was 0.92. A model for the prediction of fibrosis RTOG 2-4 following R(C)T for head and neck cancer is presented with an AUC of 0.92. Interestingly, radiodermatitis grade⩾3 at the end of R(C)T is associated with RTOG 2-4 fibrosis at 6months. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Comparison of serological assessments in the diagnosis of liver fibrosis in bile duct ligation mice.

PubMed

Xie, Chengxia; Ma, Bo; Wang, Ning; Wan, Lin

2017-08-01

Liver fibrosis assessment is essential to make a prognosis and to determine the appropriate anti-fibrosis treatment. Non-invasive serum markers are widely studied in patients to assess liver fibrosis due to the limitations of liver biopsy. When using animal models to study the mechanism and intervention of hepatic fibrosis, serum markers might be useful for the continuous assessment of liver fibrosis in individual animals, which could avoid the influence of biological differences between individuals. However, it is unclear whether serum markers can assess hepatic fibrosis in the animal model. In the present study, we evaluated and compared the ability of four serum markers to assess liver fibrosis in bile duct ligation mice. According to the stages of liver fibrosis assessed by pathological changes, mice in this study were divided into five groups (F0, F1, F2, F3, and F4). Subsequently, four serum markers, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), and Forns Index, were calculated for each group. Furthermore, the correlations between serum markers and pathological stages and the ability of serological markers to evaluate liver fibrosis were analyzed. AAR, APRI, FIB-4, and Forns Index could significantly distinguish F0-2 from F3-4 mice. APRI, FIB-4, and Forns Index could detect F0-3 from F4 mice. Among these four markers, FIB-4 was the best able to distinguish ≥F2 and ≥F3, with area under the curve values of 0.882 and 0.92, respectively. Forns Index was best for diagnosing F4 with area under the curve value of 0.879. These results demonstrated that serum markers could be used for assessing liver fibrosis in bile duct ligation mice, and therefore, these markers might lead to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. Impact statement The assessment of liver fibrosis is essential for making a prognosis and determining the appropriate anti-fibrosis treatment. In studies focusing on the mechanism and treatment of liver fibrosis using animal models, it would be more accurate to continuously evaluate liver fibrosis in a single animal to avoid individual biological differences. Unfortunately, it is difficult to perform continuous assessment through liver biopsy in the most commonly used rodent models. It is unclear whether serum markers, which have been used in hepatic fibrosis patients, could be used in animal models. Our results demonstrate that serum markers could be used for assessing liver fibrosis in bile duct ligation mice. This study might contribute to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals.

Modeling the Chagas’ disease after stem cell transplantation

NASA Astrophysics Data System (ADS)

Galvão, Viviane; Miranda, José Garcia Vivas

2009-04-01

A recent model for Chagas’ disease after stem cell transplantation is extended for a three-dimensional multi-agent-based model. The computational model includes six different types of autonomous agents: inflammatory cell, fibrosis, cardiomyocyte, proinflammatory cytokine tumor necrosis factor- α, Trypanosoma cruzi, and bone marrow stem cell. Only fibrosis is fixed and the other types of agents can move randomly through the empty spaces using the three-dimensional Moore neighborhood. Bone marrow stem cells can promote apoptosis in inflammatory cells, fibrosis regression and can differentiate in cardiomyocyte. T. cruzi can increase the number of inflammatory cells. Inflammatory cells and tumor necrosis factor- α can increase the quantity of fibrosis. Our results were compared with experimental data giving a fairly fit and they suggest that the inflammatory cells are important for the development of fibrosis.

Induced Autologous Stem Cell Transplantation for Treatment of Rabbit Renal Interstitial Fibrosis

PubMed Central

Ruan, Guang-Ping; Xu, Fan; Li, Zi-An; Zhu, Guang-Xu; Pang, Rong-Qing; Wang, Jin-Xiang; Cai, Xue-Min; He, Jie; Yao, Xiang; Ruan, Guang-Hong; Xu, Xin-Ming; Pan, Xing-Hua

2013-01-01

Introduction Renal interstitial fibrosis (RIF) is a significant cause of end-stage renal failure. The goal of this study was to characterize the distribution of transplanted induced autologous stem cells in a rabbit model of renal interstitial fibrosis and evaluate its therapeutic efficacy for treatment of renal interstitial fibrosis. Methods A rabbit model of renal interstitial fibrosis was established. Autologous fibroblasts were cultured, induced and labeled with green fluorescent protein (GFP). These labeled stem cells were transplanted into the renal artery of model animals at 8 weeks. Results Eight weeks following transplantation of induced autologous stem cells, significant reductions (P < 0.05) were observed in serum creatinine (SCr) (14.8 ± 1.9 mmol/L to 10.1 ± 2.1 mmol/L) and blood urea nitrogen (BUN) (119 ± 22 µmol/L to 97 ± 13 µmol/L), indicating improvement in renal function. Conclusions We successfully established a rabbit model of renal interstitial fibrosis and demonstrated that transplantation of induced autologous stem cells can repair kidney damage within 8 weeks. The repair occurred by both inhibition of further development of renal interstitial fibrosis and partial reversal of pre-existing renal interstitial fibrosis. These beneficial effects lead to the development of normal tissue structure and improved renal function. PMID:24367598

Development of experimental fibrotic liver diseases animal model by Carbon Tetracholoride.

PubMed

Gitiara, Atoosa; Tokhanbigli, Samaneh; Mazhari, Sogol; Baghaei, Kaveh; Hatami, Behzad; Hashemi, Seyed Mahmoud; Asadi Rad, Ali; Moradi, Afshin; Nasiri, Meyam; Zarrabi Ahrabi, Nakisa; Zali, Mohammad Reza

2017-01-01

This study is presenting an effective method of inducing liver fibrosis by CCL4 as a toxin in two different breeds of rat models. Liver fibrosis is a result of inflammation and liver injury caused by wound healing responses which ultimately lead to liver failure. Consequently, after liver fibrosis, the progression will be continued to liver cirrhosis and at the end stage hepatocellular carcinoma (HCC). Many studies have demonstrated that one of the most important causes of liver fibrosis is Non-alcoholic steatohepatitis (NASH). Fibrotic Liver is affected by an excessive accumulation of extracellular matrix (ECM) proteins like collagen and α-SMA. In two different experiments, male Vistar, and Sprague Dawley Rat models ranging from 200±60, corresponding to an age of approximately 10 weeks were utilized in order to induce CCL4 treated liver fibrosis. After 6 weeks of CCL4 injection, different tests have been carried out to verify the liver fibrosis including serum markers such as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), molecular tests containing, laminin and α-SMA and also pathological observation by Hematoxylin and eosin staining in both fibrosis and control group. The results of Pathology and Real-time PCR showed that fibrosis was induced much more effectively in Sprague Dawley rat model compared with Wistar rats.

Urethral cavernous hemangioma in a female patient: a rare entity

PubMed Central

Bolat, Mustafa Suat; Yüzüncü, Kubilay; Akdeniz, Ekrem; Demirdoven, Ayse Nurten

2015-01-01

Genitourinary hemangiomas are rare entities of the urinary system. We reported a female patient who suffered dyspareunia and intermitant hematuria that was proved as urethral cavernous hemangioma. Despite its benign nature, hemangiomas may recur due to incomplet excision. PMID:26985270

Utility of texture analysis for quantifying hepatic fibrosis on proton density MRI.

PubMed

Yu, HeiShun; Buch, Karen; Li, Baojun; O'Brien, Michael; Soto, Jorge; Jara, Hernan; Anderson, Stephan W

2015-11-01

To evaluate the potential utility of texture analysis of proton density maps for quantifying hepatic fibrosis in a murine model of hepatic fibrosis. Following Institutional Animal Care and Use Committee (IACUC) approval, a dietary model of hepatic fibrosis was used and 15 ex vivo murine liver tissues were examined. All images were acquired using a 30 mm bore 11.7T magnetic resonance imaging (MRI) scanner with a multiecho spin-echo sequence. A texture analysis was employed extracting multiple texture features including histogram-based, gray-level co-occurrence matrix-based (GLCM), gray-level run-length-based features (GLRL), gray level gradient matrix (GLGM), and Laws' features. Texture features were correlated with histopathologic and digital image analysis of hepatic fibrosis. Histogram features demonstrated very weak to moderate correlations (r = -0.29 to 0.51) with hepatic fibrosis. GLCM features correlation and contrast demonstrated moderate-to-strong correlations (r = -0.71 and 0.59, respectively) with hepatic fibrosis. Moderate correlations were seen between hepatic fibrosis and the GLRL feature short run low gray-level emphasis (SRLGE) (r = -0. 51). GLGM features demonstrate very weak to weak correlations with hepatic fibrosis (r = -0.27 to 0.09). Moderate correlations were seen between hepatic fibrosis and Laws' features L6 and L7 (r = 0.58). This study demonstrates the utility of texture analysis applied to proton density MRI in a murine liver fibrosis model and validates the potential utility of texture-based features for the noninvasive, quantitative assessment of hepatic fibrosis. © 2015 Wiley Periodicals, Inc.

Phosphoproteomic biomarkers predicting histologic nonalcoholic steatohepatitis and fibrosis.

PubMed

Younossi, Zobair M; Baranova, Ancha; Stepanova, Maria; Page, Sandra; Calvert, Valerie S; Afendy, Arian; Goodman, Zachary; Chandhoke, Vikas; Liotta, Lance; Petricoin, Emanuel

2010-06-04

The progression of nonalcoholic fatty liver disease (NAFLD) has been linked to deregulated exchange of the endocrine signaling between adipose and liver tissue. Proteomic assays for the phosphorylation events that characterize the activated or deactivated state of the kinase-driven signaling cascades in visceral adipose tissue (VAT) could shed light on the pathogenesis of nonalcoholic steatohepatitis (NASH) and related fibrosis. Reverse-phase protein microarrays (RPMA) were used to develop biomarkers for NASH and fibrosis using VAT collected from 167 NAFLD patients (training cohort, N = 117; testing cohort, N = 50). Three types of models were developed for NASH and advanced fibrosis: clinical models, proteomics models, and combination models. NASH was predicted by a model that included measurements of two components of the insulin signaling pathway: AKT kinase and insulin receptor substrate 1 (IRS1). The models for fibrosis were less reliable when predictions were based on phosphoproteomic, clinical, or the combination data. The best performing model relied on levels of the phosphorylation of GSK3 as well as on two subunits of cyclic AMP regulated protein kinase A (PKA). Phosphoproteomics technology could potentially be used to provide pathogenic information about NASH and NASH-related fibrosis. This information can lead to a clinically relevant diagnostic/prognostic biomarker for NASH.

Diagnostic accuracy of APRI and FIB-4 for predicting hepatitis B virus-related liver fibrosis accompanied with hepatocellular carcinoma.

PubMed

Xiao, Guangqin; Zhu, Feng; Wang, Min; Zhang, Hang; Ye, Dawei; Yang, Jiayin; Jiang, Li; Liu, Chang; Yan, Lunan; Qin, Renyi

2016-10-01

Aspartate aminotransferase to platelet ratio index (APRI) and the fibrosis index based on four factors (FIB-4) are the two most focused non-invasive models to assess liver fibrosis. We aimed to examine the validity of these two models for predicting hepatitis B virus (HBV)-related liver fibrosis accompanied with hepatocellular carcinoma (HCC). We enrolled HBV-infected patients with liver cancer who had received hepatectomy. The accuracy of APRI and FIB-4 for diagnosing liver fibrosis was assessed based on their sensitivity, specificity, diagnostic efficiency, positive predictive value (PPV), negative predictive value (NPV), kappa (κ) value and area under the receiver-operating characteristic curve (AUC). Finally 2176 patients were included, with 1682 retrospective subjects and 494 prospective subjects. APRI (rs=0.310) and FIB-4 (rs=0.278) were positively correlated with liver fibrosis. And χ(2) analysis demonstrated that APRI and FIB-4 values correlated with different levels of liver fibrosis with all P values less than 0.01. The AUC values for APRI and FIB-4 were 0.685 and 0.626 (P=0.73) for predicting significant fibrosis, 0.681 and 0.648 (P=0.81) for differentiation of advanced fibrosis and 0.676 and 0.652 (P=0.77) for diagnosing cirrhosis. APRI and FIB-4 correlate with liver fibrosis. However these two models have low accuracy for predicting HBV-related liver fibrosis in HCC patients. Copyright © 2016. Published by Elsevier Ltd.

Modeling of coupled thermodynamic and geomechanical performance of underground compressed air energy storage in lined rock caverns

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rutqvist, Jonny; Kim, Hyung-Mok; Ryu, Dong-Woo

We applied coupled nonisothermal, multiphase fluid flow and geomechanical numerical modeling to study the coupled thermodynamic and geomechanical performance of underground compressed air energy storage (CAES) in concrete-lined rock caverns. The paper focuses on CAES in lined caverns at relatively shallow depth (e.g., 100 m depth) in which a typical CAES operational pressure of 5 to 8 MPa is significantly higher than both ambient fluid pressure and in situ stress. We simulated a storage operation that included cyclic compression and decompression of air in the cavern, and investigated how pressure, temperature and stress evolve over several months of operation. Wemore » analyzed two different lining options, both with a 50 cm thick low permeability concrete lining, but in one case with an internal synthetic seal such as steel or rubber. For our simulated CAES system, the thermodynamic analysis showed that 96.7% of the energy injected during compression could be recovered during subsequent decompression, while 3.3% of the energy was lost by heat conduction to the surrounding media. Our geomechanical analysis showed that tensile effective stresses as high as 8 MPa could develop in the lining as a result of the air pressure exerted on the inner surface of the lining, whereas thermal stresses were relatively smaller and compressive. With the option of an internal synthetic seal, the maximum effective tensile stress was reduced from 8 to 5 MPa, but was still in substantial tension. We performed one simulation in which the tensile tangential stresses resulted in radial cracks and air leakage though the lining. This air leakage, however, was minor (about 0.16% of the air mass loss from one daily compression) in terms of CAES operational efficiency, and did not significantly impact the overall energy balance of the system. However, despite being minor in terms of energy balance, the air leakage resulted in a distinct pressure increase in the surrounding rock that could be quickly detected using pressure monitoring outside the concrete lining.« less

The Role of Palliative Radiosurgery When Cancer Invades the Cavernous Sinus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kano, Hideyuki; Niranjan, Ajay; Kondziolka, Douglas

2009-03-01

Purpose: Involvement of the cavernous sinus by direct invasion from skull base cancer or from metastatic spread of cancers is a challenging problem. We evaluated the role of stereotactic radiosurgery (SRS) in the treatment of patients who developed cavernous sinus metastases or direct invasion. Methods and Materials: We retrospectively reviewed the data from 37 patients who had cavernous sinus metastases or had cavernous sinus invasion from adjacent skull base cancers and who underwent SRS between 1992 and 2006 at University of Pittsburgh Medical Center. The median patient age was 57.8 years. Previous adjuvant management included fractionated radiotherapy in 8, chemotherapymore » in 16, and both radiotherapy and chemotherapy in 5. The primary sites of metastases or invasion were nasopharyngeal carcinoma (n = 7), parotid gland carcinoma (n = 7), and metastases from systemic cancer (n = 23). The median target volume was 6.3 cm{sup 3} (range, 0.3-33.6), and the median margin dose was 14 Gy (range, 12-20). Results: At a mean of 12.9 months (range, 0.8-63.9), 32 patients had died and 5 were living. The overall survival rate after SRS was 36.6% and 19.4% at 1 and 2 years, respectively. Progression-free survival was related to a greater marginal dose. After SRS, 12 (35.3%) of 34 patients with neurologic symptoms exhibited improvement. SRS early after diagnosis was significantly associated with improvement of cranial nerve dysfunction. Conclusion: SRS is a minimally invasive palliative option for patients whose cancer has invaded the cavernous sinus. The benefits for cranial nerve deficits are best when SRS is performed early.« less

Trans-zygomatic middle cranial fossa approach to access lesions around the cavernous sinus and anterior parahippocampus: a minimally invasive skull base approach.

PubMed

Melamed, Itay; Tubbs, R Shane; Payner, Troy D; Cohen-Gadol, Aaron A

2009-08-01

Exposure of the cavernous sinus or anterior parahippocampus often involves a wide exposure of the temporal lobe and mobilization of the temporalis muscle associated with temporal lobe retraction. The authors present a cadaveric study to illustrate the feasibility, advantages and landmarks necessary to perform a trans-zygomatic middle fossa approach to lesions around the cavernous sinus and anterior parahippocampus. The authors performed bilateral trans-zygomatic middle fossae exposures to reach the cavernous sinus and parahippocampus in five cadavers (10 sides). We assessed the morbidity associated with this procedure and compared the indications, advantages, and disadvantages of this method versus more extensive skull base approaches. A vertical linear incision along the middle portion of the zygomatic arch was extended one finger breadth inferior to the inferior edge of the zygomatic arch. Careful dissection inferior to the arch allowed preservation of facial nerve branches. A zygomatic osteotomy was followed via a linear incision through the temporalis muscle and exposure of the middle cranial fossa floor. A craniotomy along the inferolateral temporal bone and middle fossa floor allowed extradural dissection along the middle fossa floor and exposure of the cavernous sinus including all three divisions of the trigeminal nerve. Intradural inspection demonstrated adequate exposure of the parahippocampus. Exposure of the latter required minimal or no retraction of the temporal lobe. The trans-zygomatic middle fossa approach is a simplified skull base exposure using a linear incision, which may avoid the invasivity of more extensive skull base approaches while providing an adequate corridor for resection of cavernous sinus and parahippocampus lesions. The advantages of this approach include its efficiency, ease, minimalism, preservation of the temporalis muscle, and minimal retraction of the temporal lobe.

Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats.

PubMed

Mostafa, Mohamed E; Senbel, Amira M; Mostafa, Taymour

2013-06-01

To assess the effect of chronic low-dose administration of tadalafil (Td) on penile cavernous tissue in induced diabetic rats. The study investigaged 48 adult male albino rats, comprising a control group, sham controls, streptozotocin-induced diabetic rats, and induced diabetic rats that received Td low-dose daily (0.09 mg/200 g weight) for 2 months. The rats were euthanized 1 day after the last dose. Cavernous tissues were subjected to histologic, immunohistochemical, morphometric studies, and measurement of intracavernosal pressure and mean arterial pressure in anesthetized rats. Diabetic rats demonstrated dilated cavernous spaces, smooth muscles with heterochromatic nuclei, degenerated mitochondria, vacuolated cytoplasm, and negative smooth muscle immunoreactivity. Nerve fibers demonstrated a thick myelin sheath and intra-axonal edema, where blood capillaries exhibited thick basement membrane. Diabetic rats on Td showed improved cavernous organization with significant morphometric increases in the area percentage of smooth muscles and elastic tissue and a significant decrease of fibrous tissue. The Td-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values. Chronic low-dose administration of Td in diabetic rats is associated with substantial improvement of the structure of penile cavernous tissue, with increased smooth muscles and elastic tissue, decreased fibrous tissue, and functional enhancement of the erectile function. This raises the idea that the change in penile architecture with Td treatment improves erectile function beyond its half-life and its direct pharmacologic action on phosphodiesterase type 5. Copyright © 2013 Elsevier Inc. All rights reserved.

Evidence for remotely triggered micro-earthquakes during salt cavern collapse

NASA Astrophysics Data System (ADS)

Jousset, P.; Rohmer, J.

2012-04-01

Micro-seismicity is a good indicator of spatio-temporal evolution of physical properties of rocks prior to catastrophic events like volcanic eruptions or landslides and may be triggered by a number of causes including dynamic characteristics of processes in play or/and external forces. Micro-earthquake triggering has been in the recent years the subject of intense research and our work contribute to showing further evidence of possible triggering of micro-earthquakes by remote large earthquakes. We show evidence of triggered micro-seismicity in the vicinity of an underground salt cavern prone to collapse by a remote M~7.2 earthquake, which occurred ~12000 kilometres away. We demonstrate the near critical state of the cavern before the collapse by means of 2D axisymmetric elastic finite-element simulations. Pressure was lowered in the cavern by pumping operations of brine out of the cavern. We demonstrate that a very small stress increase would be sufficient to break the overburden. High-dynamic broadband records reveal a remarkable time-correlation between a dramatic increase of the local high-frequency micro-seismicity rate associated with the break of the stiffest layer stabilizing the overburden and the passage of low-frequency remote seismic waves, including body, Love and Rayleigh surface waves. Stress oscillations due to the seismic waves exceeded the strength required for the rupture of the complex media made of brine and rock triggering micro-earthquakes and leading to damage of the overburden and eventually collapse of the salt cavern. The increment of stress necessary for the failure of a Dolomite layer is of the same order or magnitude as the maximum dynamic stress magnitude observed during the passage of the earthquakes waves. On this basis, we discuss the possible contribution of the Love and Rayleigh low-frequency surfaces waves.

Intralesional hemorrhage and thrombosis without rupture in a pure spinal epidural cavernous angioma: a rare cause of acute lumbal radiculopathy

PubMed Central

Riemenschneider, Markus; Herdmann, Jörg

2010-01-01

Pure spinal epidural cavernous angiomas are extremely rare lesions, and their normal shape is that of a fusiform mass in the dorsal aspects of the spinal canal. We report a case of a lumbo-sacral epidural cavernous vascular malformation presenting with acute onset of right-sided S1 radiculopathy. Clinical aspects, imaging, intraoperative findings, and histology are demonstrated. The patient, a 27-year-old man presented with acute onset of pain, paraesthesia, and numbness within the right leg corresponding to the S1 segment. An acute lumbosacral disc herniation was suspected, but MRI revealed a cystic lesion with the shape of a balloon, a fluid level and a thickened contrast-enhancing wall. Intraoperatively, a purple-blue tumor with fibrous adhesions was located between the right S1 and S2 nerve roots. Macroscopically, no signs of epidural bleedings could be denoted. After coagulation of a reticular venous feeder network and dissection of the adhesions the rubber ball-like lesion was resected in total. Histology revealed a prominent venous vessel with a pathologically thickened, amuscular wall surrounded by smaller, hyalinized, venous vessels arranged in a back-to-back position typical for the diagnosis of a cavernous angioma. Lumina were partially occluded by thrombi. The surrounding fibrotic tissue showed signs of recurrent bleedings. There was no obvious mass hemorrhage into the surrounding tissue. In this unique case, the pathologic mechanism was not the usual rupture of the cavernous angioma with subsequent intraspinal hemorrhage, but acute mass effect by intralesional bleedings and thrombosis with subsequent increase of volume leading to nerve root compression. Thus, even without a sudden intraspinal hemorrhage a spinal cavernous malformation can cause acute symptoms identical to the clinical features of a soft disc herniation. PMID:20213297

In Situ Observation of Failure Mechanisms Controlled by Rock Masses with Weak Interlayer Zones in Large Underground Cavern Excavations Under High Geostress

NASA Astrophysics Data System (ADS)

Duan, Shu-Qian; Feng, Xia-Ting; Jiang, Quan; Liu, Guo-Feng; Pei, Shu-Feng; Fan, Yi-Lin

2017-09-01

A weak interlayer zone (WIZ) is a poor rock mass system with loose structure, weak mechanical properties, variable thickness, random distribution, strong extension, and high risk due to the shear motion of rock masses under the action of tectonism, bringing many stability problems and geological hazards, especially representing a potential threat to the overall stability of rock masses with WIZs in large underground cavern excavations. Focusing on the deformation and failure problems encountered in the process of excavation unloading, this research proposes comprehensive in situ observation schemes for rock masses with WIZs in large underground cavern on the basis of the collection of geological, construction, monitoring, and testing data. The schemes have been fully applied in two valuable project cases of an underground cavern group under construction in the southwest of China, including the plastic squeezing-out tensile failure and the structural stress-induced collapse of rock masses with WIZs. In this way, the development of rock mass failure, affected by the step-by-step excavations along the cavern's axis and the subsequent excavation downward, could be observed thoroughly. Furthermore, this paper reveals the preliminary analyses of failure mechanism of rock masses with WIZs from several aspects, including rock mass structure, strength, high stress, ground water effects, and microfracture mechanisms. Finally, the failure particularities of rock masses with WIZs and rethink on prevention and control of failures are discussed. The research results could provide important guiding reference value for stability analysis, as well as for rethinking the excavation and support optimization of rock masses with WIZs in similar large underground cavern under high geostress.

Cerebral Cavernous Malformation and Hemorrhage

MedlinePlus

... of the bleeding can be divided into three groups: “Slow ooze”: blood slowly seeps through the cavern “walls” inside the ... after a bleed. This allows time for excess blood absorption, unmasking the ... were recorded in the group over this period. A 2015 Mayo study determined ...

Brainstem cavernous malformations: Natural history versus surgical management.

PubMed

Walcott, Brian P; Choudhri, Omar; Lawton, Michael T

2016-10-01

While brainstem cavernous malformations were once considered inoperable, improvements in patient selection, surgical exposures, intraoperative MRI-guidance, MR tractography, and neurophysiologic monitoring have resulted in good outcomes in the majority of operated patients. In a consecutive series of 104 patients with brainstem cavernous malformations, only 14% of patients experienced cranial nerve or motor dysfunction that was worse at late follow-up, relative to their preoperative condition. Outcomes were predicted by several factors, including larger lesion size, lesions that crossed the midline, the presence of a developmental venous anomaly, older age, and greater time interval from lesion hemorrhage to surgery. The 14% of patients who experienced a persistent neurological deficit as a result of surgery, while substantial from any perspective, compares favorably with the risks of observation based on a recent meta-analysis. Curative resection is a safe and effective treatment for brainstem cavernous malformations that will prevent re-hemorrhage in symptomatic patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

November 2016 West Hackberry Subsidence Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moriarty, Dylan Michael; Lord, Anna C. Snider

Subsidence monitoring is a critical component to understanding the cavern integrity of salt storage caverns. This report looks at historical and recent data from two of the three West Hackberry dome cavern operators. DOE SPR and LA Storage are coordinating subsidence surveys to create a comprehensive understanding of ground movement above the dome. Data from annual level and rod surveys, GPS, and tiltmeter data show the sites are experiencing typical ground movement. The highest subsidence rate is seen in the middle of the DOE SPR site at just under one inch per year with less ground movement around the edgemore » of the site. A GPS and tiltmeter instrument in the northeast areas of the DOE SPR site has not seen any trend change since the devices were installed in 2013. Comparison between recent ground movement data and historical trends suggest that there is no reason to believe that any DOE SPR or LA Storage caverns have been structurally compromised.« less

Indocyanine Green Fluorescence Endoscopy at Endonasal Transsphenoidal Surgery for an Intracavernous Sinus Dermoid Cyst: Case Report

PubMed Central

HIDE, Takuichiro; YANO, Shigetoshi; KURATSU, Jun-ichi

2014-01-01

The complete resection of intracavernous sinus dermoid cysts is very difficult due to tumor tissue adherence to important anatomical structures such as the internal carotid artery (ICA), cavernous sinus, and cranial nerves. As residual dermoid cyst tissue sometimes induces symptoms and repeat surgery may be required after cyst recurrence, minimal invasiveness is an important consideration when selecting the surgical approach to the lesion. We addressed a recurrent intracavernous sinus dermoid cyst by the endoscopic endonasal transsphenoidal approach assisted by neuronavigation and indocyanine green (ICG) endoscopy to confirm the ICA and patency of the cavernous sinus. The ICG endoscope detected the fluorescence signal from the ICA and cavernous sinus; its intensity changed with the passage of time. The ICG endoscope was very useful for real-time imaging, and its high spatial resolution facilitated the detection of the ICA and the patent cavernous sinus. We found it to be of great value for successful endonasal transsphenoidal surgery. PMID:25446381

U.S. strategic petroleum reserve Big Hill 114 leak analysis 2012.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lord, David L.; Roberts, Barry L.; Lord, Anna C. Snider

2013-06-01

This report addresses recent well integrity issues related to cavern 114 at the Big Hill Strategic Petroleum Reserve site. DM Petroleum Operations, M&O contractor for the U.S. Strategic Petroleum Reserve, recognized an apparent leak in Big Hill cavern well 114A in late summer, 2012, and provided written notice to the State of Texas as required by law. DM has since isolated the leak in well A with a temporary plug, and is planning on remediating both 114 A- and B-wells with liners. In this report Sandia provides an analysis of the apparent leak that includes: (i) estimated leak volume, (ii)more » recommendation for operating pressure to maintain in the cavern between temporary and permanent fixes for the well integrity issues, and (iii) identification of other caverns or wells at Big Hill that should be monitored closely in light of the sequence of failures there in the last several years.« less

Experimental models of liver fibrosis.

PubMed

Yanguas, Sara Crespo; Cogliati, Bruno; Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Leclercq, Isabelle; Vinken, Mathieu

2016-05-01

Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

[Septic cavernous sinus thrombosis following ethmoiditis: a case report].

PubMed

Ben Abdallah Chabchoub, R; Kmiha, S; Turki, F; Trabelsi, L; Maalej, B; Ben Salah, M; Abdelhédi Gargouri, L; Boukédi, A; Ben Halima, N; Mahfoudh, A

2014-01-01

Acute ethmoiditis is a rare infection of ethmoidal cells. The pathognomonic sign is an edema of the internal corner of the eye. Imaging may be necessary to verify the absence of orbital or endocranial complications. Thrombophlebitis of the cavernous sinus is a serious complication of this infectious process. We report the case of an 11-year-old boy who presented with ethmoiditis complicated with thrombophlebitis of the cavernous sinus, with right hemiplegia and left Bell palsy sequelae. Early diagnosis of this disorder and urgent therapy are essential. Treatment is based on the antibiotic therapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

[Pericardial Cavernous Hemangioma；Report of a Case].

PubMed

Marui, Tsutomu; Azuma, Kenichirou; Arakawa, Yuki; Murakami, Eiji; Murakawa, Shinji

2016-03-01

A case of pericardial cavernous hemangioma is presented. A 62-year-old man had a chest pain and was referred to our hospital because of an abnormal shadow in the mediastinum. Chest computed tomography showed a hypervascular tumor of 2.0 cm in size at the left side of pulmonary artery. Magnetic resonance imaging findings suggested the mucinous part of the tumor, suggesting liposarcoma, thymoma, and neurinoma etc. At surgery, the tumor was found to be in the pericardial cavity. After pericardotomy, the tumor was resected. The diagnosis of the tumor was cavernous hemangioma. There was no evidence of recurrence 2 years after the operation.

[Clinical picture and complex treatment of septic thromboses of the cavernous sinuses].

PubMed

Mozhaev, S V; Zubkov, Iu N; Ponomarev, A M; Shimchenko, P Ia

1980-07-01

Under analysis are etiology, clinical picture and diagnosis of a septic thrombosis of cavernous sinuses in 28 patients. The authors have shown the interrelationship between local manifestations of the disease, injuries of the brain and its sheaths and septic complications (abscessing pneumonia as the most severe of them). A scheme of the complex treatment of patients with thrombosis of the cavernous sinus is proposed. The leading role in this treatment is played by intracarotid infusion of antibiotics in combination with anticoagulant drugs, vasodilatatory agents and novocaine as well as the therapy of septic complications (abscesses of the face and hairy part of the head, meningoencephalitis, pneumonia).

78 FR 38704 - Mississippi Hub, LLC; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-27

... finished drilling the injection and withdrawal wells for Cavern 3 and is presently leaching the underground salt formation. The proposed increase in capacity will entail continued leaching of Cavern 3 to reach the proposed new capacity levels. The activity will be completed using the existing leaching...

The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

PubMed Central

Moeller, Antje; Ask, Kjetil; Warburton, David; Gauldie, Jack; Kolb, Martin

2008-01-01

Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted. PMID:17936056

Effect of Rifaximin on Hepatic Fibrosis in Bile Duct-ligated Rat Model.

PubMed

Shin, Seung Kak; Kwon, Oh Sang; Lee, Jong Joon; Park, Yeon Ho; Choi, Cheol Soo; Jeong, Sung Hwan; Choi, Duck Joo; Kim, Yun Soo; Kim, Ju Hyun

2017-11-25

The translocation of bacteria and their lipopolysaccharides from the gut can promote fibrosis in cirrhotic patients. The aim of this study was to investigate the effects of rifaximin on hepatic fibrosis in a bile duct-ligated rat model. The bile duct ligation (BDL) was carried out for eight days (acute injury model: sham-operated rats [G1], BDL rats [G2], and BDL rats treated with rifaximin [G3]) or 22 days (chronic injury model: sham-operated rats [G4], BDL rats [G5], and BDL rats treated with rifaximin [G6]). Rifaximin (50 mg/kg/day) was administered daily via gavage after BDL. Liver function, serum tumor necrosis factor-alpha (TNF-α), and hepatic hydroxyproline levels were measured. Moreover, a histological analysis of fibrosis contents was performed using sirius red stain. In the acute injury model, the liver function and TNF-α level were not improved after the rifaximin treatment. The hydroxyproline levels (µg/g liver tissue) in G1, G2, and G3 were 236.4±103.1, 444.8±114.4, and 312.5±131.6, respectively; and fibrosis contents (%) were 0.22±0.04, 1.64±0.53, and 1.66±0.44, respectively. The rifaximin treatment did not ameliorate acute BDL-induced fibrosis. In the chronic injury model, the hydroxyproline levels in G4, G5, and G6 were 311.5±72.9, 1,110.3±357.9, and 944.3±209.3, respectively; and fibrosis contents (%) were 0.19±0.03, 5.04±0.18, and 4.42±0.68, respectively (G5 vs. G6, p=0.059). The rifaximin treatment marginally ameliorated chronic BDL-induced fibrosis. Rifaximin did not reduce inflammation and fibrosis in bile duct-ligated rat model.

Subgaleal Retention Sutures: Internal Pressure Dressing Technique for Dolenc Approach.

PubMed

Burrows, Anthony M; Rayan, Tarek; Van Gompel, Jamie J

2017-08-01

Extradural approach to the cavernous sinus, the "Dolenc" approach recognizing its developing Dr. Vinko Dolenc, is a critically important skull base approach. However, resection of the lateral wall of the cavernous sinus, most commonly for cavernous sinus meningiomas, results commonly in a defect that often cannot be reconstructed in a water-tight fashion. This may result in troublesome pseudomeningocele postoperatively. To describe a technique designed to mitigate the development of pseudomeningocele. We found the Dolenc approach critical for resection of cavernous lesions. However, a number of pseudomeningoceles were managed with prolonged external pressure wrapping in the early cohort. Therefore, we incorporated subgaleal to muscular sutures, which were designed to close this potential space and retrospectively analyzed our results. Twenty-one patients treated with a Dolenc approach and resection of the lateral wall of the cavernous sinus over a 2-year period were included. Prior to incorporation of this technique, 12 patients were treated and 3 (25%) experienced postoperative pseudomeningoceles requiring multiple clinic visits and frequent dressing. After incorporation of subgaleal retention sutures, no patient (0%) experienced this complication. Although basic, subgaleal to temporalis muscle retention sutures likely aid in eliminating this potential dead space, thereby preventing patient distress postoperatively. This technique is simple and further emphasizes the importance of dead space elimination in complex closures. Copyright © 2017 by the Congress of Neurological Surgeons

Detection of cavernous transformation of the portal vein by contrast-enhanced ultrasound.

PubMed

Hwang, Misun; Thimm, Matthew A; Guerrerio, Anthony L

2018-06-01

Cavernous transformation of the portal vein can be missed on color Doppler exam or arterial phase cross-sectional imaging due to their slow flow and delayed enhancement. Contrast-enhanced ultrasound (CEUS) offers many advantages over other imaging techniques and can be used to successfully detect cavernous transformations of the portal vein. A 10-month-old female was followed for repeat episodes of hematemesis. Computed tomography angiography (CTA) and magnetic resonance arteriogram (MRA) and portal venography were performed. Color Doppler exam of the portal vein was performed followed by administration of Lumason, a microbubble US contrast agent. Magnetic resonance arteriogram, CTA, and color Doppler exam at the time of initial presentation was unremarkable without obvious vascular malformation within the limits of motion degraded exam. At 8-month follow-up, esophagogastroduodenoscopy revealed a vascular malformation in the distal esophagus which was sclerosed. At 6 month after sclerosis of the lesion, portal venography revealed occlusion of the portal vein with extensive collateralization. Color Doppler revealed subtle hyperarterialization and periportal collaterals. CEUS following color Doppler exam demonstrated extensive enhancement of periportal collaterals. Repeat color Doppler after contrast administration demonstrated extensive Doppler signal in the collateral vessels, suggestive of cavernous transformation. We describe a case of cavernous transformation of the portal vein missed on initial color Doppler, CTA and MRA, but detected with contrast-enhanced ultrasound technique.

Artificial embolization of carotid-cavernous fistula with post-operative patency of internal carotid artery

PubMed Central

Isamat, Fabian; Salleras, V.; Miranda, A. M.

1970-01-01

This report deals with a patient of 86 who developed a carotid-cavernous fistula. Artificial embolization alone was considered the safest treatment for this patient and proved to be adequate. Post-operative preservation of the patency of the internal carotid artery was demonstrated by angiography. We believe this method is particularly appropriate for carotid-cavernous fistulas if it is demonstrated by angiography that the major blood flow of the carotid artery pours into the fistula. A soft-iron clip attached to the muscle can be used for external and forceful guidance of the embolus into the fistula with the help of an electromagnet, hence the patency of the internal carotid artery can be preserved. The embolus should be introduced through the external carotid artery. This is the only case known to us in which patency of the internal carotid artery was post-operatively maintained. We have reviewed 545 reported cases of surgically treated carotid-cavernous fistulas and analysed the results from simple cervical carotid ligation to the more sophisticated methods of artificial embolizations. The results obtained by artificial embolization have been consistently good, while the other techniques have failed in large percentages. Artificial embolization should be used as the primary treatment for carotid-cavernous fistula, since ligation of the internal carotid artery precludes its embolization at a later date. Images PMID:5478949

[Depiction of the cranial nerves around the cavernous sinus by 3D reversed FISP with diffusion weighted imaging (3D PSIF-DWI)].

PubMed

Ishida, Go; Oishi, Makoto; Jinguji, Shinya; Yoneoka, Yuichiro; Sato, Mitsuya; Fujii, Yukihiko

2011-10-01

To evaluate the anatomy of cranial nerves running in and around the cavernous sinus, we employed three-dimensional reversed fast imaging with steady-state precession (FISP) with diffusion weighted imaging (3D PSIF-DWI) on 3-T magnetic resonance (MR) system. After determining the proper parameters to obtain sufficient resolution of 3D PSIF-DWI, we collected imaging data of 20-side cavernous regions in 10 normal subjects. 3D PSIF-DWI provided high contrast between the cranial nerves and other soft tissues, fluid, and blood in all subjects. We also created volume-rendered images of 3D PSIF-DWI and anatomically evaluated the reliability of visualizing optic, oculomotor, trochlear, trigeminal, and abducens nerves on 3D PSIF-DWI. All 20 sets of cranial nerves were visualized and 12 trochlear nerves and 6 abducens nerves were partially identified. We also presented preliminary clinical experiences in two cases with pituitary adenomas. The anatomical relationship between the tumor and cranial nerves running in and around the cavernous sinus could be three-dimensionally comprehended by 3D PSIF-DWI and the volume-rendered images. In conclusion, 3D PSIF-DWI has great potential to provide high resolution "cranial nerve imaging", which visualizes the whole length of the cranial nerves including the parts in the blood flow as in the cavernous sinus region.

Vascular tumors of the iris in 45 patients: the 2009 Helen Keller Lecture.

PubMed

Shields, Jerry A; Bianciotto, Carlos; Kligman, Brad E; Shields, Carol L

2010-09-01

To report on a series of vascular tumors of the iris. Noncomparative case series. A retrospective medical record review of all patients with an iris vascular tumor was performed to identify the clinical features and develop a simple classification of these lesions. Included were demographics, clinical features, systemic associations, complications, management, and histopathology. There were 54 eyes in 45 patients with an iris vascular tumor. These were categorized as racemose hemangioma (41 eyes: 29 simple and 12 complex), cavernous hemangioma (3 eyes: 2 localized and 1 systemic), capillary hemangioma (1 eye, localized), varix (3 eyes, localized), and microhemangiomatosis (6 eyes, localized). The hemangiomas occurred in adults at a median age of 55 years, whereas capillary hemangioma occurred in infancy and cavernous hemangioma with systemic involvement occurred in a child. Of the 41 eyes with iris racemose hemangioma, none showed systemic involvement. Of all 54 eyes, transient hyphema was the main complication, found at some point in 30% or more of each affected eye except for iris capillary and racemose hemangioma. Surgical resection was necessary in 1 cavernous hemangioma and 1 varix. The remainder were managed with observation. There are now well-documented examples of iris racemose hemangioma, cavernous hemangioma, capillary hemangioma, varix, and microhemangiomatosis. Transient hyphema is the main complication. Observation is usually advised. Most are solitary lesions confined to the iris and some (cavernous hemangioma and microhemangiomatosis) can have important systemic associations.

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease.

PubMed

Loomba, Rohit; Seguritan, Victor; Li, Weizhong; Long, Tao; Klitgord, Niels; Bhatt, Archana; Dulai, Parambir Singh; Caussy, Cyrielle; Bettencourt, Richele; Highlander, Sarah K; Jones, Marcus B; Sirlin, Claude B; Schnabl, Bernd; Brinkac, Lauren; Schork, Nicholas; Chen, Chi-Hua; Brenner, David A; Biggs, William; Yooseph, Shibu; Venter, J Craig; Nelson, Karen E

2017-05-02

The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0-2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of 40 features (p < 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of experimental fibrotic liver diseases animal model by Carbon Tetracholoride

PubMed Central

Gitiara, Atoosa; Tokhanbigli, Samaneh; Mazhari, Sogol; Baghaei, Kaveh; Hatami, Behzad; Hashemi, Seyed Mahmoud; Asadi Rad, Ali; Moradi, Afshin; Nasiri, Meyam; Zarrabi Ahrabi, Nakisa; Zali, Mohammad Reza

2017-01-01

Aim: This study is presenting an effective method of inducing liver fibrosis by CCL4 as a toxin in two different breeds of rat models. Background: Liver fibrosis is a result of inflammation and liver injury caused by wound healing responses which ultimately lead to liver failure. Consequently, after liver fibrosis, the progression will be continued to liver cirrhosis and at the end stage hepatocellular carcinoma (HCC). Many studies have demonstrated that one of the most important causes of liver fibrosis is Non-alcoholic steatohepatitis (NASH). Fibrotic Liver is affected by an excessive accumulation of extracellular matrix (ECM) proteins like collagen and α-SMA. Methods: In two different experiments, male Vistar, and Sprague Dawley Rat models ranging from 200±60, corresponding to an age of approximately 10 weeks were utilized in order to induce CCL4 treated liver fibrosis. Results: After 6 weeks of CCL4 injection, different tests have been carried out to verify the liver fibrosis including serum markers such as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), molecular tests containing, laminin and α-SMA and also pathological observation by Hematoxylin and eosin staining in both fibrosis and control group. Conclusion: The results of Pathology and Real-time PCR showed that fibrosis was induced much more effectively in Sprague Dawley rat model compared with Wistar rats. PMID:29511482

The Association of Inbreeding With Lung Fibrosis Incidence in Beagle Dogs That Inhaled 238PuO2 or 239PuO2.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, Dulaney A.; Brigantic, Andrea M.; Morgan, William F.

Studies of health effects in animals after exposure to internally deposited radionuclides were intended to supplement observational studies in humans. Both nuclear workers and Beagle dogs have exhibited plutonium associated lung fibrosis; however, the dogs smaller gene pool may limit the applicability of findings to humans. Data on Beagles that inhaled either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide (239PuO2) were analyzed. Wright's Coefficient of Inbreeding was used to measure genetic or familial susceptibility and was assessed as an explanatory variable when modeling the association between lung fibrosis incidence and plutonium exposure. Lung fibrosis was diagnosed in approximately 80% of themore » exposed dogs compared with 23.7% of the control dogs. The maximum degree of inbreeding was 9.4%. Regardless of isotope, the addition of inbreeding significantly improved the model in female dogs but not in males. In female dogs an increased inbreeding coefficient predicted decreased hazard of a lung fibrosis diagnosis. Lung fibrosis was common in these dogs with inbreeding affecting models of lung fibrosis incidence in females but not in males. The apparent protective effect in females predicted by these models of lung fibrosis incidence is likely to be minimal given the small degree of inbreeding in these groups.« less

A service evaluation of an integrated model of palliative care of cystic fibrosis.

PubMed

Bourke, Stephen J; Booth, Zoe; Doe, Simon; Anderson, Alan; Rice, Sarah; Gascoigne, Alistair; Quibell, Rachel

2016-07-01

Patients with advanced cystic fibrosis have severe symptoms with a complex trajectory of exacerbations and recovery. They are often awaiting lung transplantation, and many die without receiving specialist palliative care. We introduced an integrated model whereby palliative specialists joined the cystic fibrosis team to provide palliative care in parallel with standard care. A service evaluation of this model of care was undertaken in a prospective case series documenting symptoms and outcomes, the views of the cystic fibrosis team and the experience of the palliative specialists. Over 3 years, 28 (10%) of 282 patients attending the cystic fibrosis centre had specialist palliative care. They had advanced lung disease (mean forced expiratory volume in 1 s (FEV1) = 0.86 L (25% predicted)), and 17 died: 6 were on a transplant waiting list at death; 10 were unsuitable and 1 died post transplantation. All who died over these 3 years had specialist palliative care. Four patients had successful transplants. Assessment showed a high prevalence of breathlessness, cough, pain, vomiting and fatigue, with a significant impact on daily life. The cystic fibrosis team rated this model of care highly, felt that palliative care should be members of the team, and thought that patients had found it helpful. The palliative specialists gained knowledge of cystic fibrosis, found it beneficial to meet patients earlier in the disease, and identified unmet needs in managing bereavement and the effects of deaths on other patients with cystic fibrosis. This model has been successful in overcoming the difficulties in access to specialist palliative care for patients with cystic fibrosis. © The Author(s) 2016.

Comparative study of two models of combined pulmonary fibrosis and emphysema in mice.

PubMed

Zhang, Wan-Guang; Wu, Si-Si; He, Li; Yang, Qun; Feng, Yi-Kuan; Chen, Yue-Tao; Zhen, Guo-Hua; Xu, Yong-Jian; Zhang, Zhen-Xiang; Zhao, Jian-Ping; Zhang, Hui-Lan

2017-04-01

Combined pulmonary fibrosis and emphysema (CPFE) is an "umbrella term" encompassing emphysema and pulmonary fibrosis, but its pathogenesis is not known. We established two models of CPFE in mice using tracheal instillation with bleomycin (BLM) or murine gammaherpesvirus 68 (MHV-68). Experimental mice were divided randomly into four groups: A (normal control, n=6), B (emphysema, n=6), C (emphysema+MHV-68, n=24), D (emphysema+BLM, n=6). Group C was subdivided into four groups: C1 (sacrificed on day 367, 7 days after tracheal instillation of MHV-68); C2 (day 374; 14days); C3 (day 381; 21days); C4 (day 388; 28days). Conspicuous emphysema and interstitial fibrosis were observed in BLM and MHV-68 CPFE mouse models. However, BLM induced diffuse pulmonary interstitial fibrosis with severely diffuse pulmonary inflammation; MHV-68 induced relatively modest inflammation and fibrosis, and the inflammation and fibrosis were not diffuse, but instead around bronchioles. Inflammation and fibrosis were detectable in the day-7 subgroup and reached a peak in the day-28 subgroup in the emphysema + MHV-68 group. Levels of macrophage chemoattractant protein-1, macrophage inflammatory protein-1α, interleukin-13, and transforming growth factor-β1 in bronchoalveolar lavage fluid were increased significantly in both models. Percentage of apoptotic type-2 lung epithelial cells was significantly higher; however, all four types of cytokine and number of macrophages were significantly lower in the emphysema+MHV-68 group compared with the emphysema +BLM group. The different changes in pathology between BLM and MHV-68 mice models demonstrated different pathology subtypes of CPFE: macrophage infiltration and apoptosis of type-II lung epithelial cells increased with increasing pathology score for pulmonary fibrosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

77 FR 74838 - Perryville Gas Storage LLC; Notice of Amendment

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-18

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. CP13-23-000] Perryville Gas Storage LLC; Notice of Amendment Take notice that on December 3, 2012, Perryville Gas Storage LLC... the approved storage cavern wells (Cavern Well PGS- 2) approximately 400 feet, all as more fully set...

Development of a transgenic goat model wih cardiac-specific overexpression of transforming growth factor - {beta} 1 to study the relationship between atrial fibrosis and atrial fibrillation

USDA-ARS?s Scientific Manuscript database

Studies on patients, large animal models and transgenic mouse models have shown a strong association of atrial fibrosis with atrial fibrillation (AF). However, it is unclear whether there is a causal relationship between atrial fibrosis and AF or whether these events appear as a result of independen...

Characterizing Fibrosis in Mouse Kidney using Label Free Fluorescence Lifetime and Second Harmonic Generation Imaging Microscopy in Unilateral Ureteral Obstruction Model

PubMed Central

Ranjit, Suman; Dobrinskikh, Evgenia; Montford, John; Dvornikov, Alexander; Lehman, Allison; Orlicky, David J.; Nemenoff, Raphael; Gratton, Enrico; Levi, Moshe; Furgeson, Seth

2017-01-01

All forms of progressive renal diseases develop a final pathway of tubulointerstitial fibrosis and glomerulosclerosis. Renal fibrosis is usually quantified using histological staining, a process that is time-consuming and pathologist dependent. The work described here shows the development of a fast and operator-independent method to measure fibrosis. To study renal fibrosis, the unilateral ureteral obstruction (UUO) model was chosen. Mice develop a time-dependent increase in obstructed kidneys; contralateral kidneys are used as controls. After UUO, kidneys were analyzed at three time points: 7 days, 14 days, and 21 days. Fibrosis was investigated using FLIM (Fluorescence Lifetime Imaging) and SHG (Second Harmonic Generation) in the deep tissue imaging microscope called DIVER (Deep Imaging via Enhanced photon Recovery). This microscope was developed for deep tissue and SHG and THG (Third Harmonic Generation) imaging and has extraordinary sensitivity towards harmonic generation. SHG data suggests the presence of more fibrillar collagen in the diseased kidneys. The combinations of short wavelength FLIM and SHG analysis results in a robust analysis procedure independent of observer interpretation and let us create a criterion to quantify the extent of fibrosis directly from the image. The progression of fibrosis in UUO model has been studied using this new FLIM-SHG technique and it shows remarkable improvement in quantification of fibrosis compared to standard histological techniques. PMID:27555119

Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

PubMed

Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

2017-09-21

To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

Predictive 5-Year Survivorship Model of Cystic Fibrosis

PubMed Central

Liou, Theodore G.; Adler, Frederick R.; FitzSimmons, Stacey C.; Cahill, Barbara C.; Hibbs, Jonathan R.; Marshall, Bruce C.

2007-01-01

The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research. PMID:11207152

Multi-class SVM model for fMRI-based classification and grading of liver fibrosis

NASA Astrophysics Data System (ADS)

Freiman, M.; Sela, Y.; Edrei, Y.; Pappo, O.; Joskowicz, L.; Abramovitch, R.

2010-03-01

We present a novel non-invasive automatic method for the classification and grading of liver fibrosis from fMRI maps based on hepatic hemodynamic changes. This method automatically creates a model for liver fibrosis grading based on training datasets. Our supervised learning method evaluates hepatic hemodynamics from an anatomical MRI image and three T2*-W fMRI signal intensity time-course scans acquired during the breathing of air, air-carbon dioxide, and carbogen. It constructs a statistical model of liver fibrosis from these fMRI scans using a binary-based one-against-all multi class Support Vector Machine (SVM) classifier. We evaluated the resulting classification model with the leave-one out technique and compared it to both full multi-class SVM and K-Nearest Neighbor (KNN) classifications. Our experimental study analyzed 57 slice sets from 13 mice, and yielded a 98.2% separation accuracy between healthy and low grade fibrotic subjects, and an overall accuracy of 84.2% for fibrosis grading. These results are better than the existing image-based methods which can only discriminate between healthy and high grade fibrosis subjects. With appropriate extensions, our method may be used for non-invasive classification and progression monitoring of liver fibrosis in human patients instead of more invasive approaches, such as biopsy or contrast-enhanced imaging.

Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease.

PubMed

Hossain, Noreen; Afendy, Arian; Stepanova, Maria; Nader, Fatema; Srishord, Manirath; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair

2009-11-01

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We investigated factors associated with advanced fibrosis in NAFLD. The study included 432 patients with histologically proven NAFLD (26.8% with nonalcoholic steatohepatitis [NASH] and 17.4% with moderate-to severe fibrosis). NASH was defined as steatosis, lobular inflammation, and ballooning degeneration with or without Mallory-Denk bodies and/or fibrosis. Fibrosis was classified into 2 groups: those with no or minimal fibrosis and those with moderate-to-severe fibrosis. Groups were compared using Mann-Whitney and chi-square method analyses. A model was constructed using a stepwise bidirectional method; its predictive power was measured using a 10-fold cross-validation technique. Patients with NASH were more likely to be male (P < .0001); have lower hip-to-waist ratios (P = .03); were less likely to be African American (P = .06); have higher levels of alanine aminotransferase (ALT; P < .0001), aspartate aminotransferase (AST; P < .0001), and serum triglycerides (P = .0154), but lower levels of high-density lipoprotein cholesterol (P < .0001). Patients with moderate-to-severe fibrosis were older (P = .0245); more likely to be male (P = .0189), Caucasian (P = .0382), have diabetes mellitus (P = .0238), and hypertension (P = .0375); and have a lower hip-to-waist ratio (P = .0077) but higher serum AST (P < .0001) and ALT (P < .0001) levels. The multivariate analysis model to predict moderate-to-severe fibrosis included male sex, Caucasian ethnicity, diabetes mellitus, and increased AST and ALT levels (model P value < .0001). In patients with NAFLD, diabetes mellitus and aminotransferase levels are independent predictors of moderate-to-severe fibrosis. They can be used to identify NAFLD patients at risk for advanced fibrosis.

Fracture Dissolution of Carbonate Rock: An Innovative Process for Gas Storage

DOE Office of Scientific and Technical Information (OSTI.GOV)

James W. Castle; Ronald W. Falta; David Bruce

2006-10-31

The goal of the project is to develop and assess the feasibility and economic viability of an innovative concept that may lead to commercialization of new gas-storage capacity near major markets. The investigation involves a new approach to developing underground gas storage in carbonate rock, which is present near major markets in many areas of the United States. Because of the lack of conventional gas storage and the projected growth in demand for storage capacity, many of these areas are likely to experience shortfalls in gas deliverability. Since depleted gas reservoirs and salt formations are nearly non-existent in many areas,more » alternatives to conventional methods of gas storage are required. The need for improved methods of gas storage, particularly for ways to meet peak demand, is increasing. Gas-market conditions are driving the need for higher deliverability and more flexibility in injection/withdrawal cycling. In order to meet these needs, the project involves an innovative approach to developing underground storage capacity by creating caverns in carbonate rock formations by acid dissolution. The basic concept of the acid-dissolution method is to drill to depth, fracture the carbonate rock layer as needed, and then create a cavern using an aqueous acid to dissolve the carbonate rock. Assessing feasibility of the acid-dissolution method included a regional geologic investigation. Data were compiled and analyzed from carbonate formations in six states: Indiana, Ohio, Kentucky, West Virginia, Pennsylvania, and New York. To analyze the requirements for creating storage volume, the following aspects of the dissolution process were examined: weight and volume of rock to be dissolved; gas storage pressure, temperature, and volume at depth; rock solubility; and acid costs. Hydrochloric acid was determined to be the best acid to use because of low cost, high acid solubility, fast reaction rates with carbonate rock, and highly soluble products (calcium chloride) that allow for the easy removal of calcium waste from the well. Physical and chemical analysis of core samples taken from prospective geologic formations for the acid dissolution process confirmed that many of the limestone samples readily dissolved in concentrated hydrochloric acid. Further, some samples contained oily residues that may help to seal the walls of the final cavern structure. These results suggest that there exist carbonate rock formations well suited for the dissolution technology and that the presence of inert impurities had no noticeable effect on the dissolution rate for the carbonate rock. A sensitivity analysis was performed for characteristics of hydraulic fractures induced in carbonate formations to enhance the dissolution process. Multiple fracture simulations were conducted using modeling software that has a fully 3-D fracture geometry package. The simulations, which predict the distribution of fracture geometry and fracture conductivity, show that the stress difference between adjacent beds is the physical property of the formations that has the greatest influence on fracture characteristics by restricting vertical growth. The results indicate that by modifying the fracturing fluid, proppant type, or pumping rate, a fracture can be created with characteristics within a predictable range, which contributes to predicting the geometry of storage caverns created by acid dissolution of carbonate formations. A series of three-dimensional simulations of cavern formation were used to investigate three different configurations of the acid-dissolution process: (a) injection into an open borehole with production from that same borehole and no fracture; (b) injection into an open borehole with production from that same borehole, with an open fracture; and (c) injection into an open borehole connected by a fracture to an adjacent borehole from which the fluids are produced. The two-well configuration maximizes the overall mass transfer from the rock to the fluid, but it results in a complex cavern shape. Numerical simulations were performed to evaluate the ability of storage caverns produced by the acid-dissolution method to store natural gas. In addition, analyses were conducted to evaluate cavern stability during gas injection and withdrawal from storage caverns created in carbonate formations by the acid-dissolution method. The stability analyses were conducted using FLAC2D, a commercially available geotechnical analysis and design software. The analyses indicate that a tall cylindrical cavern with a domed roof and floor will be stable under the expected range of in situ and operational conditions. This result suggests that it should be feasible to avoid mechanical instabilities that could potentially diminish the effectiveness of the storage facility. The feasibility of using pressure transients measured at the ground surface was investigated as a means to evaluate (Abstract truncated)« less

Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis

PubMed Central

Watanabe, Tomoya; Mlakar, Logan; Heywood, Jonathan; Malaab, Maya; Hoffman, Stanley

2017-01-01

The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model. PMID:28651005

Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis.

PubMed

Watanabe, Tomoya; Nishimoto, Tetsuya; Mlakar, Logan; Heywood, Jonathan; Malaab, Maya; Hoffman, Stanley; Feghali-Bostwick, Carol

2017-01-01

The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model.

Deep learning for staging liver fibrosis on CT: a pilot study.

PubMed

Yasaka, Koichiro; Akai, Hiroyuki; Kunimatsu, Akira; Abe, Osamu; Kiryu, Shigeru

2018-05-14

To investigate whether liver fibrosis can be staged by deep learning techniques based on CT images. This clinical retrospective study, approved by our institutional review board, included 496 CT examinations of 286 patients who underwent dynamic contrast-enhanced CT for evaluations of the liver and for whom histopathological information regarding liver fibrosis stage was available. The 396 portal phase images with age and sex data of patients (F0/F1/F2/F3/F4 = 113/36/56/66/125) were used for training a deep convolutional neural network (DCNN); the data for the other 100 (F0/F1/F2/F3/F4 = 29/9/14/16/32) were utilised for testing the trained network, with the histopathological fibrosis stage used as reference. To improve robustness, additional images for training data were generated by rotating or parallel shifting the images, or adding Gaussian noise. Supervised training was used to minimise the difference between the liver fibrosis stage and the fibrosis score obtained from deep learning based on CT images (F DLCT score) output by the model. Testing data were input into the trained DCNNs to evaluate their performance. The F DLCT scores showed a significant correlation with liver fibrosis stage (Spearman's correlation coefficient = 0.48, p < 0.001). The areas under the receiver operating characteristic curves (with 95% confidence intervals) for diagnosing significant fibrosis (≥ F2), advanced fibrosis (≥ F3) and cirrhosis (F4) by using F DLCT scores were 0.74 (0.64-0.85), 0.76 (0.66-0.85) and 0.73 (0.62-0.84), respectively. Liver fibrosis can be staged by using a deep learning model based on CT images, with moderate performance. • Liver fibrosis can be staged by a deep learning model based on magnified CT images including the liver surface, with moderate performance. • Scores from a trained deep learning model showed moderate correlation with histopathological liver fibrosis staging. • Further improvement are necessary before utilisation in clinical settings.

76 FR 63916 - Transcontinental Gas Pipe Line Company, LLC; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-14

... associated storage deliverability and capacity at the Eminence Storage Field (Eminence) in Covington County... Caverns 1, 2, 3, and 4, and reduce deliverability and capacity from 20.5 Bcf to 15.025 Bcf in Caverns 5, 6, and 7. Transco also seeks to partially abandon the total storage capacity and deliverability...

75 FR 57747 - Tres Palacios Gas Storage LLC; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-22

... Gas Storage LLC; Notice of Application September 15, 2010. Take notice that on September 3, 2010, Tres Palacios Gas Storage LLC (Tres Palacios), 53 Riverside Avenue, Westport, Connecticut 06880, filed in Docket... natural gas storage caverns to the actual capacities available in each cavern as established by the most...

Challenges of constructing salt cavern gas storage in China

NASA Astrophysics Data System (ADS)

Xia, Yan; Yuan, Guangjie; Ban, Fansheng; Zhuang, Xiaoqian; Li, Jingcui

2017-11-01

After more than ten years of research and engineering practice in salt cavern gas storage, the engineering technology of geology, drilling, leaching, completion, operation and monitoring system has been established. With the rapid growth of domestic consumption of natural gas, the requirement of underground gas storage is increasing. Because high-quality rock salt resources about 1000m depth are relatively scarce, the salt cavern gas storages will be built in deep rock salt. According to the current domestic conventional construction technical scheme, construction in deep salt formations will face many problems such as circulating pressure increasing, tubing blockage, deformation failure, higher completion risk and so on, caused by depth and the complex geological conditions. Considering these difficulties, the differences between current technical scheme and the construction scheme of twin well and big hole are analyzed, and the results show that the technical scheme of twin well and big hole have obvious advantages in reducing the circulating pressure loss, tubing blockage and failure risk, and they can be the alternative schemes to solve the technical difficulties of constructing salt cavern gas storages in the deep rock salt.

Preoperative diagnosis of orbital cavernous hemangioma: a 99mTc-RBC SPECT study.

PubMed

Burroni, Luca; Borsari, Giulia; Pichierri, Patrizia; Polito, Ennio; Toscano, Olga; Grassetto, Gaia; Al-Nahhas, Adil; Rubello, Domenico; Vattimo, Angelo Giuseppe

2012-11-01

This study aimed to describe 99mTc-labeled RBC scintigraphy as a diagnostic method for orbital cavernous hemangiomas and to evaluate this diagnostic tool according to surgical outcomes. Fifty-five patients with clinical and radiological (US, CT, and/or MRI) suspicion of unilateral cavernous hemangioma of the orbit underwent 99mTc-RBC SPECT study.Qualitative and semiquantitative evaluations were performed, and results were statistically analyzed. SPECT images showed focal uptake in the orbital mass in 36 of 55 patients. Nineteen patients had a negative scintigraphic pattern, with concordance of early and late absence of uptake of 99mTc-RBC.Our procedure showed 100% sensitivity and 88.9% specificity for the diagnosis of orbital cavernous hemangioma, with a positive predictive value of 90.9% and a negative predictive value of 100%. 99mTc-RBC imaging is safe, easy to perform, and highly accurate in providing adequate clinical and surgical management. As a noninvasive and highly specific method for diagnosing orbital hemangioma, 99mTc-RBC scintigraphy can avoid more invasive imaging or biopsy.

Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

PubMed

Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

2014-12-02

Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

Simulation of Atrial Fibrosis Using Coupled Myocyte-Fibroblast Cellular and Human Atrial Models

PubMed Central

Gao, Yuan

2017-01-01

Atrial fibrosis is characterized by expansion of extracellular matrix and increase in the number of fibroblasts which has been associated with the development and maintenance of atrial arrhythmias. However, the mechanisms how the fibrosis contributes to atrial arrhythmia remain incompletely understood. In this study, we used a proposed fibroblast model coupled with the human atrial myocyte to investigate the effects of fibrosis on atrial excitability and repolarization at both cellular and macroscopic levels. The 12-lead electrocardiogram (ECG) was also simulated to explore the index of clinical diagnosis for fibrosis. The simulation results showed that the fibrosis can modify action potential morphology of human atrial myocyte, slow down wave propagation, and have rate adaptation, thus causing the atrial electrical heterogeneity. The fibrosis alone was sufficient to cause arrhythmia, induce reentry wave, and result in low amplitude and wide P waves at normal heart rate and significant prolonged and inverse P waves at high heart rate. All these symptoms aggravated when the level of fibrosis increased. Our simulations demonstrated that fibrosis is the substrate of atrial arrhythmia and thereby may be a potential target in the treatment of atrial arrhythmias. PMID:29441121

A creative therapy in treating cavernous hemangioma of penis with copper wire.

PubMed

Zhang, Dong; Zhang, Haiyang; Sun, Peng; Li, Peng; Xue, Aibing; Jin, Xunbo

2014-10-01

Cavernous hemangiomas of penis are rare benign lesions infrequently described in the literature. No completely satisfactory treatment has been found to correct the cosmetic deformities especially the extensive hemangiomas of corpus penis. In light of the promising application of copper wire/needle in vascular malformations, we began a clinical study to investigate the safety, feasibility, and cosmetic effect of copper wire therapy in treating cavernous hemangioma of penis. Seven patients ranging in age from 12 to 32 years with penile cavernous hemangiomas entered our study from 2005 to 2011. All patients received treatments with percutaneous copper wires. Perioperative data including mean operation time, estimated blood loss, length of copper wire retention, and length of hospital stay were analyzed. All possible complications were noted, and cosmetic result was evaluated. Patients were followed up after discharge from the hospital. All operations were successful, and no obvious complications were observed. The patients were satisfied with the aesthetic results. Follow-up time ranged from 1 to 5 years. Recurrence was discovered in a patient with the largest lesion of corpus penis 2 months after the treatment. Secondary procedure was carried out with the same technique, and no lesions were found later. The shortage of studies on this topic prevented us from defining a therapeutic reference standard. The results of our study confirmed that copper wire therapy was a simple, safe, and useful option for penile cavernous hemangioma. © 2013 International Society for Sexual Medicine.

Peptidylarginine deiminase 4 promotes age-related organ fibrosis

PubMed Central

Erpenbeck, Luise; Savchenko, Alexander; Hayashi, Hideki; Cherpokova, Deya; Gallant, Maureen; Mauler, Maximilian; Cifuni, Stephen M.

2017-01-01

Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4−/− mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4−/− mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4−/− myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction. PMID:28031479

The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

PubMed

Williamson, James D; Sadofsky, Laura R; Hart, Simon P

2015-03-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

Intracavernous Delivery of a Designed Angiopoietin-1 Variant Rescues Erectile Function by Enhancing Endothelial Regeneration in the Streptozotocin-Induced Diabetic Mouse

PubMed Central

Jin, Hai-Rong; Kim, Woo Jean; Song, Jae Sook; Piao, Shuguang; Choi, Min Ji; Tumurbaatar, Munkhbayar; Shin, Sun Hwa; Yin, Guo Nan; Koh, Gou Young; Ryu, Ji-Kan; Suh, Jun-Kyu

2011-01-01

OBJECTIVE Patients with diabetic erectile dysfunction often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. We examined the effectiveness of the potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous endothelial regeneration and restoring erectile function in diabetic animals. RESEARCH DESIGN AND METHODS Four groups of mice were used: controls; streptozotocin (STZ)-induced diabetic mice; STZ-induced diabetic mice treated with repeated intracavernous injections of PBS; and STZ-induced diabetic mice treated with COMP-Ang1 protein (days −3 and 0). Two and 4 weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations, Western blot analysis, and cGMP quantification. We also performed a vascular permeability test. RESULTS Local delivery of the COMP-Ang1 protein significantly increased cavernous endothelial proliferation, endothelial nitric oxide (NO) synthase (NOS) phosphorylation, and cGMP expression compared with that in the untreated or PBS-treated STZ-induced diabetic group. The changes in the group that received COMP-Ang1 restored erectile function up to 4 weeks after treatment. Endothelial protective effects, such as marked decreases in the expression of p47phox and inducible NOS, in the generation of superoxide anion and nitrotyrosine, and in the number of apoptotic cells in the corpus cavernosum tissue, were noted in COMP-Ang1–treated STZ-induced diabetic mice. An intracavernous injection of COMP-Ang1 completely restored endothelial cell-cell junction proteins and decreased cavernous endothelial permeability. COMP-Ang1–induced promotion of cavernous angiogenesis and erectile function was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester, but not by the NADPH oxidase inhibitor, apocynin. CONCLUSIONS These findings support the concept of cavernous endothelial regeneration by use of the recombinant Ang1 protein as a curative therapy for diabetic erectile dysfunction. PMID:21270241

Technetium tc 99m-labeled red blood cells in the preoperative diagnosis of cavernous hemangioma and other vascular orbital tumors.

PubMed

Polito, Ennio; Burroni, Luca; Pichierri, Patrizia; Loffredo, Antonio; Vattimo, Angelo G

2005-12-01

To evaluate technetium Tc 99m (99mTc) red blood cell scintigraphy as a diagnostic tool for orbital cavernous hemangioma and to differentiate between orbital masses on the basis of their vascularization. We performed 99mTc red blood cell scintigraphy on 23 patients (8 female and 15 male; mean age, 47 years) affected by an orbital mass previously revealed with computed tomography (CT) and magnetic resonance imaging (MRI) and suggesting cavernous hemangioma. In our diagnosis, we considered the orbital increase delayed uptake with the typical scintigraphic pattern known as perfusion blood pool mismatch. The patients underwent biopsy or surgical treatment with transconjunctival cryosurgical extraction when possible. Single-photon emission tomography (SPET) showed intense focal uptake in the orbit corresponding to radiologic findings in 11 patients who underwent surgical treatment and pathologic evaluation (9 cavernous hemangiomas, 1 hemangiopericytoma, and 1 lymphangioma). Clinical or histologic examination of the remaining 22 patients revealed the presence of 5 lymphoid pseudotumors, 2 lymphomas, 2 pleomorphic adenomas of the lacrimal gland, 1 astrocytoma, 1 ophthalmic vein thrombosis, and 1 orbital varix. The confirmation of the preoperative diagnosis by 99mTc red blood cell scintigraphy shows that this technique is a reliable tool for differentiating cavernous hemangiomas from other orbital masses (sensitivity, 100%; specificity, 86%) when ultrasound, CT, and MRI are not diagnostic. Unfortunately, 99mTc red blood cell scintigraphy results were positive in 1 patient with hemangiopericytoma and 1 patient with lymphangioma, which showed increased uptake in the lesion on SPET images because of the vascular nature of these tumors. Therefore, in these cases, the SPET images have to be integrated with data regarding clinical preoperative evaluation and CT scans or MRI studies. On the basis of our study, a complete diagnostic picture, CT scans or MRI studies, and scintigraphic patterns can establish the preoperative diagnosis of vascular orbital tumors such as cavernous hemangioma, adult-type lymphangioma, and hemangiopericytoma.

[Morphological signs of inflammatory activity in different clinical forms of drug-resistant pulmonary tuberculosis].

PubMed

Elipashev, A A; Nikolsky, V O; Shprykov, A S

to determine whether the activity of tuberculous inflammation is associated with different clinical forms of drug-resistant pulmonary tuberculosis. The material taken from 310 patients operated on in 2010-2015 were retrospectively examined. The patients underwent economical lung resections of limited extent (typical and atypical ones of up to 3 segments) for circumscribed forms of tuberculosis with bacterial excretion. A study group consisted of 161 (51.9%) patients with drug-resistant variants of pulmonary tuberculosis. A control group included 149 (48.1%) patients with preserved susceptibility of Mycobacterium tuberculosis to anti-TB drugs. The activity of specific changes in tuberculosis was morphologically evaluated in accordance with the classification proposed by B.M. Ariel in 1998. The highest activity of fourth-to-fifth degree specific inflammation, including that outside the primary involvement focus, was obtained in the drug-resistant pulmonary tuberculosis group due to the predominance of patients with cavernous and fibrous-cavernous tuberculosis versus those in whom the susceptibility to chemotherapeutic agents was preserved. A macroscopic study showed that the primary lesion focus had a median size in one-half of the all the examinees; but large tuberculomas, caverns, and fibrous caverns over 4 cm in diameter were multiple and detected in the drug-resistant pulmonary tuberculosis group. Multidrug resistance was observed in more than 60% of the patients with fibrous-cavernous pulmonary tuberculosis, extensive drug resistance was seen in those with cavernous tuberculosis, which is an aggravating factor. The data obtained from the morphological study of the intraoperative material can specify the clinical form of tuberculosis and evaluate the efficiency of preoperative specific therapy. The highest activity of specific inflammation was observed in patients with multiple drug-resistant pulmonary tuberculosis, the prevalence of third-to-fourth degree specific changes was seen in those with multiple and extensively drug-resistant tuberculosis. The findings suggest that the activity of tuberculous inflammation is associated with different clinical forms of drug-resistant tuberculosis and with a spectrum of drug resistance.

Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

PubMed

Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M

The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients.

Red blood cell distribution width levels correlate with liver fibrosis and inflammation: a noninvasive serum marker panel to predict the severity of fibrosis and inflammation in patients with hepatitis B.

PubMed

Xu, Wen-Shen; Qiu, Xiao-Ming; Ou, Qi-shui; Liu, Can; Lin, Jin-Piao; Chen, Hui-Juan; Lin, Sheng; Wang, Wen-Hua; Lin, Shou-Rong; Chen, Jing

2015-03-01

We aimed to study whether red blood cell distribution width (RDW) could be one of the variables determining the extent of liver fibrosis and inflammation in patients with biopsy-proven hepatitis B. A total of 446 hepatitis B virus-infected patients who underwent liver biopsy were divided into 2 groups: absent or mild and moderate-severe according to the severity of liver fibrosis and inflammation. The independent variables that determine the severity of liver fibrosis and inflammation were explored. RDW values increased with progressive liver fibrosis and inflammation. After adjustments for other potent predictors, liver fibrosis (moderate-severe) was independently associated with RDW, platelet, and albumin (odds ratio = 1.121, 0.987, and 0.941, respectively), whereas increased odds ratios of significant inflammation were found for RDW, alanine aminotransferase, albumin, and PLT (odds ratio = 1.146, 1.003, 0.927, and 0.990, respectively). The sensitivity and specificity of model A were 70.0% and 62.9% for detection of significant liver fibrosis [area under the receiver-operating characteristic curve (AUC) = 0.713, P < 0.001]. The sensitivity and specificity of model B were 66.1% and 79.4% for predicting advanced liver inflammation (AUC = 0.765, P < 0.001). Compared with preexisting indicators, model A achieved the highest AUC, whereas model B showed a higher AUC than RDW to platelet ratio (0.670, P < 0.001) and FIB-4 (0.740, P = 0.32). RDW may provide a useful clinical value for predicting liver fibrosis and necroinflammation in hepatitis B-infected patients with other markers.

Interrater Reliability of the Postoperative Epidural Fibrosis Classification: A Histopathologic Study in the Rat Model.

PubMed

Sae-Jung, Surachai; Jirarattanaphochai, Kitti; Sumananont, Chat; Wittayapairoj, Kriangkrai; Sukhonthamarn, Kamolsak

2015-08-01

Agreement study. To validate the interrater reliability of the histopathological classification of the post-laminectomy epidural fibrosis in an animal model. Epidural fibrosis is a common cause of failed back surgery syndrome. Many animal experiments have been developed to investigate the prevention of epidural fibrosis. One of the common outcome measurements is the epidural fibrous adherence grading, but the classification has not yet been validated. Five identical sets of histopathological digital files of L5-L6 laminectomized adult Sprague-Dawley rats, representing various degrees of postoperative epidural fibrous adherence were randomized and evaluated by five independent assessors masked to the study processes. Epidural fibrosis was rated as grade 0 (no fibrosis), grade 1 (thin fibrous band), grade 2 (continuous fibrous adherence for less than two-thirds of the laminectomy area), or grade 3 (large fibrotic tissue for more than two-thirds of the laminectomy area). A statistical analysis was performed. Four hundred slides were independently evaluated by each assessor. The percent agreement and intraclass correlation coefficient (ICC) between each pair of assessors varied from 73.5% to 81.3% and from 0.81 to 0.86, respectively. The overall ICC was 0.83 (95% confidence interval, 0.81-0.86). The postoperative epidural fibrosis classification showed almost perfect agreement among the assessors. This classification can be used in research involving the histopathology of postoperative epidural fibrosis; for example, for the development of preventions of postoperative epidural fibrosis or treatment in an animal model.

Transcription of G-protein coupled receptors in corporeal smooth muscle is regulated by the endogenous neutral endopeptidase inhibitor sialorphin.

PubMed

Tong, Yuehong; Tiplitsky, Scott I; Tar, Moses; Melman, Arnold; Davies, Kelvin P

2008-08-01

Several reports suggest that the rat Vcsa1 gene is down-regulated in models of erectile dysfunction. The Vcsa protein product sialorphin is an endogenous neutral endopeptidase inhibitor and its down-regulation could result in prolonged activation of G-protein activated signaling pathways by their peptide agonists. We investigated whether Vcsa1 down-regulation could result in an adaptive change in GPCR (G-protein coupled receptor) expression. Gene expression in cultured rat corporeal smooth muscle cells following treatment with siRNA directed against Vcsa1 or the neutral endopeptidase gene was analyzed using microarray and quantitative reverse transcriptase-polymerase chain reaction. In rats Vcsa1 is one of the most down-regulated genes following bilateral transection of the cavernous nerves. In that animal model we also investigated whether Vcsa1 down-regulation was accompanied by similar changes in gene expression in corporeal smooth muscle cells in which Vcsa1 was knocked down in vitro. Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction demonstrated that corporeal smooth muscle cells treated in vitro with siRNA against Vcsa1 resulted in GPCR up-regulation as a functional group. In contrast, treatment of corporeal smooth muscle cells that lowered neutral endopeptidase activity resulted in decreased GPCR expression. These results suggest that the peptide product of Vcsa1, sialorphin, can effect GPCR expression by acting on neutral endopeptidase. In animals with bilaterally transected cavernous nerves the decreased Vcsa1 expression is accompanied by increased GPCR expression in cavernous tissue. These experiments suggest that the mechanism by which Vcsa1 modulates erectile function is partly mediated through changes in GPCR expression.

Mechanical Model Analysis for Quantitative Evaluation of Liver Fibrosis Based on Ultrasound Tissue Elasticity Imaging

NASA Astrophysics Data System (ADS)

Shiina, Tsuyoshi; Maki, Tomonori; Yamakawa, Makoto; Mitake, Tsuyoshi; Kudo, Masatoshi; Fujimoto, Kenji

2012-07-01

Precise evaluation of the stage of chronic hepatitis C with respect to fibrosis has become an important issue to prevent the occurrence of cirrhosis and to initiate appropriate therapeutic intervention such as viral eradication using interferon. Ultrasound tissue elasticity imaging, i.e., elastography can visualize tissue hardness/softness, and its clinical usefulness has been studied to detect and evaluate tumors. We have recently reported that the texture of elasticity image changes as fibrosis progresses. To evaluate fibrosis progression quantitatively on the basis of ultrasound tissue elasticity imaging, we introduced a mechanical model of fibrosis progression and simulated the process by which hepatic fibrosis affects elasticity images and compared the results with those clinical data analysis. As a result, it was confirmed that even in diffuse diseases like chronic hepatitis, the patterns of elasticity images are related to fibrous structural changes caused by hepatic disease and can be used to derive features for quantitative evaluation of fibrosis stage.

Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms.

PubMed

Lykiardopoulos, Byron; Hagström, Hannes; Fredrikson, Mats; Ignatova, Simone; Stål, Per; Hultcrantz, Rolf; Ekstedt, Mattias; Kechagias, Stergios

2016-01-01

Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, King´s score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). Of established algorithms FIB-4 and King´s score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts.

Fatty liver promotes fibrosis in monkeys consuming high fructose.

PubMed

Cydylo, Michael A; Davis, Ashley T; Kavanagh, Kylie

2017-02-01

Nonalcoholic fatty liver diseases (NAFLD) are related to development of liver fibrosis which currently has few therapeutic options. Rodent models of NAFLD inadequately model the fibrotic aspects of the disease and fail to demonstrate the spectrum of cardiometabolic diseases without genetic manipulation. This study aimed to document a monkey model of fatty liver and fibrosis, which naturally develop cardiometabolic disease pathophysiologies. Twenty-seven cynomolgus monkeys (Macaca fascicularis) fed diets either low or high in simple carbohydrates, supplied as fructose [control and high-fructose diet (HRr)], on low-fat, cholesterol-free background were studied. The HFr was consumed for up to 7 years, and liver tissue was histologically evaluated for fat and fibrosis extent. The HFr diet increased steatosis, and its extent was related to duration of fructose exposure. Lipid droplet size also increased with HFr duration; however, compared with control, the lipid droplets were smaller on average. Fibrosis extent was significantly greater with fructose feeding and was predicted by fructose exposure, extent of fatty liver, and age. These data are the first to demonstrate that high-carbohydrate diets alone can generate both liver fat and fibrosis and thus allow further study of mechanisms and therapeutic options in the translational animal model. © 2017 The Obesity Society.

Operative management of brainstem cavernous malformations.

PubMed

Asaad, Wael F; Walcott, Brian P; Nahed, Brian V; Ogilvy, Christopher S

2010-09-01

Brainstem cavernous malformations (CMs) are complex lesions associated with hemorrhage and neurological deficit. In this review, the authors describe the anatomical nuances relating to the operative techniques for these challenging lesions. The resection of brainstem CMs in properly selected patients has been demonstrated to reduce the risk of rehemorrhage and can be achieved relatively safely in experienced hands.

The Effect of Audio Tours on Learning and Social Interaction: An Evaluation at Carlsbad Caverns National Park

ERIC Educational Resources Information Center

Novey, Levi T.; Hall, Troy E.

2007-01-01

Auditory forms of nonpersonal communication have rarely been evaluated in informal settings like parks and museums. This study evaluated the effect of an interpretive audio tour on visitor knowledge and social behavior at Carlsbad Caverns National Park. A cross-sectional pretest/posttest quasi-experimental design compared the responses of audio…

Nasopharyngeal carcinoma presented as cavernous sinus tumour.

PubMed

Moona, Mohammad Shafi; Mehdi, Itrat

2011-12-01

A 32 year Libyan male presented with the complaints of headache and diplopia. He was diagnosed with a cavernous sinus meningioma on the basis of MRI findings but no initial biopsy was taken. Depending on the radiologic diagnosis the patient was treated with gamma knife surgery twice, abroad. During follow up he developed left ear deafness and left cervical lymph adenopathy. An ENT evaluation with biopsy from the nasopharynx and cervical lymph node was taken. The histopathologic diagnosis of the resected tumour showed a nasopharyngeal carcinoma with cervical lymph node metastasis (poorly differentiated lympho-epithelial carcinoma). The cavernous sinus tumour which was initially treated as a meningioma was in fact metastasis from the nasopharyngeal carcinoma, making this an interesting and rare occurrence.

Computed tomographic diagnosis of unilateral cavernous sinus syndrome caused by a chondrosarcoma in a dog: a case report.

PubMed

Hernández-Guerra, Angel María; Del Mar López-Murcia, María; Planells, Alicia; Corpa, Juan Manuel; Liste, Fernando

2007-07-01

An eight-year old Rottweiler dog was presented with signs of enophthalmia, ptosis, anisocoria and mydriasis of the right eye, which showed visual disturbance, reduced or absent reflexes, and ophthalmoplegia. Consensual pupillary light reflex was also absent in the left eye. These neurological deficits were compatible with cavernous sinus syndrome. Computed tomography images of the cavernous sinus and the optical fissure revealed a mildly calcified mass arising from the right presphenoid bone extending further caudally into the orbital foramina. This extension of the mass affected the normal function of several cranial nerves. The dog was euthanased within one year of the initial presentation following development of forebrain signs. A chondrosarcoma was diagnosed histologically after necropsy.

Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis.

PubMed

Meier, Remo; Lutz, Christian; Cosín-Roger, Jesus; Fagagnini, Stefania; Bollmann, Gabi; Hünerwadel, Anouk; Mamie, Celine; Lang, Silvia; Tchouboukov, Alexander; Weber, Franz E; Weber, Achim; Rogler, Gerhard; Hausmann, Martin

2016-03-01

Fibrosis as a common problem in patients with Crohn's disease is a result of an imbalance toward excessive tissue repair. At present, there is no specific treatment option. Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis with both antifibrotic and anti-inflammatory effects. We subsequently investigated the impact of pirfenidone treatment on development of fibrosis in a new mouse model of intestinal fibrosis. Small bowel resections from donor mice were transplanted subcutaneously into the neck of recipients. Animals received either pirfenidone (100 mg/kg, three times daily, orally) or vehicle. After administration of pirfenidone, a significantly decreased collagen layer thickness was revealed as compared to vehicle (9.7 ± 1.0 versus 13.5 ± 1.5 µm, respectively, **P < 0.001). Transforming growth factor-β and matrix metalloproteinase-9 were significantly decreased after treatment with pirfenidone as confirmed by real-time PCR (0.42 ± 0.13 versus 1.00 ± 0.21 and 0.46 ± 0.24 versus 1.00 ± 0.62 mRNA expression level relative to GAPDH, respectively, *P < 0.05). Significantly decreased transforming growth factor-β after administration of pirfenidone was confirmed by Western blotting. In our mouse model, intestinal fibrosis can be reliably induced and is developed within 7 days. Pirfenidone partially prevented the development of fibrosis, making it a potential treatment option against Crohn's disease-associated fibrosis.

Routine Laboratory Blood Tests May Diagnose Significant Fibrosis in Liver Transplant Recipients with Chronic Hepatitis C: A 10 Year Experience.

PubMed

Sheen, Victoria; Nguyen, Heajung; Jimenez, Melissa; Agopian, Vatche; Vangala, Sitaram; Elashoff, David; Saab, Sammy

2016-03-28

The aims of our study were to determine whether routine blood tests, the aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) and Fibrosis 4 (Fib-4) scores, were associated with advanced fibrosis and to create a novel model in liver transplant recipients with chronic hepatitis C virus (HCV). We performed a cross sectional study of patients at The University of California at Los Angeles (UCLA) Medical Center who underwent liver transplantation for HCV. We used linear mixed effects models to analyze association between fibrosis severity and individual biochemical markers and mixed effects logistic regression to construct diagnostic models for advanced fibrosis (METAVIR F3-4). Cross-validation was used to estimate a receiving operator characteristic (ROC) curve for the prediction models and to estimate the area under the curve (AUC). The mean (± standard deviation [SD]) age of our cohort was 55 (±7.7) years, and almost three quarter were male. The mean (±SD) time from transplant to liver biopsy was 19.9 (±17.1) months. The mean (±SD) APRI and Fib-4 scores were 3 (±12) and 7 (±14), respectively. Increased fibrosis was associated with lower platelet count and alanine aminotransferase (ALT) values and higher total bilirubin and Fib-4 scores. We developed a model that takes into account age, gender, platelet count, ALT, and total bilirubin, and this model outperformed APRI and Fib-4 with an AUC of 0.68 (p < 0.001). Our novel prediction model diagnosed the presence of advanced fibrosis more reliably than APRI and Fib-4 scores. This noninvasive calculation may be used clinically to identify liver transplant recipients with HCV with significant liver damage.

Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis.

PubMed

Takahashi, Takehiro; Asano, Yoshihide; Ichimura, Yohei; Toyama, Tetsuo; Taniguchi, Takashi; Noda, Shinji; Akamata, Kaname; Tada, Yayoi; Sugaya, Makoto; Kadono, Takafumi; Sato, Shinichi

2015-01-01

Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse are well-established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases, including SSc. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models. We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-) ;TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry. Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis. These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc. Copyright © 2015 by the American College of Rheumatology.

Development of a model based on biochemical, real-time tissue elastography and ultrasound data for the staging of liver fibrosis and cirrhosis in patients with chronic hepatitis B

PubMed Central

Xu, Shi-Hao; Li, Qiao; Hu, Yuan-Ping; Ying, Li

2016-01-01

The liver fibrosis index (LFI), based on real-time tissue elastography (RTE), is a method currently used to assess liver fibrosis. However, this method may not consistently distinguish between the different stages of fibrosis, which limits its accuracy. The aim of the present study was to develop novel models based on biochemical, RTE and ultrasound data for predicting significant liver fibrosis and cirrhosis. A total of 85 consecutive patients with chronic hepatitis B (CHB) were prospectively enrolled and underwent a liver biopsy and RTE. The parameters for predicting significant fibrosis and cirrhosis were determined by conducting multivariate analyses. The splenoportal index (SPI; P=0.002) and LFI (P=0.023) were confirmed as independent predictors of significant fibrosis. Using multivariate analyses for identifying parameters that predict cirrhosis, significant differences in γ-glutamyl transferase (GGT; P=0.049), SPI (P=0.002) and LFI (P=0.001) were observed. Based on these observations, the novel model LFI-SPI score (LSPS) was developed to predict the occurrence of significant liver fibrosis, with an area under receiver operating characteristic curves (AUROC) of 0.87. The diagnostic accuracy of the LSPS model was superior to that of the LFI (AUROC=0.76; P=0.0109), aspartate aminotransferase-to-platelet ratio index (APRI; AUROC=0.64; P=0.0031), fibrosis-4 index (FIB-4; AUROC= 0.67; P= 0.0044) and FibroScan (AUROC=0.68; P=0.0021) models. In addition, the LFI-SPI-GGT score (LSPGS) was developed for the purposes of predicting liver cirrhosis, demonstrating an AUROC value of 0.93. The accuracy of LSPGS was similar to that of FibroScan (AUROC=0.85; P=0.134), but was superior to LFI (AUROC= 0.81; P= 0.0113), APRI (AUROC= 0.67; P<0.0001) and FIB-4 (AUROC=0.719; P=0.0005). In conclusion, the results of the present study suggest that the use of LSPS and LSPGS may complement current methods of diagnosing significant liver fibrosis and cirrhosis in patients with CHB. PMID:27573619

Doppler ultrasonography combined with transient elastography improves the non-invasive assessment of fibrosis in patients with chronic liver diseases.

PubMed

Alempijevic, Tamara; Zec, Simon; Nikolic, Vladimir; Veljkovic, Aleksandar; Stojanovic, Zoran; Matovic, Vera; Milosavljevic, Tomica

2017-01-31

Accurate clinical assessment of liver fibrosis is essential and the aim of our study was to compare and combine hemodynamic Doppler ultrasonography, liver stiffness by transient elastography, and non-invasive serum biomarkers with the degree of fibrosis confirmed by liver biopsy, and thereby to determine the value of combining non-invasive method in the prediction significant liver fibrosis. We included 102 patients with chronic liver disease of various etiology. Each patient was evaluated using Doppler ultrasonography measurements of the velocity and flow pattern at portal trunk, hepatic and splenic artery, serum fibrosis biomarkers, and transient elastography. These parameters were then input into a multilayer perceptron artificial neural network with two hidden layers, and used to create models for predicting significant fibrosis. According to METAVIR score, clinically significant fibrosis (≥F2) was detected in 57.8% of patients. A model based only on Doppler parameters (hepatic artery diameter, hepatic artery systolic and diastolic velocity, splenic artery systolic velocity and splenic artery Resistance Index), predicted significant liver fibrosis with a sensitivity and specificity of75.0% and 60.0%. The addition of unrelated non-invasive tests improved the diagnostic accuracy of Doppler examination. The best model for prediction of significant fibrosis was obtained by combining Doppler parameters, non-invasive markers (APRI, ASPRI, and FIB-4) and transient elastography, with a sensitivity and specificity of 88.9% and 100%. Doppler parameters alone predict the presence of ≥F2 fibrosis with fair accuracy. Better prediction rates are achieved by combining Doppler variables with non-invasive markers and liver stiffness by transient elastography.

Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.

PubMed

Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R

2012-03-01

The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

PubMed

Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

2016-12-14

To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

Engineered cell and tissue models of pulmonary fibrosis.

PubMed

Sundarakrishnan, Aswin; Chen, Ying; Black, Lauren D; Aldridge, Bree B; Kaplan, David L

2018-04-01

Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis. Copyright © 2017. Published by Elsevier B.V.

Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

PubMed

von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

2016-02-01

The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease.

PubMed

Takeuchi-Yorimoto, Ayano; Yamaura, Yu; Kanki, Masayuki; Ide, Tetsuya; Nakata, Ayumi; Noto, Takahisa; Matsumoto, Masahiro

2016-09-06

Evidence indicates that hepatic fibrosis is the initial lesion of cirrhosis or hepatocellular carcinoma in diseases such as nonalcoholic steatohepatitis (NASH). To induce NASH, we fed rats a choline-deficient and iron-supplemented L-amino acid-defined (CDAA) diet. Histopathological examination revealed that fibrosis appeared from week 4 and progressed to bridging fibrosis from week 12. Using qRT-PCR assays, we detected increased expression of miR-21, Mmp-9, and Timp-1 in liver that peaked during week 4, when fibrosis was first detected. The expression pattern of miR-21 in plasma paralleled that in liver. Fibrosis tended to be resolved within 12 weeks of a recovery period after 12 weeks of feeding, and the expression of miR-21, Timp-1, and Mmp-9 decreased in liver. Comprehensive analyses of miRNA and mRNA expression in the liver using samples acquired at week 4 detected 16 miRNAs and 11 mRNAs that are mutually-interacting fibrosis-related factors. We therefore conclude that miR-21 was closely associated with fibrosis in a rat model of NASH and has potential as a plasma biomarker for hepatic fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Intestinal organoids: A model of intestinal fibrosis for evaluating anti-fibrotic drugs

PubMed Central

Rodansky, Eva S.; Johnson, Laura A.; Huang, Sha; Spence, Jason R.; Higgins, Peter D. R.

2016-01-01

Background & Aims Intestinal fibrosis is a critical complication of Crohn’s disease (CD). Current in vitro models of intestinal fibrosis cannot model the complex intestinal architecture, while in vivo rodent models do not fully recapitulate human disease and have limited utility for large-scale screening. Here, we exploit recent advances in stem cell derived human intestinal organoids (HIOs) as a new human model of fibrosis in CD. Methods Human pluripotent stem cells were differentiated into HIOs. We identified myofibroblasts, the key effector cells of fibrosis, by immunofluorescence staining for alpha-smooth muscle actin (αSMA), vimentin, and desmin. We examined the fibrogenic response of HIOs by treatment with transforming growth factor beta (TGFβ) in the presence or absence of the anti-fibrotic drug spironolactone. Fibrotic response was assayed by expression of fibrogenic genes (COL1A1 (collagen, type I, alpha 1), ACTA2 (alpha smooth muscle actin), FN1 (fibronectin 1), MYLK (myosin light chain kinase), and MKL1 (megakaryoblastic leukemia (translocation) 1)) and proteins (αSMA). Results Immunofluorescent staining of organoids identified a population of myofibroblasts within the HIO mesenchyme. TGFβ stimulation of HIOs produced a dose-dependent pro-fibrotic response. Spironolactone treatment blocked the fibrogenic response of HIOs to TGFβ. Conclusions HIOs contain myofibroblasts and respond to a pro-fibrotic stimulus in a manner that is consistent with isolated human myofibroblasts. HIOs are a promising model system that might bridge the gap between current in vitro and in vivo models of intestinal fibrosis in IBD. PMID:25828392

Relative Evaluation of the Independent Volume Measures of Caverns

DOE Office of Scientific and Technical Information (OSTI.GOV)

MUNSON,DARRELL E.

2000-08-01

Throughout the construction and operation of the caverns of the Strategic Petroleum Reserve (SPR), three types of cavern volume measurements have been maintained. These are: (1) the calculated solution volume determined during initial construction by solution mining and any subsequent solutioning during oil transfers, (2) the calculated sonar volume determined through sonar surveys of the cavern dimensions, and (3) the direct metering of oil to determine the volume of the cavern occupied by the oil. The objective of this study is to compare these measurements to each other and determine, if possible, the uncertainties associated with a given type ofmore » measurement. Over time, each type of measurement has acquired a customary, or an industry accepted, stated uncertainty. This uncertainty is not necessarily the result of a technical analysis. Ultimately there is one definitive quantity, the oil volume measure by the oil custody transfer meters, taken by all parties to the transfer as the correct ledger amount and for which the SPR Project is accountable. However, subsequent transfers within a site may not be with meters of the same accuracy. In this study, a very simple theory of the perfect relationship is used to evaluate the correlation (deviation) of the various measures. This theory permits separation of uncertainty and bias. Each of the four SPR sites are examined, first with comparisons between the calculated solution volumes and the sonar volumes determined during construction, then with comparisons of the oil inventories and the sonar volumes obtained either by surveying through brine prior to oil filling or through the oil directly.« less

Results of stereotactic radiosurgery for patients with imaging defined cavernous sinus meningiomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pollock, Bruce E.; Stafford, Scott L.

2005-08-01

Introduction: The purpose of this study was to evaluate the efficacy and safety of stereotactic radiosurgery as primary management for patients with imaging defined cavernous sinus meningiomas. Methods: Between 1992 and 2001, 49 patients had radiosurgery for dural-based masses of the cavernous sinus presumed to be meningiomas. The mean patient age was 55.5 years. The mean tumor volume was 10.2 mL; the mean tumor margin dose was 15.9 Gy. The mean follow-up was 58 months (range, 16-144 months). Results: No tumor enlarged after radiosurgery. Twelve of 38 patients (26%) with preexisting diplopia or facial numbness/pain had improvement in cranial nervemore » function. Five patients (10%) had new (n = 3) or worsened (n = 2) trigeminal dysfunction; 2 of these patients (4%) underwent surgery at 20 and 25 months after radiosurgery despite no evidence of tumor progression. Neither patient improved after partial tumor resection. One patient (2%) developed an oculomotor nerve injury. One patient (2%) had an ischemic stroke related to occlusion of the cavernous segment of the internal carotid artery. Event-free survival was 98%, 85%, and 80% at 1, 3, and 7 years after radiosurgery, respectively. Univariate analysis of patient and dosimetric factors found no analyzed factor correlated with postradiosurgical morbidity. Conclusions: Radiosurgery was an effective primary management strategy for patients with an imaging defined cavernous sinus meningioma. Except in situations of symptomatic mass effect, unusual clinical presentation, or atypical imaging features, surgery to confirm the histologic diagnosis is unlikely to provide clinical benefit.« less

Long-term high-fat consumption leads to downregulation of Akt phosphorylation of eNOS at Ser1177 and upregulation of Sirtuin-1 expression in rat cavernous tissue.

PubMed

Tomada, I; Negrão, R; Almeida, H; Neves, D

2014-04-01

Long-term consumption of high-fat diets negatively interferes with metabolic status and promotes endothelial dysfunction and inflammation. In the cavernous tissue, these outcomes become conspicuous in the elderly and strongly affect penile erection, a vascular process highly dependent on local nitric oxide bioavailability. Although epidemiological data links erectile dysfunction to nutritional patterns, the underlying molecular mechanisms remain unclear. Therefore, we investigated the effects of long-term high-fat diet on endothelial nitric oxide synthase (eNOS)-Sirtuin-1 axis and Akt/eNOS phosphorylation in the cavernous tissue of Sprague-Dawley rats, and compared with energy-restricted animals. We demonstrated that high-fat diet intake led to a noteworthy decrease in eNOS phosphorylation at Ser1177 residue through the Akt pathway, which seems to be compensated by upregulation of phosphorylation at Ser615, but without an increment in nitric oxide production. These results are accompanied by an increase of systemic inflammatory markers and upregulation of the inducible NOS and of the deacetylase Sirtuin-1 in the cavernous tissue to levels apparently detrimental to cells and to metabolic homeostasis. Conversely, in long-term energy-restricted animals, the rate of phosphorylation of eNOS at Ser1177 diminished, but the activation of the enzyme increased through phosphorylation of eNOS at Ser615, resulting in an enhancement in nitric oxide bioavailability. Taken together, our results demonstrate that long-term nutritional conditions override the influence of age on the eNOS expression and activation in rat cavernous tissue.

[Valuation of APRI and Forns models for non-invasive diagnosis of fibrosis in patients with hepatitis C in coinfected and non-coinfected with HIV].

PubMed

Ramos Paesa, C; Marcilla, F; López, G; Hueso, E; Pascual, A; Aguirre, J M

2007-08-01

APRI and Forns (IF) index are noninvasive models consisting of routine laboratory data for the prediction of liver fibrosis in patients with chronic hepatitis C. The aim of our study was to confirm the value of these models to predict significant fibrosis in these patients and if they may decrease the need for performing liver biopsy specimens in coinfected and HIVnon-coinfected. We included 60 patients with chronic hepatitis C and histologic data, 33 were coinfected with HIV. Mild fibrosis (F0-F1) was found in 73% patients, severe fibrosis (F3-F4) in 23% and cirrhosis in 18.3%. We calculated and compared APRI and IF with the stage of liver fibrosis. The APRI score < 0.5 or > 1.5 and IF < 4.2 or > 6.9, as predictors of mild or severe fibrosis, were only available in 53% and 49%. Neither laboratory nor APRI and IF were associated with liver fibrosis in non-coinfected patients. We only found association in HIV coinfected patients: severe fibrosis (F3-4) whit higher gammaglobulins [24.5% vs. 30% (p < 0.05)] and Gamma-GT levels [77 (46.5) vs. 32 (48.5) (p < 0.05)], and lower prothrombin time [72% vs. 91% (p < 0.05) ] and platelets.109 count [129 (40) vs. 170 (78) (p < 0.05)]; APRI was lower than 0.5 in 41.6% patients with mild fibrosis (F0-1) against none with severe (F3-4) (p < 0.05); specifity (E) of APRI < 0.5 for predicting mild fibrosis was 100%, but sensivity (S) was very low (41%), with a positive preditive value (VPP) of 100%, but a negative predictive value (VPN) also very low ( 36.3%). Our study showed that these models don t avoid the need for liver biopsies. More than a half of patients are not appropriately classified according to findings on liver biopsy and S and VPN are very low. The combination of these index with gammaglobulins, Gamma-GT, AST, ALT and platelet levels and protrombine time, only may be an approach to degree of fibrosis or inflammation liver in HIV co-infected patients.

Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection

PubMed Central

Zeng, Da-Wu; Dong, Jing; Liu, Yu-Rui; Jiang, Jia-Ji; Zhu, Yue-Yong

2016-01-01

There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the “gold standard” for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians. PMID:27547009

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

PubMed Central

Englert, Judson M.; Hanford, Lana E.; Kaminski, Naftali; Tobolewski, Jacob M.; Tan, Roderick J.; Fattman, Cheryl L.; Ramsgaard, Lasse; Richards, Thomas J.; Loutaev, Inna; Nawroth, Peter P.; Kasper, Michael; Bierhaus, Angelika; Oury, Tim D.

2008-01-01

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGE-null mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis. PMID:18245812

The influence of hepatic steatosis on the evaluation of fibrosis with non-alcoholic fatty liver disease by acoustic radiation force impulse.

PubMed

Yanrong Guo; Haoming Lin; Xinyu Zhang; Huiying Wen; Siping Chen; Xin Chen

2017-07-01

Acoustic radiation force impulse (ARFI) elastography is a non-invasive method for the assessment of liver by measuring liver stiffness. The aim of this study is to evaluate the accuracy of ARFI for the diagnosis of liver fibrosis and to assess impact of steatosis on liver fibrosis stiffness measurement, in rats model of non-alcoholic fatty liver disease (NAFLD). The rat models were conducted in 59 rats. The right liver lobe was processed and embedded in a fabricated gelatin solution. Liver mechanics were measured using shear wave velocity (SWV) induced by acoustic radiation force. In rats with NAFLD, the diagnostic performance of ARFI elastography in predicting severe fibrosis (F ≥ 3) and cirrhosis (F ≥ 4) had the areas under the receiver operating characteristic curves (AUROC) of 0.993 and 0.985. Among rats mean SWV values were significantly higher in rats with severe steatosis by histology compared to those mild or without steatosis for F0-F2 fibrosis stages (3.07 versus 2.51 m/s, P = 0.01). ARFI elastography is a promising method for staging hepatic fibrosis with NAFLD in rat models. The presence of severe steatosis is a significant factor for assessing the lower stage of fibrosis.

A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

PubMed

Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

2013-01-01

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

Environmental change at Kartchner Caverns: trying to separate natural and anthropogenic changes

Treesearch

Rickard S. Toomey; Ginger Nolan

2005-01-01

Cave temperature and moisture levels are important factors in the environmental health of Kartchner Caverns. Monitoring indicates the cave has warmed and moisture levels have fallen over the past 14 years. Timing and patterns of change within the cave suggest that changes are due to development as a show cave. However, changes in other caves, surface temperature and...

Performance Study of Salt Cavern Air Storage Based Non-Supplementary Fired Compressed Air Energy Storage System

NASA Astrophysics Data System (ADS)

Chen, Xiaotao; Song, Jie; Liang, Lixiao; Si, Yang; Wang, Le; Xue, Xiaodai

2017-10-01

Large-scale energy storage system (ESS) plays an important role in the planning and operation of smart grid and energy internet. Compressed air energy storage (CAES) is one of promising large-scale energy storage techniques. However, the high cost of the storage of compressed air and the low capacity remain to be solved. This paper proposes a novel non-supplementary fired compressed air energy storage system (NSF-CAES) based on salt cavern air storage to address the issues of air storage and the efficiency of CAES. Operating mechanisms of the proposed NSF-CAES are analysed based on thermodynamics principle. Key factors which has impact on the system storage efficiency are thoroughly explored. The energy storage efficiency of the proposed NSF-CAES system can be improved by reducing the maximum working pressure of the salt cavern and improving inlet air pressure of the turbine. Simulation results show that the electric-to-electric conversion efficiency of the proposed NSF-CAES can reach 63.29% with a maximum salt cavern working pressure of 9.5 MPa and 9 MPa inlet air pressure of the turbine, which is higher than the current commercial CAES plants.

Genetically diagnosed Birt-Hogg-Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report.

PubMed

Whitworth, James; Stausbøl-Grøn, Brian; Skytte, Anne-Bine

2017-01-01

When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt-Hogg-Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595-597, 10.1007/s10689-015-9807-y , 2015) but it is not yet clear whether they represent a genuine part of that conditions' phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed.

Opportunities for Multidisciplinary Research in Partnership with Rock Engineers at the Deep Underground Science and Engineering Laboratory

NASA Astrophysics Data System (ADS)

Laughton, C.

2008-12-01

For the last half century the physics community has increasingly turned to the use of underground space to conduct basic research. The community is currently planning to conduct a new generation of underground experiments at the Deep Underground Science and Engineering Laboratory (DUSEL). DUSEL will be constructed within the footprint of the defunct Homestake Gold Mine, located in Lead, South Dakota. Physics proposals call for the construction of new caverns in which to conduct major new experiments. Some of the proposed laboratory facilities will be significantly larger and deeper than any previously constructed. The talk will highlight possible opportunities for integrating multi-disciplinary research in to the cavern construction program, and will stress the need to work closely with design and construction contractors to ensure that research goals can be achieve with minimal impact on project work. The constructors of large caverns should be particularly receptive to, and encouraging of geoscience research that could improve the engineering characterization of the rock mass. An improved understanding of the rock mass, as the host construction material, would result in a more reliable cavern design and construction process, and a reduced construction risk to the Project.

Transarterial Onyx Embolization for Patients with Cavernous Sinus Dural Arteriovenous Fistulas Who Have Failed Transvenous Embolization.

PubMed

Wen, Jun; Duan, Chuan-Zhi; Huang, Li-Jing; Zhang, Xin; He, Xu-Ying; Li, Xi-Feng

2015-09-01

Transvenous embolization is the treatment of choice for cavernous sinus dural arteriovenous fistulas (csDAVFs) despite occasional difficulty in transvenous catheterization. We reported our experience in the treatment of csDAVFs by transarterial Onyx embolization in patients who had failed transvenous catheterization. We reviewed the clinical and radiographic records of csDAVFs patients receiving transarterial Onyx embolization after failed transvenous Onyx embolization at our institution over a period of 31 months. Success was defined as complete or near complete occlusion upon angiographic examination. In seven cases, the microcatheter failed to reach the cavernous sinus; in the remaining case, the internal jugular vein was occlusive. Eight sessions of the embolization and catheterization procedures via the arterial routes were conducted. Among them, five cases via the middle meningeal artery and the other three via the accessory meningeal artery. Angiography, immediately after embolization, revealed complete occlusion in seven cases (87.5 %) and partial occlusion in the remaining case. Angiographic follow-up (range, 6-10 months) showed that all patients achieved complete embolization. In cases where transvenous embolization of the cavernous sinus is difficult, transarterial embolization of the fistulas offers a safe and effective alternative.

Continuous-wave vs. pulsed infrared laser stimulation of the rat prostate cavernous nerves

NASA Astrophysics Data System (ADS)

Tozburun, Serhat; Cilip, Christopher M.; Lagoda, Gwen A.; Burnett, Arthur L.; Fried, Nathaniel M.

2011-03-01

Optical nerve stimulation has recently been developed as an alternative to electrical nerve stimulation. However, recent studies have focused primarily on pulsed delivery of the laser radiation and at relatively low pulse rates. The objective of this study is to demonstrate faster optical stimulation of the prostate cavernous nerves using continuouswave (CW) infrared laser radiation, for potential diagnostic applications. A Thulium fiber laser (λ = 1870 nm) was used for non-contact optical stimulation of the rat prostate cavernous nerves, in vivo. Optical nerve stimulation, as measured by an intracavernous pressure (ICP) response in the penis, was achieved with the laser operating in either CW mode, or with a 5-ms pulse duration at 10, 20, 30, 40, 50, and 100 Hz. Successful optical stimulation was observed to be primarily dependent on a threshold nerve temperature (42-45 °C), not an incident fluence, as previously reported. CW optical nerve stimulation provides a significantly faster ICP response time using a laser with lower power output than pulsed stimulation. CW optical nerve stimulation may therefore represent an alternative mode of stimulation for intra-operative diagnostic applications where a rapid response is critical, such as identification of the cavernous nerves during prostate cancer surgery.

[A case of multiple cavernous angioma with dementia].

PubMed

Kariya, S; Kawahara, M; Suzumura, A

2000-10-01

We reported a 65-year-old man who developed dementia since 50 years of age. His consciousness was clear but he was indifferent to his illness. Also, the luck of attention was recognized when we underwent examinations and the result of intellectual test varied every time we performed. His memory function was almost normal on the examination which was performed when he was cooperative. Magnetic resonance imaging (MRI) disclosed multiple tiny lesions (more than 130 in all) in cerebrum, brainstem, cerebellum and spinal cord. These lesions were compatible with multiple cavernous angioma. Most of lesions manifested high-density area on cranial CT. Though the multiplicity of foci indicated the possibility of familial occurrence, he was considered to be a sporadic case on his lineage investigation and the brain MRI of his only son. In this case, neither headache nor seizures which were known as the major clinical features of intracerebral cavernous angioma was observed. He was diagnosed as having white matter dementia characterized by attentional dysfunction, decrement of volition and less memory disturbance. We speculated that he developed symptomatic dementia by the sum of multiple minor degeneration, especially in frontal lobe white matter, caused by repeated minor bleeding from cavernous angiomas.

Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xing; Wu, Xiao-Qin; Xu, Tao

Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 wasmore » maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. - Highlights: • This is the first report to systematically examine expressions of HDACs during liver fibrosis and fibrosis reversal. • Aberrant expression of HDAC2 contributes to the development of liver fibrosis. • Provided important foundation for further liver fibrosis conversion studies.« less

Fibrosis progression in African Americans and Caucasian Americans with chronic hepatitis C.

PubMed

Terrault, Norah A; Im, Kelly; Boylan, Ross; Bacchetti, Peter; Kleiner, David E; Fontana, Robert J; Hoofnagle, Jay H; Belle, Steven H

2008-12-01

Prior studies suggest the rate of liver fibrosis progression is slower in African Americans (AAs) than Caucasian Americans (CAs) with chronic HCV infection. With a multi-state Markov model, fibrosis progression was evaluated in a well-characterized cohort of 143 AA and 157 CA adults with untreated chronic HCV genotype 1 infection. In subjects with a history of injection drug use, duration of infection was imputed from a fitted risk model rather than assumed to be the reported first year of use. The distribution of Ishak fibrosis stages was 0 (8.7%), 1/2 (55.7%), 3/4 (29.3%), and 5/6 (6.3%) and was similar in AAs and CAs (P = .22). After adjusting for biopsy adequacy, AAs had a 10% lower rate of fibrosis progression than did CAs, but the difference was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.72-1.12). The overall 20-year estimates of probabilities of progression from stage 0 to stages 1/2, 3/4, and 5/6 were 59.3%, 28.8%, and 4.7%, respectively. The estimated median time from no fibrosis to cirrhosis was 79 years for the entire cohort and 74 and 83 years for CAs and AAs, respectively. In 3-variable models including race and biopsy adequacy, the factors significantly associated with fibrosis progression were age when infected, steatosis, ALT level, and necroinflammatory score. The rates of fibrosis progression were slow and did not appear to differ substantially between AAs and CAs.

RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis

PubMed Central

Craciun, Florin L.; Bijol, Vanesa; Ajay, Amrendra K.; Rao, Poornima; Kumar, Ramya K.; Hutchinson, John; Hofmann, Oliver; Joshi, Nikita; Luyendyk, James P.; Kusebauch, Ulrike; Moss, Christopher L.; Srivastava, Anand; Himmelfarb, Jonathan; Waikar, Sushrut S.; Moritz, Robert L.

2016-01-01

CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid-induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD. PMID:26449608

Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD

PubMed Central

Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A.; Kleiner, David; Brunt, Elizabeth M.; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James

2015-01-01

OBJECTIVE Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. RESEARCH DESIGN AND METHODS This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. RESULTS The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. CONCLUSIONS Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. PMID:25887357

Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin β1 Interaction.

PubMed

Takawale, Abhijit; Zhang, Pu; Patel, Vaibhav B; Wang, Xiuhua; Oudit, Gavin; Kassiri, Zamaneh

2017-06-01

Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using Timp1 -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). Timp1 deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, Timp1 deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies. © 2017 American Heart Association, Inc.

Origin of honeycombs: Testing the hydraulic and case hardening hypotheses

NASA Astrophysics Data System (ADS)

Bruthans, Jiří; Filippi, Michal; Slavík, Martin; Svobodová, Eliška

2018-02-01

Cavernous weathering (cavernous rock decay) is a global phenomenon, which occurs in porous rocks around the world. Although honeycombs and tafoni are considered to be the most common products of this complex process, their origin and evolution are as yet not fully understood. The two commonly assumed formation hypotheses - hydraulic and case hardening - were tested to elucidate the origin of honeycombs on sandstone outcrops in a humid climate. Mechanical and hydraulic properties of the lips (walls between adjacent pits) and backwalls (bottoms of pits) of the honeycombs were determined via a set of established and novel approaches. While the case hardening hypothesis was not supported by the determinations of either tensile strength, drilling resistance or porosity, the hydraulic hypothesis was clearly supported by field measurements and laboratory tests. Fluorescein dye visualization of capillary zone, vapor zone, and evaporation front upon their contact, demonstrated that the evaporation front reaches the honeycomb backwalls under low water flow rate, while the honeycomb lips remain dry. During occasional excessive water flow events, however, the evaporation front may shift to the lips, while the backwalls become moist as a part of the capillary zone. As the zone of evaporation corresponds to the zone of potential salt weathering, it is the spatial distribution of the capillary and vapor zones which dictates whether honeycombs are created or the rock surface is smoothed. A hierarchical model of factors related to the hydraulic field was introduced to obtain better insights into the process of cavernous weathering.

Control and optimization in the modeling of fibrosis. Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca

NASA Astrophysics Data System (ADS)

Sivasundaram, Seenith

2016-07-01

The review paper [1] is devoted to the survey of different structures that have been developed for the modeling and analysis of various types of fibrosis. Biomathematics, bioinformatics, biomechanics and biophysics modeling have been treated by means of a brief description of the different models developed. The review is impressive and clearly written, addressed to a reader interested not only in the theoretical modeling but also in the biological description. The models have been described without recurring to technical statements or mathematical equations thus allowing the non-specialist reader to understand what framework is more suitable at a certain observation scale. The review [1] concludes with the possibility to develop a multiscale approach considering also the definition of a therapeutical strategy for pathological fibrosis. In particular the control and optimization of therapeutics action is an important issue and this article aims at commenting on this topic.

The Gamma-Glutamyl-Transpeptidase to Platelet Ratio Does not Show Advantages than APRI and Fib-4 in Diagnosing Significant Fibrosis and Cirrhosis in Patients With Chronic Hepatitis B: A Retrospective Cohort Study in China.

PubMed

Li, Qiang; Song, Jie; Huang, Yuxian; Li, Xinyan; Zhuo, Qibin; Li, Weixia; Chen, Chong; Lu, Chuan; Qi, Xun; Chen, Liang

2016-04-01

The gamma-glutamyl-transpeptidase to platelet ratio (GPR) is a new liver fibrosis model, which is reported to be more accurate than aspartate transaminase (AST) to platelet ratio index (APRI) and fibrosis index based on the four factors (Fib-4) for diagnosing significant fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) in West Africa. The aim of this study is to assess the diagnostic accuracy of GPR for significant fibrosis and cirrhosis in Chinese CHB patients, and explore whether GPR deserves to be popularized in China. A total of 372 CHB patients who underwent liver biopsies and routine laboratory tests were retrospectively studied. The Scheuer scoring system was adopted as the pathological standard of liver fibrosis. Using liver histology as a gold standard, the diagnostic accuracies of GPR, APRI, and Fib-4 for significant fibrosis and cirrhosis are evaluated and compared by the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUROCs). Of these 372 patients, 176 (47.3%), 129 (34.7%), and 72 (19.4%) were classified as having significant fibrosis (≥ S2), severe fibrosis (≥ S3), and cirrhosis (S4), respectively. The AUROCs of GPR for significant fibrosis (0.72 vs. 0.78; P = 0.01), severe fibrosis (0.75 vs. 0.80; P = 0.04), and cirrhosis (0.78 vs. 0.83; P = 0.02) were lower than those of APRI. The AUROCs of GPR and Fib-4 for diagnosing significant fibrosis (0.72 vs. 0.70; P = 0.29), severe fibrosis (0.75 vs. 0.73; P = 0.33), and cirrhosis (0.78 vs. 0.75; P = 0.38) were comparable. GPR is a new serum diagnostic model for liver fibrosis and cirrhosis, but does not show advantages than APRI and Fib-4 in identifying significant fibrosis, severe fibrosis, and cirrhosis in CHB patients in China.

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model.

PubMed

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2015-10-01

Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6-8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) was orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20 μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model

PubMed Central

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2016-01-01

Objective Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Methods Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6–8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) were orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Results Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. Conclusion E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. PMID:26315492

Red Blood Cell Distribution Width Levels Correlate With Liver Fibrosis and Inflammation

PubMed Central

Xu, Wen-Shen; Qiu, Xiao-Ming; Ou, Qi-shui; Liu, Can; Lin, Jin-Piao; Chen, Hui-Juan; Lin, Sheng; Wang, Wen-Hua; Lin, Shou-Rong; Chen, Jing

2015-01-01

Abstract We aimed to study whether red blood cell distribution width (RDW) could be one of the variables determining the extent of liver fibrosis and inflammation in patients with biopsy-proven hepatitis B. A total of 446 hepatitis B virus-infected patients who underwent liver biopsy were divided into 2 groups: absent or mild and moderate–severe according to the severity of liver fibrosis and inflammation. The independent variables that determine the severity of liver fibrosis and inflammation were explored. RDW values increased with progressive liver fibrosis and inflammation. After adjustments for other potent predictors, liver fibrosis (moderate–severe) was independently associated with RDW, platelet, and albumin (odds ratio = 1.121, 0.987, and 0.941, respectively), whereas increased odds ratios of significant inflammation were found for RDW, alanine aminotransferase, albumin, and PLT (odds ratio = 1.146, 1.003, 0.927, and 0.990, respectively). The sensitivity and specificity of model A were 70.0% and 62.9% for detection of significant liver fibrosis [area under the receiver-operating characteristic curve (AUC) = 0.713, P < 0.001]. The sensitivity and specificity of model B were 66.1% and 79.4% for predicting advanced liver inflammation (AUC = 0.765, P < 0.001). Compared with preexisting indicators, model A achieved the highest AUC, whereas model B showed a higher AUC than RDW to platelet ratio (0.670, P < 0.001) and FIB-4 (0.740, P = 0.32). RDW may provide a useful clinical value for predicting liver fibrosis and necroinflammation in hepatitis B-infected patients with other markers. PMID:25761184

The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

PubMed Central

Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

2014-01-01

Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID:24779708

Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Westra, Inge M.; Oosterhuis, Dorenda; Groothuis, Geny M.M.

Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined.more » After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only minor effects on fibrosis markers. • Rat PCLS can be used to study the early onset of fibrosis.« less

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis

PubMed Central

Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

2016-01-01

AIM To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy. PMID:28028365

Prognostic durability of liver fibrosis tests and improvement in predictive performance for mortality by combining tests.

PubMed

Bertrais, Sandrine; Boursier, Jérôme; Ducancelle, Alexandra; Oberti, Frédéric; Fouchard-Hubert, Isabelle; Moal, Valérie; Calès, Paul

2017-06-01

There is currently no recommended time interval between noninvasive fibrosis measurements for monitoring chronic liver diseases. We determined how long a single liver fibrosis evaluation may accurately predict mortality, and assessed whether combining tests improves prognostic performance. We included 1559 patients with chronic liver disease and available baseline liver stiffness measurement (LSM) by Fibroscan, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, Hepascore, and FibroMeter V2G . Median follow-up was 2.8 years during which 262 (16.8%) patients died, with 115 liver-related deaths. All fibrosis tests were able to predict mortality, although APRI (and FIB-4 for liver-related mortality) showed lower overall discriminative ability than the other tests (differences in Harrell's C-index: P < 0.050). According to time-dependent AUROCs, the time period with optimal predictive performance was 2-3 years in patients with no/mild fibrosis, 1 year in patients with significant fibrosis, and <6 months in cirrhotic patients even in those with a model of end-stage liver disease (MELD) score <15. Patients were then randomly split in training/testing sets. In the training set, blood tests and LSM were independent predictors of all-cause mortality. The best-fit multivariate model included age, sex, LSM, and FibroMeter V2G with C-index = 0.834 (95% confidence interval, 0.803-0.862). The prognostic model for liver-related mortality included the same covariates with C-index = 0.868 (0.831-0.902). In the testing set, the multivariate models had higher prognostic accuracy than FibroMeter V2G or LSM alone for all-cause mortality and FibroMeter V2G alone for liver-related mortality. The prognostic durability of a single baseline fibrosis evaluation depends on the liver fibrosis level. Combining LSM with a blood fibrosis test improves mortality risk assessment. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Cost-Effectiveness of Screening Individuals With Cystic Fibrosis for Colorectal Cancer.

PubMed

Gini, Andrea; Zauber, Ann G; Cenin, Dayna R; Omidvari, Amir-Houshang; Hempstead, Sarah E; Fink, Aliza K; Lowenfels, Albert B; Lansdorp-Vogelaar, Iris

2017-12-27

Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared to the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. We adjusted the existing Microsimulation Screening Analysis-Colon microsimulation model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess whether optimal screening strategies would change. Colonoscopy every 5 years, starting at age 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in population is not clear. Using a Microsimulation Screening Analysis-Colon microsimulation model, we found screening of patients with cystic fibrosis for CRC to be cost-effective. Due to the higher risk in these patients for CRC, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Cost Effectiveness of Screening Individuals With Cystic Fibrosis for Colorectal Cancer.

PubMed

Gini, Andrea; Zauber, Ann G; Cenin, Dayna R; Omidvari, Amir-Houshang; Hempstead, Sarah E; Fink, Aliza K; Lowenfels, Albert B; Lansdorp-Vogelaar, Iris

2018-02-01

Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared with the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. We adjusted the existing Microsimulation Screening Analysis-Colon model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess if optimal screening strategies would change. Colonoscopy every 5 years, starting at an age of 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in this population is not clear. Using a Microsimulation Screening Analysis-Colon model, we found screening of patients with cystic fibrosis for CRC to be cost effective. Because of the higher risk of CRC in these patients, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Serum proteomic MRM identify peptide ions of transferrin as new fibrosis markers in chronic hepatitis B.

PubMed

Xu, Ming-Yi; Qu, Ying; Jia, Xiao-Fang; Wang, Mei-Ling; Liu, Heng; Wang, Xing-Peng; Zhang, Li-Jun; Lu, Lun-Gen

2013-09-01

Because of the limitations of liver biopsy, reliable non-invasive serum biomarkers of liver fibrosis are needed. The aim of this study was to identify such markers by the use of serum proteomics in chronic hepatitis B (CHB). Two-dimensional gel electrophoresis (2-DE) was used to identify differentially expressed protein spots in sera from 40 CHB patients [20 with mild fibrosis (S0-S1) and 20 with severe fibrosis (S3-S4)]. Mass spectrometry (MS) based multiple reaction monitoring (MRM) was used to quantify peptide ions of differential protein spots in another set of sera from 86 CHB patients with different liver fibrosis (S0-S4). Seven differentially expressed protein spots were found by 2-DE. Fourteen peptide ions of seven target protein spots were quantified by MS-based MRM. Summed peak areas ratio (SPAR) values of peptide ions from protein spot 1, 4 and 8, identified as apo serum transferrin, complement component C3c and transferrin, were significantly different from non-fibrosis (S0) to fibrosis stage 4. AUROCs of models established by peptide ions (protein spot 1, 4, 8) and model consisting of a combination of all ions were 0.848∼0.966 (S2-S4 versus S0-S1) and 0.785∼0.875 (S3-S4 versus S0-S2). Only the peptide ions model of transferrin had better sensitivity and specificity for predicting fibrosis stages than did aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forn's index. Serum peptide ions of transferrin, detected by proteomic MRM, are new and promising biomarkers for staging liver fibrosis in CHB patients. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF-α and TGF-β1/ERK1/2 signaling pathways

PubMed Central

Zhang, Changyi; Zhou, Guichi; Chen, Yezeng; Liu, Sizheng; Chen, Fen; Xie, Lichun; Wang, Wei; Zhang, Yonggang; Wang, Tianyou; Lai, Xiulan; Ma, Lian

2018-01-01

Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord-derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin-induced rat model of DCM. Male Lewis rats (aged 8-weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1×106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle-injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF-α, extracellular-signal regulated kinase 1/2 (ERK1/2) and TGF-β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF-α and the TGF-β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM. PMID:29115435

Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes.

PubMed

Beach, Tyler A; Johnston, Carl J; Groves, Angela M; Williams, Jacqueline P; Finkelstein, Jacob N

2017-04-01

Purpose/Aim of Study: Studies of pulmonary fibrosis (PF) have resulted in DNA damage, inflammatory response, and cellular senescence being widely hypothesized to play a role in the progression of the disease. Utilizing these aforementioned terms, genomics databases were interrogated along with the term, "pulmonary fibrosis," to identify genes common among all 4 search terms. Findings were compared to data derived from a model of radiation-induced progressive pulmonary fibrosis (RIPF) to verify that these genes are similarly expressed, supporting the use of radiation as a model for diseases involving PF, such as human idiopathic pulmonary fibrosis (IPF). In an established model of RIPF, C57BL/6J mice were exposed to 12.5 Gy thorax irradiation and sacrificed at 24 hours, 1, 4, 12, and 32 weeks following exposure, and lung tissue was compared to age-matched controls by RNA sequencing. Of 176 PF associated gene transcripts identified by database interrogation, 146 (>82%) were present in our experimental model, throughout the progression of RIPF. Analysis revealed that nearly 85% of PF gene transcripts were associated with at least 1 other search term. Furthermore, of 22 genes common to all four terms, 16 were present experimentally in RIPF. This illustrates the validity of RIPF as a model of progressive PF/IPF based on the numbers of transcripts reported in both literature and observed experimentally. Well characterized genes and proteins are implicated in this model, supporting the hypotheses that DNA damage, inflammatory response and cellular senescence are associated with the pathogenesis of PF.

Development of a model based on biochemical, real‑time tissue elastography and ultrasound data for the staging of liver fibrosis and cirrhosis in patients with chronic hepatitis B.

PubMed

Xu, Shi-Hao; Li, Qiao; Hu, Yuan-Ping; Ying, Li

2016-10-01

The liver fibrosis index (LFI), based on real‑time tissue elastography (RTE), is a method currently used to assess liver fibrosis. However, this method may not consistently distinguish between the different stages of fibrosis, which limits its accuracy. The aim of the present study was to develop novel models based on biochemical, RTE and ultrasound data for predicting significant liver fibrosis and cirrhosis. A total of 85 consecutive patients with chronic hepatitis B (CHB) were prospectively enrolled and underwent a liver biopsy and RTE. The parameters for predicting significant fibrosis and cirrhosis were determined by conducting multivariate analyses. The splenoportal index (SPI; P=0.002) and LFI (P=0.023) were confirmed as independent predictors of significant fibrosis. Using multivariate analyses for identifying parameters that predict cirrhosis, significant differences in γ‑glutamyl transferase (GGT; P=0.049), SPI (P=0.002) and LFI (P=0.001) were observed. Based on these observations, the novel model LFI‑SPI score (LSPS) was developed to predict the occurrence of significant liver fibrosis, with an area under receiver operating characteristic curves (AUROC) of 0.87. The diagnostic accuracy of the LSPS model was superior to that of the LFI (AUROC=0.76; P=0.0109), aspartate aminotransferase‑to‑platelet ratio index (APRI; AUROC=0.64; P=0.0031), fibrosis‑4 index (FIB‑4; AUROC=0.67; P=0.0044) and FibroScan (AUROC=0.68; P=0.0021) models. In addition, the LFI‑SPI‑GGT score (LSPGS) was developed for the purposes of predicting liver cirrhosis, demonstrating an AUROC value of 0.93. The accuracy of LSPGS was similar to that of FibroScan (AUROC=0.85; P=0.134), but was superior to LFI (AUROC=0.81; P=0.0113), APRI (AUROC=0.67; P<0.0001) and FIB‑4 (AUROC=0.719; P=0.0005). In conclusion, the results of the present study suggest that the use of LSPS and LSPGS may complement current methods of diagnosing significant liver fibrosis and cirrhosis in patients with CHB.

A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

PubMed Central

Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

2016-01-01

Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

PubMed Central

Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

2014-01-01

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

Tranilast prevents renal interstitial fibrosis by blocking mast cell infiltration in a rat model of diabetic kidney disease.

PubMed

Yin, Dan-Dan; Luo, Jun-Hui; Zhao, Zhu-Ye; Liao, Ying-Jun; Li, Ying

2018-05-01

Renal interstitial fibrosis is a final pathway that is observed in various types of kidney diseases, including diabetic kidney disease (DKD). The present study investigated the effect of tranilast on renal interstitial fibrosis and the association between its role and mast cell infiltration in a rat model of DKD. A total of 30 healthy 6‑week‑old male Sprague‑Dawley rats were randomly divided into the following four groups: Normal control group; DKD model group; low‑dose tranilast group (200 mg/kg/day); and high‑dose tranilast group (400 mg/kg/day). The morphological alterations of tubulointerstitial fibrosis were evaluated by Masson's trichrome staining, while mast cell infiltration into the renal tubular interstitium was measured by toluidine blue staining and complement C3a receptor 1 (C3aR) immunohistochemical staining (IHC). The expression of fibronectin (FN), collagen I (Col‑I), stem cell factor (SCF) and proto‑oncogene c‑kit (c‑kit) was detected by IHC, western blotting and reverse transcription‑quantitative‑polymerase chain reaction. The results demonstrated that tubulointerstitial fibrosis and mast cell infiltration were observed in DKD model rats, and this was improved dose‑dependently in the tranilast treatment groups. The expression of FN, Col‑I, SCF and c‑kit mRNA and protein was upregulated in the tubulointerstitium of DKD model rats compared with the normal control rats, and tranilast inhibited the upregulated expression of these markers. Furthermore, the degree of SCF and c‑kit expression demonstrated a significant positive correlation with C3aR‑positive mast cells and the markers of renal interstitial fibrosis. The results of the present study indicate that mast cell infiltration may promote renal interstitial fibrosis via the SCF/c‑kit signaling pathway. Tranilast may prevent renal interstitial fibrosis through inhibition of mast cell infiltration mediated through the SCF/c-kit signaling pathway.

Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis

PubMed Central

Kimura, Kuniko; Iwano, Masayuki; Higgins, Debra F.; Yamaguchi, Yukinari; Nakatani, Kimihiko; Harada, Koji; Kubo, Atsushi; Akai, Yasuhiro; Rankin, Erinn B.; Neilson, Eric G.; Haase, Volker H.; Saito, Yoshihiko

2008-01-01

Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1α. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1α, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1α) histologically and used the anti-HIF-1α agent [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1α could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL−/− mice and in all VHL−/− mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1α appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment. PMID:18667485

A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

PubMed Central

Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi; Nishikawa, Taichiro; Soto-Gutierrez, Alejandro; Fox, Ira J.; Vodovotz, Yoram

2014-01-01

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis. PMID:25152891

The Medial Extra-Sellar Corridor to the Cavernous Sinus: Anatomic Description and Clinical Correlation.

PubMed

Theodosopoulos, Philip V; Cebula, Helene; Kurbanov, Almaz; Cabero, Arnau Benet; Osorio, Joseph A; Zimmer, Lee A; Froelich, Sebastien C; Keller, Jeffrey T

2016-12-01

The zenith of surgical interest in the cavernous sinus peaked in the 1980s, as evidenced by reports of 10 surgical triangles that could access the contents of the lateral sellar compartment (LSC). However, these transcranial approaches later became marginalized, first by radiosurgery's popularity and lower morbidity, and then by clinical potential of endoscopic corridors noted in several qualitative studies. Our anatomic study, taking a contemporary look at the medial extra-sellar corridor, gives a detailed qualitative-quantitative analysis for its use with increasingly popular endoscopic endonasal approaches to the cavernous sinus. In 20 cadaveric specimens, we re-examined the anatomic landmarks of the medial corridor into the LSC with qualitative descriptions and measurements. An illustrative case highlights a recurrent symptomatic pituitary adenoma that invaded the cavernous sinus approached through the medial corridor. The corridor's shape varied from tetrahedron to hexahedron. Comparing right and left sides, width averaged 3.6 ± 4.5 mm and 4.0 ± 4.4 mm, and height averaged 2.3 mm and 2.1 mm, respectively. About 35% of sides showed ample space for access into the cavernous sinus. Our case report of successful outcome lends support for the safety and efficacy of this endoscopic approach. Our re-examination of this particular surgical access into the LSC refines the understanding of the medial extra-sellar corridor as a main endoscopic access route to this compartment. Achieving safe access to the contents of the LSC, this 11th triangle is clinically relevant and potentially superior for select lesions in this region. Copyright © 2016 Elsevier Inc. All rights reserved.

Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture.

PubMed

Girard, Beatrice M; Merriam, Laura A; Tompkins, John D; Vizzard, Margaret A; Parsons, Rodney L

2013-11-15

Quantitative real-time PCR was used to test whether cavernous nerve injury leads to a decrease in major pelvic ganglia (MPG) neuronal nicotinic ACh receptor (nAChR) subunit and postsynaptic density (PSD)-93 transcript levels. Subunits α3, β4, and α7, commonly expressed in the MPG, were selected for analysis. After 72 h in explant culture, MPG transcript levels for α3, β4, α7, and PSD-93 were significantly depressed. Three days after cavernous nerve axotomy or crush in vivo, transcript levels for α3, β4, and PSD-93, but not for α7, were significantly depressed. Three days after dissection of the cavernous nerve free of underlying tissue and application of a 5-mm lateral stretch (manipulation), transcript levels for α3 and PSD-93 were also significantly decreased. Seven days after all three surgical procedures, α3 transcript levels remained depressed, but PSD-93 transcript levels were still decreased only after axotomy or nerve crush. At 30 days postsurgery, transcript levels for the nAChR subunits and PSD-93 had recovered. ACh-induced currents were significantly smaller in MPG neurons dissociated from 3-day explant cultured ganglia than from those recorded in neurons dissociated from acutely isolated ganglia; this observation provides direct evidence showing that a decrease in nAChR function was coincident with a decrease in nAChR subunit transcript levels. We conclude that a downregulation of nAChR subunit and PSD-93 expression after cavernous nerve injury, or even manipulation, could interrupt synaptic transmission within the MPG and thus contribute to the loss of neural control of urogenital organs after pelvic surgeries.

Surgical cannulation of the superior ophthalmic vein for the treatment of previously embolized cavernous sinus dural arteriovenous fistulas: serial studies and angiographic follow-up.

PubMed

Luo, Bin; Zhang, Xin; Duan, Chuan-Zhi; He, Xu-Ying; Li, Xi-Feng; Karuna, Tamrakar; Gu, Da-Qun; Long, Xiao-Ao; Li, Tie-Lin; Zhang, Shi-Zhong; Ke, Yi-Quan; Jiang, Xiao-Dan

2013-04-01

The purpose of this study was to evaluate the safety and efficacy of transorbital puncture for the retreatment of previously embolized cavernous sinus dural arteriovenous fistulas (DAVFs) via a superior ophthalmic vein (SOV) approach. During a 12-year period, 9 consecutive patients with previously embolized cavernous sinus DAVFs underwent retreatment via the transorbital SOV approach. All of the nine cases of previously embolized cavernous sinus DAVFs were successfully embolized. Clinical follow-ups were conducted in all nine cases at the duration of 17-141 months (61.22 ± 39.13 months). No recanalization occurred during the follow-up period. A subtle ptosis appeared in two patients and disappeared in one of the two cases after a 4-year follow-up. One patient suffered from paroxysmal positional vertigo and bruit for nearly 2 years after the treatment, but the follow-up angiography demonstrated no recurrence. One patient had persistent visual impairment caused by the initial venous stasis retinopathy. One patient with a history of a procedure-related transient decrease in visual acuity had it return to the normal level. The remaining four cases had clear improvement in the ocular symptoms and became completely asymptomatic during the follow-up period. No patient worsened or developed new symptoms. The approach of surgical cannulation of the SOV for the retreatment of previously embolized cavernous sinus DAVFs was proved feasible and efficient, especially when the transarterial and transfemoral venous approaches were inaccessible. However, if the SOV is not dilated enough or is located deeply in the orbit, transorbital venous puncture access may not be possible.

What is the origin of the arterial vascularization of the corpora cavernosa? A computer-assisted anatomic dissection study

PubMed Central

Diallo, Djibril; Zaitouna, Mazen; Alsaid, Bayan; Quillard, Jeannine; Droupy, Stéphane; Benoit, Gérard; Bessede, Thomas

2013-01-01

The purpose of this study was to identify the microscopic arterial vascularization of the corpora cavernosa (CC) of the penis using computer-assisted anatomic dissection (CAAD), determine the contribution of the different penile arteries towards this vascularization, detail the nature of cavernospongiosum shunts, and locate the anastomoses between these different arteries. Tissue specimens were taken from five donors who donated their bodies to science. The specimens were fixed in 10% formalin and sliced into a series of five 5-μm sections at intervals of 200 μm. The first section was stained with hematoxylin-eosin or Masson's trichrome and the second with anti-protein S100. The cavernous artery of the penis is not the only source of arterial vascularization of the CC. In four of the five cases studied, we found two to four perforating branches arising from the dorsal arteries of the penis that join up with the cavernous artery of the penis or that are solely responsible for the vascularization of the distal third of the penis. The bulbo-urethral and urethral arteries are situated outside of the tunica albuginea of the corpus spongiosum on their lateral and dorsal sides. The anastomoses do not occur between the cavernous artery of the penis and the corpus spongiosum but between the cavernous artery of the penis and the urethral artery on the surface of the tunica albuginea. All of these arteries are accompanied by nerve branches. The CC were found to be vascularized by both cavernous and dorsal arteries of the penis. Intrapenile vascularization is organized around four arterial axes, which are anastomosed by multiple neurovascular shunts. PMID:23981086

Severe progressive scoliosis due to huge subcutaneous cavernous hemangioma: A case report

PubMed Central

2011-01-01

Cavernous hemangioma consists mainly of congenital vascular malformations present before birth and gradually increasing in size with skeletal growth. A small number of patients with cavernous hemangioma develop scoliosis, and surgical treatment for the scoliosis in such cases has not been reported to date. Here we report a 12-year-old male patient with severe progressive scoliosis due to a huge subcutaneous cavernous hemangioma, who underwent posterior correction and fusion surgery. Upon referral to our department, radiographs revealed a scoliosis of 85° at T6-L1 and a kyphosis of 58° at T4-T10. CT and MR images revealed a huge hemangioma extending from the subcutaneous region to the paraspinal muscles and the retroperitoneal space and invading the spinal canal. Posterior correction and fusion surgery using pedicle screws between T2 and L3 were performed. Massive hemorrhage from the hemangioma occurred during the surgery, with intraoperative blood loss reaching 2800 ml. The scoliosis was corrected to 59°, and the kyphosis to 45° after surgery. Seven hours after surgery, the patient suffered from hypovolemic shock and disseminated intravascular coagulation due to postoperative hemorrhage from the hemangioma. The patient developed sensory and conduction aphasia caused by cerebral hypoxia during the shock on the day of the surgery. At present, two years after the surgery, although the patient has completely recovered from the aphasia. This case illustrates that, in correction surgery for scoliosis due to huge subcutaneous cavernous hemangioma, intraoperative and postoperative intensive care for hemodynamics should be performed, since massive hemorrhage can occur during the postoperative period as well as the intraoperative period. PMID:21414205

Potential effects of recurrent low oxygen conditions on the Illinois Cave amphipod

USGS Publications Warehouse

Panno, S.V.; Hackley, Keith C.; Kelly, W.R.; Hwang, H.-H.; Wilhelm, F.M.; Taylor, S.J.; Stiff, B.J.

2006-01-01

The caves of Illinois' sinkhole plain are the sole habitat of the Illinois Cave amphipod (Gammarus acherondytes), a federally endangered species. The sinkhole plain is a hydrologically-connected sequence of karstified limestone that constitutes an extensive karst aquifer which serves as an important source of potable water for area residents. During this investigation, we examined the ground-water quality in caves within two ground-water basins: 1) Illinois Caverns, where the amphipod is now present after previously reported to have been extirpated from the lower reaches, and 2) Stemler Cave, where the amphipod is reported to have been extirpated. The chemical composition of cave streams in Illinois Caverns and Stemler Cave were compared to determine which parameters, if any, could have contributed to the loss of G. acherondytes from Stemler Cave. Stream water in Stemler Cave contained higher concentrations of organic carbon, potassium, silica, chloride, fluoride, sulfate, iron and manganese than Illinois Caverns. Perhaps most importantly, dissolved oxygen (DO) concentrations in Stemler Cave were, during periods of low flow, substantially lower than in Illinois Caverns. Based on land use, there are probably at least eight times more private septic systems in the Stemler Cave ground-water basin than in the Illinois Caverns ground-water basin. Low DO concentrations were likely the result of microbial breakdown of soil organic matter and wastewater treatment system effluent, and the oxidation of pyrite in bedrock. The near-hypoxic DO in Stemler Cave that occurred during low-flow conditions, and, we speculate, a limited range of G. acherondytes within the Stemler Cave ground-water basin due to a metabolic advantage of the stygophilic aquatic invertebrates over the stygobitic G. acherodytes, resulted in the apparent loss of G. acherondytes from Stemler Cave.

Automated evaluation of liver fibrosis in thioacetamide, carbon tetrachloride, and bile duct ligation rodent models using second-harmonic generation/two-photon excited fluorescence microscopy.

PubMed

Liu, Feng; Chen, Long; Rao, Hui-Ying; Teng, Xiao; Ren, Ya-Yun; Lu, Yan-Qiang; Zhang, Wei; Wu, Nan; Liu, Fang-Fang; Wei, Lai

2017-01-01

Animal models provide a useful platform for developing and testing new drugs to treat liver fibrosis. Accordingly, we developed a novel automated system to evaluate liver fibrosis in rodent models. This system uses second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy to assess a total of four mouse and rat models, using chemical treatment with either thioacetamide (TAA) or carbon tetrachloride (CCl 4 ), and a surgical method, bile duct ligation (BDL). The results obtained by the new technique were compared with that using Ishak fibrosis scores and two currently used quantitative methods for determining liver fibrosis: the collagen proportionate area (CPA) and measurement of hydroxyproline (HYP) content. We show that 11 shared morphological parameters faithfully recapitulate Ishak fibrosis scores in the models, with high area under the receiver operating characteristic (ROC) curve (AUC) performance. The AUC values of 11 shared parameters were greater than that of the CPA (TAA: 0.758-0.922 vs 0.752-0.908; BDL: 0.874-0.989 vs 0.678-0.966) in the TAA mice and BDL rat models and similar to that of the CPA in the TAA rat and CCl 4 mouse models. Similarly, based on the trends in these parameters at different time points, 9, 10, 7, and 2 model-specific parameters were selected for the TAA rats, TAA mice, CCl 4 mice, and BDL rats, respectively. These parameters identified differences among the time points in the four models, with high AUC accuracy, and the corresponding AUC values of these parameters were greater compared with those of the CPA in the TAA rat and mouse models (rats: 0.769-0.894 vs 0.64-0.799; mice: 0.87-0.93 vs 0.739-0.836) and similar to those of the CPA in the CCl 4 mouse and BDL rat models. Similarly, the AUC values of 11 shared parameters and model-specific parameters were greater than those of HYP in the TAA rats, TAA mice, and CCl 4 mouse models and were similar to those of HYP in the BDL rat models. The automated evaluation system, combined with 11 shared parameters and model-specific parameters, could specifically, accurately, and quantitatively stage liver fibrosis in animal models.

Routine blood tests to predict liver fibrosis in chronic hepatitis C.

PubMed

Hsieh, Yung-Yu; Tung, Shui-Yi; Lee, Kamfai; Wu, Cheng-Shyong; Wei, Kuo-Liang; Shen, Chien-Heng; Chang, Te-Sheng; Lin, Yi-Hsiung

2012-02-28

To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C, compared with other noninvasive tests. This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), AST to platelet ratio index, cirrhosis discriminant score, age-platelet index (API), Pohl score, FIB-4 index, and Lok's model were calculated and compared. FibroQ, FIB-4, AAR, API and Lok's model results increased significantly as fibrosis advanced (analysis of variance test: P < 0.001). FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests. FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

Basic mechanisms and clinical implications of peritoneal fibrosis.

PubMed

Margetts, Peter J; Bonniaud, Philippe

2003-01-01

We have stressed the role of certain growth factors and cytokines in peritoneal fibrosis, including TGFbeta, TIMP-1, and inflammatory cytokines, especially IL-1beta. Recent research highlights the myofibroblast-like transformation of mesothelial cells as a central initiating event in peritoneal fibrosis. The induction, survival, and apoptosis of the myofibroblast cell population likely dictate the nature of the fibrogenic response. The accumulation of collagen occurs in a nondegradative environment, and collagenases and their inhibitors have a role in the maintenance of fibrosis. Fibrosis appears to be a ubiquitous response of peritoneal tissues to the damaging effects of uremia, bioincompatible dialysate, recurrent infection, and inflammation. Recent research has focused on the induction of angiogenesis, as this appears to correlate with increased solute transport and peritoneal membrane ultrafiltration failure. Fibrosis may play an integral part in peritoneal membrane dysfunction in several aspects. Angiogenesis may be induced as part of the fibrotic response, as many key fibrogenic cytokines are also strongly angiogenic. Fibrotic tissue may support and preserve angiogenesis. Changes in the interstitium may have a direct effect on the hydrodynamic properties of the peritoneum and may directly influence fluid movement. In its most extreme form, fibrosis manifests as the rare but devastating EPS. Peritoneal biopsy studies have identified a high prevalence of peritoneal fibrosis in PD patients. Research into peritoneal fibrosis will be enhanced by new animal models where the role of various cytokines and growth factors, cellular processes, and matrix interactions can be studied. With these models, the role of fibrosis in alteration of peritoneal membrane function can be better assessed. Clinical trials to assess the role of prevention of peritoneal injury using biocompatible solutions and treatments targeted directly at peritoneal fibrosis will be important, but challenging to design and carry out.

Natural gas storage in bedded salt formations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macha, G.

1996-09-01

In 1990 Western Resources Inc. (WRI) identified the need for additional natural gas storage capacity for its intrastate natural gas system operated in the state of Kansas. Western Resources primary need was identified as peak day deliverability with annual storage balancing a secondary objective. Consequently, an underground bedded salt storage facility, Yaggy Storage Field, was developed and placed in operation in November 1993. The current working capacity of the new field is 2.1 BCF. Seventy individual caverns are in service on the 300 acre site. The caverns vary in size from 310,000 CF to 2,600,000 CF. Additional capacity can bemore » added on the existing acreage by increasing the size of some of the smaller existing caverns by further solution mining and by development of an additional 30 potential well sites on the property.« less

[Cavernous sinus thrombosis as a rare cause of exophthalmos in childhood : A case report].

PubMed

Kamawal, A; Schmidt, M A; Rompel, O; Gusek-Schneider, G C; Mardin, C Y; Trollmann, R

2017-05-01

Complications of acute bacterial sinusitis mostly occur in children and adolescents. In particular, intracranial spread of the infection can lead to severe even fatal courses of the disease. This article is a case report about a 13-year-old boy suffering from left-sided headache, meningismus and exophthalmos as presenting symptoms. Cranial magnetic resonance imaging (MRI) showed merely right-sided sphenoid sinusitis; however, the diffusion-weighted MRI sequence indicated a left-sided cavernous sinus thrombosis, which could be confirmed by computed tomography (CT) angiography. Cerebrospinal fluid diagnostics showed significant leukocytosis confirming secondary meningitis. Finally, exophthalmos was explained by parainfectious cavernous sinus thrombosis and periorbital edema. This case report highlights the importance of extended and specific diagnostic imaging in cases of clinically suspected complications in children and adolescents with sinusitis and the diagnostic significance of diffusion-weighted MRI.

Spinal extradural cavernous haemangioma in an elderly man

PubMed Central

Rahman, Asifur; Hoque, Saif Ul; Bhandari, Paawan Bahadur; Abu Obaida, Abu Saleh Md

2012-01-01

Cavernous haemangiomas are vascular malformations that may affect any part of the central nervous system. Epidural haemangiomas are rare and constitute ∼4% of all epidural tumours and 12% of all intraspinal haemangiomas. These tumours enlarge slowly and produce symptoms of progressive myelopathy or radiculopathy or both. History, clinical examination, routine radiographs, MRI and histopathological studies are the aids for a definitive diagnosis. Surgery can give a very beneficial result with good functional and neurological improvement. Chance of recurrence is less after a good surgical removal. Here we present a case of spinal extradural cavernous haemangioma in a 65- year-old man who had a good functional and neurological recovery after surgery. At 9 months postoperative follow-up, he did well without any new problems with regard to recurrence. We report this case for its rarity. PMID:22878996

Trigemino-cardiac reflex: occurrence of asystole during trans-sphenoidal adenomectomy: a case report.

PubMed

Jeon, Dae Geun; Kang, Bong Jin; Hur, Tae Won

2014-09-01

The trigemino-cardiac reflex has been reported to occur during various craniofacial surgeries or procedures including manipulation of the trigeminal ganglion, tumor resection in the cerebellopontine angle, various facial reconstructions and trans-sphenoidal adenomectomy. Regarding risk factors during trans-sphenoidal adenomectomy, invasiveness closely related to the size of tumor and the degree of manipulation of cavernous sinus wall have been reported. We report the case of a 40-year-old female patient who had a relatively small-sized (< 10 mm) pituitary adenoma. Repetitive asystoles occurred during microscopic trans-sphenoidal operation of the wall of the cavernous sinus, which strongly suggests the importance of careful manipulation of the cavernous sinus wall. In addition to reporting this rare complication of trans-sphenoidal adenomectomy, we reviewed its clinical management by performing a literature search.

The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

PubMed Central

Knipe, Rachel S.; Tager, Andrew M.

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond. PMID:25395505

Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice

PubMed Central

Choi, Jaesung P.; Foley, Matthew; Zhou, Zinan; Wong, Weng-Yew; Gokoolparsadh, Naveena; Arthur, J. Simon C.; Li, Dean Y.; Zheng, Xiangjian

2016-01-01

Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5μm (leading to a minimum feature size of approximately 25μm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high-resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases. PMID:27513872

Losartan Administration Reduces Fibrosis but Hinders Functional Recovery after Volumetric Muscle Loss Injury

DTIC Science & Technology

2014-09-25

therapy. Pre - viously, losartan has been successfully used to reduce fibrosis and improve both muscle regeneration and function in several models of...efficacy of losartan has not yet been tested in a VML injury model. VML injury involves a substantial loss of muscle tissue that does not regenerate by...fibrosis development after VML injury in the rat tibialis anterior (TA) muscle. METHODS Experimental Design Male Lewis rats with VML were provided access

Dumbbell-Shaped Epidural Cavernous Hemangioma in the Thoracic Spine Mimicking Schwannoma.

PubMed

Wang, Shantao; Wang, Mingwei; Wang, Fuchao; Yuan, Xunhui; Xiao, Hang; Bai, Yun'an; Liu, Fucun

2016-10-01

Dumbbell-shaped epidural cavernous hemangiomas (CHs) are extremely rare, and they are easily misdiagnosed as spinal schwannomas. Herein, the authors report 1 rare case of dumbbell-shaped epidural CH in the thoracic spine. To the best of our knowledge, only a few cases of dumbbell-shaped epidural CHs in thoracic spine have been reported. Furthermore, the clinical characteristics and treatments for spinal epidural CHs were investigated and reviewed.

Congenital intraosseous cavernous hemangioma of the skull: an unusual case.

PubMed

Rumana, Makhdoomi; Khursheed, Nayil; Farhat, Mustafa; Othman, Salim; Masood, Laharwal

2013-01-01

Intraosseous hemangiomas are benign vascular malformations mostly seen in the spine. They rarely occur in the skull. The usual age-group involved is the 2nd to 4th decades, and females outnumber males. We hereby report a rare case of congenital intraosseous cavernous hemangioma of the skull bone in a male infant. The patient underwent total excision of the lesion. © 2014 S. Karger AG, Basel.

Fatal Peritoneal Bleeding Following Embolization of a Carotid-Cavernous Fistula in Ehlers-Danlos Syndrome Type IV

DOE Office of Scientific and Technical Information (OSTI.GOV)

Usinskiene, Jurgita; Mazighi, Mikael; Bisdorff, Annouk

2006-12-15

We report the case of a 25-year-old woman treated for a spontaneous carotid-cavernous fistula in a context of Ehlers-Danlos syndrome type IV. Embolization with a transvenous approach was achieved without complications; however, the patient died 72 hr later of massive intraperitoneal bleeding. At autopsy, no lesion of the digestive arteries was identified. Possible causes of this bleeding are discussed.

Noninvasive Classification of Hepatic Fibrosis Based on Texture Parameters From Double Contrast-Enhanced Magnetic Resonance Images

PubMed Central

Bahl, Gautam; Cruite, Irene; Wolfson, Tanya; Gamst, Anthony C.; Collins, Julie M.; Chavez, Alyssa D.; Barakat, Fatma; Hassanein, Tarek; Sirlin, Claude B.

2016-01-01

Purpose To demonstrate a proof of concept that quantitative texture feature analysis of double contrast-enhanced magnetic resonance imaging (MRI) can classify fibrosis noninvasively, using histology as a reference standard. Materials and Methods A Health Insurance Portability and Accountability Act (HIPAA)-compliant Institutional Review Board (IRB)-approved retrospective study of 68 patients with diffuse liver disease was performed at a tertiary liver center. All patients underwent double contrast-enhanced MRI, with histopathology-based staging of fibrosis obtained within 12 months of imaging. The MaZda software program was used to compute 279 texture parameters for each image. A statistical regularization technique, generalized linear model (GLM)-path, was used to develop a model based on texture features for dichotomous classification of fibrosis category (F ≤2 vs. F ≥3) of the 68 patients, with histology as the reference standard. The model's performance was assessed and cross-validated. There was no additional validation performed on an independent cohort. Results Cross-validated sensitivity, specificity, and total accuracy of the texture feature model in classifying fibrosis were 91.9%, 83.9%, and 88.2%, respectively. Conclusion This study shows proof of concept that accurate, noninvasive classification of liver fibrosis is possible by applying quantitative texture analysis to double contrast-enhanced MRI. Further studies are needed in independent cohorts of subjects. PMID:22851409

Artificial neural network aided non-invasive grading evaluation of hepatic fibrosis by duplex ultrasonography

PubMed Central

2012-01-01

Background Artificial neural networks (ANNs) are widely studied for evaluating diseases. This paper discusses the intelligence mode of an ANN in grading the diagnosis of liver fibrosis by duplex ultrasonogaphy. Methods 239 patients who were confirmed as having liver fibrosis or cirrhosis by ultrasound guided liver biopsy were investigated in this study. We quantified ultrasonographic parameters as significant parameters using a data optimization procedure applied to an ANN. 179 patients were typed at random as the training group; 60 additional patients were consequently enrolled as the validating group. Performance of the ANN was evaluated according to accuracy, sensitivity, specificity, Youden’s index and receiver operating characteristic (ROC) analysis. Results 5 ultrasonographic parameters; i.e., the liver parenchyma, thickness of spleen, hepatic vein (HV) waveform, hepatic artery pulsatile index (HAPI) and HV damping index (HVDI), were enrolled as the input neurons in the ANN model. The sensitivity, specificity and accuracy of the ANN model for quantitative diagnosis of liver fibrosis were 95.0%, 85.0% and 88.3%, respectively. The Youden’s index (YI) was 0.80. Conclusions The established ANN model had good sensitivity and specificity in quantitative diagnosis of hepatic fibrosis or liver cirrhosis. Our study suggests that the ANN model based on duplex ultrasound may help non-invasive grading diagnosis of liver fibrosis in clinical practice. PMID:22716936

The “Endothelialized Muscularis Mucosae”: A Case Report Describing a Large Cavernous Hemangioma at the Terminal Ileum and a New Histologic Clue for Preoperative Diagnosis from Endoscopic Biopsy

PubMed Central

Purdy-Payne, Erin K.; Miner, Jean F.; Foles, Brandon; Tran, Tien-Anh N.

2015-01-01

Cavernous hemangiomas of the gastrointestinal tract are quite rare and, until now, have been difficult to diagnose preoperatively due their nonspecific presentations and imaging features, as well as a lack of histologic description pertaining to small superficial biopsies such as those obtained endoscopically. We report a unique case of a 4 cm transmural cavernous hemangioma in the terminal ileum with literature review and describe a new histologic finding—the “endothelialized muscularis mucosae,” which was discovered upon review of the endoscopic biopsy and could potentially facilitate preoperative diagnosis of these lesions from endoscopic biopsies in the future. These lesions have classically required surgical resection in order to make a definitive diagnosis and rule out malignancy, with which they share many historical and radiographic features. Due to their potential to cause bowel obstruction, intussusception, perforation, and hemorrhage, these lesions may ultimately require surgical resection to relieve symptoms or prevent or treat complications—however, surgical planning and patient counseling could be greatly improved by a preoperative diagnosis. Therefore, gastroenterologists, pathologists, and surgeons should be aware of the “endothelialized muscularis mucosae” which can be very helpful in diagnosing GI cavernous hemangiomas from endoscopic biopsies. PMID:26442160

Evaluation of Computational Method of High Reynolds Number Slurry Flow for Caverns Backfilling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bettin, Giorgia

2015-05-01

The abandonment of salt caverns used for brining or product storage poses a significant environmental and economic risk. Risk mitigation can in part be address ed by the process of backfilling which can improve the cavern geomechanical stability and reduce the risk o f fluid loss to the environment. This study evaluate s a currently available computational tool , Barracuda, to simulate such process es as slurry flow at high Reynolds number with high particle loading . Using Barracuda software, a parametric sequence of simu lations evaluated slurry flow at Re ynolds number up to 15000 and loading up tomore » 25%. Li mitations come into the long time required to run these simulation s due in particular to the mesh size requirement at the jet nozzle. This study has found that slurry - jet width and centerline velocities are functions of Re ynold s number and volume fractio n The solid phase was found to spread less than the water - phase with a spreading rate smaller than 1 , dependent on the volume fraction. Particle size distribution does seem to have a large influence on the jet flow development. This study constitutes a first step to understand the behavior of highly loaded slurries and their ultimate application to cavern backfilling.« less

Coexistence of splenic hemangioma and vascular malformation of the vertebrae.

PubMed

Jalaeikhoo, Hasan; Ariana, Mehdi; Kashfi, Seyed Mohammad Hossein; Azimzadeh, Pedram; Narimani, Ahmad; Dadpay, Masoomeh; Keyhani, Manouchehr

2016-02-09

Cavernous hemangioma is an encapsulated mass of dilated, endothelial lined vascular channels filled with slowly flowing blood. Cavernous hemangioma of the spleen is a rare condition with less than 100 reports so far. Hemangioma of the vertebral is a benign vascular legion around one or two vertebrae. These are usually asymptomatic and discovered incidentally. In this study we reported an extreme rare case of splenic hemangioma coexistence with vascular malformation of the vertebrae. To our knowledge this is the first report of coexistence of splenic hemangioma and hemangioma of the vertebra. A 20-year-old iranian male with splenomegaly, abdominal pain, diarrhea and pancytopenia who was first highly suspicious for malignancy referred to our center for evaluation of the diagnostic workup. After full examination we detected a very rare case with a giant, solitary cavernous hemangioma of the spleen and multiple hemangiomas in his vertebrae. Histopathology of the spleen showed a large cavernous hemangioma occupying almost the entire spleen with large areas of infarction necrosis with multiple hemangiomas of the vertebrae. It is extremely rare to have a splenic hemangioma concurrent with vertebra hemangioma and this is clinically very important to consider splenic hemangioma in differential diagnosis of splenomegaly for a better therapeutic management in related patients.

Pythium Keratitis Leading to Fatal Cavernous Sinus Thrombophlebitis.

PubMed

Rathi, Anubha; Chakrabarti, Arunaloke; Agarwal, Tushar; Pushker, Neelam; Patil, Mukesh; Kamble, Hemant; Titiyal, Jeewan S; Mohan, Rishi; Kashyap, Seema; Sharma, Sanjay; Sen, Seema; Satpathy, Gita; Sharma, Namrata

2018-04-01

To report a case of Pythium insidiosum keratitis leading to fatal cavernous sinus thrombophlebitis. Case report. A 70-year-old man presented with excruciating pain, redness, and diminution of vision in his left eye for 2 weeks after washing his hair with tap water. A total corneal ulcer with surrounding infiltrates and associated corneal thinning was present. Corneal scraping revealed the presence of Gram-positive cocci. KOH wet mount and in vivo confocal microscopy revealed branching hyphae. Combined antibacterial and antifungal treatment was started, but 4 days later, the ulcer showed signs of worsening with perforation for which a large therapeutic penetrating keratoplasty was done. The host cornea showed branching septate hyphae on Sabarouds Dextrose Agar. Two weeks later, the patient developed left eye proptosis with associated extraocular movement restriction. Magnetic resonance imaging of the head and orbit revealed cavernous sinus thrombophlebitis. Lid sparing partial exenteration was performed. Polymerase chain reaction revealed P. insidiosum. The patient subsequently developed a cerebrovascular attack and died of its complications. Ocular pythiosis may lead to cavernous sinus thrombophlebitis and can even be life threatening. Timely diagnosis and early radical surgery are of value. A high index of suspicion must be kept for P. insidiosum in cases with suspected fungal etiology not responding to conventional treatment.

Halofuginone can worsen liver fibrosis in bile duct obstructed rats.

PubMed

Van de Casteele, Marc; Roskams, Tania; Van der Elst, Ingrid; van Pelt, Jos F; Fevery, Johan; Nevens, Frederik

2004-10-01

Halofuginone (HF) is an antifibrotic agent in rat models of liver fibrosis caused by repetitive intoxications. A beneficial effect of HF on a biliary type of liver fibrosis has not been proven yet. Bile duct-obstructed rats were given HF from the moment of obstruction onwards and compared with no treatment. After 3 weeks, respectively, 6 weeks, aminopyrine breath test (ABT) and haemodynamic measurements including of portal pressure were carried out. Liver pieces were taken for Sirius red quantitative scoring, as well as for semiquantitative determinations of collagen type I and III RNA levels. ABT was significantly worse in HF-treated rats as compared with no treatment (P=0.02). Haemodynamic data and collagen type I and III determinations were not significantly different between groups. Biliary fibrosis scores were significantly higher in HF-treated rats as compared with no treatment (P=0.03). More Sirius red staining was associated with more proliferation of bile ductules. HF may worsen biliary fibrosis. This contrasts sharply with antifibrotic effects in other models of liver fibrosis. Distinctive cellular mechanisms in biliary fibrosis may explain this discrepancy. One should be cautious for chronic application of HF in man with cholestasis.

Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function.

PubMed

Elinav, Eran; Ali, Mohammad; Bruck, Rafi; Brazowski, Eli; Phillips, Adam; Shapira, Yami; Katz, Meirav; Solomon, Gila; Halpern, Zamir; Gertler, Arieh

2009-01-01

Leptin signaling is involved in T-cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin-deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long-standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly-isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5-week to 8-week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon gamma (IFN-gamma) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin-stimulated effects such as increased expression of alpha-smooth muscle actin (alpha-SMA), and activation of alpha1 procollagen promoter. Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.

IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

EPA Science Inventory

Abstract
Idiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway.

PubMed

Hongtao, Chen; Youling, Fan; Fang, Huang; Huihua, Peng; Jiying, Zhong; Jun, Zhou

2018-05-09

As a major cause of renal failure, transient renal ischemia and reperfusion induce both acute kidney injury and late fibrosis, which are the common pathological manifestations of end-stage renal disease. Curcumin is a biologically active polyphenolic compound found in turmeric. Increasing evidence has demonstrated that curcumin has a protective action against renal fibrosis, whereas mechanisms underlying the anti-fibrosis role of curcumin remain poorly defined. Here, we found that APPL1, an important intracellular binding partner for AdipoR, was involved in the pathogenesis of acute injury or fibrosis and was significantly upregulated by curcumin in a mouse model of ischemia reperfusion-induced late kidney fibrosis. Moreover, Akt signaling was the specific signaling pathway identified downstream of APPL1 in the pathogenesis of fibrosis. Our in vitro experiment demonstrated that curcumin alleviates ischemia reperfusion-induced late kidney fibrosis via the APPL1/Akt pathway. These data are helpful for understanding the anti-fibrosis mechanism of curcumin in the pathogenesis of AKI-induced late fibrosis. © 2018 Wiley Periodicals, Inc.

Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD.

PubMed

Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A; Kleiner, David; Brunt, Elizabeth M; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James; Loomba, Rohit

2015-07-01

Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m(2), respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75-0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76-0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effect of Non-speckle Echo Signals on Tissue Characteristics for Liver Fibrosis using Probability Density Function of Ultrasonic B-mode image

NASA Astrophysics Data System (ADS)

Mori, Shohei; Hirata, Shinnosuke; Yamaguchi, Tadashi; Hachiya, Hiroyuki

To develop a quantitative diagnostic method for liver fibrosis using an ultrasound B-mode image, a probability imaging method of tissue characteristics based on a multi-Rayleigh model, which expresses a probability density function of echo signals from liver fibrosis, has been proposed. In this paper, an effect of non-speckle echo signals on tissue characteristics estimated from the multi-Rayleigh model was evaluated. Non-speckle signals were determined and removed using the modeling error of the multi-Rayleigh model. The correct tissue characteristics of fibrotic tissue could be estimated with the removal of non-speckle signals.

The diagnostic performance of shear-wave elastography for liver fibrosis in children and adolescents: A systematic review and diagnostic meta-analysis.

PubMed

Kim, Jeong Rye; Suh, Chong Hyun; Yoon, Hee Mang; Lee, Jin Seong; Cho, Young Ah; Jung, Ah Young

2018-03-01

To assess the diagnostic performance of shear-wave elastography for determining the severity of liver fibrosis in children and adolescents. An electronic literature search of PubMed and EMBASE was conducted. Bivariate modelling and hierarchical summary receiver-operating-characteristic modelling were performed to evaluate the diagnostic performance of shear-wave elastography. Meta-regression and subgroup analyses according to the modality of shear-wave imaging and the degree of liver fibrosis were also performed. Twelve eligible studies with 550 patients were included. Shear-wave elastography showed a summary sensitivity of 81 % (95 % CI: 71-88) and a specificity of 91 % (95 % CI: 83-96) for the prediction of significant liver fibrosis. The number of measurements of shear-wave elastography performed was a significant factor influencing study heterogeneity. Subgroup analysis revealed shear-wave elastography to have an excellent diagnostic performance according to each degree of liver fibrosis. Supersonic shear imaging (SSI) had a higher sensitivity (p<.01) and specificity (p<.01) than acoustic radiation force impulse imaging (ARFI). Shear-wave elastography is an excellent modality for the evaluation of the severity of liver fibrosis in children and adolescents. Compared with ARFI, SSI showed better diagnostic performance for prediction of significant liver fibrosis. • Shear-wave elastography is beneficial for determining liver fibrosis severity in children. • Shear-wave elastography showed summary sensitivity of 81 %, specificity of 91 %. • SSI showed better diagnostic performance than ARFI for significant liver fibrosis.

A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhir

Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl{sub 4})-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl{sub 4} (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day formore » 3 weeks) and with continued CCl{sub 4}. We observed that combined treatment with CCl{sub 4} and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis.« less

Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

PubMed Central

2014-01-01

Background Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies. Methods We developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice. Results These strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma. Conclusions We have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration. PMID:25157321

Experimental liver fibrosis research: update on animal models, legal issues and translational aspects

PubMed Central

2013-01-01

Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research. PMID:24274743

Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B

PubMed Central

Cheng, Jieyao; Hou, Jinlin; Ding, Huiguo; Chen, Guofeng; Xie, Qing; Wang, Yuming; Zeng, Minde; Ou, Xiaojuan; Ma, Hong; Jia, Jidong

2015-01-01

Background and Aims Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients. Methods The diagnostic performance of ten noninvasive models (HALF index, FibroScan, S index, Zeng model, Youyi model, Hui model, APAG, APRI, FIB-4 and FibroTest) was assessed against the liver histology by ROC curve analysis in CHB patients. The reproducibility of the ten models were evaluated by recalculating the diagnostic values at the given cut-off values defined by the original studies. Results Six models (HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest) had AUROCs higher than 0.70 in predicting any fibrosis stage and 2 of them had best diagnostic performance with AUROCs to predict F≥2, F≥3 and F4 being 0.83, 0.89 and 0.89 for HALF index, 0.82, 0.87 and 0.87 for FibroScan, respectively. Four models (HALF index, FibroScan, Zeng model and Youyi model) showed good diagnostic values at given cut-offs. Conclusions HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest show a good diagnostic performance and all of them, except S index and FibroTest, have good reproducibility for evaluating liver fibrosis in CHB patients. Registration Number ChiCTR-DCS-07000039. PMID:26709706

Noninvasive imaging of experimental lung fibrosis.

PubMed

Zhou, Yong; Chen, Huaping; Ambalavanan, Namasivayam; Liu, Gang; Antony, Veena B; Ding, Qiang; Nath, Hrudaya; Eary, Janet F; Thannickal, Victor J

2015-07-01

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.

Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

PubMed

Kim, Kyung-Hyun; Sung, Hyun-Jung; Lee, Woo-Ram; An, Hyun-Jin; Kim, Jung-Yeon; Pak, Sok Cheon; Han, Sang-Mi; Park, Kwan-Kyu

2015-08-25

Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice

PubMed Central

Kim, Kyung-Hyun; Sung, Hyun-Jung; Lee, Woo-Ram; An, Hyun-Jin; Kim, Jung-Yeon; Pak, Sok Cheon; Han, Sang-Mi; Park, Kwan-Kyu

2015-01-01

Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy. PMID:26308055

Refractory seizures due to a dural-based cavernoma masquerading as a meningioma.

PubMed

Zeng, Xianwei; Mahta, Ali; Kim, Ryan Y; Saad, Ali G; Kesari, Santosh

2012-04-01

A 37-year-old female presented with medically intractable complex partial seizures with secondary generalization. She was found to have a dural-based lesion with radiologic features of meningioma. A gross total resection was performed and pathology confirmed a diagnosis of cavernous angioma and she became seizure free after the surgical resection. Cavernous angioma should be considered in differential diagnosis of a dural-based lesion manifesting with refractory seizures.

Asymptotic solution of the problem for a thin axisymmetric cavern

NASA Technical Reports Server (NTRS)

Serebriakov, V. V.

1973-01-01

The boundary value problem which describes the axisymmetric separation of the flow around a body by a stationary infinite stream is considered. It is understood that the cavitation number varies over the length of the cavern. Using the asymptotic expansions for the potential of a thin body, the orders of magnitude of terms in the equations of the problem are estimated. Neglecting small quantities, a simplified boundary value problem is obtained.

Study on Excavation of Particular Part of Underground Cavern for Hydropower Station

NASA Astrophysics Data System (ADS)

Yang, Yang; Zhang, Feng; Shang, Qin; Zheng, Huakang

2018-01-01

In the present study, regarding four particular parts of underground cavern for hydropower station, i.e., crown, high sidewall, the intersection between high sidewall and tunnel and tailrace tunnel, by summarizing the previous construction experience, we have proposed the excavation approach based on “middle first and edge later, soft first and hard later”, “layered construction by excavating the thin layer first and supporting as the layer advances”, “tunnel first and wall later, small tunnels into large ones” and “excavating tunnels supported by separation piers”. In addition, the proposed excavation approach has been analyzed and verified with finite element numerical simulation. The result has indicated that the proposed special approach is reasonable and effective to reduce the turbulence on surrounding rocks, lower the influence of unloading during excavating and enhance the local and global stability of caverns and surrounding rocks.

Cataract surgery in a case of carotid cavernous fistula

PubMed Central

Nair, Akshay Gopinathan; Praveen, Smita Vittal; Noronha, Veena Olma

2014-01-01

A carotid-cavernous fistula (CCF) is an abnormal communication between the cavernous sinus and the carotid arterial system. The ocular manifestations include conjunctival chemosis, proptosis, globe displacement, raised intraocular pressure and optic neuropathy. Although management of CCF in these patients is necessary, the ophthalmologist may also have to treat other ocular morbidities such as cataract. Cataract surgery in patients with CCF may be associated with many possible complications, including suprachoroidal hemorrhage. We describe cataract extraction surgery in 60-year-old female with bilateral spontaneous low-flow CCF. She underwent phacoemulsification via a clear corneal route under topical anesthesia and had an uneventful postoperative phase and recovered successfully. Given the various possible ocular changes in CCF, one must proceed with an intraocular surgery with caution. In this communication, we wish to describe the surgical precautions and the possible pitfalls in cataract surgery in patients with CCF. PMID:25370401

Evaluation of the biomarker candidate MFAP4 for non-invasive assessment of hepatic fibrosis in hepatitis C patients.

PubMed

Bracht, Thilo; Mölleken, Christian; Ahrens, Maike; Poschmann, Gereon; Schlosser, Anders; Eisenacher, Martin; Stühler, Kai; Meyer, Helmut E; Schmiegel, Wolff H; Holmskov, Uffe; Sorensen, Grith L; Sitek, Barbara

2016-07-04

The human microfibrillar-associated protein 4 (MFAP4) is located to extracellular matrix fibers and plays a role in disease-related tissue remodeling. Previously, we identified MFAP4 as a serum biomarker candidate for hepatic fibrosis and cirrhosis in hepatitis C patients. The aim of the present study was to elucidate the potential of MFAP4 as biomarker for hepatic fibrosis with a focus on the differentiation of no to moderate (F0-F2) and severe fibrosis stages and cirrhosis (F3 and F4, Desmet-Scheuer scoring system). MFAP4 levels were measured using an AlphaLISA immunoassay in a retrospective study including n = 542 hepatitis C patients. We applied a univariate logistic regression model based on MFAP4 serum levels and furthermore derived a multivariate model including also age and gender. Youden-optimal cutoffs for binary classification were determined for both models without restrictions and considering a lower limit of 80 % sensitivity (correct classification of F3 and F4), respectively. To assess the generalization error, leave-one-out cross validation (LOOCV) was performed. MFAP4 levels were shown to differ between no to moderate fibrosis stages F0-F2 and severe stages (F3 and F4) with high statistical significance (t test on log scale, p value <2.2·10(-16)). In the LOOCV, the univariate classification resulted in 85.8 % sensitivity and 54.9 % specificity while the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity (restricted approaches). We confirmed the applicability of MFAP4 as a novel serum biomarker for assessment of hepatic fibrosis and identification of high-risk patients with severe fibrosis stages in hepatitis C. The combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals.

Leptospira Interrogans Induces Fibrosis in the Mouse Kidney through Inos-Dependent, TLR- and NLR-Independent Signaling Pathways

PubMed Central

Fanton d'Andon, Martine; Quellard, Nathalie; Fernandez, Béatrice; Ratet, Gwenn; Lacroix-Lamandé, Sonia; Vandewalle, Alain; Boneca, Ivo G.; Goujon, Jean-Michel; Werts, Catherine

2014-01-01

Background Leptospira (L.) interrogans are bacteria responsible for a worldwide reemerging zoonosis. Rodents carry L. interrogans asymptomatically in their kidneys and excrete bacteria in the urine, contaminating the environment. Humans get infected through skin contact and develop a mild or severe leptospirosis that may lead to renal failure and fibrosis. L. interrogans provoke an interstitial nephritis, but the induction of fibrosis caused by L. interrogans has not been studied in murine models. Innate immune receptors from the TLR and NLR families have recently been shown to play a role in the development and progression of tissue fibrosis in the lung, liver and kidneys under different pathophysiological situations. We recently showed that TLR2, TLR4, and NLRP3 receptors were crucial in the defense against leptospirosis. Moreover, infection of a human cell line with L. interrogans was shown to induce TLR2-dependent production of fibronectin, a component of the extracellular matrix. Therefore, we thought to assess the presence of renal fibrosis in L. interrogans infected mice and to analyze the contribution of some innate immune pathways in this process. Methodology/principal findings Here, we characterized by immunohistochemical studies and quantitative real-time PCR, a model of Leptospira-infected C57BL/6J mice, with chronic carriage of L. interrogans inducing mild renal fibrosis. Using various strains of transgenic mice, we determined that the renal infiltrates of T cells and, unexpectedly, TLR and NLR receptors, are not required to generate Leptospira-induced renal fibrosis. We also show that the iNOS enzyme, known to play a role in Leptospira-induced interstitial nephritis, also plays a role in the induction of renal fibrosis. Conclusion/significance To our knowledge, this work provides the first experimental murine model of sustained renal fibrosis induced by a chronic bacterial infection that may be peculiar, since it does not rely on TLR or NLR receptors. This model may prove useful to test future therapeutic strategies to combat Leptospira-induced renal lesions. PMID:24498450

Decreased collagen types I and IV, laminin, CK-19 and α-SMA expression after bone marrow cell transplantation in rats with liver fibrosis.

PubMed

Carvalho, S N; Lira, D C; Oliveira, G P; Thole, A A; Stumbo, A C; Caetano, C E; Marques, R G; Carvalho, L

2010-11-01

Bone marrow cells have frequently been tested in animal models of liver fibrosis to assess their role in hepatic regeneration. The mononuclear fraction of bone marrow cells is of particular interest, as many studies show that these cells may be beneficial to treat hepatic fibrosis. In this study, we used the bile duct ligation model to induce hepatic fibrosis in an irreversible manner, and rats were treated with bone marrow mononuclear (BMMN) cells after fibrosis was established. Analysis of collagen types I and IV, laminin and α-SMA showed a decreased expression of these proteins in fibrotic livers after 7 days of BMMN cell injection. Moreover, cytokeratin-19 analysis showed a reduction in bile ducts in the BMMN cell-treated group. These results were accompanied by ameliorated levels of hepatic enzymes GPT (Glutamic-pyruvic transaminase), GOT (glutamic-oxaloacetic transaminase) and alkaline phosphatase (AP). Therefore, we showed that BMMN cells decrease hepatic fibrosis by significantly reducing myofibroblast numbers and through reduction of the collagen and laminin-rich extracellular matrix of fibrotic septa and hepatic sinusoids.

Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure.

PubMed

Jin, Li; Piao, Zhe Hao; Sun, Simei; Liu, Bin; Ryu, Yuhee; Choi, Sin Young; Kim, Gwi Ran; Kim, Hyung-Seok; Kee, Hae Jin; Jeong, Myung Ho

2017-12-01

Gallic acid, a trihydroxybenzoic acid found in tea and other plants, attenuates cardiac hypertrophy, fibrosis, and hypertension in animal models. However, the role of gallic acid in heart failure remains unknown. In this study, we show that gallic acid administration prevents heart failure-induced pulmonary fibrosis. Heart failure induced in mice, 8weeks after transverse aortic constriction (TAC) surgery, was confirmed by echocardiography. Treatment for 2weeks with gallic acid but not furosemide prevented cardiac dysfunction in mice. Gallic acid significantly inhibited TAC-induced pathological changes in the lungs, such as increased lung mass, pulmonary fibrosis, and damaged alveolar morphology. It also decreased the expression of fibrosis-related genes, including collagen types I and III, fibronectin, connective tissue growth factor (CTGF), and phosphorylated Smad3. Further, it inhibited the expression of epithelial-mesenchymal transition (EMT)-related genes, such as N-cadherin, vimentin, E-cadherin, SNAI1, and TWIST1. We suggest that gallic acid has therapeutic potential for the treatment of heart failure-induced pulmonary fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis

PubMed Central

Xie, Ting; Liang, Jiurong; Liu, Ningshan; Huan, Caijuan; Zhang, Yanli; Liu, Weijia; Kumar, Maya; Xiao, Rui; D’Armiento, Jeanine; Metzger, Daniel; Chambon, Pierre; Papaioannou, Virginia E.; Stripp, Barry R.; Jiang, Dianhua

2016-01-01

Progressive tissue fibrosis is a major cause of the morbidity and mortality associated with repeated epithelial injuries and accumulation of myofibroblasts. Successful treatment options are limited by an incomplete understanding of the molecular mechanisms that regulate myofibroblast accumulation. Here, we employed in vivo lineage tracing and real-time gene expression transgenic reporting methods to analyze the early embryonic transcription factor T-box gene 4 (TBX4), and determined that TBX4-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult lung. In a murine model, ablation of TBX4-expressing cells or disruption of TBX4 signaling attenuated lung fibrosis after bleomycin-induced injury. Furthermore, TBX4 regulated hyaluronan synthase 2 production to enable fibroblast invasion of matrix both in murine models and in fibroblasts from patients with severe pulmonary fibrosis. These data identify TBX4 as a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis. Targeting TBX4 and downstream factors that regulate fibroblast invasiveness could lead to therapeutic approaches in lung fibrosis. PMID:27400124

Rating of CCl(4)-induced rat liver fibrosis by blood serum glycomics.

PubMed

Desmyter, Liesbeth; Fan, Ye-Dong; Praet, Marleen; Jaworski, Tomasz; Vervecken, Wouter; De Hemptinne, Bernard; Contreras, Roland; Chen, Cuiying

2007-07-01

Non-invasive staging of human liver fibrosis is a desirable objective that remains under extensive evaluation. Animal model systems are often used for studying human liver disease and screening antifibrotic compounds. The aim of the present study was to investigate the potential use of serum N-glycan profiles to evaluate liver fibrosis in a rat model. Liver fibrosis and cirrhosis were induced in rats by oral administration of CCl(4). Liver injury was assessed biochemically (alanine aminotransferase [ALT] activity, aspartate aminotransferase [AST] activity and total bilirubin) and histologically. The N-glycan profile (GlycoTest) was performed using DNA sequencer-assisted-fluorophore-assisted carbohydrate electrophoresis technology. In parallel, the effect of cotreatment with antifibrotic interferon-gamma (IFN-gamma) was studied. The biopsy scoring system showed that CCl(4) induced early fibrosis (F < 1-2) in rats after 3 weeks of treatment, and cirrhosis (F4) after 12 weeks. Significant increases in ALT activity, AST activity and total bilirubin levels were detected only after 12 weeks of CCl(4) treatment. GlycoTest showed three glycans were significantly altered in the CCl(4)-goup. Peak 3 started at week 6, at an early stage in fibrosis development (F < 1-2), whereas peaks 4 and 5 occurred at week 9, at which time mild liver fibrosis (F = 1-2) had developed. The changes in the CCl(4)-IFN-gamma group were intermediate between the CCl(4)- and the control groups. The GlycoTest is much more sensitive than biochemical tests for evaluating liver fibrosis/cirrhosis in the rat model. The test can also be used as a non-invasive marker for screening and monitoring the antifibrotic activity of potential therapeutic compounds.

Activation and overexpression of Sirt1 attenuates lung fibrosis via P300.

PubMed

Zeng, Zhilin; Cheng, Sheng; Chen, Huilong; Li, Qinghai; Hu, Yinan; Wang, Qi; Zhu, Xianying; Wang, Jun

2017-05-13

Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class Ⅲ histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor β1 (TGF-β1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-β1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-β1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

The effect of the angiotensin II receptor, type 1 receptor antagonists, losartan and telmisartan, on thioacetamide-induced liver fibrosis in rats.

PubMed

Czechowska, G; Celinski, K; Korolczuk, A; Wojcicka, G; Dudka, J; Bojarska, A; Madro, A; Brzozowski, T

2016-08-01

It has been reported previously that the density of angiotensin II receptors is increased in the rat liver in experimentally-induced fibrosis. We hypothesized that pharmacological blockade of angiotensin receptors may produce beneficial effects in models of liver fibrosis. In this study, we used the widely used thioacetamide (TAA)-induced model of liver fibrosis (300 mg/L TAA ad libitum for 12 weeks). Rats received daily injections (i.p), lasting 4 weeks of the angiotensin II type 1 receptor antagonists, losartan 30 mg/kg (TAA + L) or telmisartan 10 mg/kg (TAA + T) and were compared to rat that received TAA alone. Chronic treatment with losartan and telmisartan was associated with a significant reduction in the activity of alkaline phosphatase, and decreased concentrations of tumor necrosis factor-alpha and transforming growth factor beta-1 compared to controls. We also found a significant reduction interleukin-6 in rats receiving telmisartan (P < 0.05) but not losartan. Both treatments increased the concentration of liver glutathione along with a concomitant decrease of GSSG compared to controls. In addition, increased paraoxonase 1 activity was observed in the serum of rats receiving telmisartan group compared to the TAA alone controls. Finally, histological evaluation of liver sections revealed losartan and telmisartan treatment was associated with reduced inflammation and liver fibrosis. Taken together, these results indicate that both telmisartan and losartan have anti-inflammatory and anti-oxidative properties in the TAA model of liver fibrosis. These finding add support to a growing body of literature indicating a potentially important role for the angiotensin system in liver fibrosis and indicate angiotensin antagonists may be useful agents for fibrosis treatment.

Restorative effects of hydroxysafflor yellow A on hepatic function in an experimental regression model of hepatic fibrosis induced by carbon tetrachloride

PubMed Central

Li, Yanuo; Shi, Yan; Sun, Yan; Liu, Luying; Bai, Xianyong; Wang, Dong; Li, Hongxing

2017-01-01

Hepatic fibrosis is a reversible pathological process, in which fibrotic tissue is excessively deposited in the liver during the repair process that follows hepatic injury. Early prevention or treatment of hepatic fibrosis has great significance on the treatment of chronic hepatic diseases. Hydroxysafflor yellow A (HSYA) is a water-soluble monomer extracted from safflower, which serves numerous pharmacological roles. However, it remains to be elucidated how HSYA regulates hepatic fibrogenesis. The aim of the present study was to reveal the possible mechanisms underlying the effects of HSYA on the prevention and treatment of hepatic fibrosis. A rat model of hepatic fibrosis was established in the present study, and the rats were administered various doses of HSYA. The effects of HSYA on pathological alterations of the liver tissue in rats with hepatic fibrosis were observed using hematoxylin-eosin staining and Masson staining. In order to explore the anti-hepatic fibrosis effects and underlying mechanisms of HSYA, serum levels, and hepatic function and hepatic fibrosis indices were evaluated. The results demonstrated that HSYA can improve the general condition of rats with hepatic fibrosis and relieve cellular swelling of the liver, fatty degeneration, necrosis, inflammatory cell infiltration and fibroplastic proliferation. Subsequent to administration of HSYA, globulin was increased during hepatic fibrosis caused by tetrachloromethane. However, total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase and levels of hyaluronic acid, laminin, procollagen III N-terminal peptide, collagen type IV and hydroxyproline were significantly reduced. The results additionally demonstrated that HSYA could enhance superoxide dismutase activity and reduce malondialdehyde levels, inhibiting lipid peroxidation caused by free radicals. PMID:27909717

Inhibition of Myocardin-Related Transcription Factor/Serum Response Factor Signaling Decreases Lung Fibrosis and Promotes Mesenchymal Cell Apoptosis

PubMed Central

Sisson, Thomas H.; Ajayi, Iyabode O.; Subbotina, Natalya; Dodi, Amos E.; Rodansky, Eva S.; Chibucos, Lauren N.; Kim, Kevin K.; Keshamouni, Venkateshwar G.; White, Eric S.; Zhou, Yong; Higgins, Peter D.R.; Larsen, Scott D.; Neubig, Richard R.; Horowitz, Jeffrey C.

2016-01-01

Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1–induced myofibroblast differentiation; and inhibited TGF-β1–induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis. PMID:25681733

Magnetic resonance imaging of disease progression and resolution in a transgenic mouse model of pulmonary fibrosis.

PubMed

Cleveland, Zackary I; Zhou, Yu M; Akinyi, Teckla G; Dunn, R Scott; Davidson, Cynthia R; Guo, Jinbang; Woods, Jason C; Hardie, William D

2017-04-01

Pulmonary fibrosis contributes to morbidity and mortality in a range of diseases, and there are no approved therapies for reversing its progression. To understand the mechanisms underlying pulmonary fibrosis and assess potential therapies, mouse models are central to basic and translational research. Unfortunately, metrics commonly used to assess murine pulmonary fibrosis require animals to be grouped and euthanized, increasing experimental difficulty and cost. We examined the ability of magnetic resonance imaging (MRI) to noninvasively assess lung fibrosis progression and resolution in a doxycycline (Dox) regulatable, transgenic mouse model that overexpresses transforming growth factor-α (TGF-α) under control of a lung-epithelial-specific promoter. During 7 wk of Dox treatment, fibrotic lesions were readily observed as high-signal tissue. Mean weighted signal and percent signal volume were found to be the most robust MRI-derived measures of fibrosis, and these metrics correlated significantly with pleural thickness, histology scores, and hydroxyproline content ( R  = 0.75-0.89). When applied longitudinally, percent high signal volume increased by 1.5% wk -1 ( P < 0.001) and mean weighted signal increased at a rate of 0.0065 wk -1 ( P = 0.0062). Following Dox treatment, lesions partially resolved, with percent high signal volume decreasing by -3.2% wk -1 ( P = 0.0034) and weighted mean signal decreasing at -0.015 wk -1 ( P = 0.0028). Additionally, longitudinal MRI revealed dynamic remodeling in a subset of lesions, a previously unobserved behavior in this model. These results demonstrate MRI can noninvasively assess experimental lung fibrosis progression and resolution and provide unique insights into its pathobiology. Copyright © 2017 the American Physiological Society.

Imaging of retinal and choroidal vascular tumours

PubMed Central

Heimann, H; Jmor, F; Damato, B

2013-01-01

The most common intraocular vascular tumours are choroidal haemangiomas, vasoproliferative tumours, and retinal haemangioblastomas. Rarer conditions include cavernous retinal angioma and arteriovenous malformations. Options for ablating the tumour include photodynamic therapy, argon laser photocoagulation, trans-scleral diathermy, cryotherapy, anti-angiogenic agents, plaque radiotherapy, and proton beam radiotherapy. Secondary effects are common and include retinal exudates, macular oedema, epiretinal membranes, retinal fibrosis, as well as serous and tractional retinal detachment, which are treated using standard methods (ie, intravitreal anti-angiogenic agents or steroids as well as vitreoretinal procedures, such as epiretinal membrane peeling and release of retinal traction). The detection, diagnosis, and monitoring of vascular tumours and their complications have improved considerably thanks to advances in imaging. These include spectral domain and enhanced depth imaging optical coherence tomography (SD-OCT and EDI-OCT, respectively), wide-angle photography and angiography as well as wide-angle fundus autofluorescence. Such novel imaging has provided new diagnostic clues and has profoundly influenced therapeutic strategies so that vascular tumours and secondary effects are now treated concurrently instead of sequentially, enhancing any opportunities for conserving vision and the eye. In this review, we describe how SD-OCT, EDI-OCT, autofluorescence, wide-angle photography and wide-angle angiography have facilitated the evaluation of eyes with the more common vascular tumours, that is, choroidal haemangioma, retinal vasoproliferative tumours, and retinal haemangioblastoma. PMID:23196648

Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

PubMed Central

Cui, Jeffrey; Chen, Chi-Hua; Lo, Min-Tzu; Schork, Nicholas; Bettencourt, Ricki; Gonzalez, Monica P; Bhatt, Archana; Hooker, Jonathan; Shaffer, Katherine; Nelson, Karen E; Long, Michelle T; Brenner, David A; Sirlin, Claude B; Loomba, Rohit

2016-01-01

Introduction Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic risk factors including hypertension and dyslipidemia, and may progress to liver fibrosis. Previous studies have shown that hepatic steatosis and fibrosis are heritable but whether they have a significant shared gene effect is unknown. This study aimed to examine the shared gene effects between hepatic steatosis, fibrosis, and their associations with metabolic risk factors. Methods This is a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from Southern California. Hepatic steatosis was assessed with MRI-proton density fat fraction (MRI-PDFF) and hepatic fibrosis was assessed with magnetic resonance elastography (MRE). A standard bivariate twin AE model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects (A) and individual-specific environmental effects (E). Genetic correlations (rG) estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Results The mean (±SD) age and BMI were 47.1 (±21.9) years and 26.9 (±6.5) kg/m2, respectively. 20% (26/130) of the cohort had hepatic steatosis (MRI-PDFF ≥5%) and 8.2% (10/122) had hepatic fibrosis (MRE ≥3Kpa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, hemoglobin A1c (HbA1c), and low high-density lipoprotein (HDL) had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, HOMA-IR, insulin, HbA1c, and low HDL had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% CI: 0.716–1, p<0.0001). Conclusions Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. PMID:27315352

Respiratory syncytial virus infection accelerates lung fibrosis through the unfolded protein response in a bleomycin-induced pulmonary fibrosis animal model.

PubMed

Wang, Lina; Cheng, Wei; Zhang, Zhimin

2017-07-01

Emerging evidence has demonstrated that endoplasmic reticulum stress (ER) is involved in the pathogenesis of idiopathic pulmonary fibrosis, however, the underlying mechanism remains unclear. Viral infection often triggers a hyperinflammatory response by an expansion of the ER. The present study was designed to observe the role of respiratory syncytial virus infection (RSV)‑induced ER stress on lung fibrosis. In order to determine the role of ER stress on the onset and progression of pulmonary fibrosis, mice received an intratracheal combined injection of RSV and bleomycin on day 0. At day 7, 14 and 21 following combined injection, RSV in the lung tissues was assayed by immunohistochemistry, cellular classification was assayed by direct microscopic observation after Wright staining and the secretion of cytokines in the broncho‑alveolar lavage fluid (BALF) was assayed by ELISA. The expression of collagen type I was assayed by immunofluorescence and western blot analysis. The expression of ER stress related proteins was analyzed by western blot. In addition, the correlations of ER‑stress related proteins with collagen type‑1 were examined. RSV administration resulted in increased inflammation, as demonstrated by increased levels of leukocytes and pro‑inflammatory cytokines in the BALF, and increased collagen type‑1 deposition in the lung tissues of bleomycin-induced pulmonary fibrosis animal model at 7, 14 and 21 days. RSV promoted the expression of phosphorylated protein kinase R‑like endoplasmic reticulum kinase (p‑PERK), 78 kDa glucose‑regulated protein (GRP78) and activating transcription factor 6α (ATF6α), which accelerated the severity and process of fibrosis in bleomycin‑induced animal models. The present study provides evidence that RSV infection accelerated the unfolded protein response and bleomycin‑induced lung fibrosis, which may improve our understanding of the pathogenesis of pulmonary fibrosis.

Normal tissue complication probability (NTCP) parameters for breast fibrosis: pooled results from two randomised trials.

PubMed

Mukesh, Mukesh B; Harris, Emma; Collette, Sandra; Coles, Charlotte E; Bartelink, Harry; Wilkinson, Jenny; Evans, Philip M; Graham, Peter; Haviland, Jo; Poortmans, Philip; Yarnold, John; Jena, Raj

2013-08-01

The dose-volume effect of radiation therapy on breast tissue is poorly understood. We estimate NTCP parameters for breast fibrosis after external beam radiotherapy. We pooled individual patient data of 5856 patients from 2 trials including whole breast irradiation followed with or without a boost. A two-compartment dose volume histogram model was used with boost volume as the first compartment and the remaining breast volume as second compartment. Results from START-pilot trial (n=1410) were used to test the predicted models. 26.8% patients in the Cambridge trial (5 years) and 20.7% patients in the EORTC trial (10 years) developed moderate-severe breast fibrosis. The best fit NTCP parameters were BEUD3(50)=136.4 Gy, γ50=0.9 and n=0.011 for the Niemierko model and BEUD3(50)=132 Gy, m=0.35 and n=0.012 for the Lyman Kutcher Burman model. The observed rates of fibrosis in the START-pilot trial agreed well with the predicted rates. This large multi-centre pooled study suggests that the effect of volume parameter is small and the maximum RT dose is the most important parameter to influence breast fibrosis. A small value of volume parameter 'n' does not fit with the hypothesis that breast tissue is a parallel organ. However, this may reflect limitations in our current scoring system of fibrosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Osteopontin in Systemic Sclerosis and its Role in Dermal Fibrosis

PubMed Central

Wu, Minghua; Schneider, Daniel J.; Mayes, Maureen D; Assassi, Shervin; Arnett, Frank C.; Tan, Filemon K.; Blackburn, Michael R.; Agarwal, Sandeep K.

2012-01-01

Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Herein, we determined if OPN levels are increased in a large cohort of systemic sclerosis (SSc) patients and if OPN contributes dermal fibrosis. Plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared to healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin-induced dermal fibrosis model. OPN deficient (OPN−/−) mice developed less dermal fibrosis compared to wild-type mice in the bleomycin-induced dermal fibrosis model. Additional in vivo studies demonstrated that lesional skin from OPN−/− mice had fewer Mac-3+ cells, fewer myofibroblasts, decreased TGF-beta (TGFβ) and genes in the TGFβ pathway and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and ERK. In vitro, OPN−/− dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGFβ. Finally, TGFβ production by OPN deficient macrophages was reduced compared to wild type. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that OPN may be a novel therapeutic target in SSc. PMID:22402440

qFibrosis: A fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients

PubMed Central

Tai, Dean C.S.; Wang, Shi; Cheng, Chee Leong; Peng, Qiwen; Yan, Jie; Chen, Yongpeng; Sun, Jian; Liang, Xieer; Zhu, Youfu; Rajapakse, Jagath C.; Welsch, Roy E.; So, Peter T.C.; Wee, Aileen; Hou, Jinlin; Yu, Hanry

2014-01-01

Background & Aims There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients. Methods qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison. Results qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p <0.001) and human biopsies (p <0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93–0.99 for animal samples: 1–16 mm2; AUC: 0.84–0.97 for biopsies: 10–44 mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15 mm) and under- and over-scoring by different pathologists (p <0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p = 0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts. Conclusions qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice. PMID:24583249

Mast Cells: Key Contributors to Cardiac Fibrosis

PubMed Central

Widiapradja, Alexander

2018-01-01

Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis. PMID:29329223

Increased susceptibility to atrial fibrillation secondary to atrial fibrosis in transgenic goats expressing transforming growth factor - B1

USDA-ARS?s Scientific Manuscript database

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in people with significant morbidity and mortality. There is a strong association between atrial fibrosis and AF. Transforming growth factor B1 (TGF-B1) is an essential mediator of atrial fibrosis in animal models and human pat...

Precision-cut rat, mouse, and human intestinal slices as novel models for the early-onset of intestinal fibrosis.

PubMed

Pham, Bao Tung; van Haaften, Wouter Tobias; Oosterhuis, Dorenda; Nieken, Judith; de Graaf, Inge Anne Maria; Olinga, Peter

2015-04-01

Intestinal fibrosis (IF) is a major complication of inflammatory bowel disease. IF research is limited by the lack of relevant in vitro and in vivo models. We evaluated precision-cut intestinal slices (PCIS) prepared from human, rat, and mouse intestine as ex vivo models mimicking the early-onset of (human) IF. Precision-cut intestinal slices prepared from human (h), rat (r), and mouse (m) jejunum, were incubated up to 72 h, the viability of PCIS was assessed by ATP content and morphology, and the gene expression of several fibrosis markers was determined. The viability of rPCIS decreased after 24 h of incubation, whereas mPCIS and hPCIS were viable up to 72 h of culturing. Furthermore, during this period, gene expression of heat shock protein 47 and plasminogen activator inhibitor 1 increased in all PCIS in addition to augmented expression of synaptophysin in hPCIS, fibronectin (Fn2) and TGF-β1 in rPCIS, and Fn2 and connective tissue growth factor (Ctgf) in mPCIS. Addition of TGF-β1 to rPCIS or mPCIS induced the gene expression of the fibrosis markers Pro-collagen1a1, Fn2, and Ctgf in both species. However, none of the fibrosis markers was further elevated in hPCIS. We successfully developed a novel ex vivo model that can mimic the early-onset of fibrosis in the intestine using human, rat, and mouse PCIS. Furthermore, in rat and mouse PCIS, TGF-β1 was able to even further increase the gene expression of fibrosis markers. This indicates that PCIS can be used as a model for the early-onset of IF. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Cavernous hemangioma of the rib: a rare diagnosis.

PubMed

Gourgiotis, Stavros; Piyis, Anastasios; Panagiotopoulos, Nikolaos; Panayotopoulos, Panayotis; Salemis, Nikolaos S

2010-01-01

Hemangioma of the rib is an uncommon benign vascular tumour. A case of rib hemangioma in a 29-year-old woman is presented. Chest roentgenogram and computed tomography revealed a mass along the inner surface of the 7th left rib with bone destruction. She underwent resection of the 7th rib. The pathologic diagnosis was cavernous hemangioma. Hemangiomas of the rib are rare tumours but should be kept in mind in the differential diagnosis of rib tumours.

Transient pituitary enlargement with central hypogonadism secondary to bilateral cavernous sinus thrombosis: pituitary oedema?

PubMed

Joubert, Michael; Verdon, Renaud; Reznik, Yves

2009-05-01

Design We report the case of an incidental pituitary mass discovered in the context of bilateral cavernous sinus thrombosis due to a bacterial pansinusitis. Conclusions Magnetic resonance imaging features of the pituitary lesion, together with transient central hypogonadism and total regression of the mass after anticoagulation and antimicrobial therapy, suggest that this lesion is a pituitary oedema of vascular mechanism. Other possible causes of pituitary mass in such a situation are also discussed.

[The sequential use of local vacuum magnetotherapy and papaverine electrophoresis with sinusoidal modulated currents in impotence].

PubMed

Karpukhin, I V; Bogomol'nyĭ, V A

1997-01-01

105 patients with chronic nonspecific prostatitis were examined and treated with papaverin electrophoresis using sinusoidal modulated currents (SMC) and local vacuum magnetotherapy (LVMT). Papaverin SMC electrophoresis and LVMT stimulated cavernous circulation. The highest stimulation was achieved at successive use of LVMT and the electrophoresis. LVMT followed by the electrophoresis maintained good cavernous circulation for 5-6 hours after the procedure in the course of which several spontaneous erections were observed.

Brain stem venous congestion due to dural arteriovenous fistulas of the cavernous sinus.

PubMed

Kai, Y; Hamada, J I; Morioka, M; Yano, S; Ushio, Y

2004-10-01

Venous congestion of the brain stem due to dural arteriovenous fistulas (DAVFs) in the cavernous sinus is rare and presents therapeutic challenges. To assess the prognosis of patients with symptomatic DAVFs and brain stem dysfunction, we evaluated the degree of venous ischemia by examining pre- and post-treatment magnetic resonance images (MRI) in 2 patients presenting with venous congestion of the brain stem. A 56-year-old woman with left hemiparesis and a 70-year-old woman with gait disturbance attributable to right cavernous sinus DAVFs were referred to our hospital. In both cases, T2-weighted magnetic resonance imaging (MRI) disclosed a hyperintensity lesion in the brainstem due to venous congestion. Both patients underwent open surgery for direct embolization of the cavernous sinus because there were no approach routes for transvenous embolization. The patient whose pretreatment MRI demonstrated Gd enhancement continued to manifest neurological deficits and persistence of the abnormal hyperintensity on post-treatment T2-weighted MRI. In the other patient whose pretreatment MRI showed no Gd enhancement, treatment produced a complete response of her neurological deficit and disappearance of the abnormal hyperintensity area. We tentatively conclude that lesions corresponding to hyperintensity areas on non-Gd-enhanced, T2-weighted MRI may reflect a reversible condition whereas lesions identified as hyperintense areas on GD-enhanced T2-weighted MRI may be indicative of irreversibility.

Cavernous sinus syndrome in a Holstein bull.

PubMed

Jacob, Sarah I; Drees, Randi; Pinkerton, Marie E; Bentley, Ellison M; Peek, Simon F

2015-03-01

A 13-month-old Holstein bull was presented for right-sided exophthalmos. Ophthalmologic examination noted that the animal was visual in both eyes, but that the right pupil was persistently dilated and very sluggish to constrict when stimulated with a bright light and that normal ocular motility was absent. Fundic examination of the right eye was normal as was a complete ophthalmologic examination of the left eye. Radiographs at presentation did not reveal the presence of sinusitis or other skull abnormalities. Initial treatment comprised intravenous antibiotics and anti-inflammatories for orbital inflammation over a 14-day period. There was no perceptible change in the appearance or neuro-ophthalmologic examination of the right eye during hospitalization. The animal was discharged to the owner's care, but 3 weeks later was found recumbent with unilateral strabismus of the left eye and a fixed right pupil. Due to the inability to rise and rapid deterioration, humane euthanasia was performed, and a full postmortem examination, preceded by a MRI, was performed that identified abscesses extending bilaterally through the round foramina obliterating the cavernous sinus region, as well as abscessation of the right mandible, right trigeminal neuritis, right-sided sinusitis, and right-sided otitis media. Cavernous sinus syndrome should be considered in cattle with a combination of exophthalmos and neuro-ophthalmologic abnormalities involving cranial nerves III, IV, V, and VI, whose branches are located within the cavernous sinus. © 2013 American College of Veterinary Ophthalmologists.

[A case of cavernous angioma at the convexity in the dura mater: characteristics of images in the literature].

PubMed

Yonezawa, Ushio; Ikawa, Fusao; Hamasaki, Osamu; Hidaka, Toshikazu; Kurokawa, Yasuharu; Onuma, Hideyuki

2014-08-01

We describe a rare case of cavernous angioma in the dura mater and discuss published MRI findings on similar cases. The patient was a 78-year-old woman who was referred to Shimane Prefectural Central Hospital with complaints of headaches. We were subsequently able to identify a tumor at the convexity in the dura mater. The tumor showed a high intensity on T2-weighted images and was heterogeneously enhanced on contrast-enhanced T1-weighted images. The maximum size of the tumor was 35 mm. Moreover, preoperative angiography showed a slight vascularity in the tumor. We performed surgery with the expectation of finding a meningioma, metastatic brain tumor, or another mesenchymal tumor. The tumor was dark and red, attached to the dura mater, and adhered to the arachnoid. However, we were able to peel the tumor away from the meninges and achieved a total removal of the mass, successfully cutting a fine feeding cortical artery. The patient was discharged without neurological defects 9 days after surgery;the pathological diagnosis was cavernous angioma. In conclusion, it is difficult to discern between meningioma and cavernous angioma in the dura mater. However, the specificity of high intensity on T2-weighted images is relatively high, and preoperative diagnosis can be determined by MRI and angiography findings.

Posttraumatic carotid cavernous fistula that presented as seizure and focal neurological deficits with symptom resolution after therapeutic coil embolization.

PubMed

Klevtsova, Ekaterina; Nguyen-Min, Caroline; Lalani, Tania; Carlan, Stephen James; Madruga, Mario

2015-02-01

A posttraumatic carotid cavernous fistula can remain unrecognized and ultimately present with symptoms characteristic for a middle cerebral artery stroke. Progressive neurologic deterioration can occur until the condition is diagnosed and treated. If unrecognized and untreated, permanent damage may result. A 46-year-old white man with the history of a motor vehicle crash 6 months prior presented with complaints of acute onset of expressive aphasia and seizure-like activity for 3 days. On presentation, the patient was noted to have moderate proptosis and chemosis of the left eye. Magnetic resonance imaging of the brain showed an arteriovenous fistula arising from the anterolateral precavernous left internal carotid artery. This was directly communicating with the adjacent cortical veins along the medial aspect of the left temporal lobe, resulting in venous congestion in the left frontal opercular region, the left insula, and subinsular tracks. The patient underwent an intracranial coil embolization of a left carotid cavernous fistula. No complications were encountered, and the patient had near-complete resolution of neurologic deficits and left eye proptosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although posttraumatic carotid cavernous fistula is a rare condition, it is important to be aware of this entity because immediate diagnosis and treatment may improve outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Mouse and Rat Models of Induction of Hepatic Fibrosis and Assessment of Portal Hypertension.

PubMed

Klein, Sabine; Schierwagen, Robert; Uschner, Frank Erhard; Trebicka, Jonel

2017-01-01

Portal hypertension either develops due to progressive liver fibrosis or is the consequence of vascular liver diseases such as portal vein thrombosis or non-cirrhotic portal hypertension. This chapter focuses on different rodent models of liver fibrosis with portal hypertension and also in few non-cirrhotic portal hypertension models. Importantly, after the development of portal hypertension, the proper assessment of drug effects in the portal and systemic circulation should be discussed. The last part of the chapter is dedicated in these techniques to assess the in vivo hemodynamics and the ex vivo techniques of the isolated liver perfusion and vascular contractility.

Recent progress in translational cystic fibrosis research using precision medicine strategies.

PubMed

Cholon, Deborah M; Gentzsch, Martina

2018-03-01

Significant progress has been achieved in developing precision therapies for cystic fibrosis; however, highly effective treatments that target the ion channel, CFTR, are not yet available for many patients. As numerous CFTR therapeutics are currently in the clinical pipeline, reliable screening tools capable of predicting drug efficacy to support individualized treatment plans and translational research are essential. The utilization of bronchial, nasal, and rectal tissues from individual cystic fibrosis patients for drug testing using in vitro assays such as electrophysiological measurements of CFTR activity and evaluation of fluid movement in spheroid cultures, has advanced the prediction of patient-specific responses. However, for precise prediction of drug effects, in vitro models of CFTR rescue should incorporate the inflamed cystic fibrosis airway environment and mimic the complex tissue structures of airway epithelia. Furthermore, novel assays that monitor other aspects of successful CFTR rescue such as restoration of mucus characteristics, which is important for predicting mucociliary clearance, will allow for better prognoses of successful therapies in vivo. Additional cystic fibrosis treatment strategies are being intensively explored, such as development of drugs that target other ion channels, and novel technologies including pluripotent stem cells, gene therapy, and gene editing. The multiple therapeutic approaches available to treat the basic defect in cystic fibrosis combined with relevant precision medicine models provide a framework for identifying optimal and sustained treatments that will benefit all cystic fibrosis patients. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukunaga, Satoki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558; Kakehashi, Anna

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective ofmore » initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.« less

Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

PubMed Central

Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

2014-01-01

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10.

PubMed

Tager, Andrew M; Kradin, Richard L; LaCamera, Peter; Bercury, Scott D; Campanella, Gabriele S V; Leary, Carol P; Polosukhin, Vasiliy; Zhao, Long-Hai; Sakamoto, Hideo; Blackwell, Timothy S; Luster, Andrew D

2004-10-01

Pulmonary fibrosis is an enigmatic and devastating disease with few treatment options, now thought to result from abnormal wound healing in the lung in response to injury. We have previously noted a role for the chemokine interferon gamma-inducible protein of 10 kD (IP-10)/CXC chemokine ligand 10 in the regulation of cutaneous wound healing, and consequently investigated whether IP-10 regulates pulmonary fibrosis. We found that IP-10 is highly expressed in a mouse model of pulmonary fibrosis induced by bleomycin. IP-10-deficient mice exhibited increased pulmonary fibrosis after administration of bleomycin, suggesting that IP-10 limits the development of fibrosis in this model. Substantial fibroblast chemoattractant and proliferative activities were generated in the lung after bleomycin exposure. IP-10 significantly inhibited fibroblast responses to the chemotactic, but not the proliferative activity generated, suggesting that IP-10 may attenuate fibroblast accumulation in bleomycin-induced pulmonary fibrosis by limiting fibroblast migration. Consistent with this inhibitory activity of IP-10 on fibroblast migration, fibroblast accumulation in the lung after bleomycin exposure was dramatically increased in IP-10-deficient mice compared with wild-type mice. Conversely, transgenic mice overexpressing IP-10 were protected from mortality after bleomycin exposure, and demonstrated decreased fibroblast accumulation in the lung after challenge compared with wild-type mice. Our findings suggest that interruption of fibroblast recruitment may represent a novel therapeutic strategy for pulmonary fibrosis, which could have applicability to a wide range of fibrotic illnesses.

Cannabinoid receptor 2 activation restricts fibrosis and alleviates hydrocephalus after intraventricular hemorrhage.

PubMed

Tan, Qiang; Chen, Qianwei; Feng, Zhou; Shi, Xia; Tang, Jun; Tao, Yihao; Jiang, Bing; Tan, Liang; Feng, Hua; Zhu, Gang; Yang, Yunfeng; Chen, Zhi

2017-01-01

Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-β 1(TGF-β1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-β1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1. Copyright © 2016 Elsevier B.V. All rights reserved.

Chronic prostatitis/chronic pelvic pain syndrome impairs erectile function through increased endothelial dysfunction, oxidative stress, apoptosis, and corporal fibrosis in a rat model.

PubMed

Hu, Y; Niu, X; Wang, G; Huang, J; Liu, M; Peng, B

2016-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an independent risk factor for the development of erectile dysfunction (ED). But the molecular mechanisms underlying the relationship between CP/CPPS and ED are still unclear. The aim of this study was to investigate the effect of CP/CPPS on erectile function in a rat model and the possible mechanisms. A rat model of experimental autoimmune prostatitis (EAP) was established to mimic human CP⁄CPPS. Then twenty 2-month-old male Sprague-Dawley rats were divided into EAP group and control group. Intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured during cavernous nerve electrostimulation, the ratio of max ICP/MAP was calculated. Blood was collected to measure the levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and testosterone, respectively. The expression of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in corpus cavernosum were detected. We also evaluated the smooth muscle/collagen ratio and apoptotic index (AI). The ratio of max ICP/MAP in EAP group were significantly lower than that in control group. The levels of serum CRP, TNF-α, IL-1β, and IL-6 in EAP group were all significantly higher than these in control group. The expression of eNOS and cGMP levels in corpus cavernosum of EAP rats were significantly downregulated. Furthermore, decreased SOD activity and smooth muscle/collagen ratio, increased MDA levels and AI were found in corpus cavernosum of EAP rats. In conclusion, CP/CPPS impaired penile erectile function in a rat model. The declines of eNOS expression and cGMP levels in corpus cavernosum may be an important mechanism of CP/CPPS-induced ED. CP/CPPS also increased oxidative stress, cell apoptosis and decreased smooth muscle/collagen ratio in corpus cavernosum of rats, which were all important for erectile function. © 2016 American Society of Andrology and European Academy of Andrology.

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease.

PubMed

Naito, Yoshiro; Fujii, Aya; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Masuyama, Tohru

2015-07-01

Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

PubMed Central

Tashiro, Jun; Rubio, Gustavo A.; Limper, Andrew H.; Williams, Kurt; Elliot, Sharon J.; Ninou, Ioanna; Aidinis, Vassilis; Tzouvelekis, Argyrios; Glassberg, Marilyn K.

2017-01-01

Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans. PMID:28804709

[Effects of Anluohuaxianwan on transforming growth factor-β1 and related signaling pathways in rats with carbon tetrachloride-induced liver fibrosis].

PubMed

Lu, W; Gao, Y H; Wang, Z Z; Cai, Y S; Yang, Y Q; Miao, Y Q; Pei, F; Liu, X E; Zhuang, H

2017-04-20

Objective: The traditional Chinese medicine Anluohuaxianwan (ALHXW) has been used to treat liver fibrosis induced by chronic hepatitis B virus (HBV) infection. However, the anti-fibrosis mechanisms of ALHXW remain to be investigated. This study used a rat model of carbon tetrachloride (CCl(4))-induced liver fibrosis to explore the potential antifibrogenic mechanisms of ALHXW. Methods: Twenty-seven male Wistar rats were randomly assigned to control group, model group, and treatment group ( n = 9 per group). Rats in the model and treatment group were injected intraperitoneally with 40% CCl(4)(2 ml/kg), and rats in the control group were administered saline twice a week for 6 weeks. Starting at week 4 following model construction, rats in the treatment group received daily gavages with ALHXW solution (concentration 0.15 g/ml) daily, while rats in the control and model groups were given saline for a total of 6 weeks. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured from blood samples collected at the end of weeks 3, 6 and 9. Histopathological examination of liver tissue was performed to evaluate liver fibrosis at week 9. At the same time, the mRNA expression of TGF-β1 and Smads in liver tissues was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR), and TGF-β1 protein level in the liver was measured by Western blot. Inter-group comparison was performed using analysis of variance (ANOVA) when the continuous data were normally distributed and satisfied the homogeneity of variance; otherwise, nonparametric tests were used. Categorical data were compared between groups using nonparametric tests. Results: ALHXW markedly alleviated liver injury in the treatment group after 3 weeks of therapy as indicated by a significantly reduced level of ALT compared with the model group [(162.98 ± 73.14)U/L vs (322.52 ± 131.76)U/L, P = 0.047], and a 39.8% reduction in AST level compared with the model group[ (537.56 ± 306.06)U/L vs (892.98 ± 358.19)U/L, P = 0.053]. Moreover, at the end of the 6-week therapy, histopathological diagnosis showed that liver fibrosis was significantly reduced in the ALHXW-treated group compared with that in the model group ( P = 0.002). The relative expression of TGF-β1 mRNA and protein in the liver were significantly lower in ALHXW-treated rats than that in model rats (1.34 ± 0.31 vs 1.78 ± 0.45, P = 0.025; 0.39 ± 0.02 vs 0.57 ± 0.04, P = 0.003). Conclusion: ALHXW treatment can reverse CCl(4)-induced liver fibrosis in rats. Its mechanisms of anti-fibrosis may occur through the inhibition of TGF-β1 synthesis and TGF-β1/Smads signaling pathway, which in turn suppress the activation of hepatic stellate cells and thereby reverses fibrosis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neal, J.T.; Magorian, T.R.; Ahmad, S.

This report revises the original report that was published in 1980. Some of the topics covered in the earlier report were provisional and it is now practicable to reexamine them using new or revised geotechnical data and that obtained from SPR cavern operations, which involves 16 new caverns. Revised structure maps and sections show interpretative differences as compared with the 1980 report and more definition in the dome shape and caprock structural contours, especially a major southeast-northwest trending anomalous zone. The original interpretation was of westward tilt of the dome, this revision shows a tilt to the southeast, consistent withmore » other gravity and seismic data. This interpretation refines the evaluation of additional cavern space, by adding more salt buffer and allowing several more caverns. Additional storage space is constrained on this nearly full dome because of low-lying peripheral wetlands, but 60 MMBBL or more of additional volume could be gained in six or more new caverns. Subsidence values at Bryan Mound are among the lowest in the SPR system, averaging about 11 mm/yr (0.4 in/yr), but measurement and interpretation issues persist, as observed values are about the same as survey measurement accuracy. Periodic flooding is a continuing threat because of the coastal proximity and because peripheral portions of the site are at elevations less than 15 ft. This threat may increase slightly as future subsidence lowers the surface, but the amount is apt to be small. Caprock integrity may be affected by structural features, especially the faulting associated with anomalous zones. Injection wells have not been used extensively at Bryan Mound, but could be a practicable solution to future brine disposal needs. Environmental issues center on the areas of low elevation that are below 15 feet above mean sea level: the coastal proximity and lowland environment combined with the potential for flooding create conditions that require continuing surveillance.« less

Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis.

PubMed

Joshi, Nikita; Ray, Jessica L; Kopec, Anna K; Luyendyk, James P

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. © 2016 Wiley Periodicals, Inc.

Themes in fibrosis and gastrointestinal inflammation

PubMed Central

Lund, P. Kay

2011-01-01

Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease. PMID:21415411

Dose-Dependent Effects of Alpha-Naphthylisothiocyanate Disconnect Biliary Fibrosis from Hepatocellular Necrosis

PubMed Central

Joshi, Nikita; Ray, Jessica L.; Kopec, Anna K.; Luyendyk, James P.

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well-characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. PMID:27605088

Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease.

PubMed

Girard, Romuald; Zeineddine, Hussein A; Orsbon, Courtney; Tan, Huan; Moore, Thomas; Hobson, Nick; Shenkar, Robert; Lightle, Rhonda; Shi, Changbin; Fam, Maged D; Cao, Ying; Shen, Le; Neander, April I; Rorrer, Autumn; Gallione, Carol; Tang, Alan T; Kahn, Mark L; Marchuk, Douglas A; Luo, Zhe-Xi; Awad, Issam A

2016-09-15

Cerebral cavernous malformations (CCMs) are hemorrhagic brain lesions, where murine models allow major mechanistic discoveries, ushering genetic manipulations and preclinical assessment of therapies. Histology for lesion counting and morphometry is essential yet tedious and time consuming. We herein describe the application and validations of X-ray micro-computed tomography (micro-CT), a non-destructive technique allowing three-dimensional CCM lesion count and volumetric measurements, in transgenic murine brains. We hereby describe a new contrast soaking technique not previously applied to murine models of CCM disease. Volumetric segmentation and image processing paradigm allowed for histologic correlations and quantitative validations not previously reported with the micro-CT technique in brain vascular disease. Twenty-two hyper-dense areas on micro-CT images, identified as CCM lesions, were matched by histology. The inter-rater reliability analysis showed strong consistency in the CCM lesion identification and staging (K=0.89, p<0.0001) between the two techniques. Micro-CT revealed a 29% greater CCM lesion detection efficiency, and 80% improved time efficiency. Serial integrated lesional area by histology showed a strong positive correlation with micro-CT estimated volume (r(2)=0.84, p<0.0001). Micro-CT allows high throughput assessment of lesion count and volume in pre-clinical murine models of CCM. This approach complements histology with improved accuracy and efficiency, and can be applied for lesion burden assessment in other brain diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

PubMed Central

Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Li, Tianshi; Qili, Muge; Xu, Bozhi; Qian, Ming; Liang, Haihai; E, Xiaoqiang; Chege Gitau, Samuel; Wang, Lu; Huangfu, Longtao; Wu, Qiuxia; Xu, Chaoqian; Shan, Hongli

2016-01-01

Although increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis, the molecular mechanisms of pressure overload or AngII -induced cardiac interstitial fibrosis remain elusive. In this study, serpinE2/protease nexin-1 was over-expressed in a cardiac fibrosis model induced by pressure-overloaded via transverse aortic constriction (TAC) in mouse. Knockdown of serpinE2 attenuates cardiac fibrosis in a mouse model of TAC. At meantime, the results showed that serpinE2 significantly were increased with collagen accumulations induced by AngII or TGF-β stimulation in vitro. Intriguingly, extracellular collagen in myocardial fibroblast was reduced by knockdown of serpinE2 compared with the control in vitro. In stark contrast, the addition of exogenous PN-1 up-regulated the content of collagen in myocardial fibroblast. The MEK1/2- ERK1/2 signaling probably promoted the expression of serpinE2 via transcription factors Elk1 in myocardial fibroblast. In conclusion, stress-induced the ERK1/2 signaling pathway activation up-regulated serpinE2 expression, consequently led accumulation of collagen protein, and contributed to cardiac fibrosis. PMID:27876880

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

PubMed Central

Sung, Yun-Chieh; Liu, Ya-Chi; Chao, Po-Han; Chang, Chih-Chun; Jin, Pei-Ru; Lin, Ts-Ting; Lin, Ja-An; Cheng, Hui-Teng; Wang, Jane; Lai, Charles P.; Chen, Ling-Hsuan; Wu, Anthony Y.; Ho, Ting-Lun; Chiang, Tsaiyu; Gao, Dong-Yu; Duda, Dan G.; Chen, Yunching

2018-01-01

Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib—a multikinase inhibitor drug—has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo. To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro, and alleviated liver fibrosis in a CCl4-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl4-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC. PMID:29463989

Neutrophils alleviate fibrosis in the CCl4-induced mouse chronic liver injury model.

PubMed

Saijou, Eiko; Enomoto, Yutaka; Matsuda, Michitaka; Yuet-Yin Kok, Cindy; Akira, Shizuo; Tanaka, Minoru; Miyajima, Atsushi

2018-06-01

Tribbles pseudokinase 1 ( Trib1 ) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of Trib1 was previously shown to increase the neutrophil population in the spleen but lead to M2-like macrophage reduction. Because M2 macrophages are anti-inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in Trib1 -deficient mice. Interestingly, loss of Trib1 suppressed fibrosis in the CCl 4 -induced chronic liver injury model. Trib1 knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases ( Mmp ) 8 and Mmp9 were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of Trib1 . These results suggest that neutrophils are responsible for the suppression of fibrosis in Trib1 -deficient liver. Consistently, transplantation of Trib1 -deficient bone marrow cells into wild-type mice alleviated CCl 4 -induced fibrosis. Furthermore, expression of chemokine (C-X-C motif) ligand 1 ( Cxcl1 ) by adeno-associated viral vector in the normal liver recruited neutrophils and suppressed CCl 4 -induced fibrosis; infusion of wild-type neutrophils in CCl 4 -treated mice also ameliorated fibrosis. Using recombinant adeno-associated virus-mediated expression of Mmp8 and Mmp9 alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl 4 -induced fibrosis. Conclusion : While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. ( Hepatology Communications 2018;2:703-717).

Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

PubMed Central

Saijou, Eiko; Enomoto, Yutaka; Matsuda, Michitaka; Yuet‐Yin Kok, Cindy; Akira, Shizuo; Tanaka, Minoru

2018-01-01

Tribbles pseudokinase 1 (Trib1) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of Trib1 was previously shown to increase the neutrophil population in the spleen but lead to M2‐like macrophage reduction. Because M2 macrophages are anti‐inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in Trib1‐deficient mice. Interestingly, loss of Trib1 suppressed fibrosis in the CCl4‐induced chronic liver injury model. Trib1 knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases (Mmp)8 and Mmp9 were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of Trib1. These results suggest that neutrophils are responsible for the suppression of fibrosis in Trib1‐deficient liver. Consistently, transplantation of Trib1‐deficient bone marrow cells into wild‐type mice alleviated CCl4‐induced fibrosis. Furthermore, expression of chemokine (C‐X‐C motif) ligand 1 (Cxcl1) by adeno‐associated viral vector in the normal liver recruited neutrophils and suppressed CCl4‐induced fibrosis; infusion of wild‐type neutrophils in CCl4‐treated mice also ameliorated fibrosis. Using recombinant adeno‐associated virus‐mediated expression of Mmp8 and Mmp9 alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl4‐induced fibrosis. Conclusion: While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. (Hepatology Communications 2018;2:703‐717) PMID:29881822

Daikenchuto, a Kampo medicine, regulates intestinal fibrosis associated with decreasing expression of heat shock protein 47 and collagen content in a rat colitis model.

PubMed

Inoue, Ken; Naito, Yuji; Takagi, Tomohisa; Hayashi, Natsuko; Hirai, Yasuko; Mizushima, Katsura; Horie, Ryusuke; Fukumoto, Kohei; Yamada, Shinya; Harusato, Akihito; Hirata, Ikuhiro; Omatsu, Tatsushi; Yoshida, Naohisa; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Handa, Osamu; Konishi, Hideyuki; Wakabayashi, Naoki; Yagi, Nobuaki; Ichikawa, Hiroshi; Kokura, Satoshi; Yoshikawa, Toshikazu

2011-01-01

Heat shock protein (HSP) 47 may play an important role in the pathogenesis of intestinal fibrosis. Daikenchuto (DKT), a traditional Japanese herbal (Kampo) medicine, has been reported to ameliorate intestinal inflammation. The aims of this study were to determine time-course profiles of several parameters of fibrosis in a rat model, to confirm the HSP47-expressing cells in the colon, and finally to evaluate DKT's effects on intestinal fibrosis. Colitis was induced in male Wistar rats weighing 200 g using an enema of trinitrobenzene sulfonic acid (TNBS). HSP47 localization was determined by immunohistochemistry. Colonic inflammation and fibrosis were assessed by macroscopic, histological, morphometric, and immunohistochemical analyses. Colonic mRNA expression of transforming growth factor β1 (TGF-β1), HSP47, and collagen type I were assessed by real time-polymerase chain reaction (PCR). DKT was administered orally once a day from 8 to 14 d after TNBS administration. The colon was removed on the 15th day. HSP47 immunoreactivity was coexpressed with α-smooth muscle actin-positive cells located in the subepithelial space. Intracolonic administration of TNBS resulted in grossly visible ulcers. Colonic inflammation persisted for 6 weeks, and fibrosis persisted for 4 weeks after cessation of TNBS treatment. The expression levels of mRNA and proteins for TGF-β1, HSP47, and collagen I were elevated in colonic mucosa treated with TNBS. These fibrosis markers indicated that DKT treatment significantly inhibited TNBS-induced fibrosis. These findings suggest that DKT reduces intestinal fibrosis associated with decreasing expression of HSP47 and collagen content in the intestine.

Cavernous Hemangioma of the Rib: A Rare Diagnosis

PubMed Central

Gourgiotis, Stavros; Piyis, Anastasios; Panagiotopoulos, Nikolaos; Panayotopoulos, Panayotis; Salemis, Nikolaos S.

2010-01-01

Hemangioma of the rib is an uncommon benign vascular tumour. A case of rib hemangioma in a 29-year-old woman is presented. Chest roentgenogram and computed tomography revealed a mass along the inner surface of the 7th left rib with bone destruction. She underwent resection of the 7th rib. The pathologic diagnosis was cavernous hemangioma. Hemangiomas of the rib are rare tumours but should be kept in mind in the differential diagnosis of rib tumours. PMID:20585365

[Septic thrombosis of the cavernous sinus due to folliculitis].

PubMed

Tuettenberg, A; Tuettenberg, J; Knop, J; Enk, A

2003-04-01

Sinus thrombosis is an acute life-threatening disease. While cavernous sinus thrombosis secondary to facial infections is described in the literature, it is uncommon. The key clinical characteristics are a facial infection, headache, chemosis and edema of the eyelid. The main differential diagnostic consideration is meningoencephalitis. Early diagnosis by angiography, magnetic resonance imaging and examination of CSF is important as treatment should be initiated as soon as possible in order to decrease morbidity and mortality. The mainstays of therapy are heparinization and appropriate intravenous antibiotic therapy.

Hemothorax associated with telangiectatic osteosarcoma in a dog.

PubMed

Mahaffey, E A; Greene, C E

1985-08-01

Hemothorax in a dog was attributed to bleeding from an intrathoracic mass attached to the sixth through the tenth ribs. The mass contained numerous cavernous, blood-filled spaces as well as bands of osteoid and occasional foci of osseous tissue. The diagnosis was telangiectatic osteosarcoma. Telangiectatic osteosarcoma is an uncommon variant of osteosarcoma. Cavernous, blood-filled spaces and paucity of bone are important histologic features. Metastasis was described in one of the seven telangiectatic osteosarcomas reported in dogs, and none was found in this case.

Benign mass in tonsil- cavernous hemangioma.

PubMed

Joseph, Sumitha; Prakash, M; Mohammed, Hafida K; Govar, Aberna

2013-10-01

Cavernous hemangioma is also called as 'ANGIOMA CAVERNOSUM' or 'CAVERNOMA' as benign lesion of blood vessels. They are similar to strawberry hemangioma but deeply situated. Although most often associated with skin it is also sometimes found in mucous membrane, brain and the viscera. The diagnosis of hemangiomas is mainly based on clinical evaluation . Isolated hemangiomas in the tonsillar tissue is a rare occurance. In this we report had a case of adult tonsillar hemangioma of left side associated with recurrent tonsillitis . He was effectively managed surgically without any complications.

Prevention of Pulmonary Fibrosis via Trichostatin A (TSA) in Bleomycin Induced Rats.

PubMed

Ye, Qing; Li, Yanqin; Jiang, Handong; Xiong, Jianfei; Xu, Jiabo; Qin, Hui; Liu, Bin

2014-10-20

To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A (TSA)on bleomycin-induced pulmonary fibrosis. To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A ( TSA ) on HDAC2, p-SMAD2, HDAC2 mRNA, SMAD2mRNA in pulmonary fibrosis rats and investigate impossible mechanism. 46 SPF level male SD rats were randomly divided into four groups: ten for normal control group, fourteen for model control group I, twelve for model control group II and ten for treatment group. Rat pulmonary fibrosis was induced by bleomycin(5mg/kg) via single intratracheal perfusion in the two model control groups and treatment group. Normal control mice were instilled with a corresponding volume of 0.9% saline intratracheally. Treatment group was treated by the dilution of TSA 2mg/kg DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day ,once a day for three days. Model control group II was treated by the dilution of DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. Model control group I and normal control group were treated by 0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. All the animals were sacrificed on the 21 day after modeling. The pathological changes were observed by hematoxylin and eosin(HE)stain and masson trichrome stain. The expression of HDAC2 mRNA,SMAD2 mRNA were measured by real-time PCR. The protein level of HDAC2 and p-SMAD2 in serum was measured by Western blot. The pulmonary fibrosis in treatment group were significantly alleviated compared to the two model control groups (P<0.05). Real-time PCR showed that the treatment group had lower expression of lung tissue HDAC2 mRNA than the two model control groups and normal control group (P<0.05). The expression of lung tissue SMAD2 mRNA increased in the two model control groups and treatment group (P<0.05),but there were no significant differences among the three groups(P>0.05). Western blot indicated that the protein level of HDAC2 and p-SMAD2 in serum increased in the two model control groups compared with normal control group(P<0.05).But treatment group had lower protein level of HDAC2 (P<0.05) and no significant difference in the protein level of p-SMAD2 compared to the two model control groups (P>0.05). Non selective histone deacetylase inhibitors of Trichostatin A (TSA) can reduce the bleomycin induced pulmonary fibrosis in rats. TSA attenuates pulmonary fibrosis and it can inhibit HDAC2 expression at the gene and protein level. Bleomycin induced fibrosis has the relationship with p-SMAD2 in gene and protein levels, but TSA inhibit bleomycin-induced lung fibrosis effect with no relation with SMAD2 phosphorylation pathways.

Improving liver fibrosis diagnosis based on forward and backward second harmonic generation signals

NASA Astrophysics Data System (ADS)

Peng, Qiwen; Zhuo, Shuangmu; So, Peter T. C.; Yu, Hanry

2015-02-01

The correlation of forward second harmonic generation (SHG) signal and backward SHG signal in different liver fibrosis stages was investigated. We found that three features, including the collagen percentage for forward SHG, the collagen percentage for backward SHG, and the average intensity ratio of two kinds of SHG signals, can quantitatively stage liver fibrosis in thioacetamide-induced rat model. We demonstrated that the combination of all three features by using a support vector machine classification algorithm can provide a more accurate prediction than each feature alone in fibrosis diagnosis.

Assessment of non-invasive models for liver fibrosis in chronic hepatitis B virus related liver disease patients in resource limited settings.

PubMed

Shrivastava, Rakesh; Sen, Sourav; Banerji, Debabrata; Praharaj, Ashok K; Chopra, Gurvinder Singh; Gill, Satyajit Singh

2013-01-01

A total of 350 million individuals are affected by chronic hepatitis B virus infection world-wide. Historically, liver biopsy has been instrumental in adequately assessing patients with chronic liver disease. A number of non-invasive models have been studied world-wide. The aim of this study is to assess the utility of non-invasive mathematical models of liver fibrosis in chronic hepatitis B (CHB). Indian patients in a resource limited setting using routinely performed non-invasive laboratory investigations. A cross-sectional study carried out at a tertiary care center. A total of 52 consecutive chronic liver disease patients who underwent percutaneous liver biopsy and 25 healthy controls were enrolled in the study. Routine laboratory investigations included serum aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gama glutamyl transpeptidase (GGT), total bilirubin, total cholesterol, prothrombin time and platelet count. Three non-invasive models for namely aspartate aminotransferase to platelet ratio index (APRI), Fibrosis 4 (FIB-4) and Forn's index were calculated. Outcomes were compared for the assessment of best predictor of fibrosis by calculating the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each index. Medcalc online software and by Microsoft Excel Worksheet. Chi-square test was used for significance. P value < 0.05 was taken as significant. While the serum levels of AST, ALT and GGT were significantly higher in patients group as compare with the healthy controls (P < 0.01), the platelet counts were significantly lower in patient group as compared to the control group (P < 0.01). Mean value of all 3 indices were significantly higher in patients group as compare with the controls (P < 0.01). Out of the three indices, APRI index with a NPV of 95% appeared to be a better model for excluding significant liver fibrosis while FIB-4 with a PPV of 61% showed fair correlation with significant fibrosis. Thus, these two non-invasive models for predicting of liver fibrosis, namely APRI and FIB-4, can be utilized in combination as screening tools in monitoring of CHB patients, especially in resource limiting settings.

Effect of disease progression on liver apparent diffusion coefficient and T2 values in a murine model of hepatic fibrosis at 11.7 Tesla MRI.

PubMed

Anderson, Stephan W; Jara, Hernan; Ozonoff, Al; O'Brien, Michael; Hamilton, James A; Soto, Jorge A

2012-01-01

To evaluate the effects of hepatic fibrosis on ADC and T(2) values of ex vivo murine liver specimens imaged using 11.7 Tesla (T) MRI. This animal study was IACUC approved. Seventeen male, C57BL/6 mice were divided into control (n = 2) and experimental groups (n = 15), the latter fed a 3, 5-dicarbethoxy-1, 4-dihydrocollidine (DDC) supplemented diet, inducing hepatic fibrosis. Ex vivo liver specimens were imaged using an 11.7T MRI scanner. Spin-echo pulsed field gradient and multi-echo spin-echo acquisitions were used to generate parametric ADC and T(2) maps, respectively. Degrees of fibrosis were determined by the evaluation of a pathologist as well as digital image analysis. Scatterplot graphs comparing ADC and T(2) to degrees of fibrosis were generated and correlation coefficients were calculated. Strong correlation was found between degrees of hepatic fibrosis and ADC with higher degrees of fibrosis associated with lower hepatic ADC values. Moderate correlation between hepatic fibrosis and T(2) values was seen with higher degrees of fibrosis associated with lower T(2) values. Inverse relationships between degrees of fibrosis and both ADC and T(2) are seen, highlighting the utility of these parameters in the ongoing development of an MRI methodology to quantify hepatic fibrosis. Copyright © 2011 Wiley Periodicals, Inc.

Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients.

PubMed

Zanotti, Simona; Bragato, Cinzia; Zucchella, Andrea; Maggi, Lorenzo; Mantegazza, Renato; Morandi, Lucia; Mora, Marina

2016-01-15

Tissue fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the end point of diseases affecting the kidney, bladder, liver, lung, gut, skin, heart and muscle. In Duchenne muscular dystrophy (DMD), connective fibrotic tissue progressively substitutes muscle fibers. So far no specific pharmacological treatment is available for muscle fibrosis. Among promising anti-fibrotic molecules, pirfenidone has shown anti-fibrotic and anti-inflammatory activity in animal and cell models, and has already been employed in clinical trials. Therefore we tested pirfenidone anti-fibrotic properties in an in vitro model of muscle fibrosis. We evaluated effect of pirfenidone on fibroblasts isolated from DMD muscle biopsies. These cells have been previously characterized as having a pro-fibrotic phenotype. We tested cell proliferation and migration, secretion of soluble collagens, intracellular levels of collagen type I and fibronectin, and diameter of 3D fibrotic nodules. We found that pirfenidone significantly reduced proliferation and cell migration of control and DMD muscle-derived fibroblasts, decreased extracellular secretion of soluble collagens by control and DMD fibroblasts, as well as levels of collagen type I and fibronectin, and, in DMD fibroblasts only, reduced synthesis and deposition of intracellular collagen. Furthermore, pirfenidone was able to reduce the diameter of fibrotic-nodules in our 3D model of in vitro fibrosis. These pre-clinical results indicate that pirfenidone has potential anti-fibrotic effects also in skeletal muscle fibrosis, urging further studies in in vivo animal models of muscular dystrophy in order to translate the drug into the treatment of muscle fibrosis in DMD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Whey-hydrolyzed peptide-enriched immunomodulating diet prevents progression of liver cirrhosis in rats.

PubMed

Jobara, Kanta; Kaido, Toshimi; Hori, Tomohide; Iwaisako, Keiko; Endo, Kosuke; Uchida, Yoichiro; Uemoto, Shinji

2014-10-01

Liver fibrosis and subsequent cirrhosis is a major cause of death worldwide, but few effective antifibrotic therapies are reported. Whey-hydrolyzed peptide (WHP), a major peptide component of bovine milk, exerts anti-inflammatory effects in experimental models. A WHP-enriched diet is widely used for immunomodulating diets (IMD) in clinical fields. However, the effects of WHP on liver fibrosis remain unknown. The aim of this study was to investigate the antifibrotic effects of WHP in a rat cirrhosis model. Progressive liver fibrosis was induced by repeated intraperitoneal administration of dimethylnitrosamine (DMN) for 3 wk. Rats were fed either a WHP-enriched IMD (WHP group) or a control enteral diet (control group). The degree of liver fibrosis was compared between groups. Hepatocyte-protective effects were examined using hepatocytes isolated from rats fed a WHP diet. Reactive oxygen species and glutathione in liver tissue were investigated in the DMN cirrhosis model. Macroscopic and microscopic progression of liver fibrosis was remarkably suppressed in the WHP group. Elevated serum levels of liver enzymes and hyaluronic acid, and liver tissue hydroxyproline content were significantly attenuated in the WHP group. Necrotic hepatocyte rates with DMN challenge, isolated from rats fed a WHP-enriched IMD, were significantly lower. In the DMN cirrhosis model, reactive oxygen species were significantly lower, and glutathione was significantly higher in the WHP group's whole liver tissue. A WHP-enriched IMD effectively prevented progression of DMN-induced liver fibrosis in rats via a direct hepatocyte-protective effect and an antioxidant effect through glutathione synthesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Animal Models of Fibrotic Lung Disease

PubMed Central

Lawson, William E.; Oury, Tim D.; Sisson, Thomas H.; Raghavendran, Krishnan; Hogaboam, Cory M.

2013-01-01

Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell–cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease. PMID:23526222

Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

PubMed Central

Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients. PMID:27363523

Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction.

PubMed

Kato, Noritoshi; Kosugi, Tomoki; Sato, Waichi; Ishimoto, Takuji; Kojima, Hiroshi; Sato, Yuka; Sakamoto, Kazuma; Maruyama, Shoichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji

2011-02-01

Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor β. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and α-smooth muscle actin after transforming growth factor β stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Validation and comparison of seventeen noninvasive models for evaluating liver fibrosis in Chinese hepatitis B patients.

PubMed

Dong, Minhui; Wu, Jingwen; Yu, Xueping; Li, Jing; Yang, Sisi; Qi, Xun; Mao, Richeng; Zhang, Yongmei; Yu, Jie; Zhu, Haoxiang; Yang, Feifei; Qin, Yanli; Zhang, Jiming

2018-01-03

To avoid liver biopsy, many noninvasive models comprised of serum markers for liver fibrosis assessment have been developed. Given that most of them were developed in hepatitis C cohorts and few of them have been validated in Chinese hepatitis B patients, we aim to conduct this validation and compare their diagnostic accuracies in such a population. A total of 937 HBV-infected patients who underwent liver biopsy were included in this single-centre retrospective study. The diagnostic accuracies of the 17 noninvasive models were assessed by areas under the receiver-operating characteristic curves (AUROCs), using histologically evaluated fibrotic stages of the biopsy specimens as standards. To compare efficiencies of the models, a grading system based on AUROC levels was developed. For discriminating significant fibrosis in all patients, the best three noninvasive models were King's score (AUROC = 0.756), Virahep-C model (AUROC = 0.756) and GPR (AUROC = 0.744); and for diagnosing cirrhosis, Lok index (AUROC = 0.832), FI (AUROC = 0.820) and FIB-4 (AUROC = 0.818) got the first three places. AUROCs in HBeAg-positive group were generally higher than those in HBeAg-negative group. In addition, based on the grading system, Virahep-C and GPR outstood others in evaluating liver fibrosis in all patients. In Chinese HBV-infected patients, Virahep-C models and GPR had high accuracies in diagnosing liver fibrosis and cirrhosis, while the most discussed models like APRI and FIB-4 did not outstand. Assessment should take into account the HBeAg sero-status, since these noninvasive models were more appropriate for HBeAg-positive patients than HBeAg-negative ones. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The porcine lung as a potential model for cystic fibrosis

PubMed Central

Rogers, Christopher S.; Abraham, William M.; Brogden, Kim A.; Engelhardt, John F.; Fisher, John T.; McCray, Paul B.; McLennan, Geoffrey; Meyerholz, David K.; Namati, Eman; Ostedgaard, Lynda S.; Prather, Randall S.; Sabater, Juan R.; Stoltz, David Anthony; Zabner, Joseph; Welsh, Michael J.

2008-01-01

Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans. In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF. PMID:18487356

Identification of Cadherin 11 as a Mediator of Dermal Fibrosis and Possible Role in Systemic Sclerosis

PubMed Central

Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert; George, Anuh-Teresa; Mayes, Maureen D.; Assassi, Shervin; Tan, Filemon K.; Brenner, Michael B.; Agarwal, Sandeep K.

2014-01-01

Objective Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Methods Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11–deficient mice and anti–Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow–derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Results Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11–knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti–Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. Conclusion These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc. PMID:24757152

Trigeminofacial reflex: a means of detecting proximity to ophthalmic and maxillary divisions of the trigeminal nerve during surgery.

PubMed

AlMasri, Omar A; Brown, Emma E; Forster, Alan; Kamel, Mahmoud H

2014-11-01

The aim in this paper was to localize and detect incipient damage to the ophthalmic and maxillary branches of the trigeminal nerve during tumor surgery. This was an observational study of patients with skull base, retroorbital, or cavernous sinus tumors warranting dissection toward the cavernous sinus at a university hospital. Stimuli were applied as normal during approach to the cavernous sinus to localize cranial nerves (CNs) III, IV, and VI. Recordings were also obtained from the facial muscles to localize CN VII. The trigeminofacial reflex was sought simply by observing a longer time base routinely. Clear facial electromyography responses were reproduced when stimuli were applied to the region of V1, V2, and V3. Response latency was increased compared with direct CN VII stimuli seen in some cases. Responses gave early warning of approach to these sensory trigeminal branches. The authors submit this as a new technique, which may improve the chances of preserving trigeminal sensory branches during surgery in this region.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rudeen, David Keith; Weber, Paula D.; Lord, David L.

The U.S. Strategic Petroleum Reserve implemented the first stage of a leach plan in 2011-2012 to expand storage volume in the existing Bryan Mound 113 cavern from a starting volume of 7.4 million barrels (MMB) to its design volume of 11.2 MMB. The first stage was terminated several months earlier than expected in August, 2012, as the upper section of the leach zone expanded outward more quickly than design. The oil-brine interface was then re-positioned with the intent to resume leaching in the second stage configuration. This report evaluates the as-built configuration of the cavern at the end of themore » first stage, and recommends changes to the second stage plan in order to accommodate for the variance between the first stage plan and the as-built cavern. SANSMIC leach code simulations are presented and compared with sonar surveys in order to aid in the analysis and offer projections of likely outcomes from the revised plan for the second stage leach.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dachman, A.H.; Lichtenstein, J.E.; Friedman, A.C.

Infantile hemangioendothelioma is the most common symptomatic vascular liver tumor of infancy. It is considered a benign tumor; however, aggressive behavior is occasionally seen microscopically, and rarely distant metastases have been reported. The exact incidence of infantile hemangioendothelioma is difficult to determine because often it has been either misdiagnosed or mislabeled as cavernous hemangioma in the literature. Cavernous hemangioma is the most common primary liver tumor in older age groups but is rarely found in infants as a clinically significant tumor. Levick and Rubie were the first to recognize an association between hemangioendothelioma of the liver and congestive heart failure,more » and there were subsequent reports substantiating this association. However, it is our impression and the finding of others that congestive heart failure is distinctly less common than abdominal mass or hepatomegaly as the presenting sign in infantile hemangioendothelioma. Congestive heart failure is rarely a feature of cavernous hemangioma. Because of the errors in terminology and questions regarding clinical presentation, a radiologic-pathologic-clinical correlation study of infantile hemangioendothelioma and review of the literature was undertaken.« less

Characterization of mixing and yield stress of pretreated wheat straw slurries used for the production of biofuels through tomography technique.

PubMed

Naghavi-Anaraki, Yasaman; Turcotte, Ginette; Ein-Mozaffari, Farhad

2018-05-29

Wheat straw is a low-cost feedstock for the production of biofuel. Pretreatment process is an important stage in producing biofuels since it makes the fibers more accessible to enzymatic hydrolysis which is the final step of producing biofuels. Pretreated wheat straw (PWS) slurries are non-Newtonian fluids with yield stress. Mixing of fluids exhibiting yield stress such as the pretreated wheat straw slurry results in the generation of cavern, which is a fully-mixed zone, around the impeller and the stationary regions elsewhere, which causes difficulties in the production of biofuels. In this study, the non-invasive electrical resistance tomography technique was utilized to determine the cavern dimensions as a function of the impeller type and impeller speed. The cavern sizes were then used to measure the yield stress of PWS slurries as a function of fiber size (≤ 2 and ≤ 6 mm) and fiber concentration (6, 8, and 10 wt%).

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres.

PubMed

Povedano, Juan Manuel; Martinez, Paula; Serrano, Rosa; Tejera, Águeda; Gómez-López, Gonzalo; Bobadilla, Maria; Flores, Juana Maria; Bosch, Fátima; Blasco, Maria A

2018-01-30

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9- Tert -treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9- Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres. © 2018, Povedano et al.

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

PubMed Central

Serrano, Rosa; Tejera, Águeda; Gómez-López, Gonzalo; Bobadilla, Maria; Flores, Juana Maria; Bosch, Fátima

2018-01-01

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1–3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres. PMID:29378675

Continuous-wave optical stimulation of the rat prostate nerves using an all-single-mode 1455 nm diode laser and fiber system

NASA Astrophysics Data System (ADS)

Tozburun, Serhat; Lagoda, Gwen A.; Burnett, Arthur L.; Fried, Nathaniel M.

2011-03-01

Optical nerve stimulation (ONS) has recently been reported as a potential alternative to electrical nerve stimulation. Continuous-wave (CW) laser stimulation of the prostate cavernous nerves (CN) in a rat model, in vivo, has also been demonstrated in our previous studies. The objective of this study is to present a new all-single-mode-fiber configuration for ONS with the laser operating in CW mode for potential diagnostic applications. An infrared pigtailed single-mode diode laser (λ = 1455 nm) was used in this study for noncontact ONS. This new all-fiber approach introduces several advantages including: (1) a less expensive and more compact ONS system, (2) elimination of alignment of optical components, and (3) an improved spatial beam profile. Successful optical stimulation of the rat CN using this new design was observed after the CN reached a threshold temperature of ~ 41 °C with response times as short as 3 s. Upon further study, this configuration may be useful for identification and preservation of the cavernous nerves during prostate cancer surgery.

Can Contrast-Enhanced Sonography Detect Bowel Wall Fibrosis in Mixed Inflammatory and Fibrotic Crohn Disease Lesions in an Animal Model?

PubMed

Dillman, Jonathan R; Rubin, Jonathan M; Johnson, Laura A; Moons, David S; Higgins, Peter D R

2017-03-01

To determine whether contrast-enhanced sonographic quantitative perfusion parameters can detect bowel wall fibrosis in the setting of mixed inflammatory and fibrotic lesions in a Crohn disease animal model. This study was approved by the institutional Committee on the Use and Care of Animals. Multiple (range, 1-5) 2,4,6-trinitrobenzenesulfonic acid-ethanol enemas were used to create intestinal inflammatory lesions with variable fibrosis in female Lewis rats. Low-mechanical index contrast-enhanced sonography was performed 3 days after the final enema using a 0.2-mL bolus of sulfur hexafluoride microbubbles injected through a tail vein. Contrast-enhanced sonographic data were analyzed with software that converts video data into echo-power (linearized) data. Colorectal lesions were scored for histopathologic inflammation and fibrosis; bowel wall collagen was quantified by Western blotting. The Spearman correlation was used to assess associations between contrast-enhanced sonographic quantitative parameters and bowel wall collagen; the Kruskal-Wallis test was used to compare continuous results between histopathologic groups. Thirty-one animals were included in our analysis. Animals were placed into 3 histopathologic cohorts: (1) severe bowel wall inflammation/minimal or no fibrosis (n = 11); (2) severe bowel wall inflammation/moderate fibrosis (n = 9); and (3) severe bowel wall inflammation/severe fibrosis (n = 11). Western blotting showed a significant difference in bowel wall collagen between histopathologic cohorts (P = .0001). There was no correlation between any contrast-enhanced sonographic quantitative parameter and bowel wall collagen (P > .05). There was no difference between histopathologic cohorts for any contrast-enhanced sonographic quantitative parameter (P > .05). Contrast-enhanced sonographic quantitative perfusion parameters failed to effectively detect bowel wall fibrosis in the setting of superimposed inflammation in a Crohn disease animal model. © 2017 by the American Institute of Ultrasound in Medicine.

Lysyl oxidase‑like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis.

PubMed

Choi, Sung-Eun; Jeon, Nara; Choi, Hoon Young; Shin, Jae Il; Jeong, Hyeon Joo; Lim, Beom Jin

2017-09-01

Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor‑β (TGF‑β) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase‑like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK‑2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis.

A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84.

PubMed

Gagnon, Lyne; Leduc, Martin; Thibodeau, Jean-Francois; Zhang, Ming-Zhi; Grouix, Brigitte; Sarra-Bournet, Francois; Gagnon, William; Hince, Kathy; Tremblay, Mikaël; Geerts, Lilianne; Kennedy, Christopher R J; Hébert, Richard L; Gutsol, Alex; Holterman, Chet E; Kamto, Eldjonai; Gervais, Liette; Ouboudinar, Jugurtha; Richard, Jonathan; Felton, Alexandra; Laverdure, Alexandre; Simard, Jean-Christophe; Létourneau, Sylvie; Cloutier, Marie-Pier; Leblond, Francois A; Abbott, Shaun D; Penney, Christopher; Duceppe, Jean-Simon; Zacharie, Boulos; Dupuis, Jocelyn; Calderone, Angelino; Nguyen, Quang T; Harris, Raymond C; Laurin, Pierre

2018-05-01

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

PubMed Central

Mahavadi, Poornima; Sasikumar, Satish; Cushing, Leah; Hyland, Tessa; Rosser, Ann E.; Riccardi, Daniela; Lu, Jining; Kalin, Tanya V.; Kalinichenko, Vladimir V.; Guenther, Andreas; Ramirez, Maria I.; Pardo, Annie; Selman, Moisés; Warburton, David

2013-01-01

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity. PMID:24375798

Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis

PubMed Central

Stiedl, Patricia; McMahon, Robert; Blaas, Leander; Stanek, Victoria; Svinka, Jasmin; Grabner, Beatrice; Zollner, Gernot; Kessler, Sonja M.; Claudel, Thierry; Müller, Mathias; Mikulits, Wolfgang; Bilban, Martin; Esterbauer, Harald; Eferl, Robert; Haybaeck, Johannes; Trauner, Michael; Casanova, Emilio

2016-01-01

Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. Conclusion Our findings suggest that GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. PMID:25179284

Effect of Green Tea Extract Encapsulated Into Chitosan Nanoparticles on Hepatic Fibrosis Collagen Fibers Assessed by Atomic Force Microscopy in Rat Hepatic Fibrosis Model.

PubMed

Safer, Abdel-Majeed A; Hanafy, Nomany A; Bharali, Dhruba J; Cui, Huadong; Mousa, Shaker A

2015-09-01

The present study examined the effect of Green Tea Extract (GTE) encapsulated into Chitosan Nanoparticles (CS-NPs) on hepatic fibrosis in rat model as determined by atomic force microscopy (AFM). The bioactive compounds in GTE encapsulated into CS-NPs were determined using LC-MS/MS method. Additionally, the uptake of GTE-CS NPs in HepG2 cells showed enhanced uptake. In experimental fibrosis model, AFM was used as a high resolution microscopic tool to investigate collagen fibers as an indicator of hepatic fibrosis induced by treatment with CCl4. Paraffin sections of fibrotic liver tissues caused by CC4 treatment of rats and the effect of GTE-CS NPs treatment with or without CCl4 on hepatic fibrosis were examined. Liver tissues from the different groups of animals were de-waxed and processed as for normal H/E staining and Masson's trichrome staining to locate the proper area of ECM collagen in the CCl4 group versus collagen in liver tissues treated with the GTE-CS NPs with or without CCl4. Selected areas of paraffin sections were trimmed off and fixed flat on top of mica and inserted in the AFM stage. H/E staining, Masson's trichrome stained slides, and AFM images revealed that collagen fibers of 250 to 300 nm widths were abundant in the fibrotic liver samples while those of GTE-CS NPs were clear as in the control group. Data confirmed the hypothesis that GTE-CS NPs are effective in removing all the extracellular collagen caused by CCl4 in the hepatic fibrosis rat liver.

Gpr110 deficiency decelerates carcinogen-induced hepatocarcinogenesis via activation of the IL-6/STAT3 pathway

PubMed Central

Ma, Benting; Zhu, Junjie; Tan, Juan; Mao, Yulei; Tang, Lingyun; Shen, Chunling; Zhang, Hongxing; Kuang, Ying; Fei, Jian; Yang, Xiao; Wang, Zhugang

2017-01-01

Hepatocarcinogenesis is a complex process that includes pronounced necroinflammation, unregulated hepatocyte damage, subsequent extensive fibrosis, and carcinogenesis. GPR110 was an adhesion G protein-coupled receptor. Analysis of the expression pattern of Gpr110 in mice displayed that Gpr110 was expressed highly in liver, implicating the tissue compartments where Gpr110 could execute its functions, the role of Gpr110 in the physiological and pathological state of liver remains unclear. Based on a Gpr110 knockout mouse model, we evaluated the role of Gpr110 in hepatocarcinogenesis by using a carbon tetrachloride (CCl4)-induced liver injury and fibrosis model, as well as diethylnitrosamine (DEN) plus CCl4-induced liver cancer model. In this study, we found subdued chronic liver injury, reduced compensatory proliferation, lower liver fibrosis, but enhanced inflammation occurred in Gpr110-/- mice during CCl4 challenge. In addition, Gpr110-/- mice were resistant to liver tumorigenesis induced by DEN plus CCl4 injection. Molecular mechanisms underlying these differences correlated with augmented activation of the IL-6/STAT3 pathway, which exerted hepatoprotective effects during liver damage, fibrosis, and oncogenesis in Gpr110-/- mice. Furthermore, pharmacological inhibition of the activation of the IL-6/STAT3 pathway enhanced hepatic fibrosis and promoted DEN plus CCl4-induced carcinogenesis in Gpr110-/- mice. In summary, absence of Gpr110 decelerates liver fibrosis/cirrhosis progressing into tumorigenesis, due to strengthening activation of the IL-6/STAT3 pathway, leading to a weaker liver injury and fibrosis microenvironment. It is indicated that targeting Gpr110 and activating the IL-6/STAT3 pathway may be considered to be preventive methods for some cirrhosis transition. PMID:28401002

Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

PubMed

Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

2014-01-01

Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models.

PubMed

Yu, Wencheng; Guo, Fang; Song, Xiaoxia

2017-12-01

Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown. This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay. After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p < 0.05) significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-β1, TNF-α and PDGF, but the expression of Cav-1 was higher (p < 0.05). Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p < 0.05). Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores (r = -0.506, p < 0.01; r = -0.676, p < 0.01) as well as expression of TGF-β1, TNF-α and PDGF (r = -0.590, p < 0.01; r = -0.530, p < 0.01; r = -0.553, p < 0.01). Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.

Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries.

PubMed

Beaussier, Marc; Wendum, Dominique; Schiffer, Eduardo; Dumont, Sylvie; Rey, Colette; Lienhart, André; Housset, Chantal

2007-03-01

Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of alpha-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.

Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis

PubMed Central

Li, Chun-Hui; Pan, Li-Hui; Yang, Zong-Wei; Li, Chun-Yu; Xu, Wen-Xie

2008-01-01

AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10 μL/kg body weight, i.p), 3 times a week for 4 wk. The rats in the 3 treatment groups including a high-dose DMN group (10 mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4 mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type IV collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy. RESULTS: Compared with the model control group, the serum levels of HA, LN, type IV collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P < 0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P < 0.05). CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis. PMID:18567088

SENP1 attenuates the liver fibrosis through down-regulating the expression of SMAD2.

PubMed

Wu, Linshi; Qiu, Weiqing; Sun, Jianhua; Wang, Jian

2018-01-01

To investigate whether SENP1 could play a regulating role in the liver fibrosis process, the Sprague-Dawley (SD) rats were used to establish the liver fibrosis rat models by intraperitoneally injecting with 1 ml/kg of 10% CCl 4 , while the control normal rats were injected with olive oil. Then confirmation experiments to verify the successful establishment of these models were conducted by detecting the cellular and lobular architecture, and liver function indexes using hematoxylin-eosin staining, Masson's trichrome staining and microplate method, respectively. In addition, the expression levels of fibrosis markers including collagen I, collagen III, α-SMA and TGF-β1 were inspected using quantitative real-time PCR (qRT-PCR), as well as SMAD2. Subsequently, the relative mRNA and protein level of SENP1 was also determined via qRT-PCR and western blot analysis. Next, the HSC-T6 cells of SENP1 knock-down were constructed and used to test the relative protein expression levels of α-SMA and SMAD2 in these cells. The results of hematoxylin-eosin staining, Masson's trichrome staining and microplate method turned out that the rat liver fibrosis models were constructed successfully, which was further confirmed by the increased expression of collagen I, collagen III, α-SMA and TGF-β1 in mRNA and protein level, as well as SMAD2. Then the expression of SENP1 was overexpressed in the rat liver fibrosis models induced by CCl 4 and the TGF-β1 treatment could increase the protein expression level of collagen I, collagen III and α-SMA. Lastly, the SENP1 knockdown HSC-T6 cells were successfully constructed, while the silence of SENP1 down-regulated the protein expression of α-SMA and SMAD2. In conclusion, this study provided a new regulation mechanism about the liver fibrosis process. Copyright © 2017 Elsevier Inc. All rights reserved.

The Usefulness of Diffusion Tensor Imaging and Tractography in Surgery of Brainstem Cavernous Malformations.

PubMed

Januszewski, Jacob; Albert, Lauren; Black, Karen; Dehdashti, Amir R

2016-09-01

Diffusion tensor imaging (DTI) estimates the course and connectivity patterns of white matter tracts. The objective of this study is to evaluate whether findings in the brain stem modify the preoperative surgical trajectory planning or postoperative outcome in patients with brain stem cavernous malformations. Ten patients with symptomatic brainstem cavernous malformation underwent surgical resection. Five patients received preoperative DTI evaluation and the remaining 5 did not. Reconstructed DTI tracts consisted of corticospinal, medial lemnisci, and cerebellar peduncles. The surgical planning and postoperative outcome were evaluated. In 5 patients with no preoperative DTI evaluation, surgical planning was based on anatomic landmark and the 2-point technique. The other 5 patients underwent preoperative DTI, and findings were factored into the selection of the surgical approach. In 3 of the 5 cases with DTI evaluation, the 2-point technique suggested a similar trajectory. In the other 2, the DTI findings suggested a different approach to avoid damage to the white matter tract. Two patients in the group with no DTI had immediate postoperative new or worsened deficit, which improved at long-term follow-up. No patient in the DTI group had a new neurologic deficit. Compared with the standard magnetic resonance imaging, DTI provided improved visualization of cavernous malformation involvement in eloquent fiber tracts of the brainstem. This additional information might help in selecting a more appropriate surgical trajectory in selected lesions. Larger patient cohorts are needed to assess the effect of this modality in patients' outcome. Published by Elsevier Inc.

Hydatid liver cyst causing portal vein thrombosis and cavernous transformation: a case report and literature review

PubMed Central

Kirmizi, Serdar; Kayaalp, Cuneyt; Yilmaz, Sezai

2016-01-01

A 33-year-old male with abdominal distention after meals was admitted to the hospital. He had a history of surgery for hydatid liver cyst. The cyst was located at the liver hilum and there were portal venous thrombosis and cavernous transformation. It had been treated with partial cystectomy, omentoplasty and albendazole. Two years later at the admission to our center, his laboratory tests were in normal ranges. Abdominal imaging methods revealed splenomegaly, portal vein thrombosis, cavernous transformation and the previously operated hydatid liver cyst. Upper gastrointestinal endoscopy demonstrated esophageal and gastric fundal varices. Due to his young age and low risk for surgery, the patient was planned for surgical treatment of both pathologies at the same time. At laparotomy, hydatid liver cyst was obliterated with omentum and there was no sign of active viable hydatid disease. A meso-caval shunt with an 8 mm in-diameter graft was created. In the postoperative period, his symptoms and endoscopic varices were regressed. There were four similar cases reported in the literature. This one was the youngest and the only one treated by a surgical shunt. Hydatid liver cysts that located around the hilum can lead to portal vein thrombosis and cavernous thrombosis. Treatment should consist of both hydatid liver cyst and portal hypertension. To the best of our knowledge, this was the first case of surgically treated portal vein thrombosis that was originated from a hydatid liver cyst. PMID:27895860

Fractionated Proton Radiotherapy for Benign Cavernous Sinus Meningiomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slater, Jerry D., E-mail: jdslater@dominion.llumc.edu; Loredo, Lilia N.; Chung, Arthur

2012-08-01

Purpose: To evaluate the efficacy of fractionated proton radiotherapy for a population of patients with benign cavernous sinus meningiomas. Methods and Materials: Between 1991 and 2002, 72 patients were treated at Loma Linda University Medical Center with proton therapy for cavernous sinus meningiomas. Fifty-one patients had biopsy or subtotal resection; 47 had World Health Organization grade 1 pathology. Twenty-one patients had no histologic verification. Twenty-two patients received primary proton therapy; 30 had 1 previous surgery; 20 had more than 1 surgery. The mean gross tumor volume was 27.6 cm{sup 3}; mean clinical target volume was 52.9 cm{sup 3}. Median totalmore » doses for patients with and without histologic verification were 59 and 57 Gy, respectively. Mean and median follow-up periods were 74 months. Results: The overall 5-year actuarial control rate was 96%; the control rate was 99% in patients with grade 1 or absent histologic findings and 50% for those with atypical histology. All 21 patients who did not have histologic verification and 46 of 47 patients with histologic confirmation of grade 1 tumor demonstrated disease control at 5 years. Control rates for patients without previous surgery, 1 surgery, and 2 or more surgeries were 95%, 96%, and 95%, respectively. Conclusions: Fractionated proton radiotherapy for grade 1 cavernous sinus meningiomas achieves excellent control rates with minimal toxicities, regardless of surgical intervention or use of histologic diagnosis. Disease control for large lesions can be achieved by primary fractionated proton therapy.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lord, Anna C.

The U.S. Strategic Petroleum Reserve (SPR) is a stockpile of emergency crude oil to be tapped into if a disruption in the nation's oil supply occurs. The SPR is comprised of four salt dome sites. Subsidence surveys have been conducted either annually or biennially at all four sites over the life of the program. Monitoring of surface behavior is a first line defense to detecting possible subsurface cavern integrity issues. Over the life of the Bryan Mound site, subsidence rates over abandoned Cavern 3 have continuously been the highest at the site. In an effort to try and understand themore » subsurface dynamics, specifically over Bryan Mound Cavern 3, historic interferometric synthetic aperture radar (InSAR) data was acquired and processed by TRE Altamira. InSAR involves the processing of multiple satellite synthetic aperture radar scenes acquired across the same location of the Earth's surface at different times to map surface deformation. The analysis of the data has the ability to detect millimeters of motion spanning days, months, year and decades, across specific sites. The intent in regards to the Bryan Mound site was (1) to confirm the higher subsidence rates recorded over abandoned Cavern 3 indicated by land survey and (2) understand the regional surface behavior. This report describes the InSAR analysis results, how those results compare to the historical collection of land survey data, and what additional information the data has provided towards understanding the response recorded at the surface.« less

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

PubMed Central

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M.; Lineburg, Katie E.; Alexander, Kylie A.; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R.; Serody, Jonathan S.; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome; MacDonald, Kelli P.; Schacker, Timothy W.; Luznik, Leo

2017-01-01

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen–mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. PMID:28254742

Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis

PubMed Central

Hohwieler, Meike; Perkhofer, Lukas; Liebau, Stefan; Seufferlein, Thomas; Müller, Martin

2016-01-01

Cystic fibrosis (CF) is one of the most frequently occurring inherited human diseases caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which lead to ample defects in anion transport and epithelial fluid secretion. Existing models lack both access to early stages of CF development and a coeval focus on the gastrointestinal CF phenotypes, which become increasingly important due increased life span of the affected individuals. Here, we provide a comprehensive overview of gastrointestinal facets of CF and the opportunity to model these in various systems in an attempt to understand and treat CF. A particular focus is given on forward-leading organoid cultures, which may circumvent current limitations of existing models and thereby provide a platform for drug testing and understanding of disease pathophysiology in gastrointestinal organs. PMID:28815024

Agent based simulations in disease modeling Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca

NASA Astrophysics Data System (ADS)

Pappalardo, Francesco; Pennisi, Marzio

2016-07-01

Fibrosis represents a process where an excessive tissue formation in an organ follows the failure of a physiological reparative or reactive process. Mathematical and computational techniques may be used to improve the understanding of the mechanisms that lead to the disease and to test potential new treatments that may directly or indirectly have positive effects against fibrosis [1]. In this scenario, Ben Amar and Bianca [2] give us a broad picture of the existing mathematical and computational tools that have been used to model fibrotic processes at the molecular, cellular, and tissue levels. Among such techniques, agent based models (ABM) can give a valuable contribution in the understanding and better management of fibrotic diseases.

Reversal of liver fibrosis: From fiction to reality.

PubMed

Zoubek, Miguel Eugenio; Trautwein, Christian; Strnad, Pavel

2017-04-01

In chronic liver diseases, an ongoing hepatocellular injury together with inflammatory reaction results in activation of hepatic stellate cells (HSCs) and increased deposition of extracellular matrix (ECM) termed as liver fibrosis. It can progress to cirrhosis that is characterized by parenchymal and vascular architectural changes together with the presence of regenerative nodules. Even at late stage, liver fibrosis is reversible and the underlying mechanisms include a switch in the inflammatory environment, elimination or regression of activated HSCs and degradation of ECM. While animal models have been indispensable for our understanding of liver fibrosis, they possess several important limitations and need to be further refined. A better insight into the liver fibrogenesis resulted in a large number of clinical trials aiming at reversing liver fibrosis, particularly in patients with non-alcoholic steatohepatitis. Collectively, the current developments demonstrate that reversal of liver fibrosis is turning from fiction to reality. Copyright © 2017. Published by Elsevier Ltd.

Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis.

PubMed

Iacobellis, Angelo; Marcellini, Matilde; Andriulli, Angelo; Perri, Francesco; Leandro, Gioacchino; Devito, Rita; Nobili, Valerio

2006-12-28

To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). BMI helps identify children with NASH who might have fibrotic deposition in the liver.

Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

PubMed

Li, Longkai; Shen, Nan; Wang, Nan; Wang, Weidong; Tang, Qingzhu; Du, Xiangning; Carrero, Juan Jesus; Wang, Keping; Deng, Yiyao; Li, Zhitong; Lin, Hongli; Wu, Taihua

2018-06-01

Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flechsig, Paul; Hartenstein, Bettina; Teurich, Sybille

2010-06-01

Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results:more » We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.« less

Correlation of four potential biomarkers of liver fibrosis with liver function and grade of hepatic fibrosis in a neonatal cholestatic rat model.

PubMed

Tang, Ning; Zhang, Yaping; Liu, Zeyu; Ai, Xuemei; Liang, Qinghong

2017-07-01

The present study investigated the correlation between four serum biomarkers of liver fibrosis, liver function and pathological hepatic fibrosis grade in neonatal cholestatic rats. A total of 38 Sprague‑Dawley rats, aged 3 weeks, were randomly assigned to the experimental group (EG), control group (CG) and the blank control group (BCG). EG received intragastric administration of 1% α‑naphthylisothiocyanate, 75 mg/kg, to induce acute cholestasis liver injury, CG and BCG were set as control groups. Blood samples from all groups were collected 48 h following the procedure. The levels of liver function markers, and four biomarkers of liver fibrosis in serum, were measured and sections of liver tissue were stained for pathological analysis. The results of the present study demonstrated that the degree of hepatic fibrosis in EG, in the serum levels or by pathological analysis, was markedly more evident compared with the CG. Several indices of four biomarkers for liver fibrosis in serum were identified and correlated with the levels of liver function markers. The pathological hepatic fibrosis grade was correlated with γ‑glutamyl transferase (γ‑GT) and Hyaluronic acid (HA). Therefore, HA and γ‑GT were positively correlated with the grade of hepatic fibrosis, indicating their efficacy as biomarkers of infantile cholestatic hepatic fibrosis.

Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients.

PubMed

Attallah, Abdelfattah M; Abdallah, Sanaa O; Attallah, Ahmed A; Omran, Mohamed M; Farid, Khaled; Nasif, Wesam A; Shiha, Gamal E; Abdel-Aziz, Abdel-Aziz F; Rasafy, Nancy; Shaker, Yehia M

2013-01-01

Several noninvasive predictive models were developed to substitute liver biopsy for fibrosis assessment. To evaluate the diagnostic value of fibronectin which reflect extracellular matrix metabolism and standard liver functions tests which reflect alterations in hepatic functions. Chronic hepatitis C (CHC) patients (n = 145) were evaluated using ROC curves and stepwise multivariate discriminant analysis (MDA) and was validated in 180 additional patients. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, albumin, complete blood count were estimated. Fibronectin concentration was determined using monoclonal antibody and ELISA. A novel index named fibronectin discriminant score (FDS) based on fibronectin, APRI and albumin was developed. FDS produced areas under ROC curves (AUC) of 0.91 for significant fibrosis and 0.81 for advanced fibrosis. The FDS correctly classified 79% of the significant liver fibrosis patients (F2-F4) with 87% sensitivity and 75% specificity. The relative risk [odds ratio (OR)] of having significant liver fibrosis using the cut-off values determined by ROC curve analyses were 6.1 for fibronectin, 4.9 for APRI, and 4.2 for albumin. FDS predicted liver fibrosis with an OR of 16.8 for significant fibrosis and 8.6 for advanced fibrosis. The FDS had similar AUC and OR in the validation group to the estimation group without statistically significant difference. FDS predicted liver fibrosis with high degree of accuracy, potentially decreasing the number of liver biopsy required.

Protective Effect of Astaxanthin on Liver Fibrosis through Modulation of TGF-β1 Expression and Autophagy

PubMed Central

Shen, Miao; Chen, Kan; Lu, Jie; Cheng, Ping; Xu, Ling; Dai, Weiqi; Wang, Fan; He, Lei; Zhang, Yan; Chengfen, Wang; Li, Jingjing; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan; Zhou, Yingqun; Guo, Chuanyong

2014-01-01

Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors. PMID:24860243

The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

PubMed Central

Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P.; Williams, David B.; Kamp, David W.

2015-01-01

Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. PMID:26370974

Therapeutic Effects of Human Amniotic Fluid-Derived Stem Cells on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

PubMed Central

Yin, Zhongcheng; Zhou, Xudong; Li, Xiaoju; Xiao, Aiguo

2013-01-01

Interstitial fibrosis is regarded as the main pathway for the progression of chronic kidney disease (CKD) and is often associated with severe renal dysfunction. Stem cell-based therapies may provide alternative approaches for the treatment of CKD. Human amniotic fluid-derived stem cells (hAFSCs) are a novel stem cell population, which exhibit both embryonic and mesenchymal stem cell characteristics. Herein, the present study investigated whether the transplantation of hAFSCs into renal tissues could improve renal interstitial fibrosis in a murine model of unilateral ureteral obstruction (UUO). We showed that hAFSCs provided a protective effect and alleviated interstitial fibrosis as reflected by an increase in microvascular density; additionally, hAFSCs treatment beneficially modulated protein levels of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1). Therefore, we hypothesize that hAFSCs could represent an alternative, readily available source of stem cells that can be applied for the treatment of renal interstitial fibrosis. PMID:23724119

Comparative effects of torasemide and furosemide on gap junction proteins and cardiac fibrosis in a rat model of dilated cardiomyopathy.

PubMed

Watanabe, Kenichi; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Giridharan, Vijayasree V; Antony, Shanish; Harima, Meilei; Nakamura, Masahiko; Suzuki, Kenji; Suzuki, Hiroshi; Sone, Hirohito; Arumugam, Somasundaram

2017-03-01

Cardiac fibrosis is the major hallmark of adverse cardiac remodeling in chronic heart failure (CHF) and its therapeutic targeting might help against cardiac dysfunction during chronic conditions. Diuretic agents are potentially useful in these cases, but their effects on the cardiac fibrosis pathogenesis are yet to be identified. This study was designed to identify and compare the effects of diuretic drugs torasemide and furosemide on cardiac fibrosis in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin mediated experimental autoimmune myocarditis. Gap junction proteins, connexin-43 and N-cadherin, expressions were downregulated in the hearts of CHF rats, while torasemide treatment has upregulated their expression. Western blotting and immunohistochemical analysis for various cardiac fibrosis related proteins as well as histopathological studies have shown that both drugs have potential anti-fibrotic effects. Among them, torasemide has superior efficacy in offering protection against adverse cardiac remodeling in the selected rat model of dilated cardiomyopathy. In conclusion, torasemide treatment has potential anti-fibrotic effect in the hearts of CHF rats, possibly via improving the gap junction proteins expression and thereby improving the cell-cell interaction in the heart. © 2016 BioFactors, 43(2):187-194, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

PNPLA3 rs738409 polymorphism is associated with liver fibrosis progression in patients with chronic hepatitis C: A repeated measures study.

PubMed

Jiménez-Sousa, María Ángeles; Gómez-Moreno, Ana Zaida; Pineda-Tenor, Daniel; Sánchez-Ruano, Juan José; Fernández-Rodríguez, Amanda; Artaza-Varasa, Tomas; Gómez-Sanz, Alicia; Martín-Vicente, María; Vázquez-Morón, Sonia; Resino, Salvador

2018-06-01

Host genetic background has been associated with liver fibrosis progression. To analyze the association between the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. In this retrospective cohort study, 187 patients with chronic HCV infection were included, who had at least two liver stiffness measurements (LSM) by transient elastography during the follow-up. Results were expressed in kilopascals (kPa). The analysis of genetic association was carried out according to additive model by using Generalized Linear Models. No patients had advanced fibrosis/cirrhosis at baseline. During a median follow-up time of 47.9 months, 15 patients developed advanced fibrosis and 17 cirrhosis. In multivariate analysis adjusted by the main clinical and epidemiological covariates, the rs738409 G allele was related to higher increase of LSM values during the follow-up (adjusted arithmetic mean ratio (aAMR) = 1.16 (95%CI = 1.04; 1.29); p = .006) and higher odds of having progression to advanced fibrosis [aOR = 2.03 (95%CI = 1.01; 4.06); p = .045], and progression to cirrhosis [aOR = 3.03 (95%CI = 1.26; 7.30); p = .014]. PNPLA3 rs738409 polymorphism appears to be related to the increased progression of liver fibrosis in HCV infected patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Two assays for measuring fibrosis: reverse transcriptase-polymerase chain reaction of collagen alpha(1) (III) mRNA is an early predictor of subsequent collagen deposition while a novel serum N-terminal procollagen (III) propeptide assay reflects manifest fibrosis in carbon tetrachloride-treated rats.

PubMed

Kauschke, S G; Knorr, A; Heke, M; Kohlmeyer, J; Schauer, M; Theiss, G; Waehler, R; Burchardt, E R

1999-11-15

Using a novel quantitative reverse transcriptase-polymerase chain reaction assay, we have determined the amount of specific mRNA for procollagen alpha(1) (III) (PIIIP) in the carbon tetrachloride (CCl(4)) model of liver fibrosis in rats. After a single week of CCl(4) application, the amount of PIIIP mRNA was increased approximately 10 times over the untreated control group and continued to increase to approximately 30 times after 7 weeks of intoxication. In this model substantial fibrosis was demonstrated by computer-aided morphometry after 5 to 7 weeks of treatment. Using recombinant murine N-terminal procollagen alpha(1) (III) propeptide (PIIINP), a novel sensitive immunoassay for the measurement of circulating PIIINP in rodent sera was established. An increase in PIIINP serum levels was observed after 5 to 7 weeks of CCl(4) intoxication. Our results suggest PIIIP gene expression is an early marker of tissue fibrosis. Early PIIIP gene expression is correlated with the extent of the subsequent fibrosis. PIIIP mRNA levels increase much earlier than conventional histological examination or PIIINP levels. PIIINP measurements with our new serum assay, on the other hand, are a good noninvasive marker of manifest fibrosis but are a poor marker of fibrogenesis. Copyright 1999 Academic Press.

EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-alpha-induced pulmonary fibrosis.

PubMed

Hardie, William D; Davidson, Cynthia; Ikegami, Machiko; Leikauf, George D; Le Cras, Timothy D; Prestridge, Adrienne; Whitsett, Jeffrey A; Korfhagen, Thomas R

2008-06-01

Transforming growth factor-alpha (TGF-alpha) is a ligand for the EGF receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. We determined the effects of EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) on the development and progression of TGF-alpha-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha expression, we determined effects of treatment with gefitinib and erlotinib on changes in lung histology, total lung collagen, pulmonary mechanics, pulmonary hypertension, and expression of genes associated with synthesis of ECM and vascular remodeling. Induction in the lung of TGF-alpha caused progressive pulmonary fibrosis over an 8-wk period. Daily administration of gefitinib or erlotinib prevented development of fibrosis, reduced accumulation of total lung collagen, prevented weight loss, and prevented changes in pulmonary mechanics. Treatment of mice with gefitinib 4 wk after the induction of TGF-alpha prevented further increases in and partially reversed total collagen levels and changes in pulmonary mechanics and pulmonary hypertension. Increases in expression of genes associated with synthesis of ECM as well as decreases of genes associated with vascular remodeling were also prevented or partially reversed. Administration of gefitinib or erlotinib did not cause interstitial fibrosis or increases in lavage cell counts. Administration of small molecule EGFR tyrosine kinase inhibitors prevented further increases in and partially reversed pulmonary fibrosis induced directly by EGFR activation without inducing inflammatory cell influx or additional lung injury.

Successful Transarterial Guglielmi Detachable Coil Embolization of Post-Traumatic Fistula between a Posterior Communicating Artery Aneurysm and the Cavernous Sinus

PubMed Central

Chen, Y.; Jiang, D-Y.; Tan, H-Q.; Wang, L-H.; Chen, X-Y.; Sun, J-H.

2009-01-01

Summary We describe a case of a post-traumatic posterior communicating artery (PCoA) aneurysmcavernous sinus fistula, which is an extremely rare complication of craniocerebral trauma, successfully treated with endosaccular coil embolization via transarterial route. Endosaccular embolization with Guglielmi detachable coils via transarterial route appears to be a feasible, effective and minimally invasive option for the treatment of post-traumatic fistula between the PCoA aneurysm with a small ostia and the cavernous sinus in the subacute phase. PMID:20465883

[Pontine cavernous angioma (cavernoma) with initial ENT manifestations].

PubMed

Pino Rivero, V; González Palomino, A; Pantoja Hernández, C G; Trinidad Ruíz, G; Marqués Rebollo, L; Blasco Huelva, A

2006-01-01

We report the case of a 22 years old female who consulted us for facial parestesias, hearing loss in right ear and sudden tinnitus. Her audiometry showed an unilateral discreet sensorineural hipoacusia and the cranial IRM, a mass of 20 mm diameter in right pontine region and bulbus informed as cavernous angioma with signs of recent bleeding. The patient was sent to Neurosurgery but she refused the intervention. The risk of hemorrhage in the cavernomas is estimated at 0.25% to 1.6% per year and represents the main reason to advise a surgical treatment.

Ex vivo imaging and quantification of liver fibrosis using second-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Sun, Tzu-Lin; Liu, Yuan; Sung, Ming-Chin; Chen, Hsiao-Ching; Yang, Chun-Hui; Hovhannisyan, Vladimir; Lin, Wei-Chou; Jeng, Yung-Ming; Chen, Wei-Liang; Chiou, Ling-Ling; Huang, Guan-Tarn; Kim, Ki-Hean; So, Peter T. C.; Chen, Yang-Fang; Lee, Hsuan-Shu; Dong, Chen-Yuan

2010-05-01

Conventionally, liver fibrosis is diagnosed using histopathological techniques. The traditional method is time-consuming in that the specimen preparation procedure requires sample fixation, slicing, and labeling. Our goal is to apply multiphoton microscopy to efficiently image and quantitatively analyze liver fibrosis specimens bypassing steps required in histological preparation. In this work, the combined imaging modality of multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) was used for the qualitative imaging of liver fibrosis of different METAVIR grades under label-free, ex vivo conditions. We found that while MAF is effective in identifying cellular architecture in the liver specimens, it is the spectrally distinct SHG signal that allows the characterization of the extent of fibrosis. We found that qualitative SHG imaging can be used for the effective identification of the associated features of liver fibrosis specimens graded METAVIR 0 to 4. In addition, we attempted to associate quantitative SHG signal to the different METAVIR grades and found that an objective determination of the extent of disease progression can be made. Our approach demonstrates the potential of using multiphoton imaging in rapid classification of ex vivo liver fibrosis in the clinical setting and investigation of liver fibrosis-associated physiopathology in animal models in vivo.

Ex vivo imaging and quantification of liver fibrosis using second-harmonic generation microscopy.

PubMed

Sun, Tzu-Lin; Liu, Yuan; Sung, Ming-Chin; Chen, Hsiao-Ching; Yang, Chun-Hui; Hovhannisyan, Vladimir; Lin, Wei-Chou; Jeng, Yung-Ming; Chen, Wei-Liang; Chiou, Ling-Ling; Huang, Guan-Tarn; Kim, Ki-Hean; So, Peter T C; Chen, Yang-Fang; Lee, Hsuan-Shu; Dong, Chen-Yuan

2010-01-01

Conventionally, liver fibrosis is diagnosed using histopathological techniques. The traditional method is time-consuming in that the specimen preparation procedure requires sample fixation, slicing, and labeling. Our goal is to apply multiphoton microscopy to efficiently image and quantitatively analyze liver fibrosis specimens bypassing steps required in histological preparation. In this work, the combined imaging modality of multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) was used for the qualitative imaging of liver fibrosis of different METAVIR grades under label-free, ex vivo conditions. We found that while MAF is effective in identifying cellular architecture in the liver specimens, it is the spectrally distinct SHG signal that allows the characterization of the extent of fibrosis. We found that qualitative SHG imaging can be used for the effective identification of the associated features of liver fibrosis specimens graded METAVIR 0 to 4. In addition, we attempted to associate quantitative SHG signal to the different METAVIR grades and found that an objective determination of the extent of disease progression can be made. Our approach demonstrates the potential of using multiphoton imaging in rapid classification of ex vivo liver fibrosis in the clinical setting and investigation of liver fibrosis-associated physiopathology in animal models in vivo.

Cost-effectiveness of Early Treatment of Hepatitis C Virus Genotype 1 by Stage of Liver Fibrosis in a US Treatment-Naive Population

PubMed Central

Chahal, Harinder S.; Marseille, Elliot A.; Tice, Jeffrey A.; Pearson, Steve D.; Ollendorf, Daniel A.; Fox, Rena K.; Kahn, James G.

2016-01-01

IMPORTANCE Novel treatments for hepatitis C virus (HCV) infection are highly efficacious but costly. Thus, many insurers cover therapy only in advanced fibrosis stages. The added health benefits and costs of early treatment are unknown. OBJECTIVE To assess the cost-effectiveness of (1) treating all patients with HCV vs only those with advanced fibrosis and (2) treating each stage of fibrosis. DESIGN, SETTING, AND PARTICIPANTS This study used a decision-analytic model for the treatment of HCV genotype 1. The model used a lifetime horizon and societal perspective and was representative of all US patients with HCV genotype 1 who had not received previous treatment. Comparisons in the model included antiviral treatment of all fibrosis stages (METAVIR [Meta-analysis of Histological Data in Virial Hepatitis] stages F0 [no fibrosis] to F4 [cirrhosis]) vs treatment of stages F3 (numerous septa without cirrhosis) and F4 only and by specific fibrosis stage. Data were collected from March 1 to September 1, 2014, and analyzed from September 1, 2014, to June 30, 2015. INTERVENTIONS Six HCV therapy options (particularly combined sofosbuvir and ledipasvir therapy) or no treatment. MAIN OUTCOMES AND MEASURES Cost and health outcomes were measured using total medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), calculated as the difference in costs between strategies divided by the difference in QALYs. RESULTS We simulated 1000 individuals, but present the results normalized to a single HCV-infected person. In the base-case analysis, among patients receiving 8 or 12 weeks of sofosbuvir-ledipasvir treatment, treating all fibrosis stages compared with treating stages F3 and F4 adds 0.73 QALYs and $28 899, for an ICER of $39 475 per QALY gained. Treating at stage F2 (portal fibrosis with rare septa) costs $19 833 per QALY gained vs waiting until stage F3; treating at stage F1 (portal fibrosis without septa), $81 165 per QALY gained compared with waiting until stage F2; and treating at stage F0, $187 065 per QALY gained compared with waiting until stage F1. Results for other regimens show a similar pattern. At base-case drug prices, treating 50% of all eligible US patients with HCV genotype 1 would cost $53 billion. In sensitivity analyses, the ICER for treating all stages vs treating stages F3 and F4 was most sensitive to cohort age, drug costs, utility values in stages F1 and F2, and percentage of patients eligible for 8-week therapy. Except for patients aged 70 years, the ICER remains less than $100 000 per QALY gained. A 46% reduction in cost of sofosbuvir-ledipasvir therapy decreases the ICER for treating at all fibrosis stages by 48%. CONCLUSIONS AND RELEVANCE In this simulated model, treating HCV infection at early stages of fibrosis appeared to improve health outcomes and to be cost-effective but incurred substantial aggregate costs. The findings may have implications for health care coverage policies and clinical decision making. PMID:26595724

Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis

PubMed Central

Paridaens, Annelies; Raevens, Sarah; Devisscher, Lindsey; Bogaerts, Eliene; Verhelst, Xavier; Hoorens, Anne; van Vlierberghe, Hans; Van Grunsven, Leo A.; Geerts, Anja; Colle, Isabelle

2017-01-01

The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death. PMID:28117681

Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Beneden, Katrien, E-mail: kvbenede@vub.ac.be; Geers, Caroline; Pauwels, Marina

Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as didmore » the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation.« less

Yin yang 1 is a novel regulator of pulmonary fibrosis.

PubMed

Lin, Xin; Sime, Patricia J; Xu, Haodong; Williams, Marc A; LaRussa, Larry; Georas, Steve N; Guo, Jia

2011-06-15

The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1(f/f) conditional knockout mouse after being exposed to silica or bleomycin. TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β-induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1(+/-)) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1(f/f) mice reduced lung fibrosis. YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.

The hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the evaluation of hepatic fibrosis and early liver cirrhosis in a rat model: an experimental study.

PubMed

Ma, Chunmei; Liu, Ailian; Wang, Yuanyuan; Geng, Xiaoling; Hao, Li; Song, Qingwei; Sun, Bo; Wang, Heqing; Zhao, Gang

2014-07-17

To evaluate the hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the early diagnosis of hepatic fibrosis and cirrhosis and assessment of liver function in a rat model. In 2 groups of SD rats, liver fibrosis was induced in experimental animals by repetitive carbon tetrachloride injections, while the control group received saline injections. Five experimental rats and 2 control rats were randomly selected at weeks 4, 8, 12. One week after carbon tetrachloride administration, MRI (FIRM T1WI) scan was performed. Gd-EOB-DTPA (0.08mL) was injected into the rat's tail vein and hepatocyte phase images were obtained after 20min. The pre-enhanced phase and hepatocyte phase signal intensities (SI) were measured, and the relative contrast enhancement index (RCEI) was calculated. ANOVA analysis (LSD) of RCEI values in controls (n=6), hepatic fibrosis (n=7), and histopathologically-determined early cirrhosis group (n=6) was performed. RECI values showed a decreasing trend in the control group, hepatic fibrosis and early cirrhosis groups (1.11±0.43, 0.96±0.22, and 0.57±0.33, respectively). While the difference between the control and early cirrhosis groups was statistically significant (p=0.013), there was no significant difference in the hepatic fibrosis group vs the control (p=0.416) and the hepatic fibrosis group vs the early cirrhosis group (p=0.054). Hepatocyte phase RCEI values obtained with Gd-EOB-DTPA-enhanced MRI scan indicate liver injury in hepatic fibrosis and early cirrhosis. RCEI values are helpful for early diagnosis of liver cirrhosis. Copyright © 2014 Elsevier Inc. All rights reserved.

CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells.

PubMed

Yan, Zhaoyong; Qu, Kai; Zhang, Jing; Huang, Qichao; Qu, Ping; Xu, Xinsen; Yuan, Peng; Huang, Xiaojun; Shao, Yongping; Liu, Chang; Zhang, Hongxin; Xing, Jinliang

2015-10-01

Although previous evidence indicates close involvement of CD147 in the pathogenesis of liver fibrosis, the underlying molecular mechanisms and its therapeutic value remain largely unknown. In the present study, we investigated the biological roles of CD147 in liver fibrosis and assessed its therapeutic value as a target molecule in the CCl4-induced liver fibrosis mouse model. We found that CD147 was highly expressed in both hepatocytes and SECs (sinusoidal endothelial cells) in fibrotic liver tissues. Additionally, it was significantly associated with the fibrosis stage. TGF-β1 (transforming growth factor β1) was found to be mainly responsible for the up-regulation of CD147. Bioinformatic and experimental data suggest a functional link between CD147 expression and VEGF-A (vascular endothelial growth factor A)/VEGR-2 (VEGF receptor 2) signalling-mediated angiogenesis in fibrotic liver tissues. Furthermore, we observed that the CD147-induced activation of the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway promotes the production of VEGF-A in hepatocytes and expression of VEGFR-2 in SECs, which was found to enhance the angiogenic capability of SECs. Finally, our data indicate that blocking of CD147 using an mAb (monoclonal antibody) attenuated liver fibrosis progression via inhibition of VEGF-A/VEGFR-2 signalling and subsequent amelioration of microvascular abnormality in the CCl4-induced mouse model. Our findings suggest a novel functional mechanism that CD147 may promote liver fibrosis progression via inducing the VEGF-A/VEGFR-2 signalling pathway-mediated cross-talk between hepatocytes and SECs. New strategies based on the intervention of CD147 can be expected for prevention of liver fibrosis. © 2015 Authors; published by Portland Press Limited.

Moesin as a key cytoskeleton regulator in corneal fibrosis.

PubMed

Zhu, Hong-Yuan; Yeo, Sia-Wey; Ng, Jennifer; Htoon, Hla Myint; Beuerman, R W

2013-04-01

: Corneal fibrosis is the third leading cause of blindness worldwide. α-Smooth muscle actin (SMA), a marker of fibrosis, is closely regulated through an intermediate group of submembrane molecules - cytoskeleton regulators. The purpose of this study was to elucidate the role of specific cytoskeleton regulators in a mouse model of corneal fibrosis. : A mouse model of corneal fibrosis was developed using anterior keratectomy (AK) and the topical application of transforming growth factor (TGF)-β1 (1 μg/ml). The RT² Profiler™ PCR Array for cytoskeleton regulators was used to assay changes in levels of specific members of this class of proteins. Moesin siRNA was delivered into the corneal stroma by iontophoresis in vivo. Transformation of the corneal keratocyte-to-myofibroblast in corneal fibrosis, as defined by the expression of α-SMA, was determined by Western blot. : After AK and topical application of TGF-β1, moesin was the most highly upregulated gene among 84 cytoskeleton regulator genes; iontophoresing moesin siRNA into the corneal stroma reduced the expression of α-SMA to 0.22-, 0.52-, and 0.31-fold of control at postoperative (PO) day 1, 3, and 5, respectively; also, upregulation of phospho-Smad 2 induced by TGF-β1 was reduced by moesin siRNA to 0.59-, 0.56-, and 0.31-fold of control and expression of phospho-Smad 3 was reduced to 0.58-, 0.53-, and 0.47-fold of control at the same PO days. : Moesin may be a potential drug target for inhibiting corneal fibrosis, and the details of moesin-related signaling pathways would be critical for understanding corneal fibrosis. Copyright © 2013 Elsevier Inc. All rights reserved.

Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

NASA Astrophysics Data System (ADS)

Gabriel, Sherif E.; Brigman, Kristen N.; Koller, Beverly H.; Boucher, Richard C.; Stutts, M. Jackson

1994-10-01

The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in response to CT. This correlation between CFTR protein and CT-induced chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

Advances in Cell and Gene-based Therapies for Cystic Fibrosis Lung Disease

PubMed Central

Oakland, Mayumi; Sinn, Patrick L; McCray Jr, Paul B

2012-01-01

Cystic fibrosis (CF) is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Direct delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. Yet, physical and host immune barriers in the lung present challenges for successful gene transfer to the respiratory tract. Advances in gene transfer approaches, tissue engineering, and novel animal models are generating excitement within the CF research field. This review discusses current challenges and advancements in viral and nonviral vectors, cell-based therapies, and CF animal models. PMID:22371844

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, B; Yu, H; Jara, H

Purpose: To compare enhanced Laws texture derived from parametric proton density (PD) maps to other MRI-based surrogate markers (T2, PD, ADC) in assessing degrees of liver fibrosis in a murine model of hepatic fibrosis using 11.7T scanner. Methods: This animal study was IACUC approved. Fourteen mice were divided into control (n=1) and experimental (n=13). The latter were fed a DDC-supplemented diet to induce hepatic fibrosis. Liver specimens were imaged using an 11.7T scanner; the parametric PD, T2, and ADC maps were generated from spin-echo pulsed field gradient and multi-echo spin-echo acquisitions. Enhanced Laws texture analysis was applied to the PDmore » maps: first, hepatic blood vessels and liver margins were segmented/removed using an automated dual-clustering algorithm; secondly, an optimal thresholding algorithm was applied to reduce the partial volume artifact; next, mean and stdev were corrected to minimize grayscale variation across images; finally, Laws texture was extracted. Degrees of fibrosis was assessed by an experienced pathologist and digital image analysis (%Area Fibrosis). Scatterplots comparing enhanced Laws texture, T2, PD, and ADC values to degrees of fibrosis were generated and correlation coefficients were calculated. Unenhanced Laws texture was also compared to assess the effectiveness of the proposed enhancements. Results: Hepatic fibrosis and the enhanced Laws texture were strongly correlated with higher %Area Fibrosis associated with higher Laws texture (r=0.89). Only a moderate correlation was detected between %Area Fibrosis and unenhanced Laws texture (r=0.70). Strong correlation also existed between ADC and %Area Fibrosis (r=0.86). Moderate correlations were seen between %Area Fibrosis and PD (r=0.65) and T2 (r=0.66). Conclusions: Higher degrees of hepatic fibrosis are associated with increased Laws texture. The proposed enhancements improve the accuracy of Laws texture. Enhanced Laws texture features are more accurate than PD and T2 in assessing fibrosis, and can potentially serve as an accurate surrogate marker for hepatic fibrosis.« less

Protein S is protective in pulmonary fibrosis.

PubMed

Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

2016-08-01

Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis. © 2016 International Society on Thrombosis and Haemostasis.

Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney.

PubMed

Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Zong, Zhi-Hong; Du, Zhen-Xian; Li, De-Tian; Wang, Hua-Qin; Liu, Bo; Miao, Jia-Ning; Bian, Xiao-Hui

2015-01-01

BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and the expression of BAG3 and α-SMA, and the efficacy of C. sinensis on renal fibrosis induced by UUO were examined. The results showed that UUO led to collagen accumulation, which was significantly suppressed by C. sinensis. UUO increased the expression of BAG3 and α-SMA, a mesenchymal marker, while UUO induced BAG3 and α-SMA expression was significantly inhibited by C. sinensis. In addition, immunohistochemical staining demonstrated that BAG3 immunoreactivity was restricted to tubular epithelium. In conclusion, BAG3 is a potential target for the prevention and/or treatment of renal fibrosis, and C. Sinensis is a promising agent for renal fibrosis.

Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

PubMed

Glass, Lisa M; Dickson, Rolland C; Anderson, Joseph C; Suriawinata, Arief A; Putra, Juan; Berk, Brian S; Toor, Arifa

2015-04-01

Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

FIB-4 and imaging for measuring fibrosis in hepatitis C virus.

PubMed

Turner, Barbara J; Liang, Yuanyuan; Singal, Amit G

2017-02-01

Noninvasive measures are widely used to assess fibrosis and may be used to prioritize hepatitis C virus (HCV) treatment. We examined risks for likely fibrosis in patients with chronic HCV infection using fibrosis-4 (FIB-4) and imaging. A HCV screening program diagnosed chronic HCV in patients born from 1945 to 1965 admitted in a safety net hospital. Likely fibrosis was based on FIB-4 (≥1.45) alone or combined with imaging interpreted as fibrosis or cirrhosis. Logistic regression was used to calculate adjusted odds ratios (AORs) for demographic, clinical, and insurance factors associated with each outcome. Using multiple linear regression among patients with likely fibrosis, we examined associations with higher Model for End-Stage Liver Disease (MELD) scores. Using FIB-4 alone, 57% (83/146) of patients had likely fibrosis versus 43% (63/148) using FIB-4 plus imaging. Obesity/overweight and Hispanic ethnicity had over three-fold to four-fold higher AORs for fibrosis, respectively, based on FIB-4 plus imaging, but both AORs were only two-fold greater with FIB-4 alone. Being uninsured was significantly associated with fibrosis based on FIB-4 alone [AOR=2.40 (95% confidence interval 1.01-5.70)] but not with imaging. Heavy alcohol use and older age were associated with higher AORs of fibrosis with both measures (all P<0.004). MELD scores were ∼3 points higher for uninsured patients, regardless of measure (both P<0.05). Using FIB-4 plus imaging to identify fibrosis in chronic HCV, higher risks are seen for Hispanics and overweight/obese individuals than using FIB-4 alone. Higher MELD scores at diagnosis for the uninsured indicate delayed access to care.

Contrast-enhanced ultrasonography for the evaluation of liver fibrosis after biliary obstruction.

PubMed

Shin, Hyun Joo; Chang, Eun Young; Lee, Hye Sun; Hong, Jung Hwa; Park, Gyuri; Kim, Hyun Gi; Kim, Myung-Joon; Lee, Mi-Jung

2015-03-07

To investigate perfusion change in contrast-enhanced ultrasonography (CEUS) to evaluate liver fibrosis based on biliary obstruction using an animal model. New Zealand white rabbits (3-4 kg) underwent bile duct ligation to form a biliary obstruction model. We performed liver CEUS and laboratory tests on the day before the operation (day 0) and every 7 postoperative days until the rabbits were sacrificed. After CEUS, signal intensity of liver parenchyma with a time-intensity curve was analyzed. Perfusion parameters were automatically calculated from region-of-interests, including peak signal intensity, mean transit time, area under the curve and time to peak. Histological grades of liver fibrosis were assessed according to the Metavir score system immediately after sacrifice. Generalized estimating equations were used to analyze the association between liver fibrosis grades and perfusion parameters for statistical analysis. The perfusion parameters were measured on the last day and the difference between day 0 and the last day were evaluated. From the nine rabbits, histological grades of liver fibrosis were grade 1 in one rabbit, grade 2 and 3 in three rabbits each, and grade 4 in two rabbits. Among the four CEUS parameters, only the peak signal intensity measured on the last day demonstrated a significant association with liver fibrosis grades (OR = 1.392, 95%CI: 1.114-1.741, P = 0.004). The difference in peak signal intensity between day 0 and the last day also demonstrated an association with liver fibrosis (OR = 1.191, 95%CI: 0.999-1.419, P = 0.051). The other parameters tested, including mean transit time, area under the curve, and time to peak, showed no significant correlation with liver fibrosis grades. This animal study demonstrates that CEUS can be used to evaluate liver fibrosis from biliary obstruction using peak signal intensity as a parameter.

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis.

PubMed

Gilhodes, Jean-Claude; Julé, Yvon; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

2017-01-01

Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes automated analysis as a novel end-point measure of BLM-induced lung fibrosis in mice, which will be very valuable for future preclinical drug explorations.

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

PubMed Central

Gilhodes, Jean-Claude; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

2017-01-01

Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes automated analysis as a novel end-point measure of BLM-induced lung fibrosis in mice, which will be very valuable for future preclinical drug explorations. PMID:28107543

A role of pancreatic stellate cells in islet fibrosis and β-cell dysfunction in type 2 diabetes mellitus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Esder; Ryu, Gyeong Ryul; Ko, Seung-Hyun

Objectives: To investigate whether the activation of pancreatic stellate cells (PSCs) leads to pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). Methods: The pancreases of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of T2DM, and patient with T2DM were analyzed. And the in vitro and in vivo effects of pirfenidone, an antifibrotic agent, on PSC activation, islet fibrosis, and β-cells were studied. Results: The extent of islet fibrosis and the percentage of activated PSCs, positive for α-smooth muscle actin, in the islets were significantly greater in OLETF rats compared with non-diabetic rats. Also, the extent of islet fibrosis inmore » patients with T2DM was slightly greater compared with age- and BMI-matched non-diabetic patients. In rat PSCs cultured with high glucose for 72 h, pirfenidone produced decreases in cell proliferation, release of collagen, and the expression of fibronectin and connective tissue growth factor. Treatment of OLETF rats with pirfenidone for 16 weeks decreased the activation of PSCs and the extent of islet fibrosis, but did not enhance glucose tolerance, pancreatic insulin content, or β-cell mass. Conclusions: Activated PSCs in islets might lead to islet fibrosis in T2DM. However, PSC activation itself might not contribute significantly to progressive β-cell failure in T2DM. - Highlights: • Islet fibrosis developed progressively in OLETF rats, a model of type 2 diabetes. • PSCs in the islets became activated in OLETF rats. • Islet fibrosis was increased in patients with type 2 diabetes. • Pirfenidone attenuated the activation of PSCs and islet fibrosis in OLETF rats. • Pirfenidonet had no effects on glucose tolerance or on β-cells in OLETF rats.« less

Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice.

PubMed

Marques, Ana Patrícia; Cunha-Santos, Janete; Leal, Helena; Sousa-Ferreira, Lígia; Pereira de Almeida, Luís; Cavadas, Cláudia; Rosmaninho-Salgado, Joana

2018-03-01

During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect. We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFβ1). Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y 1 receptor activation prevents ECM deposition and fibrosis markers increase induced by TGFβ1 treatment. Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y 1 receptor activation. This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity. Copyright © 2017 Elsevier B.V. All rights reserved.

[Effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats].

PubMed

Wang, Shixiang; Lu, Zhifeng; Xu, Wei; Chen, Youquan; Chen, Ximing

2015-11-01

To investigate the effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats. Fifty male SD rats were randomly divided into 5 groups, including a control group, a myocardial fibrosis model (established by injections of isopropyl adrenaline for 10 days) group, and 3 edaravone groups with edaravone treatment at low, medium, or high doses for 14 days. After the treatments, the rats were examined for the degree of myocardial fibrosis, left ventricular mass index (LVMI), collagen volume fraction (CVF), and myocardial contents of collagen I (Col I), collage III (Col III), hydroxyproline (Hyp), superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO); The expression of transforming growth factor-β1 (TGF-β1) in the myocardial tissues was examined by immunofluorescence assay and Western blotting. Compared with the control rats, the rat models of myocardial fibrosis showed significantly increased CVF and LVMI (P=0.000), which were lowered by edaravone treatments in a dose-dependent manner (P<0.05). The myocardial contents of Col I, Col III and Hyp also increased in the model group (P=0.000) and were lowered dose-dependently by edaravone; the contents of MDA was higher (P=0.000) and SOD and NO were lower in the model group (P=0.000), and edaravone treatments obviously increased SOD and NO contents (P<0.05). The model rats showed significantly increased myocardial expression of TGF-β1 (P=0.000), which was markedly lowered by edaravone treatments (P=0.000). The myocardial content of MDA was positively correlated while SOD and NO were negatively with LVMI, CVF, Col I, Col III and Hyp; TGF-β1 was positively correlated with LVMI, CVF, Col I, Col III, Hyp and MDA but negatively with SOD and NO. Edaravone can relieve oxidative stress and inhibit TGF-β1 activation to ameliorate myocardial fibrosis in rats.

Airway disease phenotypes in animal models of cystic fibrosis.

PubMed

McCarron, Alexandra; Donnelley, Martin; Parsons, David

2018-04-02

In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.

The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload.

PubMed

Noly, Pierre-Emmanuel; Haddad, François; Arthur-Ataam, Jennifer; Langer, Nathaniel; Dorfmüller, Peter; Loisel, Fanny; Guihaire, Julien; Decante, Benoit; Lamrani, Lilia; Fadel, Elie; Mercier, Olaf

2017-12-01

Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling. We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression. Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm 2 ; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression. The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

A new strategic neurosurgical planning tool for brainstem cavernous malformations using interactive computer graphics with multimodal fusion images.

PubMed

Kin, Taichi; Nakatomi, Hirofumi; Shojima, Masaaki; Tanaka, Minoru; Ino, Kenji; Mori, Harushi; Kunimatsu, Akira; Oyama, Hiroshi; Saito, Nobuhito

2012-07-01

In this study, the authors used preoperative simulation employing 3D computer graphics (interactive computer graphics) to fuse all imaging data for brainstem cavernous malformations. The authors evaluated whether interactive computer graphics or 2D imaging correlated better with the actual operative field, particularly in identifying a developmental venous anomaly (DVA). The study population consisted of 10 patients scheduled for surgical treatment of brainstem cavernous malformations. Data from preoperative imaging (MRI, CT, and 3D rotational angiography) were automatically fused using a normalized mutual information method, and then reconstructed by a hybrid method combining surface rendering and volume rendering methods. With surface rendering, multimodality and multithreshold techniques for 1 tissue were applied. The completed interactive computer graphics were used for simulation of surgical approaches and assumed surgical fields. Preoperative diagnostic rates for a DVA associated with brainstem cavernous malformation were compared between conventional 2D imaging and interactive computer graphics employing receiver operating characteristic (ROC) analysis. The time required for reconstruction of 3D images was 3-6 hours for interactive computer graphics. Observation in interactive mode required approximately 15 minutes. Detailed anatomical information for operative procedures, from the craniotomy to microsurgical operations, could be visualized and simulated three-dimensionally as 1 computer graphic using interactive computer graphics. Virtual surgical views were consistent with actual operative views. This technique was very useful for examining various surgical approaches. Mean (±SEM) area under the ROC curve for rate of DVA diagnosis was significantly better for interactive computer graphics (1.000±0.000) than for 2D imaging (0.766±0.091; p<0.001, Mann-Whitney U-test). The authors report a new method for automatic registration of preoperative imaging data from CT, MRI, and 3D rotational angiography for reconstruction into 1 computer graphic. The diagnostic rate of DVA associated with brainstem cavernous malformation was significantly better using interactive computer graphics than with 2D images. Interactive computer graphics was also useful in helping to plan the surgical access corridor.

Limited endoscopic transsphenoidal approach for cavernous sinus biopsy: illustration of 3 cases and discussion.

PubMed

Graillon, T; Fuentes, S; Metellus, P; Adetchessi, T; Gras, R; Dufour, H

2014-01-01

Advances in transsphenoidal surgery and endoscopic techniques have opened new perspectives for cavernous sinus (CS) approaches. The aim of this study was to assess the advantages and disadvantages of limited endoscopic transsphenoidal approach, as performed in pituitary adenoma surgery, for CS tumor biopsy illustrated with three clinical cases. The first case was a 46-year-old woman with a prior medical history of parotid adenocarcinoma successfully treated 10 years previously. The cavernous sinus tumor was revealed by right third and sixth nerve palsy and increased over the past three years. A tumor biopsy using a limited endoscopic transsphenoidal approach revealed an adenocarcinoma metastasis. Complementary radiosurgery was performed. The second case was a 36-year-old woman who consulted for diplopia with right sixth nerve palsy and amenorrhea with hyperprolactinemia. Dopamine agonist treatment was used to restore the patient's menstrual cycle. Cerebral magnetic resonance imaging (MRI) revealed a right sided CS tumor. CS biopsy, via a limited endoscopic transsphenoidal approach, confirmed a meningothelial grade 1 meningioma. Complementary radiosurgery was performed. The third case was a 63-year-old woman with progressive installation of left third nerve palsy and visual acuity loss, revealing a left cavernous sinus tumor invading the optic canal. Surgical biopsy was performed using an enlarged endoscopic transsphenoidal approach to the decompress optic nerve. Biopsy results revealed a meningothelial grade 1 meningioma. Complementary radiotherapy was performed. In these three cases, no complications were observed. Mean hospitalization duration was 4 days. Reported anatomical studies and clinical series have shown the feasibility of reaching the cavernous sinus using an endoscopic endonasal approach. Trans-foramen ovale CS percutaneous biopsy is an interesting procedure but only provides cell analysis results, and not tissue analysis. However, radiotherapy and radiosurgery have proven effective for SC meningiomas. When histological diagnosis is required, limited endoscopic transsphenoidal approach appears as a safe, fast, and useful alternative to the classical endocranial approach. Also, a tailored enlargement of the approach could be performed if optic nerve decompression is required. The feasibility of CS endoscopic transsphenoidal biopsy has prompted us to consider CS biopsy when the diagnosis of CS meningioma is uncertain. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.

PubMed

Bhat, Mamatha; Tazari, Mahmood; Sebastiani, Giada

2017-01-01

Recurrent fibrosis after liver transplantation (LT) impacts on long-term graft and patient survival. We performed a meta-analysis to compare the accuracy of non-invasive methods to diagnose significant recurrent fibrosis (stage F2-F4) following LT. Studies comparing serum fibrosis biomarkers, namely AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), or transient elastography (TE) with liver biopsy in LT recipients were systematically identified through electronic databases. In the meta-analysis, we calculated the weighted pooled odds ratio and used a fixed effect model, as there was no significant heterogeneity between studies. Eight studies were included for APRI, four for FIB-4, and twelve for TE. The mean prevalence of significant liver fibrosis was 37.4%. The summary odds ratio was significantly higher for TE (21.17, 95% CI confidence interval 14.10-31.77, p = 1X10-30) as compared to APRI (9.02, 95% CI 5.79-14.07; p = 1X10-30) and FIB-4 (7.08, 95% CI 4.00-12.55; p = 1.93X10-11). In conclusion, TE performs best to diagnose recurrent fibrosis in LT recipients. APRI and FIB-4 can be used as an estimate of significant fibrosis at centres where TE is not available. Longitudinal assessment of fibrosis by means of these non-invasive tests may reduce the need for liver biopsy.

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production.

PubMed

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M; Lineburg, Katie E; Alexander, Kylie A; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R; Serody, Jonathan S; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S; Antin, Joseph H; Ritz, Jerome; MacDonald, Kelli P; Schacker, Timothy W; Luznik, Leo; Blazar, Bruce R

2017-05-04

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen-mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. © 2017 by The American Society of Hematology.

Epicatechin as a Therapeutic Strategy to Mitigate the Development of Cardiac Remodeling and Fibrosis

DTIC Science & Technology

2017-09-01

Currently, no drugs target HFpEF and the development of animal models can assist in therapy evaluation. We developed a female rat model of aging...allocated into an aging group, aging + ovariectomy and aging + ovariectomy + 10% fructose in drinking water. At 22 months of age, animals were...epicatechin (Epi) will ameliorate adverse tissue remodeling and cardiac fibrosis in female animal models developing diastolic dysfunction as seen in women

Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.

PubMed

Huang, Chung-Feng; Dai, Chia-Yen; Yeh, Ming-Lun; Huang, Ching-I; Tai, Chi-Ming; Hsieh, Meng-Hsuan; Liang, Po-Cheng; Lin, Yi-Hung; Hsieh, Ming-Yen; Yang, Hua-Ling; Huang, Jee-Fu; Lin, Zu-Yau; Chen, Shinn-Cherng; Yu, Ming-Lung; Chuang, Wan-Long

2015-03-01

Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Inositol-requiring enzyme 1-mediated endoplasmic reticulum stress triggers apoptosis and fibrosis formation in liver cirrhosis rat models.

PubMed

Jiang, Tianpeng; Wang, Lizhou; Li, Xing; Song, Jie; Wu, Xiaoping; Zhou, Shi

2015-04-01

Long‑term and advanced cirrhosis is usually irreversible and often coincides with variceal hemorrhage or development of hepatocellular carcinoma; therefore, liver cirrhosis is a major cause of morbidity and mortality globally. The aim of the present study was to investigate the specific mechanism behind the formation of fibrosis or cirrhosis using rat models of hepatic fibrosis. The cirrhosis model was established by intraperitoneally administering dimethylnitrosamine to the rats. Hematoxylin and eosin staining was performed on the hepatic tissues of the rats to observe the fibrosis or cirrhosis, and western blot analysis was employed to detect α‑smooth muscle actin and desmin protein expression. Flow cytometric analysis was used to examine early and late apoptosis, and the protein and mRNA expression of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) pathway proteins and apoptotic proteins [C/EBP homologous protein (CHOP) and caspase‑12] was detected by western blotting and the reverse-transcription polymerase chain reaction, respectively. The results indicated that the cirrhosis model was established successfully and that fibrosis was significantly increased in the cirrhosis model group compared with that in the normal control group. Flow cytometric analysis showed that early and late apoptosis in the cirrhosis model was significantly higher compared with that in the control group. The expression of the UPR pathway protein inositol-requiring enzyme (IRE) 1, as well as the expression of CHOP, was increased significantly in the cirrhotic rat tissues compared with that in the control group tissues (P<0.05). In conclusion, apoptosis was clearly observed in the hepatic tissue of cirrhotic rats, and the apoptosis was caused by activation of the ER stress-mediated IRE1 and CHOP.

Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study.

PubMed

Stephenson, Anne L; Sykes, Jenna; Stanojevic, Sanja; Quon, Bradley S; Marshall, Bruce C; Petren, Kristofer; Ostrenga, Josh; Fink, Aliza K; Elbert, Alexander; Goss, Christopher H

2017-04-18

In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias. To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States. Population-based study. 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers. Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013. Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival. Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status. Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results. Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage. U.S. Cystic Fibrosis Foundation.

OX40L blockade protects against inflammation-driven fibrosis

PubMed Central

Elhai, Muriel; Avouac, Jérôme; Hoffmann-Vold, Anna Maria; Ruzehaji, Nadira; Amiar, Olivia; Ruiz, Barbara; Brahiti, Hassina; Ponsoye, Matthieu; Fréchet, Maxime; Burgevin, Anne; Pezet, Sonia; Sadoine, Jérémy; Guilbert, Thomas; Nicco, Carole; Akiba, Hisaya; Heissmeyer, Vigo; Subramaniam, Arun; Resnick, Robert; Molberg, Øyvind; Kahan, André; Chiocchia, Gilles; Allanore, Yannick

2016-01-01

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation. PMID:27298374

Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis.

PubMed

Lei, Ling; Zhao, Cheng; Qin, Fang; He, Zhi-Yi; Wang, Xu; Zhong, Xiao-Ning

2016-01-01

Systemic sclerosis (SSc) is characterised by fibrosis of the skin and internal organs, such as the lungs. Enhanced Th17 responses are associated with skin fibrosis in patients with SSc, however, whether they are associated with lung fibrosis has not been clarified. This study aimed to investigate the potential association of Th17 responses with the skin and pulmonary fibrosis as well as the potential mechanisms in a mouse bleomycin (BLM) model of SSc. BALB/c mice were injected subcutaneously with phosphate buffered saline (PBS) (control) or BLM for 28 days and the skin and pulmonary inflammation and fibrosis were characterized by histology. The percentages of circulating, skin and pulmonary infiltrating Th17 cells and the contents of collagen in mice were analysed. The levels of RORγt, IL-17A, IL-6 and TGF-β1 mRNA transcripts in the skin and lungs were determined by quantitative RTPCR and the levels of serum IL-17A, IL-6 and TGF-β1 were determined by ELISA. Furthermore, the effect of rIL-17A on the proliferation of pulmonary fibroblasts and their cytokine expression was analysed. The potential association of Th17 responses with the severity of skin and lung fibrosis was analysed. In comparison with the control mice, significantly increased skin and pulmonary inflammation and fibrosis and higher levels of hydroxyproline were detected in the BLM mice. Significantly higher frequency of circulating, skin and lung infiltrating Th17 cells and higher levels of serum, skin and lung IL-17A, TGF-β1, IL-6 and RORγt were detected in the BLM mice. The concentrations of serum IL-17A were correlated positively with the percentages of Th17 cells and the contents of skin hydroxyproline in the BLM mice. The levels of IL-17A expression were positively correlated with the skin and lung inflammatory scores as well as the skin fibrosis in the BLM mice. In addition, IL-17A significantly enhanced pulmonary fibroblast proliferation and their type I collagen, TGF-β and IL-6 expression in vitro, which were attenuated by treatment with anti-IL-17A. Our results indicate that Th17 cells participate in the pathogenesis of skin and lung fibrosis by enhancing fibroblast proliferation and cytokine production in a mouse BLM model of SSc.

Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis.

PubMed

Sun, Xuejiao; Liu, Yi; Li, Cheng; Wang, Xiting; Zhu, Ruyuan; Liu, Chenyue; Liu, Haixia; Wang, Lili; Ma, Rufeng; Fu, Min; Zhang, Dongwei; Li, Yu

2017-01-01

Curcumin, a polyphenol derived from the turmeric, has received attention as a potential treatment for renal fibrosis primarily because it is a relatively safe and inexpensive compound that contributes to kidney health. Here, we review the literatures on the applications of curcumin in resolving renal fibrosis in animal models and summarize the mechanisms of curcumin and its analogs (C66 and (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one(B06)) in preventing inflammatory molecules release and reducing the deposition of extracellular matrix at the priming and activation stage of renal fibrosis in animal models by consulting PubMed and Cnki databases over the past 15 years. Curcumin exerts antifibrotic effect through reducing inflammation related factors (MCP-1, NF- κ B, TNF- α , IL-1 β , COX-2, and cav-1) and inducing the expression of anti-inflammation factors (HO-1, M6PRBP1, and NEDD4) as well as targeting TGF- β /Smads, MAPK/ERK, and PPAR- γ pathways in animal models. As a food derived compound, curcumin is becoming a promising drug candidate for improving renal health.

The lipid A of Burkholderia multivorans C1576 smooth-type lipopolysaccharide and its pro-inflammatory activity in a cystic fibrosis airways model.

PubMed

Ieranò, Teresa; Cescutti, Paola; Leone, Maria Rosaria; Luciani, Alessandro; Rizzo, Roberto; Raia, Valeria; Lanzetta, Rosa; Parrilli, Michelangelo; Maiuri, Luigi; Silipo, Alba; Molinaro, Antonio

2010-12-01

Cystic fibrosis is an autosomal recessive disorder and it is characterised by chronic bacterial airway infection which leads to progressive lung deterioration, sometimes with fatal outcome. Burkholderia multivorans and Burkholderia cenocepacia are the species responsible for most of the infections of cystic fibrosis patients. Lipopolysaccharide endotoxins (LPSs) are among the foremost factors of pathogenesis of Gram-negative infection and, in particular, lipid A is the endotoxic portion of LPS responsible for eliciting host innate immune response. In this work, the complete primary structure of the lipid A from B. multivorans C1576 has been defined and, further, its pro-inflammatory activity in a cystic fibrosis airways model is shown. The structure of B. multivorans lipid A was attained by chemical, mass spectrometry and nuclear magnetic resonance analyses whereas its biological activity was assessed on the intestinal epithelial cell line CACO-2 cells, on the airway epithelial IB3-1 cells, carrying the ΔF508/W1282X CFTR mutation and on an ex vivo model of culture explants of nasal polyps.

Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study

PubMed Central

Zhao, Ming-ming

2017-01-01

The objective of this study is to investigate if sinomenine hydrochloride (SIN-HCl) could be effective against adriamycin-induced renal fibrosis by regulating autophagy in a rat model. Forty male Sprague-Dawley (SD) rats were randomly divided into control group, model group, telmisartan group, and SIN-HCl group; rat model was induced by adriamycin; all rats were given intragastric administration for 6 weeks. Urine was collected from rats in metabolic cages to determine 24 h protein level. This was done after intragastric administration for the first two weeks and then once for every two weeks. Renal pathological changes were examined by the staining of HE, Masson, and PASM. Expressions and distributions of fibronectin (FN), laminin (LN), light chain 3 (LC3), and Beclin-1 were observed by immunohistochemistry. SIN-HCl ameliorates proteinuria, meanwhile attenuating the renal pathological changes in adriamycin-induced rats and also attenuating renal fibrosis and excessive autophagy by reducing the expression of FN, LN, LC3, and Beclin-1. SIN-HCl attenuates renal fibrosis by inhibiting excessive autophagy induced by adriamycin and upregulates the basal autophagy. PMID:28798804

Atrial Fibrosis Hampers Non-invasive Localization of Atrial Ectopic Foci From Multi-Electrode Signals: A 3D Simulation Study

PubMed Central

Godoy, Eduardo Jorge; Lozano, Miguel; García-Fernández, Ignacio; Ferrer-Albero, Ana; MacLeod, Rob; Saiz, Javier; Sebastian, Rafael

2018-01-01

Introduction: Focal atrial tachycardia is commonly treated by radio frequency ablation with an acceptable long-term success. Although the location of ectopic foci tends to appear in specific hot-spots, they can be located virtually in any atrial region. Multi-electrode surface ECG systems allow acquiring dense body surface potential maps (BSPM) for non-invasive therapy planning of cardiac arrhythmia. However, the activation of the atria could be affected by fibrosis and therefore biomarkers based on BSPM need to take these effects into account. We aim to analyze the effect of fibrosis on a BSPM derived index, and its potential application to predict the location of ectopic foci in the atria. Methodology: We have developed a 3D atrial model that includes 5 distributions of patchy fibrosis in the left atrium at 5 different stages. Each stage corresponds to a different amount of fibrosis that ranges from 2 to 40%. The 25 resulting 3D models were used for simulation of Focal Atrial Tachycardia (FAT), triggered from 19 different locations described in clinical studies. BSPM were obtained for all simulations, and the body surface potential integral maps (BSPiM) were calculated to describe atrial activations. A machine learning (ML) pipeline using a supervised learning model and support vector machine was developed to learn the BSPM patterns of each of the 475 activation sequences and relate them to the origin of the FAT source. Results: Activation maps for stages with more than 15% of fibrosis were greatly affected, producing conduction blocks and delays in propagation. BSPiMs did not always cluster into non-overlapped groups since BSPiMs were highly altered by the conduction blocks. From stage 3 (15% fibrosis) the BSPiMs showed differences for ectopic beats placed around the area of the pulmonary veins. Classification results were mostly above 84% for all the configurations studied when a large enough number of electrodes were used to map the torso. However, the presence of fibrosis increases the area of the ectopic focus location and therefore decreases the utility for the electrophysiologist. Conclusions: The results indicate that the proposed ML pipeline is a promising methodology for non-invasive ectopic foci localization from BSPM signal even when fibrosis is present. PMID:29867517

Actin - Lysozyme Interactions in Model Cystic Fibrosis Sputum

NASA Astrophysics Data System (ADS)

Sanders, Lori; Slimmer, Scott; Angelini, Thomas; Wong, Gerard C. L.

2003-03-01

Cystic fibrosis sputum is a complex fluid consisting of mucin (a glycoprotein), lysozyme (a cationic polypeptide), water, salt, as well as a high concentration of a number of anionic biological polyelectrolytes such as DNA and F-actin. The interactions governing these components are poorly understood, but may have important clinical consequences. For example, the formation of these biological polyelectrolytes into ordered gel phases may contribute significantly to the observed high viscosity of CF sputum. In this work, a number of model systems containing actin, lysozyme, and KCl were created to simulate CF sputum in vitro. These model systems were studied using small angle x-ray scattering and confocal fluorescence microscopy. Preliminary results will be presented. This work was supported by NSF DMR-0071761, the Beckman Young Investigator Program, and the Cystic Fibrosis Foundation.

Dural cavernous sinus fistula: an unusual presentation.

PubMed Central

Procope, J. A.; Kidwell, E. D.; Copeland, R. A.; Perry, A. F.

1994-01-01

This article describes a 22-year-old man who presented to the Howard University Hospital emergency room with acute onset of swelling, proptosis, and decreased vision in the right eye preceded by 24 hours of nausea and vomiting. The patient's visual acuity was count fingers in the involved eye with marked proptosis and limitation of ocular motility. There was no history given of any ocular or head trauma. A computed tomography scan of the orbits showed diffuse symmetric enlargement of the extraocular muscles of the right eye, felt to be consistent with an orbital inflammatory pseudotumor. The patient was treated with intravenous steroids initially, then placed on oral prednisone. After minimal improvement on the steroids, a selective external carotid angiogram showed a moderate-sized dural cavernous sinus fistula. The patient underwent selective embolization of the fistula with rapid resolution of periorbital edema and proptosis. Visual acuity was stabilized at 20/200 in the right eye. The differential diagnosis and pathogenesis of carotid cavernous sinus fistulas and the likely pathogenesis of the fistula in this case are discussed. Images Figure 1 Figure 2 Figure 3 PMID:8046763

EVOKED CAVERNOUS ACTIVITY: NEUROANATOMIC IMPLICATIONS

PubMed Central

Yilmaz, Ugur; Vicars, Brenda; Yang, Claire C.

2013-01-01

We investigated the autonomic innervation of the penis by using evoked cavernous activity (ECA). We recruited 7 males with thoracic spinal cord injury (SCI) and sexual dysfunction and 6 males who were scheduled to have pelvic surgery (PS), specifically non-nerve-sparing radical cystoprostatectomy. In the PS subjects, ECA was performed both pre- and postoperatively. The left median nerve was electrically stimulated and ECA was recorded with two concentric electromyography needles placed into the right and left cavernous bodies. We simultaneously recorded hand and foot sympathetic skin responses (SSRs) as controls. In the SCI group, all but one subject had reproducible hand SSRs. None of these subjects had ECA or foot SSRs. All the PS subjects had reproducible ECA and SSRs, both preoperatively and postoperatively. There was no difference in the latency and amplitude measurements of ECA and SSRs in the postoperative compared to the preoperative period (p>0.05). In conclusion, ECA is absent in men with SCI above the sympathetic outflow to the genitalia. In men following radical pelvic surgery, ECA is preserved, indicating the preservation of sympathetic fibers. PMID:19609298

Quiescent Volcano-Chest Wall Hemangioma.

PubMed

Saldanha, Elroy; Martis, John J S; Kumar, B Vinod; D'Cunha, Rithesh J; Vijin, V

2017-08-01

Chest wall hemangiomas are rare tumors that may originate within the soft tissue or from the ribs. Intramuscular hemangioma is infrequent, representing less than 1 % of all hemangiomas, and the localization in the chest wall is even less frequent. They are typically cutaneous in location, large, and poorly circumscribed and can be locally destructive. We present a case of a 34-year-old lady presented with firm lump 3 × 3 cm in left upper and inner quadrant of left breast well defined borders, non-pulsatile and restricted mobility. Sono-mammogram was suggestive of ill-defined lesion at 10 o'clock position. CT chest was conclusive of chest wall hemangioma. The patient underwent excision of the lump. HPE was suggestive of cavernous hemangioma. Cavernous hemangioma typically manifest at birth or before the age of 30 years. CT is more sensitive than plain radiography in detecting phleboliths, which are present in approximately 30 % of cavernous hemangiomas. Surgical excision would be treatment of choice. In this case, the site of the lesion was in the breast clinically mimicking that of a fibroadenoma which warrants hemangioma as a differential diagnosis.