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Sample records for fibrotic tissue utilizing

  1. Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats.

    Sandra Geschka

    Full Text Available A direct pharmacological stimulation of soluble guanylate cyclase (sGC is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521, have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1 and plasminogen activator inhibitor-1 (PAI-1 in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

  2. Transurethral resection of fibrotic scar tissue combined with temporary urethral stent placement for patients with in anterior urethral stricture

    Cheol Yong Yoon

    2014-08-01

    Full Text Available Introduction Fibrotic scar formation is a main cause of recurrent urethral stricture after initial management with direct vision internal urethrotomy (DVIU. In the present study, we devised a new technique of combined the transurethral resection of fibrotic scar tissue and temporary urethral stenting, using a thermo-expandable urethral stent (MemokathTM 044TW in patients with anterior urethral stricture. Materials and Methods As a first step, multiple incisions were made around stricture site with cold-cutting knife and Collins knife electrode to release a stricture band. Fibrotic tissue was then resected with a 13Fr pediatric resectoscope before deployment of a MemokathTM 044TW stent (40 – 60mm on a pre-mounted sheath using 0° cystoscopy. Stents were removed within 12 months after initial placement. Results We performed this technique on 11 consecutive patients with initial (n = 4 and recurrent (n = 7 anterior urethral stricture (April 2009 – February 2013. At 18.9 months of mean follow-up (12-34 months, mean Qmax (7.8±3.9ml/sec vs 16.8 ± 4.8ml/sec, p < 0.001, IPSS (20.7 vs 12.5, p = 0.001 , and QoL score (4.7 vs 2.2, p < 0.001 were significantly improved. There were no significant procedure-related complications except two cases of tissue ingrowth at the edge of stent, which were amenable by transurethral resection. In 7 patients, an average 1.4 times (1-5 times of palliative urethral dilatation was carried out and no patients underwent open surgical urethroplasty during the follow-up period. Conclusion Combined transurethral resection and temporary urethral stenting is a effective therapeutic option for anterior urethral stricture. Further investigations to determine the long-term effects, and safety profile of this new technique are warranted.

  3. Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: A Model for Soft Tissue Mechanics.

    Maryna Perepelyuk

    Full Text Available Tissues including liver stiffen and acquire more extracellular matrix with fibrosis. The relationship between matrix content and stiffness, however, is non-linear, and stiffness is only one component of tissue mechanics. The mechanical response of tissues such as liver to physiological stresses is not well described, and models of tissue mechanics are limited. To better understand the mechanics of the normal and fibrotic rat liver, we carried out a series of studies using parallel plate rheometry, measuring the response to compressive, extensional, and shear strains. We found that the shear storage and loss moduli G' and G" and the apparent Young's moduli measured by uniaxial strain orthogonal to the shear direction increased markedly with both progressive fibrosis and increasing compression, that livers shear strain softened, and that significant increases in shear modulus with compressional stress occurred within a range consistent with increased sinusoidal pressures in liver disease. Proteoglycan content and integrin-matrix interactions were significant determinants of liver mechanics, particularly in compression. We propose a new non-linear constitutive model of the liver. A key feature of this model is that, while it assumes overall liver incompressibility, it takes into account water flow and solid phase compressibility. In sum, we report a detailed study of non-linear liver mechanics under physiological strains in the normal state, early fibrosis, and late fibrosis. We propose a constitutive model that captures compression stiffening, tension softening, and shear softening, and can be understood in terms of the cellular and matrix components of the liver.

  4. A higher volume of fibrotic tissue on virtual histology prior to coronary stent implantation predisposes to more pronounced neointima proliferation.

    Haine, Steven; Wouters, Kristien; Miljoen, Hielko; Vandendriessche, Tom; Claeys, Marc; Bosmans, Johan; Vrints, Christiaan

    2018-04-01

    Since neointima smooth muscle cells (SMC) mainly originate from the vessel wall, we investigated whether atherosclerotic plaque composition influences subsequent in-stent neointima proliferation and restenosis. We performed intravascular ultrasound (IVUS) with virtual histology in 98 patients prior to elective bare-metal stent (BMS) implantation in de novo coronary artery lesions. Virtual histology variables pre-percutaneous coronary intervention (PCI) were related to in-stent neointima proliferation six months after implantation assessed as late luminal loss of 0.88 mm (interquartile range (IQR) 0.37-1.23 mm) on angiography and as maximal percentage area stenosis of 42% (IQR 33-59%) and percentage volume intima hyperplasia of 27% (IQR 20-36%) on IVUS. A ridge-trace based multiple linear regression model was constructed to account for multicollinearity of the virtual histology variables and was corrected for implanted stent length (18 mm, IQR 15-23 mm), stent diameter (3.0 mm, IQR 2.75-3.5 mm) and lesion volume (146 mm³, IQR 80-201 mm³) prior to PCI. Fibrous tissue volume prior to PCI (49 mm³, IQR 30-77 mm³) was significantly and independently related to late luminal loss (p = .038), maximal percentage area stenosis (p = .041) and percentage volume intima hyperplasia (p = .004). Neither absolute nor relative amounts of fibrofatty, calcified or necrotic core tissue appeared related to any of the restenosis parameters. Subgroup analysis after exclusion of acute coronary syndrome (ACS) patients yielded similar results. Lesions with more voluminous fibrotic tissue pre-PCI show more pronounced in-stent neointima proliferation, even after correction for lesion plaque volume.

  5. Proteoglycan and proteome profiling of central human pulmonary fibrotic tissue utilizing miniaturized sample preparation

    Malmström, Johan; Larsen, Kristoffer; Hansson, Lennart

    2002-01-01

    -dimensional electrophoresis was interfaced to miniaturized sample preparation techniques using microcapillary extraction. Four protein groups were identified; cytoskeletal, adhesion, scavenger and metabolic proteins. These patient's proteomes showed a high degree of heterogeneity between patients but larger homogeneity...

  6. Connective Tissue Growth Factor Domain 4 Amplifies Fibrotic Kidney Disease through Activation of LDL Receptor-Related Protein 6.

    Johnson, Bryce G; Ren, Shuyu; Karaca, Gamze; Gomez, Ivan G; Fligny, Cécile; Smith, Benjamin; Ergun, Ayla; Locke, George; Gao, Benbo; Hayes, Sebastian; MacDonnell, Scott; Duffield, Jeremy S

    2017-06-01

    Connective tissue growth factor (CTGF), a matrix-associated protein with four distinct cytokine binding domains, has roles in vasculogenesis, wound healing responses, and fibrogenesis and is upregulated in fibroblasts and myofibroblasts in disease. Here, we investigated the role of CTGF in fibrogenic cells. In mice, tissue-specific inducible overexpression of CTGF by kidney pericytes and fibroblasts had no bearing on nephrogenesis or kidney homeostasis but exacerbated inflammation and fibrosis after ureteral obstruction. These effects required the WNT receptor LDL receptor-related protein 6 (LRP6). Additionally, pericytes isolated from these mice became hypermigratory and hyperproliferative on overexpression of CTGF. CTGF is cleaved in vivo into distinct domains. Treatment with recombinant domain 1, 1+2 (N terminus), or 4 (C terminus) independently activated myofibroblast differentiation and wound healing responses in cultured pericytes, but domain 4 showed the broadest profibrotic activity. Domain 4 exhibited low-affinity binding to LRP6 in in vitro binding assays, and inhibition of LRP6 or critical signaling cascades downstream of LRP6, including JNK and WNT/ β -catenin, inhibited the biologic activity of domain 4. Administration of blocking antibodies specifically against CTGF domain 4 or recombinant Dickkopf-related protein-1, an endogenous inhibitor of LRP6, effectively inhibited inflammation and fibrosis associated with ureteral obstruction in vivo Therefore, domain 4 of CTGF and the WNT signaling pathway are important new targets in fibrosis. Copyright © 2017 by the American Society of Nephrology.

  7. Are mast cells instrumental for fibrotic diseases?

    Catherine eOvered-Sayer

    2014-01-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a fatal lung disorder of unknown etiology characterised by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. IPF has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF.The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodelling, as well as its pathological role in fibrotic diseases such as IPF, where the process of tissue repair and remodelling is thought to be dysregulated.

  8. Biodegradable microspheres for the sustained release of PDGF-receptor directed pPB-HSA targeted to the fibrotic kidney

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Hinrichs, Wouter; Steendam, Rob; Zuidema, Johan; Poelstra, Klaas; Frijlink, H.W.; Olinga, Peter

    2016-01-01

    Platelet Derived Growth Factor (PDGF) plays a key role in the development of fibrotic processes in several tissues. Accordingly, the PDGF receptor is abundantly present in these fibrotic tissues. Specific targeting to this receptor is established for a series of compounds in different animal models,

  9. Biodegradable microspheres for the sustained release of PDGF-receptor directed PPB-HSA targeted to the fibrotic kidney

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Hinrichs, Wouter; Poelstra, Klaas; Frijlink, H.W.; Olinga, Peter

    2016-01-01

    Platelet Derived Growth Factor (PDGF) plays a key role in the development of fibrotic processes in several tissues. Accordingly, the PDGFβ receptor is abundantly present in these fibrotic tissues. Specific targeting to this receptor is established for a series of compounds in different animal

  10. Absorbed dose in fibrotic microenvironment models employing Monte Carlo simulation

    Zambrano Ramírez, O.D.; Rojas Calderón, E.L.; Azorín Vega, E.P.; Ferro Flores, G.; Martínez Caballero, E.

    2015-01-01

    The presence or absence of fibrosis and yet more, the multimeric and multivalent nature of the radiopharmaceutical have recently been reported to have an effect on the radiation absorbed dose in tumor microenvironment models. Fibroblast and myofibroblast cells produce the extracellular matrix by the secretion of proteins which provide structural and biochemical support to cells. The reactive and reparative mechanisms triggered during the inflammatory process causes the production and deposition of extracellular matrix proteins, the abnormal excessive growth of the connective tissue leads to fibrosis. In this work, microenvironment (either not fibrotic or fibrotic) models composed of seven spheres representing cancer cells of 10 μm in diameter each with a 5 μm diameter inner sphere (cell nucleus) were created in two distinct radiation transport codes (PENELOPE and MCNP). The purpose of creating these models was to determine the radiation absorbed dose in the nucleus of cancer cells, based on previously reported radiopharmaceutical retain (by HeLa cells) percentages of the 177 Lu-Tyr 3 -octreotate (monomeric) and 177 Lu-Tyr 3 -octreotate-AuNP (multimeric) radiopharmaceuticals. A comparison in the results between the PENELOPE and MCNP was done. We found a good agreement in the results of the codes. The percent difference between the increase percentages of the absorbed dose in the not fibrotic model with respect to the fibrotic model of the codes PENELOPE and MCNP was found to be under 1% for both radiopharmaceuticals. (authors)

  11. AKAP12 mediates barrier functions of fibrotic scars during CNS repair.

    Jong-Ho Cha

    Full Text Available The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process.

  12. Prevention of the Post-traumatic Fibrotic Response in Joints

    2014-10-01

    The American journal of forensic medicine and pathology . 1988; 9(4):310-2. 14 APPENDICES: An abstract submitted for the ORS conference...clinical problem of posttraumatic joint stiffness, a pathology that reduces the range of motion (ROM) of injured joints and contributes to the...development of osteoarthritis. The fundamental hypothesis that drives the current study is that pathological fibrotic response of injured joint tissues

  13. Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients.

    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.

  14. Rac inhibition reverses the phenotype of fibrotic fibroblasts.

    Shi-wen Xu

    Full Text Available BACKGROUND: Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA, type I collagen and CCN2 (connective tissue growth factor, CTGF. The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. METHODS AND FINDINGS: Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766. CONCLUSION: Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc.

  15. Reconstruction of complicated skull base defects utilizing free tissue transfer.

    Djalilian, Hamid R; Gapany, Markus; Levine, Samuel C

    2002-11-01

    We managed five patients with large skull base defects complicated by complex infections with microvascular free tissue transfer. The first patient developed an infection, cerebrospinal fluid (CSF) leak, and meningitis after undergoing a translabyrinthine resection of an acoustic neuroma. The second patient had a history of a gunshot wound to the temporal bone, with a large defect and an infected cholesteatoma that caused several episodes of meningitis. The third through the fifth patients had persistent CSF leakage and infection refractory to conventional therapy. In all cases prior attempts of closure with fat grafts or regional flaps had failed. Rectus abdominis myofascial free flap, radial forearm free flap or a gracilis muscle free flap was used after debridement of the infected cavities. The CSF leaks, local infections, and meningitis were controlled within a week. In our experience, microvascular free tissue provides the necessary bulk of viable, well-vascularized tissue, which not only assures a mechanical seal but also helps clear the local infection.

  16. Assessment of fibrotic liver disease with multimodal nonlinear optical microscopy

    Lu, Fake; Zheng, Wei; Tai, Dean C. S.; Lin, Jian; Yu, Hanry; Huang, Zhiwei

    2010-02-01

    Liver fibrosis is the excessive accumulation of extracellular matrix proteins such as collagens, which may result in cirrhosis, liver failure, and portal hypertension. In this study, we apply a multimodal nonlinear optical microscopy platform developed to investigate the fibrotic liver diseases in rat models established by performing bile duct ligation (BDL) surgery. The three nonlinear microscopy imaging modalities are implemented on the same sectioned tissues of diseased model sequentially: i.e., second harmonic generation (SHG) imaging quantifies the contents of the collagens, the two-photon excitation fluorescence (TPEF) imaging reveals the morphology of hepatic cells, while coherent anti-Stokes Raman scattering (CARS) imaging maps the distributions of fats or lipids quantitatively across the tissue. Our imaging results show that during the development of liver fibrosis (collagens) in BDL model, fatty liver disease also occurs. The aggregated concentrations of collagen and fat constituents in liver fibrosis model show a certain correlationship between each other.

  17. Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases.

    Zhang, Yi; Tang, Jun; Tian, Zhiqiang; van Velkinburgh, Jennifer C; Song, Jianxun; Wu, Yuzhang; Ni, Bing

    2016-09-02

    Fibrosis is a consequence of chronic inflammation and the persistent accumulation of extracellular matrix, for which the cycle of tissue injury and repair becomes a predominant feature. Both the innate and adaptive immune systems play key roles in the progress of fibrosis. The recently identified subsets of innate lymphoid cells (ILCs), which are mainly localize to epithelial surfaces, have been characterized as regulators of chronic inflammation and tissue remodeling, representing a functional bridge between the innate and adaptive immunity. Moreover, recent research has implicated ILCs as potential contributing factors to several kinds of fibrosis diseases, such as hepatic fibrosis and pulmonary fibrosis. Here, we will summarize and discuss the key roles of ILCs and their related factors in fibrotic diseases and their potential for translation to the clinic.

  18. Anti-pulmonary fibrotic activity of salvianolic acid B was screened by a novel method based on the cyto-biophysical properties.

    Liu, Miao; Zheng, Mingjing; Xu, Hanying; Liu, Lianqing; Li, Yanchun; Xiao, Wei; Li, Jianchun; Ma, Enlong

    Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in vitro were stimulated with transforming growth factor-β1 (TGF-β1), and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and stiffness were measured utilizing atomic force microscopy (AFM). It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. TGF-β1-stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-L-cysteine (NAC) as a positive drug on ameliorating fibrogenesis in TGF-β1-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that stiffness was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B (SalB), a natural anti-oxidant, was detected by AFM to protect TGF-β1-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin (BLM) -induced pulmonary fibrosis. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced α-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Traumatic hallux varus repair utilizing a soft-tissue anchor: a case report.

    Labovitz, J M; Kaczander, B I

    2000-01-01

    Hallux varus is usually iatrogenic in nature; however, congenital and acquired etiologies have been described in the literature. The authors present a case of traumatic hallux varus secondary to rupture of the adductor tendon. Surgical correction was performed using a soft tissue anchor for maintenance of the soft tissues utilized for repair.

  20. Anti-pulmonary fibrotic activity of salvianolic acid B was screened by a novel method based on the cyto-biophysical properties

    Liu, Miao; Zheng, Mingjing; Xu, Hanying [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016 (China); Liu, Lianqing [Shenyang Institute of Automation China Academy of Sciences, Shenyang, 110016 (China); Li, Yanchun [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016 (China); Xiao, Wei [Jiangsu Kanion Pharmaceutical Co., Ltd., Nanjing, 222001 (China); Li, Jianchun, E-mail: lijianchun0317@sina.com.cn [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016 (China); Ma, Enlong, E-mail: enlong_ma2014@hotmail.com [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016 (China); Jiangsu Kanion Pharmaceutical Co., Ltd., Nanjing, 222001 (China)

    2015-12-04

    Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in vitro were stimulated with transforming growth factor-β1 (TGF-β1), and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and stiffness were measured utilizing atomic force microscopy (AFM). It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. TGF-β1-stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-L-cysteine (NAC) as a positive drug on ameliorating fibrogenesis in TGF-β1-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that stiffness was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B (SalB), a natural anti-oxidant, was detected by AFM to protect TGF-β1-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin (BLM) -induced pulmonary fibrosis. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced α-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening. - Highlights: • Fibrogenesis was accompanied with the changes of cyto-biophysical properties. • Cyto-biophysical properties could be markers for anti-fibrotic drugs screening. • Stiffness is a leading index among all biophysical markers. • SalB was

  1. Anti-pulmonary fibrotic activity of salvianolic acid B was screened by a novel method based on the cyto-biophysical properties

    Liu, Miao; Zheng, Mingjing; Xu, Hanying; Liu, Lianqing; Li, Yanchun; Xiao, Wei; Li, Jianchun; Ma, Enlong

    2015-01-01

    Various methods have been used to evaluate anti-fibrotic activity of drugs. However, most of them are complicated, labor-intensive and lack of efficiency. This study was intended to develop a rapid method for anti-fibrotic drugs screening based on biophysical properties. A549 cells in vitro were stimulated with transforming growth factor-β1 (TGF-β1), and fibrogenesis was confirmed by conventional immunological assays. Meanwhile, the alterations of cyto-biophysical properties including morphology, roughness and stiffness were measured utilizing atomic force microscopy (AFM). It was found that fibrogenesis was accompanied with changes of cellular biophysical properties. TGF-β1-stimulated A549 cells became remarkably longer, rougher and stiffer than the control. Then, the effect of N-acetyl-L-cysteine (NAC) as a positive drug on ameliorating fibrogenesis in TGF-β1-stimulated A549 cells was verified respectively by immunological and biophysical markers. The result of Principal Component Analysis showed that stiffness was a leading index among all biophysical markers during fibrogenesis. Salvianolic acid B (SalB), a natural anti-oxidant, was detected by AFM to protect TGF-β1-stimulated A549 cells against stiffening. Then, SalB treatment was provided in preventive mode on a rat model of bleomycin (BLM) -induced pulmonary fibrosis. The results showed that SalB treatment significantly ameliorated BLM-induced histological alterations, blocked collagen accumulations and reduced α-SMA expression in lung tissues. All these results revealed the anti-pulmonary fibrotic activity of SalB. Detection of cyto-biophysical properties were therefore recommended as a rapid method for anti-pulmonary fibrotic drugs screening. - Highlights: • Fibrogenesis was accompanied with the changes of cyto-biophysical properties. • Cyto-biophysical properties could be markers for anti-fibrotic drugs screening. • Stiffness is a leading index among all biophysical markers. • SalB was

  2. Fibrocytes in the Fibrotic Lung: Altered Phenotype Detected by Flow Cytometry

    Charles eReese

    2014-06-01

    Full Text Available Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells before recruitment into target tissues. While most previous studies focused on circulating fibrocytes, here we focus on the fibrocyte phenotype in fibrotic tissue. The study’s relevance to human disease is heightened by use of a model in which bleomycin is delivered systemically, recapitulating several features of human scleroderma including multi-organ fibrosis not observed when bleomycin is delivered directly into the lungs. Using flow cytometry, we find in the fibrotic lung a large population of CD45high fibrocytes (called Region I rarely found in vehicle-treated control mice. A second population of CD45+ fibrocytes (called Region II is observed in both control and fibrotic lung. The level of CD45 in circulating fibrocytes is far lower than in either Region I or II lung fibrocytes. The chemokine receptors CXCR4 and CCR5 are expressed at higher levels in Region I than in Region II and are present at very low levels in all other lung cells including CD45+/collagen I- leucocytes. The collagen chaperone HSP47 is present at similar high levels in both Regions I and II, but at a higher level in fibrotic lung than in control lung. There is also a major population of HSP47high/CD45- cells in fibrotic lung not present in control lung. CD44 is present at higher levels in Region I than in Region II and at much lower levels in all other cells including CD45+/collagen I- leucocytes. When lung fibrosis is inhibited by restoring caveolin-1 activity using a caveolin-1 scaffolding domain peptide (CSD, a strong correlation is observed between fibrocyte number and fibrosis score. In summary, the distinctive phenotype of fibrotic lung fibrocytes suggests that fibrocyte differentiation occurs primarily within the

  3. Inflammation and angiogenesis in fibrotic lung disease.

    Keane, Michael P; Strieter, Robert M; Lynch, Joseph P; Belperio, John A

    2006-12-01

    The pathogenesis of pulmonary fibrosis is poorly understood. Although inflammation has been presumed to have an important role in the development of fibrosis this has been questioned recently, particularly with regard to idiopathic pulmonary fibrosis (IPF). It is, however, increasingly recognized that the polarization of the inflammatory response toward a type 2 phenotype supports fibroproliferation. Increased attention has been on the role of noninflammatory structural cells such as the fibroblast, myofibroblast, epithelial cell, and endothelial cells. Furthermore, the origin of these cells appears to be multifactorial and includes resident cells, bone marrow-derived cells, and epithelial to mesenchymal transition. Increasing evidence supports the presence of vascular remodeling in fibrotic lung disease, although the precise role in the pathogenesis of fibrosis remains to be determined. Therefore, the pathogenesis of pulmonary fibrosis is complex and involves the interaction of multiple cell types and compartments within the lung.

  4. Gene expression profile of the fibrotic response in the peritoneal cavity.

    Le, S J; Gongora, M; Zhang, B; Grimmond, S; Campbell, G R; Campbell, J H; Rolfe, B E

    2010-01-01

    The cellular response to materials implanted in the peritoneal cavity has been utilised to produce tissue for grafting to hollow smooth muscle organs (blood vessels, bladder, uterus and vas deferens). To gain insight into the regulatory mechanisms involved in encapsulation of a foreign object, and subsequent differentiation of encapsulating cells, the present study used microarray technology and real-time RT-PCR to identify the temporal changes in gene expression associated with tissue development. Immunohistochemical analysis showed that 3-7 days post-implantation of foreign objects (cubes of boiled egg white) into rats, they were encapsulated by tissue comprised primarily of haemopoietic (CD45(+)) cells, mainly macrophages (CD68(+), CCR1(+)). By day 14, tissue capsule cells no longer expressed CD68, but were positive for myofibroblast markers alpha-smooth muscle (SM) actin and SM22. In accordance with these results, gene expression data showed that early capsule (days 3-7) development was dominated by the expression of monocyte/macrophage-specific genes (CD14, CSF-1, CSF-1R, MCP-1) and pro-inflammatory mediators such as transforming growth factor (TGF-beta). As tissue capsule development progressed (days 14-21), myofibroblast-associated and pro-fibrotic genes (associated with TGF-beta and Wnt/beta-catenin signalling pathways, including Wnt 4, TGFbetaRII, connective tissue growth factor (CTGF), SMADs-1, -2, -4 and collagen-1 subunits) were significantly up-regulated. The up-regulation of genes associated with Cardiovascular and Skeletal and Muscular System Development at later time-points suggests the capacity of cells within the tissue capsule for further differentiation to smooth muscle, and possibly other cell types. The identification of key regulatory pathways and molecules associated with the fibrotic response to implanted materials has important applications not only for optimising tissue engineering strategies, but also to control deleterious fibrotic

  5. Utilization of 14C-tyrosine in brain and peripheral tissues of developmentally protein malnourished rats

    Miller, M.; Leahy, J.P.; McConville, F.; Morgane, P.J.; Resnick, O.

    1978-01-01

    Prior studies of developmentally protein malnourished rats have reported substantial changes in brain and peripheral utilization of 14 C-leucine, 14 C-phenylalanine, and 14 C-tryptophan. In the present study rats born to dams fed a low protein diet (8% casein) compared to the offspring of control rats fed a normal diet (25% casein) showed few significant differences in the uptake and incorporation of 14 C-tyrosine into brain and peripheral tissues from birth to age 21 days. At birth, the 8% casein pups exhibited significant decreases in brain and peripheral tissue incorporation of tracer only at short post-injection times (10 and 20 min), but not at longer intervals (90 and 180 min). During ontogenetic development (Days 5-21), the 8% casein rats showed significant increases in uptake of 14 C-tyrosine into the brain and peripheral tissues on Day 11 and a significantly higher percent incorporation of tracer into brain protein on Day 21 as compared to the 25% casein rats. For the most part, there were no significant changes in incorporation of radioactivity in peripheral tissues for the 2 diet groups on these post-birth days. Overall, the data indicates that developmental protein malnutrition causes relatively fewer changes in brain and peripheral utilization of the semi-essential amino acid tyrosine than those observed in previous studies with essential amino acids

  6. The Role of γδ T Cells in Fibrotic Diseases.

    Bank, Ilan

    2016-10-31

    Inflammation induced by toxins, micro-organisms, or autoimmunity may result in pathogenic fibrosis, leading to long-term tissue dysfunction, morbidity, and mortality. Immune cells play a role in both induction and resolution of fibrosis. γδ T cells are an important group of unconventional T cells characterized by their expression of non-major histocompatibility complex restricted clonotypic T cell receptors for non-peptide antigens. Accumulating evidence suggests that subsets of γδ T cells in experimentally induced fibrosis following bleomycin treatment, or infection with Bacillus subtilis, play pro-inflammatory roles that instigate fibrosis, whereas the same cells may also play a role in resolving fibrosis. These processes appear to be linked at least in part to the cytokines produced by the cells at various stages, with interleukin (IL)-17 playing a central role in the inflammatory phase driving fibrosis, but later secretion of IL-22, interferon γ, and CXCL10 preventing pathologic fibrosis. Moreover, γδ T cells appear to be involved, in an antigen-driven manner, in the prototypic human fibrotic disease, systemic sclerosis (SSc). In this paper we review in brief the scientific publications that have implicated γδ T cells in fibrotic diseases and their pro- and anti-fibrotic effects.

  7. A simple method for measuring glucose utilization of insulin-sensitive tissues by using the brain as a reference

    Namba, Hiroki; Nakagawa, Keiichi; Iyo, Masaomi; Fukushi, Kiyoshi; Irie, Toshiaki

    1994-01-01

    A simple method, without measurement of the plasma input function, to obtain semiquantitative values of glucose utilization in tissues other than the brain with radioactive deoxyglucose is reported. The brain, in which glucose utilization is essentially insensitive to plasma glucose and insulin concentrations, was used as an internal reference. The effects of graded doses of oral glucose loading (0.5, 1 and 2 mg/g body weight) on insulin-sensitive tissues (heart, muscle and fat tissue) were studied in the rat. By using the brain-reference method, dose-dependent increases in glucose utilization were clearly shown in all the insulin-sensitive tissues examined. The method seems to be of value for measurement of glucose utilization using radioactive deoxyglucose and positron emission tomography in the heart or other insulin-sensitive tissues, especially during glucose loading. (orig.)

  8. Fibrotic encapsulation of orthodontic appliance in palate.

    Muthu, Jananni; Muthanandam, Sivaramakrishnan; Umapathy, Gubernath; Kannan, Anitha Logaranjani

    2017-01-01

    Iatrogenic trauma though not serious is very common in dental practice. Orthodontic treatment can inflict such injuries as they are prolonged over a long period of time. Ill-fabricated orthodontic appliances, such as wires and brackets, or the patients' habits such as application of constant pressure over the appliance can traumatize the adjacent oral soft tissues. In rare cases, these appliances can get embedded into the mucosa and gingival tissues. This case report describes one such case of iatrogenic trauma to the palatal mucosa due to entrapment of a tongue spike appliance and its surgical management.

  9. Re-expression of pro-fibrotic, embryonic preserved mediators in irradiated arterial vessels of the head and neck region.

    Möbius, Patrick; Preidl, Raimund H M; Weber, Manuel; Amann, Kerstin; Neukam, Friedrich W; Wehrhan, Falk

    2017-11-01

    Surgical treatment of head and neck malignancies frequently includes microvascular free tissue transfer. Preoperative radiotherapy increases postoperative fibrosis-related complications up to transplant loss. Fibrogenesis is associated with re-expression of embryonic preserved tissue developmental mediators: osteopontin (OPN), regulated by sex-determining region Y‑box 9 (Sox9), and homeobox A9 (HoxA9) play important roles in pathologic tissue remodeling and are upregulated in atherosclerotic vascular lesions; dickkopf-1 (DKK1) inhibits pro-fibrotic and atherogenic Wnt signaling. We evaluated the influence of irradiation on expression of these mediators in arteries of the head and neck region. DKK1, HoxA9, OPN, and Sox9 expression was examined immunohistochemically in 24 irradiated and 24 nonirradiated arteries of the lower head and neck region. The ratio of positive cells to total cell number (labeling index) in the investigated vessel walls was assessed semiquantitatively. DKK1 expression was significantly decreased, whereas HoxA9, OPN, and Sox9 expression were significantly increased in irradiated compared to nonirradiated arterial vessels. Preoperative radiotherapy induces re-expression of embryonic preserved mediators in arterial vessels and may thus contribute to enhanced activation of pro-fibrotic downstream signaling leading to media hypertrophy and intima degeneration comparable to fibrotic development steps in atherosclerosis. These histopathological changes may be promoted by HoxA9-, OPN-, and Sox9-related inflammation and vascular remodeling, supported by downregulation of anti-fibrotic DKK1. Future pharmaceutical strategies targeting these vessel alterations, e. g., bisphosphonates, might reduce postoperative complications in free tissue transfer.

  10. Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

    Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

    2015-03-01

    Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

  11. Application of Electrocautery Needle Knife Combined with Balloon Dilatation versus Balloon Dilatation in the Treatment of Tracheal Fibrotic Scar Stenosis.

    Bo, Liyan; Li, Congcong; Chen, Min; Mu, Deguang; Jin, Faguang

    Electrocautery needle knives can largely reduce scar and granulation tissue hyperplasia and play an important role in treating patients with benign stricture. The aim of this retrospective study was to evaluate the efficacy and safety of electrocautery needle knife combined with balloon dilatation versus balloon dilatation alone in the treatment of tracheal stenosis caused by tracheal intubation or tracheotomy. We retrospectively analysed the clinical data of 43 patients with tracheal stenosis caused by tracheotomy or tracheal intubation in our department from January 2013 to January 2016. Among these 43 patients, 23 had simple web-like stenosis and 20 had complex steno sis. All patients were treated under general anaesthesia, and the treatment methods were (1) balloon dilatation alone, (2) needle knife excision of fibrotic tissue combined with balloon dilatation, and (3) needle knife radial incision of fibrotic tissue combined with balloon dilatation. After treatment the symptoms, such as shortness of breath, were markedly improved immediately in all cases. The stenosis degree of patients who were treated with the elec-trocautery needle knife combined with balloon dilatation had better improvement compared with that of those treated with balloon dilatation treatment alone after 3 months (0.45 ± 0.04 vs. 0.67 ± 0.05, p knife combined with balloon dilatation is an effective and safe treatment for tracheal fibrotic stenosis compared with balloon dilatation alone. © 2017 S. Karger AG, Basel.

  12. Modification of polysaccharides: Pharmaceutical and tissue engineering applications with commercial utility (patents).

    Malviya, Rishabha; Sharma, Pramod Kumar; Dubey, Susheel Kumar

    2016-11-01

    Polymer modifications open new era for the development of polymers with requisite properties. Use of modified polymers is practically boundless. Different studies focus on biomedical applications of chemically modified polysaccharides. Development and utilization of modified polysaccharides get attention to be used as carrier for pharmaceutical drug delivery as well as tissue engineering scaffolds. Grafted polymer shows better cellular regeneration, signal transmission, diagnostic and imaging material than putative form. This review article aims to discuss various approaches to modify naturally derived polymer and their applications as pharmaceutical drug carrier and as a material for wound dressing and artificial cartilage due to better biophysical cues. Manuscript included various patents based on the applications of modified polymers and techniques used to modify polymers. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Anti-fibrotic effects of Ginsan

    Shim, Ji-young; Lee, Jung-woo; Son, Hyeog-jin; Kim, Hyung-doo; Han, Young-soo; Yun, Yeon-sook; Song, Jie-young [Korea institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2006-07-01

    Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. It has been proposed that fibrogenesis is not a unique pathologic process but rather, is due to an excess of the same biologic events involved in normal tissue repair. Persistent and exaggerated wound healing ultimately leads to an excess of fibroblast replication and matrix deposition. Several studies revealed that TGF-{beta}1, collagen 1, fibronectin, various chemokine and some anti-oxidant are overexpressed in radiation induced pulmonary fibrosis. A number of studies were performed that polysaccharide extracted from Panax ginseng C.A. Meyer, ginsan, has been demonstrated to be a potent promising biological response modifier (BRM), including proliferation of lymphocytes, generation of lymphokine activated killer cells, and production of several cytokines. On the basis of several results of the ability of ginsan on modulation of redox system and cytokine balance, we examined whether ginsan directly regulates fibroblast proliferation, differentiation factors, and also investigated the mechanism of the antifibrotic effects of ginsan.

  14. Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.

    Kim, Ha Ryong; Lee, Kyuhong; Park, Chang We; Song, Jeong Ah; Shin, Da Young; Park, Yong Joo; Chung, Kyu Hyuck

    2016-03-01

    aerosol particles would induce an airway barrier injury via ROS, release fibrotic inflammatory cytokines, and trigger a wound-healing response, leading to pulmonary fibrosis. A simultaneous state of tissue destruction and inflammation caused by PHMG-phosphate had whipped up a "perfect storm" in the respiratory tract.

  15. Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

    Kinashi, Hiroshi; Falke, Lucas L.; Nguyen, Tri Q.; Bovenschen, Niels; Aten, Jan; Leask, Andrew; Ito, Yasuhiko; Goldschmeding, Roel

    2017-01-01

    Lymphangiogenesis is correlated with the degree of renal interstitial fibrosis. Pro-fibrotic transforming growth factor beta induces VEGF-C production, the main driver of lymphangiogenesis. Connective tissue growth factor (CTGF) is an important determinant of fibrotic tissue remodeling, but its

  16. Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

    Kinashi, Hiroshi; Falke, Lucas L.; Nguyen, Tri Q.; Bovenschen, Niels; Aten, Jan; Leask, Andrew; Ito, Yasuhiko; Goldschmeding, Roel

    2017-01-01

    Lymphangiogenesis is correlated with the degree of renal interstitial fibrosis. Pro-fibrotic transforming growth factor β induces VEGF-C production, the main driver of lymphangiogenesis. Connective tissue growth factor (CTGF) is an important determinant of fibrotic tissue remodeling, but its

  17. Immunofluorescence in multiple tissues utilizing serum from a patient affected by systemic lupus erythematosus

    Piotr Brzezinski

    2012-01-01

    Full Text Available Introduction: Lupus erythematosus is a chronic, inflammatory autoimmune disease that can affect multiple organs. Lupus can affect many parts of the body, especially in systemic lupus erythematosus (SLE; affected tissues may include the joints, skin, kidneys, heart, lungs, blood vessels, and brain. Case report: A 46-year-old female presented with pruritus, photosensitivity and edema of the cheeks of about 2 years duration, and was evaluated by a dermatologist. On examination, multiple telangiectasias were present on the cheeks, with erythema, edema and a malar rash observed. A review of systems documented breathing difficulty and pleuitic pain, joint pain and joint edema, photosensitivity, cardiac dysrhythmia, and periodic pain in the back close to the kidneys. Methods: Skin biopsies for hematoxylin and eosin testing, as well for direct and indirect immunofluorescence were performed, in addition to multiple diagnostic blood tests, chest radiography and directed immunologic testing. Results: The blood testing showed elevated C-reactive protein. Direct and indirect immunofluorescence testing utilizing monkey esophagus, mouse and pig heart and kidney, normal human eyelid skin and veal brain demonstrated strong reactivity to several components of smooth muscle, nerves, blood vessels, skin basement membrane zone and sweat gland ducts and skin meibomian glands. Anti-endomysium antibodies were detected as well as others, especially using FITC conjugated Complement/C1q, FITC conjugated anti-human immunoglobulin IgG and FITC conjugated anti-human fibrinogen. Conclusions: We conclude that both direct and indirect immunofluorescence using several substrates can unveil previously undocumented autoantibodies in multiple organs in lupus erythematosus, and that these findings could be utilized to complement existing diagnostic testing for this disorder.

  18. Inactive fibrotic lesions versus pulmonary tuberculosis with negative bacteriology.

    Solsona Peiró, Jordi; de Souza Galvão, Maria Luiza; Altet Gómez, Maria Neus

    2014-11-01

    This article analyzes the concept of inactive fibrotic lesions of presumed tuberculous origin (old healed tuberculosis), defined by radiological characteristics and a positive tuberculin skin test (TST), and we examine the evidence-based foundation for the indication of treatment of latent tuberculosis infection in these cases. We explore the risk of reactivation in older and recent literature, and the problems raised by the differential diagnosis with active tuberculosis with negative bacteriology. We also analyze data on the prevalence of fibrotic lesions in the recent literature. We examine the possible role of Interferon Gamma Release Assays (IGRAs) versus TST and other molecular antigen detection techniques in sputum that can aid in establishing the diagnosis and we discuss the current indications for chemoprophylaxis and the different options available. We propose diagnostic guidelines and therapeutic algorithms based on risk stratification by age and other factors in the management of radiological lesions that raise a differential diagnosis between fibrotic lesions and active pulmonary tuberculosis with negative bacteriology. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  19. Canine visceral leishmaniasis as a systemic fibrotic disease

    Silva, Lucelia C; Castro, Rodrigo S; Figueiredo, Maria M; Michalick, Marilene S M; Tafuri, Washington L; Tafuri, Wagner L

    2013-01-01

    We propose that canine visceral leishmaniasis (CVL) is a systemic fibrotic disease, as evidenced by the wide distribution of fibrosis that we have found in the dogs suffering from chronic condition. The inflammatory cells apparently direct fibrosis formation. Twenty-four cases (symptomatic dogs) were identified from a total of one hundred and five cases that had been naturally infected with Leishmania chagasi and had been documented during an epidemiological survey of CVL carried out by the metropolitan area of the municipality of Belo Horizonte, MG, Brazil. The histological criterion was intralobular liver fibrosis, as has been described previously in dogs with visceral leishmaniasis. In addition to the findings in the liver, here we describe and quantify conspicuous and systemic deposition of collagen in other organs, including spleen, cervical lymph nodes, lung and kidney of all the infected symptomatic dogs. Thus we report that there is a systematic fibrotic picture in these animals, where inflammatory cells appear to direct fibrosis in all organs that have been studied. Therefore we propose that CVL is a systemic fibrotic disease. PMID:23419132

  20. Fibrotic idiopathic interstitial pneumonias: HRCT findings that predict mortality

    Edey, Anthony J.; Hansell, David M. [The Royal Brompton Hospital, Department of Radiology, London (United Kingdom); Devaraj, Anand A. [St. George' s NHS Foundation Trust, Department of Radiology, Tooting (United Kingdom); Barker, Robert P. [Frimley Park Hosptal, Department of Radiology, Frimley, Surrey (United Kingdom); Nicholson, Andrew G. [The Royal Brompton Hospital, Department of Histopathology, London (United Kingdom); Wells, Athol U. [The Royal Brompton Hospital, Interstitial Lung Disease Unit, London (United Kingdom)

    2011-08-15

    The study aims were to identify CT features that predict outcome of fibrotic idiopathic interstitial pneumonia (IIP) when information from lung biopsy data is unavailable. HRCTs of 146 consecutive patients presenting with fibrotic IIP were studied. Visual estimates were made of the extent of abnormal lung and proportional contribution of fine and coarse reticulation, microcystic (cysts {<=}4 mm) and macrocystic honeycombing. A score for severity of traction bronchiectasis was also assigned. Using death as our primary outcome measure, variables were analysed using the Cox proportional hazards model. CT features predictive of a worse outcome were coarse reticulation, microcystic and macrocystic honeycombing, as well as overall extent of lung abnormality (p < 0.001). Importantly, increased severity of traction bronchiectasis, corrected for extent of parenchymal abnormality, was predictive of poor prognosis regardless of the background pattern of abnormal lung (HR = 1.04, CI = 1.03-1.06, p < 0.001). On bivariate Cox analysis microcystic honeycombing was a more powerful determinant of a poor prognosis than macrocystic honeycombing. In fibrotic IIPs we have shown that increasingly severe traction bronchiectasis is indicative of higher mortality irrespective of the HRCT pattern and extent of disease. Extent of microcystic honeycombing is a more powerful determinant of outcome than macrocystic honeycombing. (orig.)

  1. Modification of polysaccharides: Pharmaceutical and tissue engineering applications with commercial utility (patents)

    Malviya, Rishabha, E-mail: rishabhamalviya19@gmail.com [Polymer Science Laboratory, Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greator Noida, UP (India); Department of Pharmacy, Uttarkhand Technical University, Dehradun, Uttarkhand (India); Sharma, Pramod Kumar [Polymer Science Laboratory, Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greator Noida, UP (India); Dubey, Susheel Kumar [Siddarth Institute of Pharmacy, Dehradun, Uttarkhand (India)

    2016-11-01

    Polymer modifications open new era for the development of polymers with requisite properties. Use of modified polymers is practically boundless. Different studies focus on biomedical applications of chemically modified polysaccharides. Development and utilization of modified polysaccharides get attention to be used as carrier for pharmaceutical drug delivery as well as tissue engineering scaffolds. Grafted polymer shows better cellular regeneration, signal transmission, diagnostic and imaging material than putative form. This review article aims to discuss various approaches to modify naturally derived polymer and their applications as pharmaceutical drug carrier and as a material for wound dressing and artificial cartilage due to better biophysical cues. Manuscript included various patents based on the applications of modified polymers and techniques used to modify polymers. - Highlights: • Properties of natural polysaccharides can be modulated by modification in their basic backbone. • Polysaccharides can be easily modified using microwave irradiation as compared to conventional closed vessel modification. • Biodegradable and biocompatible nature of modified polymer promotes their use in targeted cellular delivery of pharmaceuticals. • Studies show strong support that biodegradable polymers have ability to modulate cell signaling, cellular attachment, migration, proliferation and differentiation. • Manuscript reveals the fact that various commercial patents have been granted for the use of modified polymer.

  2. A cadaveric study of bone tissue temperature during pin site drilling utilizing fluoroptic thermography.

    Muffly, Matthew; Winegar, Corbett; Miller, Mark Carl; Altman, Gregory

    2018-05-03

    Using fluoroptic thermography, temperature was measured during pin site drilling of intact cortical human cadaver bone with a combination of one-step drilling, graduated drilling, and one-step drilling with irrigation of 5.0 mm Schanz pins. A 1440 rpm constant force drilling was used to on tibial diaphyses while a sensor probe placed 0.5 mm adjacent to the drill hole measured temperature. Four drilling techniques on each of the tibial segments were performed: 3.5mm drill bit, 5.0mm Schanz pin, 5.0 mm Schanz pin in 3.5 mm pre-drilled entry site, 5.0 mm Schanz pin utilizing irrigation. One-step drilling using a 5.0 mm Schanz pin without irrigation produced a temperature that exceeded the threshold temperature for heat-induced injury in 5 of the 8 trials. With the other three drilling techniques, only one in24 trials produced a temperature that would result in thermal injury. This difference was found to be statistically significant (p = 0.003). The use of irrigation significantly reduced the maximum bone tissue temperature in one-step drilling of a 5.0 mm Schanz pin (p = 0.02). One-step drilling with a 3.5 mm drill bit achieved maximum temperature significantly faster than graduated drilling and drilling with irrigation using a 5.0 mm Schanz pin (p drilling with a 5.0 mm Schanz pin into cortical bone can produce temperatures that can lead to heat-induced injury. Irrigation alone can reduce the temperatures sufficiently to avoid damage. Pre-drilling can increase temperatures significantly but the extent of any injury should be small.

  3. Increased in vivo glucose utilization in 30-day-old obese Zucker rat: Role of white adipose tissue

    Krief, S.; Bazin, R.; Dupuy, F.; Lavau, M.

    1988-01-01

    In vivo whole-body glucose utilization and uptake in multiple individual tissues were investigated in conscious 30-day-old Zucker rats, which when obese are hyperphagic, hyperinsulinemic, and normoglycemic. Whole-body glucose metabolism (assessed by [3- 3 H]glucose) was 40% higher in obese (fa/fa) than in lean (Fa/fa) rats, suggesting that obese rats were quite responsive to their hyperinsulinemia. In obese compared with lean rats, tissue glucose uptake was increased by 15, 12, and 6 times in dorsal, inguinal, perigonadal white depots, respectively; multiplied by 2.5 in brown adipose tissue; increased by 50% in skin from inguinal region but not in that from cranial, thoracic, or dorsal area; and increased twofold in diaphragm but similar in heart in proximal intestine, and in total muscular mass of limbs. The data establish that in young obese rats the hypertrophied white adipose tissue was a major glucose-utilizing tissue whose capacity for glucose disposal compared with that of half the muscular mass. Adipose tissue could therefore play an important role in the homeostasis of glucose in obese rats in the face of their increased carbohydrate intake

  4. Balancing photosynthetic light-harvesting and light-utilization capacities in potato leaf tissue during acclimation to different growth temperatures

    Steffen, K. L.; Wheeler, R. M.; Arora, R.; Palta, J. P.; Tibbitts, T. W.

    1995-01-01

    We investigated the effect of temperature during growth and development on the relationship between light-harvesting capacity, indicated by chlorophyll concentration, and light-utilization potential, indicated by light- and bicarbonate-saturated photosynthetic oxygen evolution, in Solanum tuberosum L. cv. Norland. Clonal plantlets were transplanted and grown at 20 degrees C for 2 weeks before transfer to 12, 16, 20, 24 and 28 degrees C for 6 weeks. After 4 weeks of the temperature treatments, leaf tissue fresh weights per area were one-third higher in plants grown at 12 degrees C vs those grown at 28 degrees C. Conversely, chlorophyll content per area in tissue grown at 12 degrees C was less than one-half of that of tissue grown at 28 degrees C at 4 weeks. Photosynthetic capacity measured at a common temperature of 20 degrees C and expressed on a chlorophyll basis was inversely proportional to growth temperature. Leaf tissue from plants grown at 12 degrees C for 4 weeks had photosynthetic rates that were 3-fold higher on a chlorophyll basis than comparable tissue from plants grown at 28 degrees C. These results suggest that the relationship between light-harvesting capacity and light-utilization potential varies 3-fold in response to the growth temperatures examined. The role of this response in avoidance of photoinhibition is discussed.

  5. Effects of heat stress on dynamic absorption process, tissue distribution and utilization efficiency of vitamin C in broilers

    Liu Guohua; Chen Guosheng; Cai Huiyi

    1998-01-01

    The experiment was conducted to determine the effects of heat stress on ascorbic acid nutritional physiology of broilers with radioisotope technology. 3 H-Vc was fed to broilers and then the blood, liver, kidney, breast muscle, and excreta were sampled to determine the dynamic absorption process, the tissue distribution and the utilization efficiency of vitamin C. The results indicated that the absorption, metabolism and mobilization of supplemented vitamin C in broilers with heat stress was faster than that in broilers without heat stress. However, the utilization efficiency of supplemented vitamin C in broilers with heat stress was not higher than that of broilers without heat stress

  6. Co-transfection of decorin and interleukin-10 modulates pro-fibrotic extracellular matrix gene expression in human tenocyte culture

    Abbah, Sunny A.; Thomas, Dilip; Browne, Shane; O'Brien, Timothy; Pandit, Abhay; Zeugolis, Dimitrios I.

    2016-02-01

    Extracellular matrix synthesis and remodelling are driven by increased activity of transforming growth factor beta 1 (TGF-β1). In tendon tissue repair, increased activity of TGF-β1 leads to progressive fibrosis. Decorin (DCN) and interleukin 10 (IL-10) antagonise pathological collagen synthesis by exerting a neutralising effect via downregulation of TGF-β1. Herein, we report that the delivery of DCN and IL-10 transgenes from a collagen hydrogel system supresses the constitutive expression of TGF-β1 and a range of pro-fibrotic extracellular matrix genes.

  7. Hemorrhagic lesions in soft tissue: utility and limitations of magnetic resonance

    Legorburu, A.; Oleaga, L.; Ibarra, V.; Grande, D.

    1998-01-01

    We present four patients with hemorrhagic soft tissue tumors. The diagnosis was malignant fibrous histiocytoma in three of the patients and hematoma in the fourth. We show the magnetic resonance findings in these four cases, stressing the value of this technique in the assessment of the extension of soft tissue tumors. The difficulty in differentiating tumors with bleeding, as often occurs with malignant fibrous histiocytoma, from true hematomas. (Author) 8 refs

  8. Differential diagnosis between benign and malignant soft tissue tumors utilizing ultrasound parameters.

    Morii, Takeshi; Kishino, Tomonori; Shimamori, Naoko; Motohashi, Mitsue; Ohnishi, Hiroaki; Honya, Keita; Aoyagi, Takayuki; Tajima, Takashi; Ichimura, Shoichi

    2018-01-01

    Preoperative discrimination between benign and malignant soft tissue tumors is critical for the prevention of excess application of magnetic resonance imaging and biopsy as well as unplanned resection. Although ultrasound, including power Doppler imaging, is an easy, noninvasive, and cost-effective modality for screening soft tissue tumors, few studies have investigated reliable discrimination between benign and malignant soft tissue tumors. To establish a modality for discrimination between benign and malignant soft tissue tumors using ultrasound, we extracted the significant risk factors for malignancy based on ultrasound information from 40 malignant and 56 benign pathologically diagnosed soft tissue tumors and established a scoring system based on these risk factors. The maximum size, tumor margin, and vascularity evaluated using ultrasound were extracted as significant risk factors. Using the odds ratio from a multivariate regression model, a scoring system was established. Receiver operating characteristic analyses revealed a high area under the curve value (0.85), confirming the accuracy of the scoring system. Ultrasound is a useful modality for establishing the differential diagnosis between benign and malignant soft tissue tumors.

  9. Bioprinting of Cartilage and Skin Tissue Analogs Utilizing a Novel Passive Mixing Unit Technique for Bioink Precellularization

    Thayer, Patrick Scott; Orrhult, Linnea Stridh; Martínez, Héctor

    2018-01-01

    Bioprinting is a powerful technique for the rapid and reproducible fabrication of constructs for tissue engineering applications. In this study, both cartilage and skin analogs were fabricated after bioink pre-cellularization utilizing a novel passive mixing unit technique. This technique was developed with the aim to simplify the steps involved in the mixing of a cell suspension into a highly viscous bioink. The resolution of filaments deposited through bioprinting necessitates the assurance of uniformity in cell distribution prior to printing to avoid the deposition of regions without cells or retention of large cell clumps that can clog the needle. We demonstrate the ability to rapidly blend a cell suspension with a bioink prior to bioprinting of both cartilage and skin analogs. Both tissue analogs could be cultured for up to 4 weeks. Histological analysis demonstrated both cell viability and deposition of tissue specific extracellular matrix (ECM) markers such as glycosaminoglycans (GAGs) and collagen I respectively. PMID:29364216

  10. Macrophages during the fibrotic process: M2 as friend and foe.

    Tarcio Teodoro Braga

    2015-11-01

    Full Text Available Macrophages play essential activities in homeostasis maintenance, tissue regeneration and wound healing. However, when the physiological process of wound healing is deregulated by persistent insults and chronic diseases, macrophages can participate actively in the development of fibrosis. In this regard, the exacerbation or resolution of fibrosis depends on the type of macrophages polarized and the severity and duration of the inflammatory insult. M1 macrophages use glycolytic metabolism to optimize oxygen consumption and activate myofibroblasts and fibrocytes. On the other hand, M2 macrophages, which use oxidative metabolism, have anti-inflammatory properties due to their capacity to produce and secrete IL-10, TGFβ and arginase that promotes tissue repair. However, when the primary insult is not controlled and there is a persistent M2 macrophage activity, these cells promote ECM deposition through the continuous production of TGFβ and growth factors. In this scenario, M2 macrophages act as a break point between normal wound healing and the pro-fibrotic process. Here, we review the aspects of tissue repair based on macrophage biology and we evidence scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages.

  11. Experimental study on active specific immunotherapy utilizing the immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue, 3

    Ogawa, Yasuhiro; Imanaka, Kazufumi; Gose, Kyuhei; Imajo, Yoshinari; Kimura, Shuji

    1982-01-01

    We have already demonstrated the remarkable effect of the active specific immunotherapy utilizing tumor cells and infiltrating lymphocytes prepared from a low-dose irradiated tumor tissue after cytoreductive radiotherapy. In the present study, the active specific immunotherapy using the tumor cells and infiltrating lymphocytes which were cryopreserved at -196 0 C in liquid nitrogen was investigated in female C3H/He mice inoculated MM46 tumor. Irradiation with the dose of 3,000 rads was performed on the sixth day. The tumor cells and lymphocytes which were separated from 2,000 rads-irradiated tumor tissue were frozen by the program freezer to be preserved at -196 0 C for two months and were thawed to inject into the tumor-bearing mice on the thirteenth day. Anti-tumor effect was evaluated by the regression of the tumor and survival curves. The remarkable regression of the tumor (p < 0.01) and significant elongation of the survival period (p < 0.1) were observed in the group which received the active specific immunotherapy using the cryopreserved tumor cells and lymphocytes as well as the group using the fresh tumor cells and lymphocytes prepared from a low-dose irradiated tumor tissue. (author)

  12. Hole Burning Imaging Studies of Cancerous and Analogous Normal Ovarian Tissues Utilizing Organelle Specific Dyes

    Matsuzaki, Satoshi [Iowa State Univ., Ames, IA (United States)

    2004-01-01

    Presented in this dissertation is the successful demonstration that nonphotochemical hole burning (NPWB) imaging can be used to study in vitro tissue cellular systems for discerning differences in cellular ultrastructures due to cancer development. This has been accomplished with the surgically removed cancerous ovarian and analogous normal peritoneal tissues from the same patient and the application of a fluorescent mitochondrion specific dye, Molecular Probe MitoFluor Far Red 680 (MF680), commonly known as rhodamine 800, that has been proven to exhibit efficient NPHB. From the results presented in Chapters 4 and 5 , and Appendix B, the following conclusions were made: (1) fluorescence excitation spectra of MF680 and confocal microscopy images of thin sliced tissues incubated with MF680 confirm the site-specificity of the probe molecules in the cellular systems. (2) Tunneling parameters, {lambda}{sub 0} and σΛ, as well as the standard hole burning parameters (namely, γ and S), have been determined for the tissue samples by hole growth kinetics (HGK) analyses. Unlike the preliminary cultured cell studies, these parameters have not shown the ability to distinguish tissue cellular matrices surrounding the chromophores. (3) Effects of an external electric (Stark) field on the nonphotochemical holes have been used to determine the changes in permanent dipole moment (fΔμ) for MF680 in tissue samples when burn laser polarization is parallel to the Stark field. Differences are detected between fΔμs in the two tissue samples, with the cancerous tissue exhibiting a more pronounced change (1.35-fold increase) in permanent dipole moment change relative to the normal analogs. It is speculated that the difference may be related to differences in mitochondrial membrane potentials in these tissue samples. (4) In the HGK mode, hole burning imaging (HBI) of cells adhered to coverslips and cooled to liquid helium temperatures in the complete absence of

  13. Mast Cells Density in Fibrotic Capsule of Enchondroma and Well-Differentiated Chondrosarcoma: A Method for Histopathologic Differentiation

    Mohammad Javad Kharazi Fard

    2012-02-01

    Full Text Available Background: An enchondroma is a benign and a well-differentiated chondrosarcoma is an invasive chondroid tumor with high recurrence potential. In spite of biologic differences, these two tumors have very similar histopathologic appearance. It has been shown that the biologic nature of the connective tissue around benign and malignant tumors varies in the number of mast cells. The aim of this study was to study the histopathologic distinction of enchondroma and well-differentiated chondrosarcoma using the density of the mast cells in fibrotic capsule. Methods: Twelve enchondroma and 15 well-differentiated chondrosarcoma were collected from Pathology department of Cancer Institute and Central Pathology department of Imam Khomeini Hospital in Tehran. 3 micron paraffin embedded tissue sections were stained by toluidine blue for mast cells counting. Mast cells were counted in fibrous capsule of all cases. Mast cells counts were accomplished in 10 high power fields .The average number of mast cells in 10HPF was determined as an index for each lesion. Mann-Whitney U test was used for statistical analysis. Results: Mean index in enchondroma and well-differentiated chondrosarcoma groups were 0.1±0.12 and 0.31±0.33 respectively, showing a significant difference between number of mast cells in the fibrotic capsule in these two lesions (p=0.028. Comparison of the corresponding points in ROC curve, showed a cut-off point = 0.15, with positive predictive value of 61%, negative predictive value 71%, specificity of 33.3% and sensitivity of 66.7%, (p=0.025. Conclusion: Average density of the mast cells in the surrounding fibrotic capsules of enchondroma and well-differentiated chondrosarcoma along with other criterions, could be a beneficial factor for histologically differentiation between these two lesions.

  14. Utility Values for Advanced Soft Tissue Sarcoma Health States from the General Public in the United Kingdom

    Julian F. Guest

    2013-01-01

    Full Text Available Soft tissue sarcomas are a rare type of cancer generally treated with palliative chemotherapy when in the advanced stage. There is a lack of published health utility data for locally advanced “inoperable”/metastatic disease (ASTS, essential for calculating the cost-effectiveness of current and future treatments. This study estimated time trade-off (TTO and standard gamble (SG preference values associated with four ASTS health states (progressive disease, stable disease, partial response, complete response among members of the general public in the UK (n=207. The four health states were associated with decreases in preference values from full health. Complete response was the most preferred health state (mean utility of 0.60 using TTO. The second most preferred health state was partial response followed by stable disease (mean utilities were 0.51 and 0.43, respectively, using TTO. The least preferred health state was progressive disease (mean utility of 0.30 using TTO. The utility value for each state was significantly different from one another (P<0.001. This study demonstrated and quantified the impact that different treatment responses may have on the health-related quality of life of patients with ASTS.

  15. Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy.

    Tlucek, Paul S; Folk, James C; Sobol, Warren M; Mahajan, Vinit B

    2013-01-01

    To review fibrosis of fluocinolone acetonide (FA) implants in subjects with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). A retrospective case series was assembled from ADNIV patients in which there was fibrotic encapsulation of a fluocinolone acetonide implant. CAPN5 genotypes and surgical repair techniques were reviewed. Two eyes of two ADNIV patients developed a fibrotic capsule over the fluocinolone acetonide implant. Both patients had Stage IV disease. Patient A had a c.731T > C mutation in the CAPN5 gene and patient B had a c.728G > T mutation. The fibrotic membrane was surgically excised and the implant function was restored. The exuberant fibrotic response in later stages of ADNIV may be resistant to local immunosuppression with steroids. Surgical excision of fibrotic membranes over FA implants can reestablish local steroid delivery in cases of severe proliferative vitreoretinopathy.

  16. Tissue

    David Morrissey

    2012-01-01

    Full Text Available Purpose. In vivo gene therapy directed at tissues of mesenchymal origin could potentially augment healing. We aimed to assess the duration and magnitude of transene expression in vivo in mice and ex vivo in human tissues. Methods. Using bioluminescence imaging, plasmid and adenoviral vector-based transgene expression in murine quadriceps in vivo was examined. Temporal control was assessed using a doxycycline-inducible system. An ex vivo model was developed and optimised using murine tissue, and applied in ex vivo human tissue. Results. In vivo plasmid-based transgene expression did not silence in murine muscle, unlike in liver. Although maximum luciferase expression was higher in muscle with adenoviral delivery compared with plasmid, expression reduced over time. The inducible promoter cassette successfully regulated gene expression with maximum levels a factor of 11 greater than baseline. Expression was re-induced to a similar level on a temporal basis. Luciferase expression was readily detected ex vivo in human muscle and tendon. Conclusions. Plasmid constructs resulted in long-term in vivo gene expression in skeletal muscle, in a controllable fashion utilising an inducible promoter in combination with oral agents. Successful plasmid gene transfection in human ex vivo mesenchymal tissue was demonstrated for the first time.

  17. Sensitivity of reentrant driver localization to electrophysiological parameter variability in image-based computational models of persistent atrial fibrillation sustained by a fibrotic substrate

    Deng, Dongdong; Murphy, Michael J.; Hakim, Joe B.; Franceschi, William H.; Zahid, Sohail; Pashakhanloo, Farhad; Trayanova, Natalia A.; Boyle, Patrick M.

    2017-09-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, causing morbidity and mortality in millions worldwide. The atria of patients with persistent AF (PsAF) are characterized by the presence of extensive and distributed atrial fibrosis, which facilitates the formation of persistent reentrant drivers (RDs, i.e., spiral waves), which promote fibrillatory activity. Targeted catheter ablation of RD-harboring tissues has shown promise as a clinical treatment for PsAF, but the outcomes remain sub-par. Personalized computational modeling has been proposed as a means of non-invasively predicting optimal ablation targets in individual PsAF patients, but it remains unclear how RD localization dynamics are influenced by inter-patient variability in the spatial distribution of atrial fibrosis, action potential duration (APD), and conduction velocity (CV). Here, we conduct simulations in computational models of fibrotic atria derived from the clinical imaging of PsAF patients to characterize the sensitivity of RD locations to these three factors. We show that RDs consistently anchor to boundaries between fibrotic and non-fibrotic tissues, as delineated by late gadolinium-enhanced magnetic resonance imaging, but those changes in APD/CV can enhance or attenuate the likelihood that an RD will anchor to a specific site. These findings show that the level of uncertainty present in patient-specific atrial models reconstructed without any invasive measurements (i.e., incorporating each individual's unique distribution of fibrotic tissue from medical imaging alongside an average representation of AF-remodeled electrophysiology) is sufficiently high that a personalized ablation strategy based on targeting simulation-predicted RD trajectories alone may not produce the desired result.

  18. Utility of bone scintigraphy in the study of hereditary disorders of the connective tissues (HDCT)

    Bravo, J.F; Arteaga M P; Coelho, L

    2003-01-01

    Introduction: Collagen fiber genetic alterations predispose to pain and instability of joints, with a tendency to osteoarthritis, and may also cause fragility of other tissues. Objective: To demonstrate that Bone Scintigraphy is useful in the diagnosis of Heritable Disorders of Connective Tissues (HDCT). Material and methods: We studied the scintigraphic changes of wrists, carpal bones and hands of 22 adult patients with HDCT who were diagnosed clinically using both the Brighton Criteria(1), as well as own criteria**. We compared them to 22 controls with similar age and sex, who had a bone scintigram done for other purposes. Results: Statistically significant scintigraphic positivity was found in the areas studied in the patients as compared to controls (p ≤ 0.05), with a sensitivity of 95% and specificity of 73%. There was no correlation of the degree of positivity with age, sex or type of HDCT studied. A scintigraphic positivity was seen both in patients with lax joints, as well as in those with a lesser degree of joint mobility. Conclusions: We concluded that bone scintigraphic studies are useful in the diagnosis of adult HDCT patients (including Benign Joint Hyper mobility Syndrome (BJHS) and other forms of Ehlers-Danlos). We suggest that not only hypermobility of joints, but also cartilage fragility are important pathogenic factors in the genesis of these alterations. We formulate a new hypothesis of the importance of low folic acid intake during pregnancy, as a cause for mutations that would give rise to HDCT (Au)

  19. Utility of bone scintigraphy in the study of hereditary disorders of the connective tissues (HDCT)

    Bravo, J F; P, Arteaga M; Coelho, L [Departments of Rheumatology and Nuclear Medicine. Clinica Arauco. Santiago (Chile)

    2003-10-01

    Introduction: Collagen fiber genetic alterations predispose to pain and instability of joints, with a tendency to osteoarthritis, and may also cause fragility of other tissues. Objective: To demonstrate that Bone Scintigraphy is useful in the diagnosis of Heritable Disorders of Connective Tissues (HDCT). Material and methods: We studied the scintigraphic changes of wrists, carpal bones and hands of 22 adult patients with HDCT who were diagnosed clinically using both the Brighton Criteria(1), as well as own criteria**. We compared them to 22 controls with similar age and sex, who had a bone scintigram done for other purposes. Results: Statistically significant scintigraphic positivity was found in the areas studied in the patients as compared to controls (p {<=} 0.05), with a sensitivity of 95% and specificity of 73%. There was no correlation of the degree of positivity with age, sex or type of HDCT studied. A scintigraphic positivity was seen both in patients with lax joints, as well as in those with a lesser degree of joint mobility. Conclusions: We concluded that bone scintigraphic studies are useful in the diagnosis of adult HDCT patients (including Benign Joint Hyper mobility Syndrome (BJHS) and other forms of Ehlers-Danlos). We suggest that not only hypermobility of joints, but also cartilage fragility are important pathogenic factors in the genesis of these alterations. We formulate a new hypothesis of the importance of low folic acid intake during pregnancy, as a cause for mutations that would give rise to HDCT (Au)

  20. UTILIZATION OF 940 NM WAVELENGTH DIODE LASERS AND THE MORPHO‐HISTOLOGICAL MODIFICATIONS IN PERIODONTAL TISSUES

    I. LUCHIAN

    2013-07-01

    Full Text Available Introduction: Non‐conventional techniques represent a more and more frequently employed alternative in medi‐ cine, firstly due to their minimally invasive character. Laser technologies represent forward‐looking methods to which numerous stomatologists resort, mainly because of their multiple applications in periodontology.The scope of the study was to identify the possible morpho‐histological differences on microscopic preparati‐ ons obtained by the two ‐ conventional and non‐conventi‐ onal – laser‐assisted techniques.Materials and method: Gingivectomies have been rea‐ lized on a mandible of freshly sacrificed pig, by the classi‐ cal surgical technique, 10 tissue samples of comparable size being taken over. On the same mandible, in the opposite quadrant, gingivectomies were realized by means of a diode‐type laser with a wavelength of 940 nm, followed by taking over of other 10 tissue samples. All specimens were conserved in a fixing solution and histological cups were obtained for subsequent analysis in the laboratory of pathological anatomy.Results and discussion: Histological evaluation evi‐ denced no significant morpho‐histological differences between the two techniques applied. The clinical advanta‐ ges of the photo‐mecanical interactions provided by laser‐assisted periodontal surgery include mainly reduc‐ tion of bleeding, absence of oedema, a higher confort for the patient (who suffers less pain and a much more rapid healing (by a faster tissular repair.Conclusions: Laser‐assisted technologies may be the‐ refore viewed as extremely useful alternatives in the new periodontal therapies, which recommends their applica‐ tion in periodontal surgery for at least three reasons: they are minimally invasive, they induce minor morpho‐histo‐ logical modifications and the technique of their application is simple to learn.

  1. Spatial and dose–response analysis of fibrotic lung changes after stereotactic body radiation therapy

    Vinogradskiy, Yevegeniy; Diot, Quentin; Kavanagh, Brian; Schefter, Tracey; Gaspar, Laurie; Miften, Moyed

    2013-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) is becoming the standard of care for early stage nonoperable lung cancers. Accurate dose–response modeling is challenging for SBRT because of the decreased number of clinical toxicity events. As a surrogate for a clinical toxicity endpoint, studies have proposed to use radiographic changes in follow up computed tomography (CT) scans to evaluate lung SBRT normal tissue effects. The purpose of the current study was to use local fibrotic lung regions to spatially and dosimetrically evaluate lung changes in patients that underwent SBRT.Methods: Forty seven SBRT patients treated at our institution from 2003 to 2009 were used for the current study. Our patient cohort had a total of 148 follow up CT scans ranging from 3 to 48 months post-therapy. Post-treatment scans were binned into intervals of 3, 6, 12, 18, 24, 30, and 36 months after the completion of treatment. Deformable image registration was used to align the follow up CT scans with the pretreatment CT and dose distribution. Areas of visible fibrotic changes were contoured. The centroid of each gross tumor volume (GTV) and contoured fibrosis volume was calculated and the fibrosis volume location and movement (magnitude and direction) relative to the GTV and 30 Gy isodose centroid were analyzed. To perform a dose–response analysis, each voxel in the fibrosis volume was sorted into 10 Gy dose bins and the average CT number value for each dose bin was calculated. Dose–response curves were generated by plotting the CT number as a function of dose bin and time posttherapy.Results: Both fibrosis and GTV centroids were concentrated in the upper third of the lung. The average radial movement of fibrosis centroids relative to the GTV centroids was 2.6 cm with movement greater than 5 cm occurring in 11% of patients. Evaluating dose–response curves revealed an overall trend of increasing CT number as a function of dose. The authors observed a CT number plateau at

  2. Nonparenchymal cells cultivated from explants of fibrotic liver resemble endothelial and smooth muscle cells from blood vessel walls

    Voss, B.; Rauterberg, J.; Pott, G.; Brehmer, U.; Allam, S.; Lehmann, R.; von Bassewitz, D.B.

    1982-01-01

    Tissue specimens from human fibrotic liver obtained by needle biopsy were cultured. Two cell types emerged from the tissue explants. From their morphology and biosynthetic products they resembled smooth muscle cells and endothelial cells from blood vessel walls. In the endothelial cells, factor VIII-associated protein was demonstrated by indirect immunofluorescence. Synthesis of collagen types I and III, basement membrane collagen types IV and V, and fibronectin by both cell types was observed by immunofluorescence microscopy. Homogeneous cultures of smooth muscle cells were observed in subcultures. After incubation with [ 14 C]glycine, collagen was isolated and characterized by CM cellulose chromatography, and consisted mainly of types I and III. These data suggest involvement of mesenchymal cells in hepatic fibrosis; they presumably originate from blood vessel or sinusoidal walls

  3. OM-101 Decreases the Fibrotic Response Associated with Proliferative Vitreoretinopathy

    Dvashi, Zeev; Ben-Yaakov, Keren; Weinberg, Tamir; Greenwald, Yoel

    2017-01-01

    Purpose This study aimed to investigate the effect of OM-101 on the fibrotic response occurring in proliferative vitreoretinopathy (PVR) in an animal model. Methods Antifibrotic effect of OM-101 was investigated in vivo. As control, eight weeks old c57black mice underwent intravitreal injection with Hepes (group A) or dispase (0.3 units), to induce retinal detachment (RD) and PVR. The dispase-injected mice were randomly divided into two groups B and C (N = 25 mice); in group C, the eyes were treated with intravitreal injection of OM-101 (3 μl), and group B with PBS, as a control. After additional five days, mice were injected with the same initial treatment. Three days later, mice were euthanized, and the eyes were enucleated and processed for histological analysis. Results Intravitreal injection of dispase caused RD in 64% of the mice in group B, and 93% of those mice had PVR. Only 32% of mice treated with OM-101 and dispase (group C) developed RD, and only 25% of those developed PVR. Conclusions OM-101 was found effective in reducing the incidence of RD and PVR maintaining the normal architecture of the retina. This study suggests that OM-101 is a potentially effective and safe drug for the treatment of PVR patients. PMID:29109865

  4. Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis.

    Gimenez, Andrea; Storrer, Karin; Kuranishi, Lilian; Soares, Maria Raquel; Ferreira, Rimarcs Gomes; Pereira, Carlos A C

    2018-04-01

    The predictive value of the decline in FVC by ≥10% on survival in patients with fibrotic hypersensitivity pneumonitis is unknown. Of 112 patients included, 66 (59%) had surgical lung biopsies. Patients with ≥10% decline in predicted FVC after 6-12 months had a significantly increased risk of all-cause mortality (median survival 53 months, 95% CI 37 to 69 vs 139 months, 95% CI 66 to 212 months, p=0.007). On multivariate analysis remained associated with increasing mortality: decline in FVC by ≥10% (HR 4.13, 95% CI 1.96 to 8.70, p=0.005), lower FVC% (HR 1.03, 95% CI 1.01 to 1.05, p=0.003) and with decreasing mortality improvement with antigen avoidance (HR 0.18, 95% CI 0.04 to 0.77, p=0.021). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  5. Anti-fibrotic effects of theophylline on lung fibroblasts

    Yano, Yukihiro; Yoshida, Mitsuhiro; Hoshino, Shigenori; Inoue, Koji; Kida, Hiroshi; Yanagita, Masahiko; Takimoto, Takayuki; Hirata, Haruhiko; Kijima, Takashi; Kumagai, Toru; Osaki, Tadashi; Tachibana, Isao; Kawase, Ichiro

    2006-01-01

    Theophylline has been used in the management of bronchial asthma and chronic obstructive pulmonary disease for over 50 years. It has not only a bronchodilating effect, but also an anti-inflammatory one conducive to the inhibition of airway remodeling, including subepithelial fibrosis. To date however, whether theophylline has a direct inhibitory effect on airway fibrosis has not been established. To clarify this question, we examined whether theophylline affected the function of lung fibroblasts. Theophylline suppressed TGF-β-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited fibroblast proliferation stimulated by FBS and TGF-β-induced α-SMA protein. A cAMP analog also inhibited TGF-β-induced COL1 mRNA expression in lung fibroblasts. A PKA inhibitor reduced the inhibitory effect of theophylline on TGF-β-induced COL1 mRNA expression. These results indicate that theophylline exerts anti-fibrotic effects, at least partly, through the cAMP-PKA pathway

  6. Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo.

    Venalis, Paulius; Maurer, Britta; Akhmetshina, Alfiya; Busch, Nicole; Dees, Clara; Stürzl, Michael; Zwerina, Jochen; Jüngel, Astrid; Gay, Steffen; Schett, Georg; Distler, Oliver; Distler, Jörg H W

    2009-10-01

    Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

  7. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells.

    Li, Chen Xi; Talele, Nilesh P; Boo, Stellar; Koehler, Anne; Knee-Walden, Ericka; Balestrini, Jenna L; Speight, Pam; Kapus, Andras; Hinz, Boris

    2017-03-01

    Expansion on stiff culture substrates activates pro-fibrotic cell programs that are retained by mechanical memory. Here, we show that priming on physiologically soft silicone substrates suppresses fibrogenesis and desensitizes mesenchymal stem cells (MSCs) against subsequent mechanical activation in vitro and in vivo, and identify the microRNA miR-21 as a long-term memory keeper of the fibrogenic program in MSCs. During stiff priming, miR-21 levels were gradually increased by continued regulation through the acutely mechanosensitive myocardin-related transcription factor-A (MRTF-A/MLK-1) and remained high over 2 weeks after removal of the mechanical stimulus. Knocking down miR-21 once by the end of the stiff-priming period was sufficient to erase the mechanical memory and sensitize MSCs to subsequent exposure to soft substrates. Soft priming and erasing mechanical memory following cell culture expansion protects MSCs from fibrogenesis in the host wound environment and increases the chances for success of MSC therapy in tissue-repair applications.

  8. Anti-fibrotic effect of natural toxin bee venom on animal model of unilateral ureteral obstruction.

    An, Hyun Jin; Kim, Kyung Hyun; Lee, Woo Ram; Kim, Jung Yeon; Lee, Sun Jae; Pak, Sok Cheon; Han, Sang Mi; Park, Kwan Kyu

    2015-05-29

    Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV) has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is not fully understood. To investigate the therapeutic effects of BV against unilateral ureteral obstruction (UUO)-induced renal fibrosis, BV was given intraperitoneally after ureteral ligation. At seven days after UUO surgery, the kidney tissues were collected for protein analysis and histologic examination. Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, BV treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of TNF-α and IL-1β were significantly reduced in BV treated mice compared with UUO mice. In addition, treatment with BV significantly inhibited TGF-β1 and fibronectin expression in UUO mice. Moreover, the expression of α-SMA was markedly withdrawn after treatment with BV. These findings suggest that BV attenuates renal fibrosis and reduces inflammatory responses by suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, BV may be a useful therapeutic agent for the prevention of fibrosis that characterizes progression of chronic kidney disease.

  9. Anti-Fibrotic Effect of Natural Toxin Bee Venom on Animal Model of Unilateral Ureteral Obstruction

    Hyun Jin An

    2015-05-01

    Full Text Available Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is not fully understood. To investigate the therapeutic effects of BV against unilateral ureteral obstruction (UUO-induced renal fibrosis, BV was given intraperitoneally after ureteral ligation. At seven days after UUO surgery, the kidney tissues were collected for protein analysis and histologic examination. Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, BV treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of TNF-α and IL-1β were significantly reduced in BV treated mice compared with UUO mice. In addition, treatment with BV significantly inhibited TGF-β1 and fibronectin expression in UUO mice. Moreover, the expression of α-SMA was markedly withdrawn after treatment with BV. These findings suggest that BV attenuates renal fibrosis and reduces inflammatory responses by suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, BV may be a useful therapeutic agent for the prevention of fibrosis that characterizes progression of chronic kidney disease.

  10. Rac1 GTPase regulates 11β hydroxysteroid dehydrogenase type 2 and fibrotic remodeling.

    Lavall, Daniel; Schuster, Pia; Jacobs, Nadine; Kazakov, Andrey; Böhm, Michael; Laufs, Ulrich

    2017-05-05

    The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) was age-dependently up-regulated in the atria and the left ventricles of RacET mice on mRNA and protein levels. Statin treatment inhibiting Rac1 geranylgeranylation reduced 11β-HSD2 up-regulation. Samples of human left atrial myocardium showed a positive correlation between Rac1 activity and 11β-HSD2 expression ( r = 0.7169). Immunoprecipitation showed enhanced Rac1-bound 11β-HSD2 relative to Rac1 expression in RacET mice that was diminished with statin treatment. Both basal and phorbol 12-myristate 13-acetate (PMA)-induced NADPH oxidase activity were increased in RacET and correlated positively with 11β-HSD2 expression ( r = 0.788 and r = 0.843, respectively). In cultured H9c2 cardiomyocytes, Rac1 activation with l-buthionine sulfoximine increased; Rac1 inhibition with NSC23766 decreased 11β-HSD2 mRNA and protein expression. Connective tissue growth factor (CTGF) up-regulation induced by aldosterone was prevented with NSC23766. Cardiomyocyte transfection with 11β-HSD2 siRNA abolished the aldosterone-induced CTGF up-regulation. Aldosterone-stimulated MR nuclear translocation was blocked by the 11β-HSD2 inhibitor carbenoxolone. In cardiac fibroblasts, nuclear MR translocation induced by aldosterone was inhibited with NSC23766 and spironolactone. NSC23766 prevented the aldosterone-induced proliferation and migration of cardiac fibroblasts and the up-regulation of CTGF and fibronectin. In conclusion, Rac1 GTPase regulates 11β-HSD2 expression, MR activation, and MR-mediated pro-fibrotic signaling. © 2017 by The American Society for

  11. Fibrotic scar formation in central serous chorioretinopathy developed during systemic treatment with corticosteroids

    Hooymans, JMM

    1998-01-01

    Background: The purpose of the study is to demonstrate the development of subretinal fibrotic scar formation in central serous chorioretinopathy (CSCR) that developed during systemic corticosteroid treatment. Methods: The clinical and photographic records of a patient in whom an unusual

  12. Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

    Martinez, Laisel; Duque, Juan C; Tabbara, Marwan; Paez, Angela; Selman, Guillermo; Hernandez, Diana R; Sundberg, Chad A; Tey, Jason Chieh Sheng; Shiu, Yan-Ting; Cheung, Alfred K; Allon, Michael; Velazquez, Omaida C; Salman, Loay H; Vazquez-Padron, Roberto I

    2018-03-01

    The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P =0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P =0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P =0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH. Copyright © 2018 by the American Society of Nephrology.

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

    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.

  14. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis

    Liu, Longwei; You, Zhifeng; Yu, Hongsheng; Zhou, Lyu; Zhao, Hui; Yan, Xiaojun; Li, Dulei; Wang, Bingjie; Zhu, Lu; Xu, Yuzhou; Xia, Tie; Shi, Yan; Huang, Chenyu; Hou, Wei; Du, Yanan

    2017-12-01

    The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FμNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FμNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FμNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FμNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

  15. Experimental study on active specific immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue, 7

    Ogawa, Yasuhiro; Maeda, Tomoho; Yoshida, Shoji; Yamamoto, Yoichi; Morita, Masaru

    1983-01-01

    We have already reported the remarkable effect of the active specific immunotherapy utilizing cryopreserved tumor cells and infiltrating mononuclear cells prepared from a lowdose irradiated tumor tissue after cytoreductive radiotherapy. In the present study, the effect of a biological response modifier, PSK combined with this active specific immunotherapy was investigated. Twelve-week-aged female C3H/He mice transplanted with MM46 tumor cells were received local radiotherapy with the dose of 3,000 rads by high energy electron beam on the fifth day after tumor inoculation. This active specific immunotherapy was performed on the twelveth day, and daily dose of 200 mg/kg of PSK was injected intraperitoneally from the sixth day to the tenth day. The more inhibition of the tumor growth was observed in the group which received this active specific immunotherapy combined with a biological response modifier, PSK compared with that received this active specific immunotherapy alone. (author)

  16. Experimental study on active specific immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue, 5

    Ogawa, Yasuhiro; Imanaka, Kazufumi; Gose, Kyuhei; Imajo, Yoshinari; Kimura, Shuji

    1982-01-01

    We have already reported the remarkable effect of the active specific immunotherapy utilizing cryopreserved tumor cells and infiltrating mononuclear cells prepared from a low-dose irradiated tumor tissue after cytoreductive radiotherapy. In the present study, the effect of a biological response modifier, OK-432 combined with this active specific immunotherapy was investigated. Twelve-week-aged female C3H/He mice transplanted with MM46 tumor cells were received local radiotherapy with the dose of 3,000 rads by high energy electron beam on the sixth day after inoculation. This active specific immunotherapy was performed on the thirteenth day, and daily dose of 1.0 KE of OK-432 was injected intraperitoneally from the thirteenth day to the seventeenth day. The inhibition of the tumor growth was observed in the group which received this active specific immunotherapy combined with a biological response modifier, OK-432 compared with that received this active specific immunotherapy alone. (author)

  17. Effects of protein-coated nanofibers on conformation of gingival fibroblast spheroids: potential utility for connective tissues regeneration.

    Kaufman, Gili; Whitescarver, Ryan; Nunes, Laiz; Palmer, Xavier-Lewis; Skrtic, Drago; Tutak, Wojtek

    2017-10-09

    Deep wounds in the gingiva caused by trauma or surgery require a rapid and robust healing of connective tissues. We propose utilizing gas-brushed nanofibers coated with collagen and fibrin for that purpose. Our hypotheses are that protein-coated nanofibers will: (i) attract and mobilize cells in various spatial orientations, and (ii) regulate the expression levels of specific extracellular matrix (ECM)-associated proteins, determining the initial conformational nature of dense and soft connective tissues. Gingival fibroblast monolayers and 3D spheroids were cultured on ECM substrate and covered with gas-blown poly-(DL-lactide-co-glycolide) (PLGA) nanofibers (uncoated/coated with collagen and fibrin). Cell attraction and rearrangement was followed by F-actin staining and confocal microscopy. Thicknesses of the cell layers, developed within the nanofibers, were quantified by imageJ software. The expression of collagen1α1 chain (Col1α1), fibronectin, and metalloproteinase 2 (MMP2) encoding genes was determined by quantitative reverse transcription analysis. Collagen- and fibrin- coated nanofibers induced cell migration toward fibers and supported cellular growth within the scaffolds. Both proteins affected the spatial rearrangement of fibroblasts by favoring packed cell clusters or intermittent cell spreading. These cell arrangements resembled the structural characteristic of dense and soft connective tissues, respectively. Within 3 days of incubation, fibroblast spheroids interacted with the fibers and grew robustly by increasing their thickness compared to monolayers. While the ECM key components, such as fibronectin and MMP2 encoding genes, were expressed in both protein groups, Col1α1 was predominantly expressed in bundled fibroblasts grown on collagen fibers. This enhanced expression of collagen1 is typical for dense connective tissue. Based on results of this study, our gas-blown, collagen- and fibrin-coated PLGA nanofibers are viable candidates for

  18. Effects of protein-coated nanofibers on conformation of gingival fibroblast spheroids: potential utility for connective tissue regeneration.

    Kaufman, Gili; Whitescarver, Ryan A; Nunes, Laiz; Palmer, Xavier-Lewis; Skrtic, Drago; Tutak, Wojtek

    2018-01-24

    Deep wounds in the gingiva caused by trauma or surgery require a rapid and robust healing of connective tissues. We propose utilizing gas-brushed nanofibers coated with collagen and fibrin for that purpose. Our hypotheses are that protein-coated nanofibers will: (i) attract and mobilize cells in various spatial orientations, and (ii) regulate the expression levels of specific extracellular matrix (ECM)-associated proteins, determining the initial conformational nature of dense and soft connective tissues. Gingival fibroblast monolayers and 3D spheroids were cultured on ECM substrate and covered with gas-blown poly-(DL-lactide-co-glycolide) (PLGA) nanofibers (uncoated/coated with collagen and fibrin). Cell attraction and rearrangement was followed by F-actin staining and confocal microscopy. Thicknesses of the cell layers, developed within the nanofibers, were quantified by ImageJ software. The expression of collagen1α1 chain (Col1α1), fibronectin, and metalloproteinase 2 (MMP2) encoding genes was determined by quantitative reverse transcription analysis. Collagen- and fibrin- coated nanofibers induced cell migration toward fibers and supported cellular growth within the scaffolds. Both proteins affected the spatial rearrangement of fibroblasts by favoring packed cell clusters or intermittent cell spreading. These cell arrangements resembled the structural characteristic of dense and soft connective tissues, respectively. Within three days of incubation, fibroblast spheroids interacted with the fibers, and grew robustly by increasing their thickness compared to monolayers. While the ECM key components, such as fibronectin and MMP2 encoding genes, were expressed in both protein groups, Col1α1 was predominantly expressed in bundled fibroblasts grown on collagen fibers. This enhanced expression of collagen1 is typical for dense connective tissue. Based on results of this study, our gas-blown, collagen- and fibrin-coated PLGA nanofibers are viable candidates for

  19. Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy

    Tlucek PS

    2013-06-01

    Full Text Available Paul S Tlucek,1 James C Folk,1 Warren M Sobol,2 Vinit B Mahajan1,3 1Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; 2Retina Physicians and Surgeons, Dayton, OH, USA; 3Omics Laboratory, University of Iowa, Iowa City, IA, USA Objective: To review fibrosis of fluocinolone acetonide (FA implants in subjects with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV. Methods: A retrospective case series was assembled from ADNIV patients in which there was fibrotic encapsulation of a fluocinolone acetonide implant. CAPN5 genotypes and surgical repair techniques were reviewed. Results: Two eyes of two ADNIV patients developed a fibrotic capsule over the fluocinolone acetonide implant. Both patients had Stage IV disease. Patient A had a c.731T > C mutation in the CAPN5 gene and patient B had a c.728G > T mutation. The fibrotic membrane was surgically excised and the implant function was restored. Conclusion: The exuberant fibrotic response in later stages of ADNIV may be resistant to local immunosuppression with steroids. Surgical excision of fibrotic membranes over FA implants can reestablish local steroid delivery in cases of severe proliferative vitreoretinopathy. Keywords: autosomal dominant neovascular inflammatory vitreoretinopathy, ADNIV, CAPN5, calpain-5, Retisert, fluocinolone acetonide, fibrotic encapsulation

  20. Transient activation of Wnt/β-catenin signaling reporter in fibrotic scar formation after compression spinal cord injury in adult mice.

    Yamagami, Takashi; Pleasure, David E; Lam, Kit S; Zhou, Chengji J

    2018-02-19

    After traumatic spinal cord injury (SCI), a scar may form with a fibrotic core (fibrotic scar) and surrounding reactive astrocytes (glial scar) at the lesion site. The scar tissue is considered a major obstacle preventing regeneration both as a physical barrier and as a source for secretion of inhibitors of axonal regeneration. Understanding the mechanism of scar formation and how to control it may lead to effective SCI therapies. Using a compression-SCI model on adult transgenic mice, we demonstrate that the canonical Wnt/β-catenin signaling reporter TOPgal (TCF/Lef1-lacZ) positive cells appeared at the lesion site by 5 days, peaked on 7 days, and diminished by 14 days post injury. Using various representative cell lineage markers, we demonstrate that, these transiently TOPgal positive cells are a group of Fibronectin(+);GFAP(-) fibroblast-like cells in the core scar region. Some of them are proliferative. These results indicate that Wnt/β-catenin signaling may play a key role in fibrotic scar formation after traumatic spinal cord injury. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Re-expression of pro-fibrotic, embryonic preserved mediators in irradiated arterial vessels of the head and neck region

    Moebius, Patrick; Preidl, Raimund H.M.; Weber, Manuel; Neukam, Friedrich W.; Wehrhan, Falk [Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Department of Oral and Maxillofacial Surgery, University Hospital of Erlangen, Erlangen (Germany); Amann, Kerstin [Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Department of Nephropathology, Institute of Pathology, University Hospital of Erlangen, Erlangen (Germany)

    2017-11-15

    Surgical treatment of head and neck malignancies frequently includes microvascular free tissue transfer. Preoperative radiotherapy increases postoperative fibrosis-related complications up to transplant loss. Fibrogenesis is associated with re-expression of embryonic preserved tissue developmental mediators: osteopontin (OPN), regulated by sex-determining region Y-box 9 (Sox9), and homeobox A9 (HoxA9) play important roles in pathologic tissue remodeling and are upregulated in atherosclerotic vascular lesions; dickkopf-1 (DKK1) inhibits pro-fibrotic and atherogenic Wnt signaling. We evaluated the influence of irradiation on expression of these mediators in arteries of the head and neck region. DKK1, HoxA9, OPN, and Sox9 expression was examined immunohistochemically in 24 irradiated and 24 nonirradiated arteries of the lower head and neck region. The ratio of positive cells to total cell number (labeling index) in the investigated vessel walls was assessed semiquantitatively. DKK1 expression was significantly decreased, whereas HoxA9, OPN, and Sox9 expression were significantly increased in irradiated compared to nonirradiated arterial vessels. Preoperative radiotherapy induces re-expression of embryonic preserved mediators in arterial vessels and may thus contribute to enhanced activation of pro-fibrotic downstream signaling leading to media hypertrophy and intima degeneration comparable to fibrotic development steps in atherosclerosis. These histopathological changes may be promoted by HoxA9-, OPN-, and Sox9-related inflammation and vascular remodeling, supported by downregulation of anti-fibrotic DKK1. Future pharmaceutical strategies targeting these vessel alterations, e. g., bisphosphonates, might reduce postoperative complications in free tissue transfer. (orig.) [German] Die operative Behandlung von Tumoren im Kopf- und Halsbereich umfasst den Transfer mikrovaskulaerer Gewebetransplantate. Praeoperative Bestrahlung verursacht eine erhoehte Inzidenz

  2. Development and Implementation of Discrete Polymeric Microstructural Cues for Applications in Cardiac Tissue Engineering

    Pinney, James Richardson

    Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. Despite care in the acute setting of MI, subsequent development of scar tissue and a lack of treatments for this maladaptive response lead to a poor prognosis. This has increased burdens on the cost of healthcare due to chronic disability. Here a novel therapeutic strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructural cues to attenuate the fibrotic response and improve functional outcomes is presented. Additionally, applications of integrated chemical functionalizations into discrete, micro-scale polymer structures are discussed in the realm of tissue engineering in order to impart enhancements in in vivo localization, three-dimensional manipulation and drug delivery. Polymeric microstructures, termed "microrods" and "microcubes", were fabricated using photolithographic techniques and studied in three-dimensional culture models of the fibrotic environment and by direct injection into the infarct zone of adult Sprague-Dawley rats. In vitro gene expression and functional and histological results were analyzed, showing a dose-dependent down-regulation fibrotic indicators and improvement in cardiac function. Furthermore, iron oxide nanoparticles and functionalized fluorocarbons were incorporated into the polymeric microdevices to promote in situ visualization by magnetic resonance imaging as well as to facilitate the manipulation and alignment of microstructural cues in a tissue-realistic environment. Lastly, successful encapsulation of native MGF peptide within microrods is demonstrated with release over two weeks as a proof of concept in the ability to locally deliver myogenic or supportive pharmacotherapeutics to the injured myocardium. This work demonstrates the efficacy and versatility of discrete microtopographical cues to attenuate the fibrotic response after MI and suggests a novel

  3. The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-l-phenylalanine) prodrug.

    Wang, Bing; Wen, Aiping; Feng, Chengmin; Niu, Lijing; Xiao, Xin; Luo, Le; Shen, Chengyi; Zhu, Jiang; Lei, Jun; Zhang, Xiaoming

    2018-04-13

    In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca 2+ stores; disruption of intracellular Ca 2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca 2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-β1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca 2+ stores were released

  4. Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

    Espindola, Milena S; Habiel, David M; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana L; Murray, Lynne A; Jiang, Dianhua; Noble, Paul W; Hogaboam, Cory M

    2018-06-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

  5. Pulmonary MR imaging with ultra-short TEs: Utility for disease severity assessment of connective tissue disease patients

    Ohno, Yoshiharu; Nishio, Mizuho; Koyama, Hisanobu; Takenaka, Daisuke; Takahashi, Masaya; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Obara, Makoto; Cauteren, Marc van; Sugimura, Kazuro

    2013-01-01

    Purpose: To evaluate the utility of pulmonary magnetic resonance (MR) imaging with ultra-short echo times (UTEs) at a 3.0 T MR system for pulmonary functional loss and disease severity assessments of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Materials and methods: This prospective study was approved by the institutional review board, and written informed consent was obtained from 18 CTD patients (eight men and ten women) and eight normal subjects with suspected chest disease (three men and five women). All subjects underwent thin-section MDCT, pulmonary MR imaging with UTEs, pulmonary function test and serum KL-6. Regional T2* maps were generated from each MR data set, and mean T2* values were determined from ROI measurements. From each thin-section MDCT data set, CT-based disease severity was evaluated with a visual scoring system. Mean T2* values for normal and CTD subjects were statistically compared by using Student's t-test. To assess capability for pulmonary functional loss and disease severity assessments, mean T2* values were statistically correlated with pulmonary functional parameters, serum KL-6 and CT-based disease severity. Results: Mean T2* values for normal and CTD subjects were significantly different (p = 0.0019) and showed significant correlations with %VC, %DL CO , serum KL-6 and CT-based disease severity of CTD patients (p < 0.05). Conclusion: Pulmonary MR imaging with UTEs is useful for pulmonary functional loss and disease severity assessments of CTD patients with ILD

  6. Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients

    Buckley Michael T

    2008-11-01

    Full Text Available Abstract Background Different Insulin-like Growth Factor Binding Proteins (IGFBPs have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. Methods The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56 prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. Results Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01 A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 μg/ml vs. 3.4 μg/ml, respectively, p = 0.09. However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. Conclusion Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients.

  7. Pulmonary MR imaging with ultra-short TEs: Utility for disease severity assessment of connective tissue disease patients

    Ohno, Yoshiharu, E-mail: yosirad@kobe-u.ac.jp [Advanced Biomedical Imaging Research Center, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Nishio, Mizuho [Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Koyama, Hisanobu [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Takenaka, Daisuke [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Department of Radiology, Hyogo Cancer Center, Akashi, Hyogo (Japan); Takahashi, Masaya [Advanced Imaging Research Center, Department of Radiology, University of Texas Southwestern Medical Center, Houston, TX (United States); Yoshikawa, Takeshi; Matsumoto, Sumiaki [Advanced Biomedical Imaging Research Center, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan); Obara, Makoto; Cauteren, Marc van [Philips Electronics Japan, Tokyo (Japan); Sugimura, Kazuro [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo (Japan)

    2013-08-15

    Purpose: To evaluate the utility of pulmonary magnetic resonance (MR) imaging with ultra-short echo times (UTEs) at a 3.0 T MR system for pulmonary functional loss and disease severity assessments of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Materials and methods: This prospective study was approved by the institutional review board, and written informed consent was obtained from 18 CTD patients (eight men and ten women) and eight normal subjects with suspected chest disease (three men and five women). All subjects underwent thin-section MDCT, pulmonary MR imaging with UTEs, pulmonary function test and serum KL-6. Regional T2* maps were generated from each MR data set, and mean T2* values were determined from ROI measurements. From each thin-section MDCT data set, CT-based disease severity was evaluated with a visual scoring system. Mean T2* values for normal and CTD subjects were statistically compared by using Student's t-test. To assess capability for pulmonary functional loss and disease severity assessments, mean T2* values were statistically correlated with pulmonary functional parameters, serum KL-6 and CT-based disease severity. Results: Mean T2* values for normal and CTD subjects were significantly different (p = 0.0019) and showed significant correlations with %VC, %DL{sub CO}, serum KL-6 and CT-based disease severity of CTD patients (p < 0.05). Conclusion: Pulmonary MR imaging with UTEs is useful for pulmonary functional loss and disease severity assessments of CTD patients with ILD.

  8. Microwave-assisted fibrous decoration of mPE surface utilizing Aloe vera extract for tissue engineering applications.

    Balaji, Arunpandian; Jaganathan, Saravana Kumar; Supriyanto, Eko; Muhamad, Ida Idayu; Khudzari, Ahmad Zahran Md

    2015-01-01

    Developing multifaceted, biocompatible, artificial implants for tissue engineering is a growing field of research. In recent times, several works have been reported about the utilization of biomolecules in combination with synthetic materials to achieve this process. Accordingly, in this study, the ability of an extract obtained from Aloe vera, a commonly used medicinal plant in influencing the biocompatibility of artificial material, is scrutinized using metallocene polyethylene (mPE). The process of coating dense fibrous Aloe vera extract on the surface of mPE was carried out using microwaves. Then, several physicochemical and blood compatibility characterization experiments were performed to disclose the effects of corresponding surface modification. The Fourier transform infrared spectrum showed characteristic vibrations of several active constituents available in Aloe vera and exhibited peak shifts at far infrared regions due to aloe-based mineral deposition. Meanwhile, the contact angle analysis demonstrated a drastic increase in wettability of coated samples, which confirmed the presence of active components on glazed mPE surface. Moreover, the bio-mimic structure of Aloe vera fibers and the influence of microwaves in enhancing the coating characteristics were also meticulously displayed through scanning electron microscopy micrographs and Hirox 3D images. The existence of nanoscale roughness was interpreted through high-resolution profiles obtained from atomic force microscopy. And the extent of variations in irregularities was delineated by measuring average roughness. Aloe vera-induced enrichment in the hemocompatible properties of mPE was established by carrying out in vitro tests such as activated partial thromboplastin time, prothrombin time, platelet adhesion, and hemolysis assay. In conclusion, the Aloe vera-glazed mPE substrate was inferred to attain desirable properties required for multifaceted biomedical implants.

  9. Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis

    Imai, Jin [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Gastroenterology, Tokai University School of Medicine, Kanagawa (Japan); Hozumi, Katsuto, E-mail: hozumi@is.icc.u-tokai.ac.jp [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Immunology, Tokai University School of Medicine, Kanagawa (Japan); Sumiyoshi, Hideaki [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa (Japan); Yazawa, Masaki; Hirano, Ken-ichi [Department of Immunology, Tokai University School of Medicine, Kanagawa (Japan); Abe, Jun; Higashi, Kiyoshi [Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka (Japan); Inagaki, Yutaka [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa (Japan); Mine, Tetsuya [Department of Gastroenterology, Tokai University School of Medicine, Kanagawa (Japan)

    2015-12-25

    Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production. - Highlights: • Colorectal fibrosis of TNBS-induced colitis was attenuated by HSc025 administration. • Local production of TGF-b was suppressed by the modulation of TGF-b/IFN-g signaling. • Derepression of IFN-g production was induced by the drug treatment.

  10. Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis

    Imai, Jin; Hozumi, Katsuto; Sumiyoshi, Hideaki; Yazawa, Masaki; Hirano, Ken-ichi; Abe, Jun; Higashi, Kiyoshi; Inagaki, Yutaka; Mine, Tetsuya

    2015-01-01

    Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production. - Highlights: • Colorectal fibrosis of TNBS-induced colitis was attenuated by HSc025 administration. • Local production of TGF-b was suppressed by the modulation of TGF-b/IFN-g signaling. • Derepression of IFN-g production was induced by the drug treatment.

  11. Utility of Normal Tissue-to-Tumor {alpha}/{beta} Ratio When Evaluating Isodoses of Isoeffective Radiation Therapy Treatment Plans

    Gay, Hiram A., E-mail: hgay@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Jin Jianyue [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Chang, Albert J. [Department of Radiation Oncology, University of California, San Francisco, California (United States); Ten Haken, Randall K. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-01-01

    Purpose: To achieve a better understanding of the effect of the number of fractions on normal tissue sparing for equivalent tumor control in radiation therapy plans by using equivalent biologically effective dose (BED) isoeffect calculations. Methods and Materials: The simple linear quadratic (LQ) model was assumed to be valid up to 10 Gy per fraction. Using the model, we formulated a well-known mathematical equality for the tumor prescription dose and probed and solved a second mathematical problem for normal tissue isoeffect. That is, for a given arbitrary relative isodose distribution (treatment plan in percentages), 2 isoeffective tumor treatment regimens (N fractions of the dose D and n fractions of the dose d) were denoted, which resulted in the same BED (corresponding to 100% prescription isodose). Given these situations, the LQ model was further exploited to mathematically establish a unique relative isodose level, z (%), for the same arbitrary treatment plan, where the BED to normal tissues was also isoeffective for both fractionation regimens. Results: For the previously stated problem, the relative isodose level z (%), where the BEDs to the normal tissue were also equal, was defined by the normal tissue {alpha}/{beta} ratio divided by the tumor {alpha}/{beta} times 100%. Fewer fractions offers a therapeutic advantage for those portions of the normal tissue located outside the isodose surface, z, whereas more fractions offer a therapeutic advantage for those portions of the normal tissue within the isodose surface, z. Conclusions: Relative isodose-based treatment plan evaluations may be useful for comparing isoeffective tumor regimens in terms of normal tissue effects. Regions of tissues that would benefit from hypofractionation or standard fractionation can be identified.

  12. Synergistic effect of bolus exposure to zinc oxide nanoparticles on bleomycin-induced secretion of pro-fibrotic cytokines without lasting fibrotic changes in murine lungs.

    Wu, Wenting; Ichihara, Gaku; Hashimoto, Naozumi; Hasegawa, Yoshinori; Hayashi, Yasuhiko; Tada-Oikawa, Saeko; Suzuki, Yuka; Chang, Jie; Kato, Masashi; D'Alessandro-Gabazza, Corina N; Gabazza, Esteban C; Ichihara, Sahoko

    2014-12-30

    Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.

  13. The use of Compton scattering to differentiate between classifications of normal and diseased breast tissue

    Ryan, Elaine A; Farquharson, Michael J; Flinton, David M [School of Allied Health Sciences, City University, Charterhouse Square, London EC1M 6PA (United Kingdom)

    2005-07-21

    This study describes a technique for measuring the electron density of breast tissue utilizing Compton scattered photons. The K{sub {alpha}}{sub 2} line from a tungsten target industrial x-ray tube (57.97 keV) was used and the scattered x-rays collected at an angle of 30{sup 0}. At this angle the Compton and coherent photon peaks can be resolved using an energy dispersive detector and a peak fitting algorithm. The system was calibrated using solutions of known electron density. The results obtained from a pilot study of 22 tissues are presented. The tissue samples investigated comprise four different tissue classifications: adipose, malignancy, fibroadenoma and fibrocystic change (FCC). It is shown that there is a difference between adipose and malignant tissue, to a value of 9.0%, and between adipose and FCC, to a value of 12.7%. These figures are found to be significant by statistical analysis. The differences between adipose and fibroadenoma tissues (2.2%) and between malignancy and FCC (3.4%) are not significant. It is hypothesized that the alteration in glucose uptake within malignant cells may cause these tissues to have an elevated electron density. The fibrotic nature of tissue that has undergone FCC gives the highest measure of all tissue types.

  14. The use of Compton scattering to differentiate between classifications of normal and diseased breast tissue

    Ryan, Elaine A.; Farquharson, Michael J.; Flinton, David M.

    2005-07-01

    This study describes a technique for measuring the electron density of breast tissue utilizing Compton scattered photons. The Kα2 line from a tungsten target industrial x-ray tube (57.97 keV) was used and the scattered x-rays collected at an angle of 30°. At this angle the Compton and coherent photon peaks can be resolved using an energy dispersive detector and a peak fitting algorithm. The system was calibrated using solutions of known electron density. The results obtained from a pilot study of 22 tissues are presented. The tissue samples investigated comprise four different tissue classifications: adipose, malignancy, fibroadenoma and fibrocystic change (FCC). It is shown that there is a difference between adipose and malignant tissue, to a value of 9.0%, and between adipose and FCC, to a value of 12.7%. These figures are found to be significant by statistical analysis. The differences between adipose and fibroadenoma tissues (2.2%) and between malignancy and FCC (3.4%) are not significant. It is hypothesized that the alteration in glucose uptake within malignant cells may cause these tissues to have an elevated electron density. The fibrotic nature of tissue that has undergone FCC gives the highest measure of all tissue types.

  15. The use of Compton scattering to differentiate between classifications of normal and diseased breast tissue

    Ryan, Elaine A; Farquharson, Michael J; Flinton, David M

    2005-01-01

    This study describes a technique for measuring the electron density of breast tissue utilizing Compton scattered photons. The K α2 line from a tungsten target industrial x-ray tube (57.97 keV) was used and the scattered x-rays collected at an angle of 30 0 . At this angle the Compton and coherent photon peaks can be resolved using an energy dispersive detector and a peak fitting algorithm. The system was calibrated using solutions of known electron density. The results obtained from a pilot study of 22 tissues are presented. The tissue samples investigated comprise four different tissue classifications: adipose, malignancy, fibroadenoma and fibrocystic change (FCC). It is shown that there is a difference between adipose and malignant tissue, to a value of 9.0%, and between adipose and FCC, to a value of 12.7%. These figures are found to be significant by statistical analysis. The differences between adipose and fibroadenoma tissues (2.2%) and between malignancy and FCC (3.4%) are not significant. It is hypothesized that the alteration in glucose uptake within malignant cells may cause these tissues to have an elevated electron density. The fibrotic nature of tissue that has undergone FCC gives the highest measure of all tissue types

  16. Diagnostic utility of melanin production by fungi: Study on tissue sections and culture smears with Masson-Fontana stain

    Challa Sundaram

    2014-01-01

    Full Text Available Background: Dematiaceous fungi appear brown in tissue section due to melanin in their cell walls. When the brown color is not seen on routine H and E and culture is not available, differentiation of dematiaceous fungi from other fungi is difficult on morphology alone. Aims and Objective: To study if melanin production by dematiaceous fungi can help differentiate them from other types of fungi. Materials and Methods: Fifty tissue sections of various fungal infections and 13 smears from cultures of different species of fungi were stained with Masson Fontana stain to assess melanin production. The tissue sections included biopsies from 26 culture-proven fungi and 24 biopsies of filamentous fungi diagnosed on morphology alone with no culture confirmation. Results: All culture-proven dematiaceous fungi and Zygomycetes showed strong positivity in sections and culture smears. Aspergillus sp showed variable positivity and intensity. Cryptococcus neoformans showed strong positivity in tissue sections and culture smears. Tissue sections of septate filamentous fungi (9/15, Zygomycetes (4/5, and fungi with both hyphal and yeast morphology (4/4 showed positivity for melanin. The septate filamentous fungi negative for melanin were from biopsy samples of fungal sinusitis including both allergic and invasive fungal sinusitis and colonizing fungal balls. Conclusion: Melanin is produced by both dematiaceous and non-dematiaceous fungi. Masson-Fontana stain cannot reliably differentiate dematiaceous fungi from other filamentous fungi like Aspergillus sp; however, absence of melanin in the hyphae may be used to rule out dematiaceous fungi from other filamentous fungi. In the differential diagnosis of yeast fungi, Cryptococcus sp can be differentiated from Candida sp by Masson-Fontana stain in tissue sections.

  17. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice

    van Gameren, Ingrid I.; Hazenberg, BPC; Bijzet, J.; van Rijswijk, M.H.

    Objective. Aspiration of subcutaneous abdominal fat is a simple and fast method for detecting systemic amyloidosis; however, the sensitivity of this approach remains undetermined. The aim of this study was to assess the accuracy of fat tissue aspiration for detecting systemic amyloidosis and the

  18. Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.

    Beiert, Thomas; Tiyerili, Vedat; Knappe, Vincent; Effelsberg, Verena; Linhart, Markus; Stöckigt, Florian; Klein, Sabine; Schierwagen, Robert; Trebicka, Jonel; Nickenig, Georg; Schrickel, Jan W; Andrié, René P

    2017-08-26

    Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Nootkatone confers hepatoprotective and anti-fibrotic actions in a murine model of liver fibrosis by suppressing oxidative stress, inflammation, and apoptosis.

    Kurdi, Amani; Hassan, Kamal; Venkataraman, Balaji; Rajesh, Mohanraj

    2018-02-01

    In this study, the hepatoprotective and anti-fibrotic actions of nootkatone (NTK) were investigated using carbon tetrachloride (CCl 4 )-induced liver fibrosis in mice. CCl 4 administration elevated serum aspartate and alanine transaminases levels, respectively. In addition, CCl 4 produced hepatic oxidative and nitrative stress, characterized by diminished hemeoxygenase-1 expression, antioxidant defenses, and accumulation of 4-hydroxynonenal and 3-nitrotyrosine. Furthermore, CCl 4 administration evoked profound expression of pro-inflammatory cytokine expressions such as tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-1β in hepatic tissues, which corroborated with nuclear factor κB activation. Additionally, CCl 4 -treated animals exhibited higher apoptosis, characterized by increased caspase 3 activity, DNA fragmentation, and poly (ADP-ribose) polymerase activation. Moreover, histological and biochemical investigations revealed marked fibrosis in the livers of CCl 4 -administered animals. However, NTK treatment mitigated CCl 4 -induced phenotypic changes. In conclusion, our findings suggest that NTK exerts hepatoprotective and anti-fibrotic actions by suppressing oxidative stress, inflammation, and apoptosis. © 2017 Wiley Periodicals, Inc.

  20. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling.

    Horn, Margaux A; Trafford, Andrew W

    2016-04-01

    Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Do We Need Exercise Tests to Detect Gas Exchange Impairment in Fibrotic Idiopathic Interstitial Pneumonias?

    Benoit Wallaert

    2012-01-01

    Full Text Available In patients with fibrotic idiopathic interstitial pneumonia (f-IIP, the diffusing capacity for carbon monoxide (DLCO has been used to predict abnormal gas exchange in the lung. However, abnormal values for arterial blood gases during exercise are likely to be the most sensitive manifestations of lung disease. The aim of this study was to compare DLCO, resting PaO2, P(A-aO2 at cardiopulmonary exercise testing peak, and oxygen desaturation during a 6-min walk test (6MWT. Results were obtained in 121 patients with idiopathic pulmonary fibrosis (IPF, n=88 and fibrotic nonspecific interstitial pneumonias (NSIP, n=33. All but 3 patients (97.5% had low DLCO values (35 mmHg and 100 (83% demonstrated significant oxygen desaturation during 6MWT (>4%. Interestingly 27 patients had low DLCO and normal P(A-aO2, peak and/or no desaturation during the 6MWT. The 3 patients with normal DLCO also had normal PaO2, normal P(A-aO2, peak, and normal oxygen saturation during 6MWT. Our results demonstrate that in fibrotic IIP, DLCO better defines impairment of pulmonary gas exchange than resting PaO2, exercise P(A-aO2, peak, or 6MWT SpO2.

  2. Effect of ionizing radiations on connective tissue

    Altman, K.I.; Gerber, G.B.

    1980-01-01

    The effects of ionizing radiations on connective tissue in lung, heart, vasculature, kidney, skin, and skeletal tissues are reviewed. Special emphasis is given to the effect of ionizing radiations on vasculo-connective tissue and fibrotic changes following radiation-induced injury to organs and tissues. In order to put the subject matter in proper prospective, the general biochemistry, physiology, and pathology of connective tissue is reviewed briefly together with the participation of connective tissue in disease. The review closes with an assessment of future problems and an enumeration and discussion of important, as yet unanswered questions

  3. The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat

    Kristina Wallenius

    2013-01-01

    Full Text Available Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR agonist, tesaglitazar, 3 μmol/kg/day for 3 weeks. Whole body glucose disposal rate ( and hepatic glucose output (HGO were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,3H]glucose. Indices of tissue specific glucose utilization ( were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-3H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-13C]glucose, 2-deoxy-D-[U-14C]glucose, [U-14C]palmitate, and [9,10-3H]-(R-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of compared to obese controls. This involved increased insulin stimulation of in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (, and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats.

  4. Experimental study on active specific immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue

    Imanaka, Kazufumi; Tanaka, Koji; Sasai, Keisuke

    1984-01-01

    We have already reported the effectiveness of active specific immunotherapy based on the immune reaction of low-dose irradiated tumor tissue. In the present study, three kinds of immunotherapeutic methods subdivided by used cells were performed in order to compare each effectiveness. C3H/He mice bearing MM 46 tumor transplanted in the right hind paws received local irradiation with the dose of 3,000 rad on the 6th day, and the above-mentioned three methods, using tumor cells, lymphocytes, and tumor cells combining lymphocytes which were all separated from the topical tumor tissue exposed to 2,000 rad, were applied respectively on the 14 th day. The most effective data were obtained from two groups treated by the immunotherapy with tumor cells combining lymphocytes, which virtually caused the longest survival and best tumor growth control. (author)

  5. MR imaging of skeletal soft tissue infection: utility of diffusion-weighted imaging in detecting abscess formation

    Harish, Srinivasan; Rebello, Ryan; Chiavaras, Mary M.; Kotnis, Nikhil

    2011-01-01

    Our objectives were to assess if diffusion-weighted imaging (DWI) can help identify abscess formation in the setting of soft tissue infection and to assess whether abscess formation can be diagnosed confidently with a combination of DWI and other unenhanced sequences. Eight cases of soft tissue infection imaged with MRI including DWI were retrospectively reviewed. Two male and six female patients were studied (age range 23-50 years). Unenhanced MRI including DWI was performed in all patients. Post-contrast images were obtained in seven patients. All patients had clinically or surgically confirmed abscesses. Abscesses demonstrated restricted diffusion. DWI in conjunction with other unenhanced imaging showed similar confidence levels as post-contrast images in diagnosing abscess formation in four cases. In two cases, although the combined use of DWI and other unenhanced imaging yielded the same confidence levels as post-contrast imaging, DWI was more definitive for demonstrating abscess formation. In one case, post-contrast images had a better confidence for suggesting abscess. In one case, DWI helped detected the abscess, where gadolinium could not be administered because of a contraindication. This preliminary study suggests that DWI is a useful adjunct in the diagnosis of skeletal soft tissue abscesses. (orig.)

  6. Quality of Life and Utility in Patients with Metastatic Soft Tissue and Bone Sarcoma: The Sarcoma Treatment and Burden of Illness in North America and Europe (SABINE Study

    Peter Reichardt

    2012-01-01

    Full Text Available The aim of the study was to assess health-related quality of life (HRQoL among metastatic soft tissue (mSTS or bone sarcoma (mBS patients who had attained a favourable response to chemotherapy. We employed the EORTC QLQ-C30, the 3-item Cancer-Related Symptoms Questionnaire, and the EQ-5D instrument. HRQoL was evaluated overall and by health state in 120 mSTS/mBS patients enrolled in the SABINE study across nine countries in Europe and North America. Utility was estimated from responses to the EQ-5D instrument using UK population-based weights. The mean EQ-5D utility score was 0.69 for the pooled patient sample with little variation across health states. However, patients with progressive disease reported a clinically significant lower utility (0.56. Among disease symptoms, pain and respiratory symptoms are common. This study showed that mSTS/mBS is associated with reduced HRQoL and utility among patients with metastatic disease.

  7. Utilization of laser Doppler flowmetry and tissue spectrophotometry for burn depth assessment using a miniature swine model.

    Lotter, Oliver; Held, Manuel; Schiefer, Jennifer; Werner, Ole; Medved, Fabian; Schaller, Hans-Eberhard; Rahmanian-Schwarz, Afshin; Jaminet, Patrick; Rothenberger, Jens

    2015-01-01

    Currently, the diagnosis of burn depth is primarily based on a visual assessment and can be dependent on the surgeons' experience. The goal of this study was to determine the ability of laser Doppler flowmeter combined with a tissue spectrophotometer to discriminate burn depth in a miniature swine burn model. Burn injuries of varying depth, including superficial-partial, deep-partial, and full thickness, were created in seven Göttingen minipigs using an aluminium bar (100 °C), which was applied to the abdominal skin for periods of 1, 3, 6, 12, 30, and 60 seconds with gravity alone. The depth of injury was evaluated histologically using hematoxylin and eosin staining. All burns were assessed 3 hours after injury using a device that combines a laser light and a white light to determine blood flow, hemoglobin oxygenation, and relative amount of hemoglobin. The blood flow (41 vs. 124 arbitrary units [AU]) and relative amount of hemoglobin (32 vs. 52 AU) were significantly lower in full thickness compared with superficial-partial thickness burns. However, no significant differences in hemoglobin oxygenation were observed between these depths of burns (61 vs. 60%). These results show the ability of laser Doppler flowmeter and tissue spectrophotometer in combination to discriminate between various depths of injury in the minipig model, suggesting that this device may offer a valuable tool for burn depth assessment influencing burn management. © 2014 by the Wound Healing Society.

  8. Volumetric segmentation of ADC maps and utility of standard deviation as measure of tumor heterogeneity in soft tissue tumors.

    Singer, Adam D; Pattany, Pradip M; Fayad, Laura M; Tresley, Jonathan; Subhawong, Ty K

    2016-01-01

    Determine interobserver concordance of semiautomated three-dimensional volumetric and two-dimensional manual measurements of apparent diffusion coefficient (ADC) values in soft tissue masses (STMs) and explore standard deviation (SD) as a measure of tumor ADC heterogeneity. Concordance correlation coefficients for mean ADC increased with more extensive sampling. Agreement on the SD of tumor ADC values was better for large regions of interest and multislice methods. Correlation between mean and SD ADC was low, suggesting that these parameters are relatively independent. Mean ADC of STMs can be determined by volumetric quantification with high interobserver agreement. STM heterogeneity merits further investigation as a potential imaging biomarker that complements other functional magnetic resonance imaging parameters. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Downregulation of the S1P Transporter Spinster Homology Protein 2 (Spns2 Exerts an Anti-Fibrotic and Anti-Inflammatory Effect in Human Renal Proximal Tubular Epithelial Cells

    Olivier Blanchard

    2018-05-01

    Full Text Available Sphingosine kinase (SK catalyses the formation of sphingosine 1-phosphate (S1P, which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1 by the pro-inflammatory cytokines tumor necrosis factor (TNFα and interleukin (IL-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.

  10. Tissue response to silicone rubber when used as a root canal filling.

    Kasman, F G; Goldman, M

    1977-04-01

    To test the tissue compatibility of silicone rubber when it is used as a root canal filler, excess material was intentionally forced into the apical tissues in primates. The tissue response was one of general acceptance, with the usual response being fibrotic encapsulation. A low degree of inflammation was noted. Further studies are in progress.

  11. Utility of bronchial lavage fluids for epithelial growth factor receptor mutation assay in lung cancer patients: Comparison between cell pellets, cell blocks and matching tissue specimens

    Asaka, Shiho; Yoshizawa, Akihiko; Nakata, Rie; Negishi, Tatsuya; Yamamoto, Hiroshi; Shiina, Takayuki; Shigeto, Shohei; Matsuda, Kazuyuki; Kobayashi, Yukihiro; Honda, Takayuki

    2018-01-01

    The detection of epidermal growth factor receptor (EGFR) mutations is necessary for the selection of suitable patients with non-small cell lung cancer (NSCLC) for treatment with EGFR tyrosine kinase inhibitors. Cytology specimens are known to be suitable for EGFR mutation detection, although tissue specimens should be prioritized; however, there are limited studies that examine the utility of bronchial lavage fluid (BLF) in mutation detection. The purpose of the present study was to investigate the utility of BLF specimens for the detection of EGFR mutations using a conventional quantitative EGFR polymerase chain reaction (PCR) assay. Initially, quantification cycle (Cq) values of cell pellets, cell-free supernatants and cell blocks obtained from three series of 1% EGFR mutation-positive lung cancer cell line samples were compared for mutation detection. In addition, PCR analysis of BLF specimens obtained from 77 consecutive NSCLC patients, detecting EGFR mutations was validated, and these results were compared with those for the corresponding formalin-fixed paraffin-embedded (FFPE) tissue specimens obtained by surgical resection or biopsy of 49 of these patients. The Cq values for mutation detection were significantly lower in the cell pellet group (average, 29.58) compared with the other groups, followed by those in cell-free supernatants (average, 34.15) and in cell blocks (average, 37.12) for all three series (P<0.05). Mutational status was successfully analyzed in 77 BLF specimens, and the results obtained were concordant with those of the 49 matching FFPE tissue specimens. Notably, EGFR mutations were even detected in 10 cytological specimens that contained insufficient tumor cells. EGFR mutation testing with BLF specimens is therefore a useful and reliable method, particularly when sufficient cancer cells are not obtained. PMID:29399190

  12. Natural killer cell-dependent anti-fibrotic pathway in liver injury via Toll-like receptor-9.

    Lina Abu-Tair

    Full Text Available The toll-like receptor-9 (TLR9 agonist cytosine phosphate guanine (CpG, activates hepatic stellate cells (HSCs and mediates fibrosis. We investigated the TLR9 effects on lymphocyte/HSCs interactions. Liver fibrosis was induced in wild-type (WT mice by intra-peritoneal carbon-tetrachloride (CCl4 induction for 6 weeks. Fibrotic groups were intravenously treated by a vehicle versus CpG along last 2 weeks. Compared to vehicle-treated fibrotic WT, the in-vivo CpG-treatment significantly attenuated hepatic fibrosis and inflammation, associated with decreased CD8 and increased NK liver cells. In-vitro, co-cultures with vehicle-treated fibrotic NK cells increased HSCs proliferation (P<0.001 while their CpG-treated counterparts achieved a significant decrease. To investigate the role of lymphocytes, TLR9(-/- mice induced-hepatic fibrosis were used. Although TLR9(-/- mice manifested lower fibrotic profile as compared to their wild-type (WT counterparts, senescence (SA-β-Gal activity in the liver and ALT serum levels were significantly greater. In an adoptive transfer model; irradiated WT and TLR9(-/- recipients were reconstituted with naïve WT or TLR9(-/- lymphocytes. The adoptive transfer of TLR9(-/- versus WT lymphocytes led to increased fibrosis of WT recipients. TLR9(-/- fibrotic recipients reconstituted with TLR9(-/- or WT lymphocytes showed no changes in hepatic fibrosis severity or ALT serum levels. TLR9 activation had inconsistent effects on lymphocytes and HSCs. The net balance of TLR9 activation in WT, displayed significant anti-fibrotic activity, accompanied by CD8 suppression and increased NK-cells, activity and adherence to HSCs. The pro-fibrotic and pro-inflammatory properties of TLR9(-/- lymphocytes fail to activate HSCs with an early senescence in TLR9(-/- mice.

  13. Primary cutaneous marginal zone lymphoma associated with juxta-articular fibrotic nodules in a teenager.

    Ghatalia, Pooja; Porter, Joanne; Wroblewski, Danielle; Carlson, John Andrew

    2013-05-01

    Primary cutaneous marginal zone lymphoma (PCMZL) has rarely been reported in teenagers and is occasionally associated with Borrelia burgdorferi infection. Juxta-articular fibrotic nodules represent a unique, localized fibrosing response to spirochete infections, namely Borreliosis. Herein, we report a 15-year-old healthy boy who presented with a 4-year history of progressive acquisition of asymptomatic, erythematous nodules, ≤ 3 cm, beginning with his right forearm (3), then right arm (1) and lastly his right inner thigh (1). Biopsy showed PCMZL in three of five samples, and inflamed, fibrotic nodules, near the elbow in two. The bottom heavy lymphomatous nodules consisted of mostly small CD20+ CD43+ lymphocytes, some with plasmacytoid features. Mature plasma cells were lambda light chain restricted by in situ hybridization. The juxta-articular fibrotic nodules were located in the deep dermis and subcutis, had peripheral plasma cell-rich infiltrates, and showed nodular sclerosis (morphea profunda-like) in one, and lamellar and angiocentric sclerosis in the other reminiscent of quiescent lesions of chronic localized fibrosing leukocytoclastic vasculitis. Immunohistochemistry for B. burgdorferi revealed rare positive organisms; however, polymerase chain reaction (PCR) and serology were negative for B. burgdorferi as were serologic and/or PCR assays for Bartonella henselae, Ba. quintana, Ehrlichia chaffeensis, Treponema pallidum, Helicobacter pylori and Babesia microti. No evidence of extracutaneous disease was found by the review of systems and imaging studies. A 4-week trial of doxycycline therapy failed, whereas intralesional (IL) corticosteroid therapy induced rapid regression of his nodules. After two local recurrences, also treated with IL corticosteroids, he is well, without cutaneous disease, 20 months later. A literature review of 19 pediatric cases PCMZL reveals a similar natural history as adult PCMZL. Despite negative serology and PCR for B. burgdorferi

  14. Experimental study on active specific immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue, 8

    Imanaka, Kazufumi; Gose, Kyuhei; Ichiyanagi, Akihiro

    1983-01-01

    The effectiveness of active specific immunotherapy prepared from a low-dose irradiated tumor tissue has already reported. The present study was designed to investigate the effect of Mitomycin C-treated active specific immunotherapy. Twelve-week-aged female C3H/He mice transplanted with MM 46 tumors were exposed to local electron radiotherapy with a dose of 3,000 rad on the 5th day after tumor inoculation. Tumor cells prepared for active specific immunotherapy were pretreated with Mitomycin C at concentration of 20 μg/10 7 cells in Eagle MEM Earle containing 100 IU/ml penicillin. The cell suspension was incubated at 37 0 C for 15 minutes. Mitomycin C-treated active specific immunotherapy was performed on the 12th day. Antitumor effect was evaluated by the regression of the tumor and survival curve. The remarkable regression of the tumor and significant elongation of the survival period were observed in the group which received Mitomycin C-treated active specific immunotherapy and the group which received active specific immunotherapy without the treatment of Mitomycin C. (author)

  15. Experimental study on active specific immunotherapy utilizing the immune reaction of low-dose irradiated tumor tissue, 9

    Ogawa, Yasuhiro; Maeda, Tomoho; Yoshida, Shoji

    1983-01-01

    We have already reported the remarkable effect of an active specific immunotherapy using cryopreserved tumor cells and infiltrating mononuclear cells prepared from a low-dose irradiated tumor tissue after cytoreductive radiotherapy. In the present study, the effect of a biological response modifier, OK-432 combined with the active specific immunotherapy was investigated. Twelve-week-aged female C3H/He mice transplanted with MM 46 tumor cells were received local radiotherapy with a dose of 3,000 rads by high energy electron beams on the fifth day after inoculation. The tumor cells and infiltrating mononuclear cells cryopreserved for two months were thawed and treated with mitomycin-C at concentration of 20 μg/10 7 cells at 37 0 C for 30 min. Then, these cells were injected subcutaneously into the left hind paws as a mitomycin C-treated, cryopreserved active specific immunotherapy on the thirteenth day, and daily dose of 1 KE of OK-432 was injected intraperitoneally from the sixth to the tenth days. The inhibition of the tumor growth was similarly observed in the group which received this active specific immunotherapy combined with a biological response modifier, OK-432. (author)

  16. Rapid Chemometric X-Ray Fluorescence approaches for spectral Diagnostics of Cancer utilizing Tissue Trace Metals and Speciation profiles

    Okonda, J.J.

    2015-01-01

    Energy dispersive X-ray fluorescence (EDXRF) spectroscopy is an analytical method for identification and quantification of elements in materials by measurement of their spectral energy and intensity. EDXRFS spectroscopic technique involves simultaneous non-invasive acquisition of both fluorescence and scatter spectra from samples for quantitative determination of trace elemental content in complex matrix materials. The objective is develop a chemometric-aided EDXRFS method for rapid diagnosis of cancer and its severity (staging) based on analysis of trace elements (Cu, Zn, Fe, Se and Mn), their speciation and multivariate alterations of the elements in cancerous body tissue samples as cancer biomarkers. The quest for early diagnosis of cancer is based on the fact that early intervention translates to higher survival rate and better quality of life. Chemometric aided EDXRFS cancer diagnostic model has been evaluated as a direct and rapid superior alternative for the traditional quantitative methods used in XRF such as FP method. PCA results of cultured samples indicate that it is possible to characterize cancer at early and late stage of development based on trace elemental profiles

  17. Utility of Shear Wave Elastography for Diagnosing Chronic Autoimmune Thyroiditis

    Takahiro Fukuhara

    2015-01-01

    Full Text Available The aims of this study were to evaluate the utility of shear wave elastography (SWE using acoustic radiation force impulse (ARFI for diagnosing chronic autoimmune thyroiditis (CAT and to verify the effect of fibrotic thyroid tissue on shear wave velocity (SWV. The subjects were 229 patients with 253 normal thyroid lobes (controls and 150 CAT lobes. The SWV for CAT (2.47 ± 0.57 m/s was significantly higher than that for controls (1.59 ± 0.41 m/s (P<0.001. The area under the receiver operating characteristics (ROC curve for CAT was 0.899, and the SWV cut-off value was 1.96 m/s. The sensitivity, specificity, and diagnostic accuracy were 87.4%, 78.7%, and 85.1%, respectively. Levels of anti-thyroperoxidase antibodies and thyroid isthmus thickness were correlated with tissue stiffness in CAT. However, there was no correlation between levels of anti-thyroglobulin antibodies and tissue stiffness. Quantitative SWE is useful for diagnosing CAT, and it is possible that SWE can be used to evaluate the degree of fibrosis in patients with CAT.

  18. Full-length cDNA sequences from Rhesus monkey placenta tissue: analysis and utility for comparative mapping

    Lee Sang-Rae

    2010-07-01

    Full Text Available Abstract Background Rhesus monkeys (Macaca mulatta are widely-used as experimental animals in biomedical research and are closely related to other laboratory macaques, such as cynomolgus monkeys (Macaca fascicularis, and to humans, sharing a last common ancestor from about 25 million years ago. Although rhesus monkeys have been studied extensively under field and laboratory conditions, research has been limited by the lack of genetic resources. The present study generated placenta full-length cDNA libraries, characterized the resulting expressed sequence tags, and described their utility for comparative mapping with human RefSeq mRNA transcripts. Results From rhesus monkey placenta full-length cDNA libraries, 2000 full-length cDNA sequences were determined and 1835 rhesus placenta cDNA sequences longer than 100 bp were collected. These sequences were annotated based on homology to human genes. Homology search against human RefSeq mRNAs revealed that our collection included the sequences of 1462 putative rhesus monkey genes. Moreover, we identified 207 genes containing exon alterations in the coding region and the untranslated region of rhesus monkey transcripts, despite the highly conserved structure of the coding regions. Approximately 10% (187 of all full-length cDNA sequences did not represent any public human RefSeq mRNAs. Intriguingly, two rhesus monkey specific exons derived from the transposable elements of AluYRa2 (SINE family and MER11B (LTR family were also identified. Conclusion The 1835 rhesus monkey placenta full-length cDNA sequences described here could expand genomic resources and information of rhesus monkeys. This increased genomic information will greatly contribute to the development of evolutionary biology and biomedical research.

  19. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

    Wang, Cong, E-mail: wangcongweihai@126.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Dai, Jinghong, E-mail: daijinghongnew@163.com [Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China); Sun, Zhaorui, E-mail: lanseyunduan@163.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Shi, Chaowen, E-mail: willscw@live.cn [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Cao, Honghui, E-mail: caohonghui92@gmail.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); and others

    2015-02-01

    In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.

  20. High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation

    Tan, Xiaoying [Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen (Germany); Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen (Germany); Xu, Xingbo [Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen (Germany); Zeisberg, Elisabeth M. [Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen (Germany); German Center for Cardiovascular Research (DZHK), Göttingen (Germany); Zeisberg, Michael, E-mail: mzeisberg@med.uni-goettingen.de [Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen (Germany); German Center for Cardiovascular Research (DZHK), Göttingen (Germany)

    2016-04-08

    Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of α-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones. - Highlights: • We exposed human kidney fibroblasts to media containing 1 mM or 3 mM phosphate. • Increased phosphate influx causes phosphorylation of DNA methyltransferase Dnmt1. • Phosphorylated Dnmt1 causes promoter methylation and transcriptional silencing of RASAL1. • Depletion of RASAL1 causes increased intrinsic Ras-GTP activity and fibroblast activation. • Inorganic phosphate causes fibroblast activation independent of phospho-regulatory hormones.

  1. Connective matrix organization in human pulmonary fibrosis. Collagen polymorphism analysis in fibrotic deposits by immunohistological methods.

    Takiya, C; Peyrol, S; Cordier, J F; Grimaud, J A

    1983-01-01

    In the interstitium of the alveolar septa in the peripheral parts of the lung, four molecular types of collagen (I, III, IV and V) each with different morphological appearances, can be identified. The structural integrity of collagens accounts for the physiological efficiency of the lung. Fibrous thickening of alveolar septa is an invariable result of various diseases affecting the interstitium of the lung. The light and electron microscopic findings, and the immunological typing of collagens in six cases of fibrotic alveolar disease, are described. In the alveolar septa, two different compartments (the alveolo-capillary junction and the supportive axis) were affected by fibrosis: the alveolo-capillary junction was widened by the addition of interstitial collagens to basement membranes. In the axis, the increase of interstitial (types I and III) collagen gave rise to different patterns of connective matrix organization, graded as Loose or Dense depending on quantitative alterations of the type I/III ratio. The mode of organization of the fibrotic lung connective matrix, which depends on the quality of deposits in the matrix, may be correlated with the evolution of interstitial pulmonary fibrosis, in terms of its stability, remodelling ability and reversibility.

  2. Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity.

    Sato, Seidai; Shinohara, Shintaro; Hayashi, Shinya; Morizumi, Shun; Abe, Shuichi; Okazaki, Hiroyasu; Chen, Yanjuan; Goto, Hisatsugu; Aono, Yoshinori; Ogawa, Hirohisa; Koyama, Kazuya; Nishimura, Haruka; Kawano, Hiroshi; Toyoda, Yuko; Uehara, Hisanori; Nishioka, Yasuhiko

    2017-09-15

    Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.

  3. Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

    Mohamed, Hoda E; Elswefy, Sahar E; Rashed, Laila A; Younis, Nahla N; Shaheen, Mohamed A; Ghanim, Amal M H

    2016-03-01

    Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA. © 2016 by the Society for Experimental Biology and Medicine.

  4. Erhuang Formula ameliorates renal damage in adenine-induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses.

    Zhang, Chun-Yan; Zhu, Jian-Yong; Ye, Ying; Zhang, Miao; Zhang, Li-Jun; Wang, Su-Juan; Song, Ya-Nan; Zhang, Hong

    2017-11-01

    The present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF). The compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, β-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-κB, TNF-α, TGF-β1, α-SMA and osteopontin (OPN). Ten compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3',4'-heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of β-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARγ and high expression of NF-κB, TNF-α, TGF-β1, α-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner. EHF ameliorated renal damage in adenine-induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARγ, NF-κB and TGF-β signaling pathways. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Utilization pattern and survival outcomes of adjuvant therapies in high-grade nonretroperitoneal abdominal soft tissue sarcoma: A population-based study.

    Green, William Ross; Chokshi, Ravi; Jabbour, Salma K; DeLaney, Thomas F; Mahmoud, Omar

    2018-02-01

    Nonretroperitoneal abdominal soft tissue sarcoma (NRA-STS) is a rare disease with limited data supporting its management. Our study aimed to reveal the utilization patterns of adjuvant therapy and its potential survival benefits using the National Cancer Data Base. The analysis included patients with resected high-grade NRA-STS. Chi-square analysis was used to evaluate distribution of patient and tumor-related factors within treatment groups. The Kaplan-Meier and Cox proportional hazards model were utilized to evaluate overall survival according to treatment approach. Multivariate analysis was used to determine the impact of these factors on patients' outcome. Matched propensity score analysis was implemented to control for imbalance of confounding variables. At median follow-up of 49 months, 5-year overall survival improved from 46% without adjuvant radiation therapy to 52% (P = 0.009) with radiotherapy delivery with a 30% reduction in hazard of death (95% confidence interval = 0.58-0.84). On multivariate analysis, age <50, tumor <8 cm, negative margins and radiotherapy delivery were significant predictors of improved survival. Chemotherapy was not associated with significant survival improvement (Hazard Ratios [HR]: 0.89, P = 0.28). Adjuvant radiotherapy was associated with improved survival in high-grade NRA-STS. Chemotherapy was not associated with a survival improvement; however, further studies are needed to refine treatment strategies. © 2017 John Wiley & Sons Australia, Ltd.

  6. Utility of Tissue Transglutaminase Immunohistochemistry in Pediatric Duodenal Biopsies: Patterns of Expression and Role in Celiac Disease—A Clinicopathologic Review

    Saeeda Almarzooqi

    2013-01-01

    Full Text Available Tissue transglutaminase (tTG is a ubiquitous multifunctional protein. It has roles in various cellular processes. tTG is a major target of autoantibodies in celiac disease, and its expression by immunohistochemistry in pediatric celiac disease has not been fully examined. We studied tTG expression in 78 pediatric duodenal biopsies by utilizing an antibody to transglutaminase 2. Serum tTG was positive in all celiac cases evaluated. Serum antiserum endomysial antibody (EMA and tTG were negative in all control subjects and in inflammatory bowel disease and eosinophilic gastroenteritis. There was a statistically significant difference between cases of celiac disease and normal controls in terms of tTG immunohistochemical staining in duodenal biopsies surface epithelium ( value = 0.0012. There was no significant statistical difference in terms of staining of the villous surface or crypt between the cases of celiac disease and cases with IBD ( value = 0.5970 and 0.5227, resp.. There was no detected correlation between serum tTG values and immunohistochemical positivity on duodenal biopsy in cases of celiac disease ( value = 1. There was no relationship between Marsh classification and positivity of villous surface for tTG ( value = 0.4955. We conclude that tTG has limited utility in diagnosis of celiac disease in pediatric duodenal biopsies.

  7. Tissue engineering

    Fisher, John P; Bronzino, Joseph D

    2007-01-01

    Increasingly viewed as the future of medicine, the field of tissue engineering is still in its infancy. As evidenced in both the scientific and popular press, there exists considerable excitement surrounding the strategy of regenerative medicine. To achieve its highest potential, a series of technological advances must be made. Putting the numerous breakthroughs made in this field into a broad context, Tissue Engineering disseminates current thinking on the development of engineered tissues. Divided into three sections, the book covers the fundamentals of tissue engineering, enabling technologies, and tissue engineering applications. It examines the properties of stem cells, primary cells, growth factors, and extracellular matrix as well as their impact on the development of tissue engineered devices. Contributions focus on those strategies typically incorporated into tissue engineered devices or utilized in their development, including scaffolds, nanocomposites, bioreactors, drug delivery systems, and gene t...

  8. Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors.

    Sugita, Shintaro; Aoyama, Tomoyuki; Kondo, Kei; Keira, Yoshiko; Ogino, Jiro; Nakanishi, Katsuya; Kaya, Mitsunori; Emori, Makoto; Tsukahara, Tomohide; Nakajima, Hisaya; Takagi, Masayuki; Hasegawa, Tadashi

    2014-08-01

    Soft tissue angiofibroma (STA), a recently suggested new histologic entity, is a benign fibrovascular soft tissue tumor composed of bland spindle-shaped tumor cells with abundant collagenous to myxoid stroma and branching small vessels. The lesion has a characteristic AHRR-NCOA2 fusion gene derived from chromosomal translocation of t(5;8)(p15;q13). However, morphologically similar tumors containing abundant fibrovascular and myxoid stroma can complicate diagnosis. We designed an original DNA probe for detecting NCOA2 split signals on fluorescence in situ hybridization (FISH) and estimated its utility with 20 fibrovascular tumors: 4 each of STAs, solitary fibrous tumors (SFTs), and cellular angiofibromas and 3 each of low-grade myxofibrosarcomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. We also performed FISH for 13q14 deletion and immunohistochemistry (IHC) staining for estrogen receptor, progesterone receptor, retinoblastoma protein, and MUC-4 expression. Furthermore, IHC for Stat6 was conducted in the 20 cases analyzed by FISH and in an additional 26 SFTs. We found moderate to strong nuclear Stat6 expression in all SFTs but no expression in the other tumors. Both estrogen receptor and progesterone receptor expressions were observed in STAs, SFTs, and cellular angiofibromas. Expression of retinoblastoma protein was found in less than 10% of cells in all tumor types except myxoid liposarcoma. The low-grade fibromyxoid sarcomas were strongly positive for MUC-4. All STAs showed NCOA2 split signals on FISH. All tumors, regardless of histologic type, had 13q14 deletion. The NCOA2 FISH technique is a practical method for confirming STA diagnosis. The combination of NCOA2 FISH and Stat6 IHC proved effective for the differential diagnosis of STA, even when using small biopsy specimens. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Dietary fish oil replacement by linseed oil: Effect on growth, nutrient utilization, tissue fatty acid composition and desaturase gene expression in silver barb (Puntius gonionotus) fingerlings.

    Nayak, Madhusmita; Saha, Ashis; Pradhan, Avinash; Samanta, Mrinal; Giri, Shiba Shankar

    2017-03-01

    Silver barb (Puntius gonionotus) is considered a promising medium carp species for freshwater aquaculture in Asia. This study in silver barb was carried out to evaluate the effects of total or partial substitution of dietary fish oil (FO) with linseed oil (LO) on growth, nutrient utilization, whole-body composition, muscle and liver fatty acid composition. Fish (12.1±0.4g of initial body weight) were fed for 60days with five experimental iso-proteinous, iso-lipidic and iso-caloric diets in which FO (control diet) was replaced by 33.3%, 50%, 66.7% and 100% LO. Final weight, weight gain, percent weight gain, SGR decreased linearly (p0.05) affect the feed conversion ratio (FCR), protein efficiency ratio (PER) and whole body proximate composition. Furthermore, enhanced level of LO increased α-linolenic acid (ALA; 18:3n3) and linoleic acid (LA; 18:2n6) and decreased eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3) in muscle and liver. To understand the molecular mechanism of long chain-polyunsaturated fatty acid (LC-PUFA) biosynthesis, we cloned and characterized the fatty acyl Δ6 desaturase (Δ6 fad) cDNA and investigated its expression in various organs/tissues following replacement of FO with LO in the diet. The full-length Δ6 fad cDNA was 2056bp encoding 444 amino acids and was widely expressed in various organs/tissues. Replacement of FO with LO increased the expression of Δ6 fad mRNA in liver, muscle and intestine but no significant difference was found in the brain. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells.

    Tsang, Siu Wai; Bian, Zhao-Xiang

    2015-03-01

    Anthraquinone compounds have been recognized to possess antiinflammatory, anti-fibrotic and anti-tumour properties and thus applied in human and veterinary therapeutics as active substances of medicinal products. Amongst the anthraquinones isolated from Rheum palmatum, also known as da-huang, rhein was detected as one of the highest metabolite contents in the bloodstream of mammals. The biological activities of rhein therefore deserve detailed investigation. In this study, we aimed to delineate the mechanism of inhibitory actions of rhein on fibrotic and tumorigenic processes by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction (PCR) and western blotting analyses in rat pancreatic stellate cells (LTC-14), human pancreatic ductal adenocarcinoma cells (PANC-1) and human colon carcinoma cells (SW480 and SW620). Our results demonstrated that the application of rhein notably suppressed the mRNA and protein levels of various fibrotic and tumorigenic mediators including alpha-smooth muscle actin, type I collagen, fibronectin, N-cadherin and matrix metalloproteinases in the testing mammalian cells. The mechanism of the suppressive actions of rhein was associated with the modulation of the sonic hedgehog and serine-threonine kinase signalling pathways. In conclusion, we suggest that rhein may serve as a therapeutic or an adjuvant agent in anti-fibrotic and anti-tumorigenic approaches. Copyright © 2014 John Wiley & Sons, Ltd.

  11. A case-control study of the effectiveness of tissue plasminogen activator on 6 month patients--reported outcomes and health care utilization.

    Lang, Catherine E; Bland, Marghuretta D; Cheng, Nuo; Corbetta, Maurizio; Lee, Jin-Moo

    2014-01-01

    We examined the benefit of tissue plasminogen activator (tPA), delivered as part of usual stroke management, on patient-reported outcomes and health care utilization. Using a case control design, patients who received tPA as part of usual stroke management were compared with patients who would have received tPA had they arrived to the hospital within the therapeutic time window. Data were collected from surveys 6 months after stroke using standardized patient-reported outcome measures and questions about health care utilization. Demographic and medical data were acquired from hospital records. Patients were matched on stroke severity, age, race, and gender. Matching was done with 1:2 ratio of tPA to controls. Results were compared between groups with 1-tailed tests because of a directionally specific hypothesis in favor of the tPA group. The tPA (n = 78) and control (n = 156) groups were matched across variables, except for stroke severity, which was better in the control group; subsequent analyses controlled for this mismatch. The tPA group reported better physical function, communication, cognitive ability, depressive symptomatology, and quality of life/participation compared with the control group. Fewer people in the tPA group reported skilled nursing facility stays, emergency department visits, and rehospitalizations after their stroke compared with controls. Reports of other postacute services were not different between groups. Although it is known that tPA reduces disability, this is the first study to demonstrate the effectiveness of tPA in improving meaningful, patient-reported outcomes. Thus, use of tPA provides a large benefit to the daily lives of people with ischemic stroke. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  12. Reinforced chitosan-based heart valve scaffold and utility of bone marrow-derived mesenchymal stem cells for cardiovascular tissue engineering

    Albanna, Mohammad Zaki

    utility for cardiovascular tissue engineering applications. Moreover, we evaluated the effect of various glycosaminoglycans (GAGs) on MSCs morphology and proliferation. Lastly, we studied the effect of stiffness of mechanically improved chitosan fibers on MSCs viability, attachment and proliferation. Results showed that MSCs proliferation improved in proportion to fiber stiffness.

  13. Determination of a tissue-level failure evaluation standard for rat femoral cortical bone utilizing a hybrid computational-experimental method.

    Fan, Ruoxun; Liu, Jie; Jia, Zhengbin; Deng, Ying; Liu, Jun

    2018-01-01

    Macro-level failure in bone structure could be diagnosed by pain or physical examination. However, diagnosing tissue-level failure in a timely manner is challenging due to the difficulty in observing the interior mechanical environment of bone tissue. Because most fractures begin with tissue-level failure in bone tissue caused by continually applied loading, people attempt to monitor the tissue-level failure of bone and provide corresponding measures to prevent fracture. Many tissue-level mechanical parameters of bone could be predicted or measured; however, the value of the parameter may vary among different specimens belonging to a kind of bone structure even at the same age and anatomical site. These variations cause difficulty in representing tissue-level bone failure. Therefore, determining an appropriate tissue-level failure evaluation standard is necessary to represent tissue-level bone failure. In this study, the yield and failure processes of rat femoral cortical bones were primarily simulated through a hybrid computational-experimental method. Subsequently, the tissue-level strains and the ratio between tissue-level failure and yield strains in cortical bones were predicted. The results indicated that certain differences existed in tissue-level strains; however, slight variations in the ratio were observed among different cortical bones. Therefore, the ratio between tissue-level failure and yield strains for a kind of bone structure could be determined. This ratio may then be regarded as an appropriate tissue-level failure evaluation standard to represent the mechanical status of bone tissue.

  14. Biodegradable microspheres for the sustained release of ppB-HSA to target PDGFβ-receptors in fibrotic tissues

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Post, Eduard; Hinrichs, Wouter; Poelstra, Klaas; Olinga, Peter

    2016-01-01

    Introduction pPB-HSA is a protein construct, which consists of human serum albumin (HSA), coupled to a cyclic peptide (pPB). This cyclic peptide binds specifically to the PDGF receptor without eliciting an intracellular response. Hence, this construct can be used as a carrier vehicle to target drugs

  15. Impact of Fibrotic Tissue on Shear Wave Velocity in Thyroid: An Ex Vivo Study with Fresh Thyroid Specimens

    Takahiro Fukuhara

    2015-01-01

    Full Text Available We sought to elucidate the correlation between shear wave velocity (SWV and fibrosis in thyroid by precisely assessing pathological structures inside 5 × 5 mm2 regions of interest (ROIs of resected specimens, under conditions that excluded physical artifacts. The materials were unselected thyroid and lymph node specimens resected during thyroid surgery. Immediately after surgery, fresh unfixed thyroid and metastatic lymph node specimens were suspended in gel phantoms, and SWV was measured. Upon pathological examination of each specimen, the extent of fibrosis was graded as none, moderate, or severe. A total of 109 specimens were evaluated: 15 normal thyroid, 16 autoimmune thyroiditis, 40 malignant nodules, 19 benign thyroid nodules, and 19 metastatic lymph nodes. When all specimens were classified according to the degree of fibrosis determined by pathological imaging, the mean SWV was 1.49±0.39 m/s for no fibrosis, 2.13±0.66 m/s for moderate fibrosis, and 2.68±0.82 m/s for severe fibrosis. The SWVs of samples with moderate and severe fibrosis were significantly higher than those of samples without fibrosis. The results of this study demonstrate that fibrosis plays an important role in determining stiffness, as measured by SWV in thyroid.

  16. Adventitial Fibroblasts induce a distinct Pro-inflammatory/Pro-fibrotic Macrophage Phenotype in Pulmonary Hypertension

    El Kasmi, Karim C.; Pugliese, Steven C.; Riddle, Suzette R.; Poth, Jens M.; Anderson, Aimee L.; Frid, Maria G.; Li, Min; Pullamsetti, Soni S.; Savai, Rajkumar; Nagel, Maria A.; Fini, Mehdi A.; Graham, Brian B.; Tuder, Rubin M.; Friedman, Jacob E.; Eltzschig, Holger K.; Sokol, Ronald J.; Stenmark, Kurt R.

    2014-01-01

    Macrophage accumulation is not only a characteristic hallmark but also a critical component of pulmonary artery (PA) remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Utilizing multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, as well as primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive Pas (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL4/IL13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation while complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, while deficiency in C/EBPβ or HIF1 attenuated fibroblast driven macrophage activation. These findings challenge the current paradigm of IL4/IL13-STAT6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPβ signaling is critical for macrophage activation and polarization. Thus, targeting IL6 signaling in macrophages by completely inhibiting C/EBPβ, HIF1a or partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL6 and absent IL4/IL13 signaling. PMID:24928992

  17. Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells

    Okumura, Takashi; Ohuchida, Kenoki; Sada, Masafumi; Abe, Toshiya; Endo, Sho; Koikawa, Kazuhiro; Iwamoto, Chika; Miura, Daisuke; Mizuuchi, Yusuke; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Manabe, Tatsuya; Ohtsuka, Takao; Nagai, Eishi; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi

    2017-01-01

    Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells. PMID:28407685

  18. Deletion of nardilysin prevents the development of steatohepatitis and liver fibrotic changes.

    Shoko Ishizu-Higashi

    Full Text Available Nonalcoholic steatohepatitis (NASH is an inflammatory form of nonalcoholic fatty liver disease that progresses to liver cirrhosis. It is still unknown how only limited patients with fatty liver develop NASH. Tumor necrosis factor (TNF-α is one of the key molecules in initiating the vicious circle of inflammations. Nardilysin (N-arginine dibasic convertase; Nrd1, a zinc metalloendopeptidase of the M16 family, enhances ectodomain shedding of TNF-α, resulting in the activation of inflammatory responses. In this study, we aimed to examine the role of Nrd1 in the development of NASH. Nrd1+/+ and Nrd1-/- mice were fed a control choline-supplemented amino acid-defined (CSAA diet or a choline-deficient amino acid-defined (CDAA diet. Fatty deposits were accumulated in the livers of both Nrd1+/+ and Nrd1-/- mice by the administration of the CSAA or CDAA diets, although the amount of liver triglyceride in Nrd1-/- mice was lower than that in Nrd1+/+ mice. Serum alanine aminotransferase levels were increased in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. mRNA expression of inflammatory cytokines were decreased in Nrd1-/- mice than in Nrd1+/+ mice fed the CDAA diet. While TNF-α protein was detected in both Nrd1+/+ and Nrd1-/- mouse livers fed the CDAA diet, secretion of TNF-α in Nrd1-/- mice was significantly less than that in Nrd1+/+ mice, indicating the decreased TNF-α shedding in Nrd1-/- mouse liver. Notably, fibrotic changes of the liver, accompanied by the increase of fibrogenic markers, were observed in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. Similar to the CDAA diet, fibrotic changes were not observed in Nrd1-/- mice fed a high-fat diet. Thus, deletion of nardilysin prevents the development of diet-induced steatohepatitis and liver fibrogenesis. Nardilysin could be an attractive target for anti-inflammatory therapy against NASH.

  19. Serial changes and prognostic implications of CT findings in combined pulmonary fibrosis and emphysema: comparison with fibrotic idiopathic interstitial pneumonias alone.

    Lee, Geewon; Kim, Ki Uk; Lee, Ji Won; Suh, Young Ju; Jeong, Yeon Joo

    2017-05-01

    Background Although fibrotic idiopathic interstitial pneumonias (IIPs) alone and those combined with pulmonary emphysema are naturally progressive diseases, the process of deterioration and outcomes are variable. Purpose To evaluate and compare serial changes of computed tomography (CT) abnormalities and prognostic predictive factors in fibrotic IIPs alone and those combined with pulmonary emphysema. Material and Methods A total of 148 patients with fibrotic IIPs alone (82 patients) and those combined with pulmonary emphysema (66 patients) were enrolled. Semi-quantitative CT analysis was used to assess the extents of CT characteristics which were evaluated on initial and follow-up CT images. Univariate and multivariate analyses were performed to assess the effects of clinical and CT variables on survival. Results Significant differences were noted between fibrotic scores, as determined using initial CT scans, in the fibrotic IIPs alone (21.22 ± 9.83) and those combined with pulmonary emphysema groups (14.70 ± 7.28) ( P pulmonary emphysema group. Multivariate Cox proportional hazards analysis showed changes in the extent of GGO (hazard ratio, 1.056) and the presence of lung cancer (hazard ratio, 4.631) were predictive factors of poor survivals. Conclusion Although patients with fibrotic IIPs alone and those combined with pulmonary emphysema have similar mortalities, lung cancer was more prevalent in patients with fibrotic IIPs combined with pulmonary emphysema. Furthermore, changes in the extent of GGO and the presence of lung cancer were independent prognostic factors of poor survivals.

  20. Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4.

    Liu, Xin-Hua; Pan, Li-Long; Deng, Hai-Yan; Xiong, Qing-Hui; Wu, Dan; Huang, Guo-Ying; Gong, Qi-Hai; Zhu, Yi-Zhun

    2013-01-01

    In our previous studies, we have reported that leonurine, a plant phenolic alkaloid in Herba leonuri, exerted cardioprotective properties in a number of preclinical experiments. Herein, we investigated the roles and the possible mechanisms of leonurine for reducing fibrotic responses in angiotensin II (Ang II)-stimulated primary neonatal rat cardiac fibroblasts and post-myocardial infarction (MI) rats. In in vitro experiments performed in neonatal rat cardiac fibroblasts, leonurine (10-20 μM) pretreatment attenuated Ang II-induced activation of extracellular signal-regulated kinase 1/2, production of intracellular reactive oxygen species (ROS), expression and activity of matrix metalloproteinase (MMP)-2/9, and expression of α-smooth muscle actin and types I and III collagen. A small interfering RNA-mediated knockdown strategy for NADPH oxidase 4 (Nox4) revealed that Nox4 was required for Ang II-induced activation of cardiac fibroblasts. In vivo studies using a post-MI model in rats indicated that administration of leonurine inhibited myocardial fibrosis while reducing cardiac Nox4 expression, ROS production, NF-κB activation, and plasma MMP-2 activity. In conclusion, our results provide the first evidence that leonurine could prevent cardiac fibrosis and the activation of cardiac fibroblasts partly through modulation of a Nox4-ROS pathway. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy.

    Cui, Chang; Jiang, Xiaohong; Ju, Weizhu; Wang, Jiaxian; Wang, Daowu; Sun, Zheng; Chen, Minglong

    2018-04-26

    Idiopathic isolated fibrotic atrial cardiomyopathy (IIF-ACM) is a novel subtype of cardiomyopathy characterized by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia. The mechanisms underlying its pathogenesis are unknown. Atrium samples were obtained from 3 patients with IIF-ACM via surgical intervention. Control samples were consisted of 3 atrium biopsies from patients with congenital heart disease and normal sinus rhythm, matched for gender, age and basic clinical characteristics. Comparative histology, immunofluorescence staining, electron microscopy and proteomics analyses were carried out to explore the unique pathogenesis of IIF-ACM. IIF-ACM atria displayed disordered myofibrils, profound fibrosis and mitochondrial damages compared to the control atria. Proteomics profiling identified metabolic pathways as the most profound changes in IIF-ACM. Our study suggested that metabolic changes in the atrial myocardium caused mitochondrial oxidative stress and potential cell damage, which further led to atrial fibrosis and myofibril disorganization, the characteristic phenotype of IIF-ACM. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Acquired RhD mosaicism identifies fibrotic transformation of thrombopoietin receptor-mutated essential thrombocythemia.

    Montemayor-Garcia, Celina; Coward, Rebecca; Albitar, Maher; Udani, Rupa; Jain, Prachi; Koklanaris, Eleftheria; Battiwalla, Minoo; Keel, Siobán; Klein, Harvey G; Barrett, A John; Ito, Sawa

    2017-09-01

    Acquired copy-neutral loss of heterozygosity has been described in myeloid malignant progression with an otherwise normal karyotype. A 65-year-old woman with MPL-mutated essential thrombocythemia and progression to myelofibrosis was noted upon routine pretransplant testing to have mixed field reactivity with anti-D and an historic discrepancy in RhD type. The patient had never received transfusions or transplantation. Gel immunoagglutination revealed group A red blood cells and a mixed-field reaction for the D phenotype, with a predominant D-negative population and a small subset of circulating red blood cells carrying the D antigen. Subsequent genomic microarray single nucleotide polymorphism profiling revealed copy-neutral loss of heterozygosity of chromosome 1 p36.33-p34.2, a known molecular mechanism underlying fibrotic progression of MPL-mutated essential thrombocythemia. The chromosomal region affected by this copy-neutral loss of heterozygosity encompassed the RHD, RHCE, and MPL genes. We propose a model of chronological molecular events that is supported by RHD zygosity assays in peripheral lymphoid and myeloid-derived cells. Copy-neutral loss of heterozygosity events that lead to clonal selection and myeloid malignant progression may also affect the expression of adjacent unrelated genes, including those encoding for blood group antigens. Detection of mixed-field reactions and investigation of discrepant blood typing results are important for proper transfusion support of these patients and can provide useful surrogate markers of myeloproliferative disease progression. © 2017 AABB.

  3. Treatment patterns, resource utilization, and outcomes among hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections in Lebanon and Saudi Arabia

    Matar MJ

    2017-02-01

    Full Text Available Madonna J Matar,1 Rima Moghnieh,2 Adel F Alothman,3 Abdulhakeem O Althaqafi,4 Thamer H Alenazi,3 Fayssal M Farahat,4 Shelby Corman,5 Caitlyn T Solem,5 Nirvana Raghubir,6 Cynthia Macahilig,7 Seema Haider,8 Jennifer M Stephens5 1Department of Infectious Diseases, Notre Dame des Secours University Hospital, Jbeil, Lebanon; 2Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon; 3College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 4King Abdullah International Medical Research Center, Infection Prevention and Control, King AbdulAziz Medical City, King Saud bin AbdulAziz University for Health Sciences, Jeddah, Saudi Arabia; 5Pharmerit International, Real-World Evidence/Data Analytics, Bethesda, MD, 6Pfizer, New York, NY, 7Medical Data Analytics, Parsippany, NJ, 8Pfizer, Groton, CT, USA Objectives: To describe treatment patterns and medical resource use for methicillin-resistant Staphylococcus aureus (MRSA complicated skin and soft tissue infections (cSSTI in Saudi Arabia and Lebanon in terms of drug selection against the infecting pathogen as well as hospital resource utilization and clinical outcomes among patients with these infections. Methods: This retrospective chart review study evaluated 2011–2012 data from five hospitals in Saudi Arabia and Lebanon. Patients were included if they had been discharged with a diagnosis of MRSA cSSTI, which was culture-proven or suspected based on clinical criteria. Hospital data were abstracted for a random sample of patients with each infection type to capture demographics, treatment patterns, hospital resource utilization, and clinical outcomes. Statistical analysis was descriptive. Results: Data were abstracted from medical records of 87 patients with MRSA cSSTI; mean age 52.4±25.9 years and 61% male. Only 64% of patients received an MRSA active initial therapy, with 56% of first

  4. Scleral fixation of a subluxated intraocular lens-capsular bag complex through a fibrotic continuous curvilinear capsulorhexis.

    Gimbel, Howard V; Brucks, Matthew; Dardzhikova, Albena A; Camoriano, Gerardo D

    2011-04-01

    Several strategies have been devised to manage in-the-bag intraocular lens (IOL) subluxation. We describe a method of fixating the IOL-capsular bag complex to the sclera using the fibrotic ring that develops around the continuous curvilinear capsulorhexis (CCC). Two, preferably 3, double-armed 10-0 polypropylene sutures are passed around the fibrotic CCC rim of the capsule and out the Hoffman scleral pockets and then tied in the scleral tunnels to center the IOL-bag complex. This technique provides an alternative approach to repositioning and fixating the IOL-bag complex that is especially useful in cases in which removal and replacement of the IOL would be difficult. It also provides more than 2-point fixation to achieve perfect IOL centration. No author has a financial or proprietary interest in any material or method mentioned. Copyright © 2011 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  5. Serum Metabolomic Characterization of Liver Fibrosis in Rats and Anti-Fibrotic Effects of Yin-Chen-Hao-Tang

    Hongyang Zhang

    2016-01-01

    Full Text Available Yin-Chen-Hao-Tang (YCHT is a famous Chinese medicine formula which has long been used in clinical practice for treating various liver diseases, such as liver fibrosis. However, to date, the mechanism for its anti-fibrotic effects remains unclear. In this paper, an ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOF-MS-based metabolomic study was performed to characterize dimethylnitrosamine (DMN-induced liver fibrosis in rats and evaluate the therapeutic effects of YCHT. Partial least squares-discriminant analysis (PLS-DA showed that the model group was well separated from the control group, whereas the YCHT-treated group exhibited a tendency to restore to the controls. Seven significantly changed fibrosis-related metabolites, including unsaturated fatty acids and lysophosphatidylcholines (Lyso-PCs, were identified. Moreover, statistical analysis demonstrated that YCHT treatment could reverse the levels of most metabolites close to the normal levels. These results, along with histological and biochemical examinations, indicate that YCHT has anti-fibrotic effects, which may be due to the suppression of oxidative stress and resulting lipid peroxidation involved in hepatic fibrogenesis. This study offers new opportunities to improve our understanding of liver fibrosis and the anti-fibrotic mechanisms of YCHT.

  6. The Role of Transforming Growth Factor Beta-1 in the Progression of HIV/AIDS and Development of Non-AIDS-Defining Fibrotic Disorders

    Annette J. Theron

    2017-11-01

    Full Text Available Even after attainment of sustained viral suppression following implementation of highly active antiretroviral therapy, HIV-infected persons continue to experience persistent, low-grade, systemic inflammation. Among other mechanisms, this appears to result from ongoing microbial translocation from a damaged gastrointestinal tract. This HIV-related chronic inflammatory response is paralleled by counteracting, but only partially effective, biological anti-inflammatory processes. Paradoxically, however, this anti-inflammatory response not only exacerbates immunosuppression but also predisposes for development of non-AIDS-related, non-communicable disorders. With respect to the pathogenesis of both sustained immunosuppression and the increased frequency of non-AIDS-related disorders, the anti-inflammatory/profibrotic cytokine, transforming growth factor-β1 (TGF-β1, which remains persistently elevated in both untreated and virally suppressed HIV-infected persons, may provide a common link. In this context, the current review is focused on two different, albeit related, harmful activities of TGF-β1 in HIV infection. First, on the spectrum of anti-inflammatory/immunosuppressive activities of TGF-β1 and the involvement of this cytokine, derived predominantly from T regulatory cells, in driving disease progression in HIV-infected persons via both non-fibrotic and profibrotic mechanisms. Second, the possible involvement of sustained elevations in circulating and tissue TGF-β1 in the pathogenesis of non-AIDS-defining cardiovascular, hepatic, pulmonary and renal disorders, together with a brief comment on potential TGF-β1-targeted therapeutic strategies.

  7. Plant tissue culture techniques

    Rolf Dieter Illg

    1991-01-01

    Full Text Available Plant cell and tissue culture in a simple fashion refers to techniques which utilize either single plant cells, groups of unorganized cells (callus or organized tissues or organs put in culture, under controlled sterile conditions.

  8. Epithelial-mesenchymal transition: An emerging target in tissue fibrosis

    Li, Meirong; Luan, Fuxin; Zhao, Yali; Hao, Haojie; Zhou, Yong; Han, Weidong

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibroses. Fibroblasts/myofibroblasts derived from epithelial cells contribute to the excessive accumulation of fibrous connective tissue in damaged tissue, which can lead to permanent scarring or organ malfunction. Therefore, EMT-related fibrosis cannot be neglected. This review highlights the findings that demonstrate the EMT to be a direct contributor to the fibroblast/myofibroblast population in the development of tissue fibrosis and helps to elucidate EMT-related anti-fibrotic strategies, which may enable the development of therapeutic interventions to suppress EMT and potentially reverse organ fibrosis. PMID:26361988

  9. Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts

    Samoszuk, Michael; Kanakubo, Emi; Chan, John K

    2005-01-01

    The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells. Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts. Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors

  10. Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts

    Kanakubo Emi

    2005-09-01

    Full Text Available Abstract Background The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. Methods We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7, a powerful, heparin-binding growth factor for breast epithelial cells. Results Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts. Conclusion Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors.

  11. Construction of engineering adipose-like tissue in vivo utilizing human insulin gene-modified umbilical cord mesenchymal stromal cells with silk fibroin 3D scaffolds.

    Li, Shi-Long; Liu, Yi; Hui, Ling

    2015-12-01

    We evaluated the use of a combination of human insulin gene-modified umbilical cord mesenchymal stromal cells (hUMSCs) with silk fibroin 3D scaffolds for adipose tissue engineering. In this study hUMSCs were isolated and cultured. HUMSCs infected with Ade-insulin-EGFP were seeded in fibroin 3D scaffolds with uniform 50-60 µm pore size. Silk fibroin scaffolds with untransfected hUMSCs were used as control. They were cultured for 4 days in adipogenic medium and transplanted under the dorsal skins of female Wistar rats after the hUMSCs had been labelled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (CM-Dil). Macroscopical impression, fluorescence observation, histology and SEM were used for assessment after transplantation at 8 and 12 weeks. Macroscopically, newly formed adipose tissue was observed in the experimental group and control group after 8 and 12 weeks. Fluorescence observation supported that the formed adipose tissue originated from seeded hUMSCs rather than from possible infiltrating perivascular tissue. Oil red O staining of newly formed tissue showed that there was substantially more tissue regeneration in the experimental group than in the control group. SEM showed that experimental group cells had more fat-like cells, whose volume was larger than that of the control group, and degradation of the silk fibroin scaffold was greater under SEM observation. This study provides significant evidence that hUMSCs transfected by adenovirus vector have good compatibility with silk fibroin scaffold, and adenoviral transfection of the human insulin gene can be used for the construction of tissue-engineered adipose. Copyright © 2013 John Wiley & Sons, Ltd.

  12. Nuclear magnetic resonance relaxation times for human lung cancer and lung tissues

    Matsuura, Yoshifumi; Shioya, Sumie; Kurita, Daisaku; Ohta, Takashi; Haida, Munetaka; Ohta, Yasuyo; Suda, Syuichi; Fukuzaki, Minoru.

    1994-01-01

    We investigated the nuclear magnetic resonance (NMR) relaxation times, T 1 and T 2 , for lung cancer tissue, and other samples of lung tissue obtained from surgical specimens. The samples were nine squamous cell carcinomas, five necrotic squamous cell carcinomas, 15 adenocarcinomas, two benign mesotheliomas, and 13 fibrotic lungs. The relaxation times were measured with a 90 MHz NMR spectrometer and the results were correlated with histological changes. The values of T 1 and T 2 for squamous cell carcinoma and mesothelioma were significantly longer than those of adenocarcinoma and fibrotic lung tissue. There were no significant differences in values of T 1 and T 2 between adenocarcinoma and lung tissue. The values of T 1 and T 2 for benign mesothelioma were similar to those of squamous cell carcinoma, which suggested that increases in T 1 and T 2 are not specific to malignant tissues. (author)

  13. Efficacy and Safety of the Collagenase of the Bacterium Clostridium Histolyticum for the Treatment of Capsular Contracture after Silicone Implants: Ex-Vivo Study on Human Tissue.

    Sebastian Fischer

    Full Text Available The fibrotic capsule that surrounds silicone implants consists mainly of collagen. The FDA-approved collagenase of the bacterium clostridium histolyticum provides a reasonable treatment option. Safety and efficacy at the female breast site must be evaluated before clinical utilization.We incubated 20 samples of fibrotic capsule as well as 12 full thickness skin grafts harvested from the female breast site for 24 hours with different doses of collagenase. Outcome measures involved histological assessment of thickness and density of the capsule tissue as well as the skin grafts. Furthermore, we performed a collagen assay and immunohistochemistry staining for collagen subtypes.Collagenase treatment was able to degrade human capsule contracture tissue ex-vivo. The remaining collagen subtype after degradation was type 4 only. 0.3 mg/ml of collagenase was most effective in reducing capsule thickness when compared with higher concentrations. Of note, effectiveness was inversely related to capsule density, such that there was less reduction in thickness with higher capsule densities and vice versa. Furthermore, the application of 0.3mg/ml collagenase did not lead to thinning or perforation of full thickness skin grafts.Adjustment of collagenase dose will depend on thickness and density of the contracted capsule. A concentration of 0.3mg/ml seems to be safe and effective in an ex-vivo setting. The remaining collagen subtype 4 is suitable to serve as a neo-capsule/acellular tissue matrix. Collagenase treatment for capsular contracture may soon become a clinical reality.

  14. Utility of imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer in the analysis of drugs and metabolites in biological tissues.

    Drexler, Dieter M; Garrett, Timothy J; Cantone, Joseph L; Diters, Richard W; Mitroka, James G; Prieto Conaway, Maria C; Adams, Stephen P; Yost, Richard A; Sanders, Mark

    2007-01-01

    The properties and potential liabilities of drug candidate are investigated in detailed ADME assays and in toxicity studies, where findings are placed in context of exposure to dosed drug and metabolites. The complex nature of biological samples may necessitate work-up procedures prior to high performance liquid chromatography-mass spectrometric (HPLC-MS) analysis of endogenous or xenobiotic compounds. This concept can readily be applied to biological fluids such as blood or urine, but in localized samples such as organs and tissues potentially important spatial, thus anatomical, information is lost during sample preparation as the result of homogenization and extraction procedures. However, the localization of test article or spatial identification of metabolites may be critical to the understanding of the mechanism of target-organ toxicity and its relevance to clinical safety. Tissue imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) and ion trap mass spectrometry (MS) with higher order mass spectrometric scanning functions was utilized for localization of dosed drug or metabolite in tissue. Laser capture microscopy (LCM) was used to obtain related samples from tissue for analyses by standard MALDI-MS and HPLC-MS. In a toxicology study, rats were administered with a high dosage of a prodrug for 2 weeks. Birefringent microcrystalline material (10-25 microm) was observed in histopathologic formalin-fixed tissue samples. Direct analysis by IMS provided the identity of material in the microcrystals as circulating active drug while maintaining spatial orientation. Complementary data from visual cross-polarized light microscopy as well as standard MALDI-MS and HPLC-MS experiments on LCM samples validated the qualitative results obtained by IMS. Furthermore, the HPLC-MS analysis on the LCM samples afforded a semi-quantitative assessment of the crystalline material in the tissue samples. IMS by MALDI ion trap MS proved sensitive

  15. Cellular targeting of the apoptosis-inducing compound gliotoxin to fibrotic rat livers

    Hagens, W. I.; Beljaars, L.; Mann, D. A.; Wright, M. C.; Julien, B.; Lotersztajn, S.; Reker-Smit, C.; Poelstra, K.

    Liver fibrosis is associated with proliferation of hepatic stellate cells (HSCs) and their transformation into myofibroblastic cells that synthesize scar tissue. Several studies indicate that induction of apoptosis in myofibroblastic cells may prevent fibrogenesis. Gliotoxin (GTX) was found to

  16. NAMPT-mediated NAD+ biosynthesis is indispensable for adipose tissue plasticity and development of obesity

    Karen Nørgaard Nielsen

    2018-05-01

    Full Text Available Objective: The ability of adipose tissue to expand and contract in response to fluctuations in nutrient availability is essential for the maintenance of whole-body metabolic homeostasis. Given the nutrient scarcity that mammals faced for millions of years, programs involved in this adipose plasticity were likely evolved to be highly efficient in promoting lipid storage. Ironically, this previously advantageous feature may now represent a metabolic liability given the caloric excess of modern society. We speculate that nicotinamide adenine dinucleotide (NAD+ biosynthesis exemplifies this concept. Indeed NAD+/NADH metabolism in fat tissue has been previously linked with obesity, yet whether it plays a causal role in diet-induced adiposity is unknown. Here we investigated how the NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT supports adipose plasticity and the pathological progression to obesity. Methods: We utilized a newly generated Nampt loss-of-function model to investigate the tissue-specific and systemic metabolic consequences of adipose NAD+ deficiency. Energy expenditure, glycemic control, tissue structure, and gene expression were assessed in the contexts of a high dietary fat burden as well as the transition back to normal chow diet. Results: Fat-specific Nampt knockout (FANKO mice were completely resistant to high fat diet (HFD-induced obesity. This was driven in part by reduced food intake. Furthermore, HFD-fed FANKO mice were unable to undergo healthy expansion of adipose tissue mass, and adipose depots were rendered fibrotic with markedly reduced mitochondrial respiratory capacity. Yet, surprisingly, HFD-fed FANKO mice exhibited improved glucose tolerance compared to control littermates. Removing the HFD burden largely reversed adipose fibrosis and dysfunction in FANKO animals whereas the improved glucose tolerance persisted. Conclusions: These findings indicate that adipose NAMPT plays an essential role in

  17. Box Isolation of Fibrotic Areas (BIFA): A Patient-Tailored Substrate Modification Approach for Ablation of Atrial Fibrillation.

    Kottkamp, Hans; Berg, Jan; Bender, Roderich; Rieger, Andreas; Schreiber, Doreen

    2016-01-01

    Catheter ablation strategies beyond pulmonary vein isolation (PVI) for treatment of atrial fibrillation (AF) are less well defined. Increasing clinical data indicate that atrial fibrosis is a critical common left atrial (LA) substrate in AF patients (pts). We applied a new substrate modification concept according to the individual fibrotic substrate as estimated from electroanatomic voltage mapping (EAVM) in 41 pts undergoing catheter ablation of AF. First, EAVM during sinus rhythm was done in redo cases of 10 pts with paroxysmal AF despite durable PVI. Confluent low-voltage areas (LVA) were found in all pts and were targeted with circumferential isolation, so-called box isolation of fibrotic areas (BIFA). This strategy led to stable sinus rhythm in 9/10 pts and was transferred prospectively to first procedures of 31 pts with nonparoxysmal AF. In 13 pts (42%), no LVA (atrial tachycardia was achieved in 72.2% of pts and in 83.3% of pts with 1.17 procedures/patient. In approximately 40% of pts with nonparoxysmal AF, no substantial LVA were identified, and PVI alone showed high success rate. In pts with paroxysmal AF despite durable PVI and in approximately 60% of pts with nonparoxysmal AF, individually localized LVA were identified and could be targeted successfully with the BIFA strategy. © 2015 Wiley Periodicals, Inc.

  18. Impact of improving dietary amino acid balance for lactating sows on efficiency of dietary amino acid utilization and transcript abundance of genes encoding lysine transporters in mammary tissue

    Huber, L; de Lange, C F M; Ernst, Cathy

    2016-01-01

    Lactating multiparous Yorkshire sows (n = 64) were used in 2 experiments to test the hypothesis that reducing dietary CP intake and improving AA balance through crystalline AA (CAA) supplementation improves apparent dietary AA utilization efficiency for milk production and increases transcript ab...

  19. Expected utility without utility

    Castagnoli, E.; Licalzi, M.

    1996-01-01

    This paper advances an interpretation of Von Neumann–Morgenstern’s expected utility model for preferences over lotteries which does not require the notion of a cardinal utility over prizes and can be phrased entirely in the language of probability. According to it, the expected utility of a lottery can be read as the probability that this lottery outperforms another given independent lottery. The implications of this interpretation for some topics and models in decision theory are considered....

  20. Early onset of disc degeneration in SM/J mice is associated with changes in ion transport systems and fibrotic events.

    Zhang, Ying; Xiong, Chi; Kudelko, Mateusz; Li, Yan; Wang, Cheng; Wong, Yuk Lun; Tam, Vivian; Rai, Muhammad Farooq; Cheverud, James; Lawson, Heather A; Sandell, Linda; Chan, Wilson C W; Cheah, Kathryn S E; Sham, Pak C; Chan, Danny

    2018-04-09

    Intervertebral disc degeneration (IDD) causes back pain and sciatica, affecting quality of life and resulting in high economic/social burden. The etiology of IDD is not well understood. Along with aging and environmental factors, genetic factors also influence the onset, progression and severity of IDD. Genetic studies of risk factors for IDD using human cohorts are limited by small sample size and low statistical power. Animal models amenable to genetic and functional studies of IDD provide desirable alternatives. Despite differences in size and cellular content as compared to human intervertebral discs (IVDs), the mouse is a powerful model for genetics and assessment of cellular changes relevant to human biology. Here, we provide evidence for early onset disc degeneration in SM/J relative to LG/J mice with poor and good tissue healing capacity respectively. In the first few months of life, LG/J mice maintain a relatively constant pool of notochordal-like cells in the nucleus pulposus (NP) of the IVD. In contrast, chondrogenic events are observed in SM/J mice beginning as early as one-week-old, with progressive fibrotic changes. Further, the extracellular matrix changes in the NP are consistent with IVD degeneration. Leveraging on the genomic data of two parental and two recombinant inbred lines, we assessed the genetic contribution to the NP changes and identified processes linked to the regulation of ion transport systems. Significantly, "transport" system is also in the top three gene ontology (GO) terms from a comparative proteomic analysis of the mouse NP. These findings support the potential of the SM/J, LG/J and their recombinant inbred lines for future genetic and biological analysis in mice and validation of candidate genes and biological relevance in human cohort studies. The proteomic data has been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD008784. Copyright © 2017. Published by

  1. Correlations between transmembrane 4 L6 family member 5 (TM4SF5, CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities.

    Minkyung Kang

    Full Text Available Transmembrane 4 L6 family member 5 (TM4SF5 is overexpressed during CCl4-mediated murine liver fibrosis and in human hepatocellular carcinomas. The tetraspanins form tetraspanin-enriched microdomains (TEMs consisting of large membrane protein complexes on the cell surface. Thus, TM4SF5 may be involved in the signal coordination that controls liver malignancy. We investigated the relationship between TM4SF5-positive TEMs with liver fibrosis and tumorigenesis, using normal Chang hepatocytes that lack TM4SF5 expression and chronically TGFβ1-treated Chang cells that express TM4SF5. TM4SF5 expression is positively correlated with tumorigenic CD151 expression, but is negatively correlated with tumor-suppressive CD63 expression in mouse fibrotic and human hepatic carcinoma tissues, indicating cooperative roles of the tetraspanins in liver malignancies. Although CD151 did not control the expression of TM4SF5, TM4SF5 appeared to control the expression levels of CD151 and CD63. TM4SF5 interacted with CD151, and caused the internalization of CD63 from the cell surface into late lysosomal membranes, presumably leading to terminating the tumor-suppressive functions of CD63. TM4SF5 could overcome the tumorigenic effects of CD151, especially cell migration and extracellular matrix (ECM-degradation. Taken together, TM4SF5 appears to play a role in liver malignancy by controlling the levels of tetraspanins on the cell surface, and could provide a promising therapeutic target for the treatment of liver malignancies.

  2. Utility of supplemental screening with breast ultrasound in asymptomatic women with dense breast tissue who are not at high risk for breast cancer

    Klevos, Geetika A; Collado-Mesa, Fernando; Net, Jose M; Yepes, Monica M

    2017-01-01

    Objective: To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. Materials and Methods: A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A system...

  3. Utility of supplemental screening with breast ultrasound in asymptomatic women with dense breast tissue who are not at high risk for breast cancer.

    Klevos, Geetika A; Collado-Mesa, Fernando; Net, Jose M; Yepes, Monica M

    2017-01-01

    To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A systematic review of the breast imaging center database was conducted to identify and retrieve data for all asymptomatic women, who were found to have heterogeneously dense or extremely dense breast tissue on screening bilateral mammograms performed from July 1, 2010 through June 30, 2012 and who received a mammographic final assessment American College of Radiology's (ACR) Breast Imaging Reporting and Data System (BI-RADS) category 1 or BI-RADS category 2. Hand-held screening ultrasound was performed initially by a technologist followed by a radiologist. Chi-square and t -test were used and statistical significance was considered at P ultrasound. BI-RADS category 1 or 2 was assigned to 323 women (81.9%). BI-RADS category 3 was assigned to 50 women (12.9%). A total of 26 biopsies/aspirations were recommended and performed in 26 women (6.6%). The most common finding for which biopsy was recommended was a solid mass (88.5%) with an average size of 0.9 cm (0.5-1.7 cm). Most frequent pathology result was fibroadenoma (60.8%). No carcinoma was found. Our data support the reported occurrence of a relatively high number of false positives at supplemental screening with breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue, who are not at a high risk of developing breast cancer, and suggests that caution is necessary in establishing wide implementation of this type of supplemental screening for all women with dense breast tissue without considering other risk factors for

  4. Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages

    Rombaldová, Martina; Janovská, Petra; Kopecký, Jan; Kuda, Ondřej

    2017-01-01

    Roč. 490, č. 3 (2017), s. 1080-1085 ISSN 0006-291X R&D Projects: GA ČR(CZ) GA16-05151S; GA MŠk(CZ) LTAUSA17173 Institutional support: RVO:67985823 Keywords : adipose tissue * macrophages * omega-3 PUFA * fatty acid re-esterification * lipolysis * lipid mediators Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition OBOR OECD: Endocrinology and metabolism (including diabetes, hormones) Impact factor: 2.466, year: 2016

  5. Limited utility of tissue micro-arrays in detecting intra-tumoral heterogeneity in stem cell characteristics and tumor progression markers in breast cancer.

    Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna

    2018-05-08

    Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the

  6. Validating continuous digital light processing (cDLP) additive manufacturing accuracy and tissue engineering utility of a dye-initiator package.

    Wallace, Jonathan; Wang, Martha O; Thompson, Paul; Busso, Mallory; Belle, Vaijayantee; Mammoser, Nicole; Kim, Kyobum; Fisher, John P; Siblani, Ali; Xu, Yueshuo; Welter, Jean F; Lennon, Donald P; Sun, Jiayang; Caplan, Arnold I; Dean, David

    2014-03-01

    This study tested the accuracy of tissue engineering scaffold rendering via the continuous digital light processing (cDLP) light-based additive manufacturing technology. High accuracy (i.e., <50 µm) allows the designed performance of features relevant to three scale spaces: cell-scaffold, scaffold-tissue, and tissue-organ interactions. The biodegradable polymer poly (propylene fumarate) was used to render highly accurate scaffolds through the use of a dye-initiator package, TiO2 and bis (2,4,6-trimethylbenzoyl)phenylphosphine oxide. This dye-initiator package facilitates high accuracy in the Z dimension. Linear, round, and right-angle features were measured to gauge accuracy. Most features showed accuracies between 5.4-15% of the design. However, one feature, an 800 µm diameter circular pore, exhibited a 35.7% average reduction of patency. Light scattered in the x, y directions by the dye may have reduced this feature's accuracy. Our new fine-grained understanding of accuracy could be used to make further improvements by including corrections in the scaffold design software. Successful cell attachment occurred with both canine and human mesenchymal stem cells (MSCs). Highly accurate cDLP scaffold rendering is critical to the design of scaffolds that both guide bone regeneration and that fully resorb. Scaffold resorption must occur for regenerated bone to be remodeled and, thereby, achieve optimal strength.

  7. Validating continuous digital light processing (cDLP) additive manufacturing accuracy and tissue engineering utility of a dye-initiator package

    Wallace, Jonathan; Wang, Martha O; Kim, Kyobum

    2014-01-01

    This study tested the accuracy of tissue engineering scaffold rendering via the continuous digital light processing (cDLP) light-based additive manufacturing technology. High accuracy (i.e., <50 µm) allows the designed performance of features relevant to three scale spaces: cell-scaffold, scaffold-tissue, and tissue-organ interactions. The biodegradable polymer poly (propylene fumarate) was used to render highly accurate scaffolds through the use of a dye-initiator package, TiO 2  and bis (2,4,6-trimethylbenzoyl)phenylphosphine oxide. This dye-initiator package facilitates high accuracy in the Z dimension. Linear, round, and right-angle features were measured to gauge accuracy. Most features showed accuracies between 5.4–15% of the design. However, one feature, an 800 µm diameter circular pore, exhibited a 35.7% average reduction of patency. Light scattered in the x, y directions by the dye may have reduced this feature's accuracy. Our new fine-grained understanding of accuracy could be used to make further improvements by including corrections in the scaffold design software. Successful cell attachment occurred with both canine and human mesenchymal stem cells (MSCs). Highly accurate cDLP scaffold rendering is critical to the design of scaffolds that both guide bone regeneration and that fully resorb. Scaffold resorption must occur for regenerated bone to be remodeled and, thereby, achieve optimal strength. (paper)

  8. Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages.

    Rombaldova, Martina; Janovska, Petra; Kopecky, Jan; Kuda, Ondrej

    2017-08-26

    It is becoming increasingly apparent that mutual interactions between adipocytes and immune cells are key to the integrated control of adipose tissue inflammation and lipid metabolism in obesity, but little is known about the non-inflammatory functions of adipose tissue macrophages (ATMs) and how they might be impacted by neighboring adipocytes. In the current study we used metabolipidomic analysis to examine the adaptations to lipid overload of M1 or M2 polarized macrophages co-incubated with adipocytes and explored potential benefits of omega-3 polyunsaturated fatty acids (PUFA). Macrophages adjust their metabolism to process excess lipids and M2 macrophages in turn modulate lipolysis and fatty acids (FA) re-esterification of adipocytes. While M1 macrophages tend to store surplus FA as triacylglycerols and cholesteryl esters in lipid droplets, M2 macrophages channel FA toward re-esterification and β-oxidation. Dietary omega-3 PUFA enhance β-oxidation in both M1 and M2. Our data document that ATMs contribute to lipid trafficking in adipose tissue and that omega-3 PUFA could modulate FA metabolism of ATMs. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Utility of supplemental screening with breast ultrasound in asymptomatic women with dense breast tissue who are not at high risk for breast cancer

    Geetika A Klevos

    2017-01-01

    Full Text Available Objective: To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. Materials and Methods: A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A systematic review of the breast imaging center database was conducted to identify and retrieve data for all asymptomatic women, who were found to have heterogeneously dense or extremely dense breast tissue on screening bilateral mammograms performed from July 1, 2010 through June 30, 2012 and who received a mammographic final assessment American College of Radiology's (ACR Breast Imaging Reporting and Data System (BI-RADS category 1 or BI-RADS category 2. Hand-held screening ultrasound was performed initially by a technologist followed by a radiologist. Chi-square and t-test were used and statistical significance was considered at P< 0.05. Results: A total of 1210 women were identified. Of these, 394 underwent the offered supplemental screening ultrasound. BI-RADS category 1 or 2 was assigned to 323 women (81.9%. BI-RADS category 3 was assigned to 50 women (12.9%. A total of 26 biopsies/aspirations were recommended and performed in 26 women (6.6%. The most common finding for which biopsy was recommended was a solid mass (88.5% with an average size of 0.9 cm (0.5–1.7 cm. Most frequent pathology result was fibroadenoma (60.8%. No carcinoma was found. Conclusion: Our data support the reported occurrence of a relatively high number of false positives at supplemental screening with breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue, who are not at a high risk of developing breast cancer, and suggests that caution

  10. The hepatic stellate cell in sight : targeting antiproliferative drugs to the fibrotic liver

    Greupink, Albert Hendrikus

    2006-01-01

    Liver fibrosis is characterized by the accumulation of excessive amounts of scar tissue in response to chronic liver injury. Important causes of chronic liver injury are viral hepatitis, metabolic disorders such as Wilson’s disease, autoimmune diseases and chronic exposure to certain chemicals,

  11. Vitrification and xenografting of human ovarian tissue.

    Amorim, Christiani Andrade; Dolmans, Marie-Madeleine; David, Anu; Jaeger, Jonathan; Vanacker, Julie; Camboni, Alessandra; Donnez, Jacques; Van Langendonckt, Anne

    2012-11-01

    To assess the efficiency of two vitrification protocols to cryopreserve human preantral follicles with the use of a xenografting model. Pilot study. Gynecology research unit in a university hospital. Ovarian biopsies were obtained from seven women aged 30-41 years. Ovarian tissue fragments were subjected to one of three cryopreservation protocols (slow freezing, vitrification protocol 1, and vitrification protocol 2) and xenografted for 1 week to nude mice. The number of morphologically normal follicles after cryopreservation and grafting and fibrotic surface area were determined by histologic analysis. Apoptosis was assessed by the TUNEL method. Morphometric analysis of TUNEL-positive surface area also was performed. Follicle proliferation was evaluated by immunohistochemistry. After xenografting, a difference was observed between the cryopreservation procedures applied. According to TUNEL analysis, both vitrification protocols showed better preservation of preantral follicles than the conventional freezing method. Moreover, histologic evaluation showed a significantly higher proportion of primordial follicles in vitrified (protocol 2)-warmed ovarian tissue than in frozen-thawed tissue. The proportion of growing follicles and fibrotic surface area was similar in all groups. Vitrification procedures appeared to preserve not only the morphology and survival of preantral follicles after 1 week of xenografting, but also their ability to resume folliculogenesis. In addition, vitrification protocol 2 had a positive impact on the quiescent state of primordial follicles after xenografting. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  12. Results from the ASPIRE study for breast reconstruction utilizing the AeroForm™ patient controlled carbon dioxide-inflated tissue expanders.

    Connell, Tony F

    2015-09-01

    Therapeutic or prophylactic mastectomy is often indicated for women with breast cancer, or for those at a high risk of developing cancer due to familial history or genetic mutations. Favorable aesthetic and psychological results make prosthetic reconstruction of the breast with placement of tissue expanders followed by permanent implant a popular choice for women diagnosed with breast cancer. This study describes the results of the ASPIRE trial, the objective of which was to provide supportive data to demonstrate the performance and safety of the AeroForm™ System in a population with broader selection criteria than previous studies. Results of the earlier PACE clinical studies (PACE 1 and 2) demonstrated that the AeroForm™ System could be used safely and effectively to achieve the desired expansion necessary for successful breast reconstruction. In the current ASPIRE trial described in the paper, performance of the device was evaluated by successful tissue expansion and exchange to breast implant(s) unless precluded by a non-device related event. Safety data was evaluated based on reported adverse events. A prospective, single center, open-label study in which subjects who met the inclusion criteria and agreed to participate were enrolled and implanted with the AeroForm expander either at the time of mastectomy (immediate) or sometime after mastectomy (delayed). In the event of a bilateral procedure, the expander was implanted in each side. Subjects were followed until the explant of the tissue expander(s) and exchange for silicone or saline breast implant(s). Thirty-four expanders were placed in 21 subjects in the clinical trial; the average age of subjects was 49.7 ± 8.6 years with average BMI of 26.1 ± 4.7. Bilateral procedures accounted for 62% of the total and 88% of the reconstructions were completed with a latissimus dorsi flap (anterior approach) per the investigators standard procedure. Four (12%) of the cases (12%) were completed in two subjects

  13. Utilization of Cell-Transfer Technique for Molecular Testing on Hematoxylin-Eosin-Stained Sections: A Viable Option for Small Biopsies That Lack Tumor Tissues in Paraffin Block.

    Wu, Howard H; Jovonovich, Stephen M; Randolph, Melissa; Post, Kristin M; Sen, Joyashree D; Curless, Kendra; Cheng, Liang

    2016-12-01

    - In some instances the standard method of doing molecular testing from formalin-fixed, paraffin-embedded block is not possible because of limited tissue. Tumor cell-enriched cell-transfer technique has been proven useful for performing immunocytochemistry and molecular testing on cytologic smears. - To establish the cell-transfer technique as a viable option for isolating tumor cells from hematoxylin-eosin (H&E)-stained slides. - Molecular testing was performed by using the cell-transfer technique on 97 archived H&E-stained slides from a variety of different tumors. Results were compared to the conventional method of molecular testing. - Polymerase chain reaction-based molecular testing via the cell-transfer technique was successfully performed on 82 of 97 samples (85%). This included 39 of 47 cases for EGFR, 10 of 11 cases for BRAF, and 33 of 39 cases for KRAS mutations. Eighty-one of 82 cell-transfer technique samples (99%) showed agreement with previous standard method results, including 4 mutations and 35 wild-type alleles for EGFR, 4 mutations and 6 wild-type alleles for BRAF, and 11 mutations and 21 wild-type alleles for KRAS. There was only 1 discrepancy: a cell-transfer technique with a false-negative >KRAS result (wild type versus G12C). - Molecular testing performed on H&E-stained sections via cell-transfer technique is useful when tissue from cell blocks and small surgical biopsy samples is exhausted and the only available material for testing is on H&E-stained slides.

  14. Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

    Natalie Sampson

    2012-01-01

    Full Text Available Myofibroblast activation plays a central role during normal wound healing. Whereas insufficient myofibroblast activation impairs wound healing, excessive myofibroblast activation promotes fibrosis in diverse tissues (including benign prostatic hyperplasia, BPH leading to organ dysfunction and also promotes a stromal response that supports tumor progression. The incidence of impaired wound healing, tissue fibrosis, BPH, and certain cancers strongly increases with age. This paper summarizes findings from in vitro fibroblast-to-myofibroblast differentiation systems that serve as cellular models to study fibrogenesis of diverse tissues. Supported by substantial in vivo data, a large body of evidence indicates that myofibroblast differentiation induced by the profibrotic cytokine transforming growth factor beta is driven by a prooxidant shift in redox homeostasis due to elevated production of NADPH oxidase 4 (NOX4-derived hydrogen peroxide and supported by concomitant decreases in nitric oxide/cGMP signaling and reactive oxygen species (ROS scavenging enzymes. Fibroblast-to-myofibroblast differentiation can be inhibited and reversed by restoring redox homeostasis using antioxidants or NOX4 inactivation as well as enhancing nitric oxide/cGMP signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases. Current evidence indicates the therapeutic potential of targeting the prooxidant shift in redox homeostasis for the treatment of age-related diseases associated with myofibroblast dysregulation.

  15. Fibrotic changes after postmastectomy radiotherapy and reconstructive surgery in breast cancer. A retrospective analysis in 109 patients

    Classen, Johannes; St. Vincentius-Kliniken, Karlsruhe; Nitzsche, Sibille; Wallwiener, Diethelm; Brucker, Sara; Kristen, Peter; Souchon, Rainer; Bamberg, Michael

    2010-01-01

    The purpose of this study was to analyze the probability and time course of fibrotic changes in breast reconstruction before or after postmastectomy radiotherapy (PMRT). Between 1995 and 2004, 109 patients were treated with PMRT at Tuebingen University and underwent heterologous (HL) or autologous (AL) breast reconstruction prior or subsequent to radiation therapy. Fibrosis of the reconstructed breast after radiotherapy was assessed using the Baker score for HL reconstructions and the Common Terminology Criteria for Adverse Events (CTCAE) for all patients. Actuarial rates of fibrosis were calculated for the maximum degree acquired during follow- up and at the last follow-up visit documented. Median time to follow-up was 34 months (3-227 months). Radiotherapy was applied with a median total dose of 50.4 Gy. A total of 44 patients (40.4%) received a boost treatment with a median dose of 10 Gy. Breast reconstruction was performed with AL, HL, or combined techniques in 20, 82, and 7 patients, respectively. The 3-year incidence of ≥ grade III maximum fibrosis was 20% and 43% for Baker and CTCAE scores, respectively. The corresponding figures for fibrosis at last follow-up visit were 18% and 2%. The 3-year rate of surgical correction of the contralateral breast was 30%. Initially unplanned surgery of the reconstructed breast was performed in 39 patients (35.8%). Boost treatment and type of cosmetic surgery (HL vs. AL) were not significantly associated with the incidence of fibrosis. We found severe fibrosis to be a frequent complication after PMRT radiotherapy and breast reconstruction. However, surgical intervention can ameliorate the majority of high grade fibrotic events leading to acceptable long-term results. No treatment parameters associated with the rate of fibrosis could be identified. (orig.)

  16. The anti-fibrotic agent pirfenidone synergizes with cisplatin in killing tumor cells and cancer-associated fibroblasts

    Mediavilla-Varela, Melanie; Boateng, Kingsley; Noyes, David; Antonia, Scott J.

    2016-01-01

    Anti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis. Because activated fibroblasts in inflammatory conditions have similar characteristics as cancer-associated fibroblasts (CAFs) and CAFs contribute actively to the malignant phenotype, we believe that anti-fibrotic drugs have the potential to be repurposed as anti-cancer drugs. The effects of pirfenidone alone and in combination with cisplatin on human patient-derived CAF cell lines and non-small cell lung cancer (NSCLC) cell lines were examined. The impact on cell death in vitro as well as tumor growth in a mouse model was determined. Annexin V/PI staining and Western blot analysis were used to characterize cell death. Synergy was assessed with the combination index method using Calcusyn software. Pirfenidone alone induced apoptotic cell death in lung CAFs at a high concentration (1.5 mg/mL). However, co-culture in vitro experiments and co-implantation in vivo experiments showed that the combination of low doses of cisplatin (10 μM) and low doses of pirfenidone (0.5 mg/mL), in both CAFs and tumors, lead to increased cell death and decreased tumor progression, respectively. Furthermore, the combination of cisplatin and pirfenidone in NSCLC cells (A549 and H157 cells) leads to increased apoptosis and synergistic cell death. Our studies reveal for the first time that the combination of cisplatin and pirfenidone is active in preclinical models of NSCLC and therefore may be a new therapeutic approach in this disease. The online version of this article (doi:10.1186/s12885-016-2162-z) contains supplementary material, which is available to authorized users

  17. Serial High-Resolution Computed Tomography Imaging in Patients with Wegener Granulomatosis: Differentiation Between Active Inflammatory and Chronic Fibrotic Lesions

    Lohrmann, C.; Uhl, M.; Schaefer, O.; Ghanem, N.; Kotter, E.; Langer, M.

    2005-01-01

    PURPOSE: To evaluate pulmonary pathologies in Wegener granulomatosis with sequential computed tomography (CT) in order to differentiate active inflammatory lesions from chronic fibrotic lesions. MATERIAL AND METHODS: Serial CT findings in 38 patients with Wegener granulomatosis were retrospectively analyzed (mean follow-up period, 21 months). The presence, extension, and distribution of the following findings were evaluated with CT: parenchymal nodules, masses, ground-glass attenuation, airspace consolidation, bronchial wall-thickening, bronchiectasis, linear areas of attenuation, pleural irregularities, pleural effusions, hilar and mediastinal lymphadenopathy. RESULTS: Observed in 92% of patients, nodules were the most common CT pathology. Areas of ground-glass attenuation, consolidation, masses of linear attenuation, and tracheal/bronchial wall-thickening were detected in 24%, 26%, 32%, 39%, and 68% of patients. At follow-up, the clearance of lesions was most consistent for areas of ground-glass attenuation (89%), masses (87%), and cavitated nodules (85%). In the follow-up scan, 58% of all nodules, 47% of pulmonary consolidations, and 66% of bronchial wall-thickening were completely resolved. Areas of bronchiectasis and septal/non-septal lines remained stable in 70% and 71% of patients. CONCLUSION: The majority of the lesions decreased or resolved completely with or without areas of linear attenuation. Ground-glass attenuation, cavitated nodules and masses appear to represent active inflammatory lesions. In most probability, areas of bronchiectasis and septal/non-septal lines more often represent chronic fibrotic changes rather than active inflammatory changes. In combination with clinical evaluation and bronchoscopy, CT assists in the assessment of disease activity

  18. Serial High-Resolution Computed Tomography Imaging in Patients with Wegener Granulomatosis: Differentiation Between Active Inflammatory and Chronic Fibrotic Lesions

    Lohrmann, C.; Uhl, M.; Schaefer, O.; Ghanem, N.; Kotter, E.; Langer, M. [Univ. Hospital of Freiburg (Germany). Dept. of Radiology

    2005-08-01

    PURPOSE: To evaluate pulmonary pathologies in Wegener granulomatosis with sequential computed tomography (CT) in order to differentiate active inflammatory lesions from chronic fibrotic lesions. MATERIAL AND METHODS: Serial CT findings in 38 patients with Wegener granulomatosis were retrospectively analyzed (mean follow-up period, 21 months). The presence, extension, and distribution of the following findings were evaluated with CT: parenchymal nodules, masses, ground-glass attenuation, airspace consolidation, bronchial wall-thickening, bronchiectasis, linear areas of attenuation, pleural irregularities, pleural effusions, hilar and mediastinal lymphadenopathy. RESULTS: Observed in 92% of patients, nodules were the most common CT pathology. Areas of ground-glass attenuation, consolidation, masses of linear attenuation, and tracheal/bronchial wall-thickening were detected in 24%, 26%, 32%, 39%, and 68% of patients. At follow-up, the clearance of lesions was most consistent for areas of ground-glass attenuation (89%), masses (87%), and cavitated nodules (85%). In the follow-up scan, 58% of all nodules, 47% of pulmonary consolidations, and 66% of bronchial wall-thickening were completely resolved. Areas of bronchiectasis and septal/non-septal lines remained stable in 70% and 71% of patients. CONCLUSION: The majority of the lesions decreased or resolved completely with or without areas of linear attenuation. Ground-glass attenuation, cavitated nodules and masses appear to represent active inflammatory lesions. In most probability, areas of bronchiectasis and septal/non-septal lines more often represent chronic fibrotic changes rather than active inflammatory changes. In combination with clinical evaluation and bronchoscopy, CT assists in the assessment of disease activity.

  19. Tissue bionics: examples in biomimetic tissue engineering

    Green, David W [Bone and Joint Research Group, Developmental Origins of Health and Disease, General Hospital, University of Southampton, SO16 6YD (United Kingdom)], E-mail: Hindoostuart@googlemail.com

    2008-09-01

    Many important lessons can be learnt from the study of biological form and the functional design of organisms as design criteria for the development of tissue engineering products. This merging of biomimetics and regenerative medicine is termed 'tissue bionics'. Clinically useful analogues can be generated by appropriating, modifying and mimicking structures from a diversity of natural biomatrices ranging from marine plankton shells to sea urchin spines. Methods in biomimetic materials chemistry can also be used to fabricate tissue engineering scaffolds with added functional utility that promise human tissues fit for the clinic.

  20. Tissue bionics: examples in biomimetic tissue engineering

    Green, David W

    2008-01-01

    Many important lessons can be learnt from the study of biological form and the functional design of organisms as design criteria for the development of tissue engineering products. This merging of biomimetics and regenerative medicine is termed 'tissue bionics'. Clinically useful analogues can be generated by appropriating, modifying and mimicking structures from a diversity of natural biomatrices ranging from marine plankton shells to sea urchin spines. Methods in biomimetic materials chemistry can also be used to fabricate tissue engineering scaffolds with added functional utility that promise human tissues fit for the clinic

  1. Gene expression profiles associated with the presence of a fibrotic focus and the growth pattern in lymph node-negative breast cancer

    G. van den Eynden; M. Smid (Marcel); S.J. van Laere (Steven); C.G. Colpaert (Cecile); U.D. van Auwera; T.X. Bich; P. van Dam (Peter); M.A. den Bakker (Michael); L.Y. Dirix (Luc); E.A. van Marck (Eric); P.B. Vermeulen (Peter); J.A. Foekens (John)

    2008-01-01

    textabstractPurpose: A fibrotic focus, the scar-like area found in the center of an invasive breast tumor, is a prognostic parameter associated with an expansive growth pattern, hypoxia, and (lymph) angiogenesis. Little is known about the molecular pathways involved. Experimental Design: Sixty-five

  2. Myocardial fibrosis and pro-fibrotic markers in end-stage heart failure patients during continuous-flow left ventricular assist device support

    Lok, Sjoukje I.; Nous, Fay M. A.; van Kuik, Joyce; van der Weide, Petra; Winkens, Bjorn; Kemperman, Hans; Huisman, Andre; Lahpor, Jaap R; de Weger, Roel A.; de Jonge, Nicolaas

    OBJECTIVES: During support with a left ventricular assist device (LVAD), partial reverse remodelling takes place in which fibrosis plays an important role. In this study, we analysed the histological changes and expression of fibrotic markers in patients with advanced heart failure (HF) during

  3. Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.

    Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S; Hollingsworth, John W; Jiang, Dianhua; Lancaster, Lisa H; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K; Noble, Paul W; Kimata, Koji; Schwartz, David A

    2008-11-01

    The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

  4. Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

    Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S.; Hollingsworth, John W.; Jiang, Dianhua; Lancaster, Lisa H.; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K.; Noble, Paul W.; Kimata, Koji; Schwartz, David A.

    2008-01-01

    Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). PMID:18703791

  5. Rapid Discrimination of Malignant Breast Lesions from Normal Tissues Utilizing Raman Spectroscopy System: A Systematic Review and Meta-Analysis of In Vitro Studies.

    Ke Deng

    Full Text Available The aim of this study is to evaluate the diagnostic accuracy of Raman spectroscopy system in the detection of malignant breast lesions through a systemic review and meta-analysis of published studies.We conducted a comprehensive literature search of PubMed and Embase from 2000 to June 2015. Published studies that evaluated the diagnostic performance of Raman spectroscopy in distinguishing malignant breast lesions from benign lesions and normal tissues were included in our study. The pooled sensitivity, specificity, diagnostic odds ratio, and the area under the curve of summary receiver-operating characteristic curves was derived. A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies guidelines was used to assess the quality of included studies.The initial search produced a total of 157 articles after removing duplicates. Nine studies (8 in vitro and 1 in vivo were eligible in this meta-analysis. We analyzed the eight in vitro studies with 1756 lesions, the pooled sensitivity and specificity of Raman spectroscopy system for the diagnosis of malignant breast lesions were 0.92 (95% CI 0.86-0.96 and 0.97 (97% CI 0.93-0.98, respectively. Diagnostic odds ratio was 266.70 (95% CI 89.38-795.79, and the area under the curve of summary receiver-operating characteristic curves was 0.98 (95% CI 0.97-0.99. Significant heterogeneity was found between studies. There was no evidence of considerable publication bias.Raman spectroscopy system is an optical diagnostic technology with great value for detecting malignant breast lesions. At the same time, it has advantages of being non-invasive, real-time, and easy to use. Thus it deserves to be further explored for intra-operatory breast tumor margin detection.

  6. Utility of Tissue Doppler Imaging in the Echocardiographic Evaluation of Left and Right Ventricular Function in Dogs with Myxomatous Mitral Valve Disease with or without Pulmonary Hypertension.

    Baron Toaldo, M; Poser, H; Menciotti, G; Battaia, S; Contiero, B; Cipone, M; Diana, A; Mazzotta, E; Guglielmini, C

    2016-05-01

    In human medicine, right ventricular (RV) functional parameters represent a tool for risk stratification in patients with congestive heart failure caused by left heart disease. Little is known about RV alterations in dogs with left-sided cardiac disorders. To assess RV and left ventricular (LV) function in dogs with myxomatous mitral valve disease (MMVD) with or without pulmonary hypertension (PH). One-hundred and fourteen dogs: 28 healthy controls and 86 dogs with MMVD at different stages. Prospective observational study. Animals were classified as healthy or having MMVD at different stages of severity and according to presence or absence of PH. Twenty-eight morphological, echo-Doppler, and tissue Doppler imaging (TDI) variables were measured and comparison among groups and correlations between LV and RV parameters were studied. No differences were found among groups regarding RV echo-Doppler and TDI variables. Sixteen significant correlations were found between RV TDI and left heart echocardiographic variables. Dogs with PH had significantly higher transmitral E wave peak velocity and higher E/e' ratio of septal (sMV) and lateral (pMV) mitral annulus. These 2 variables were found to predict presence of PH with a sensitivity of 84 and 72%, and a specificity of 71 and 80% at cut-off values of 10 and 9.33 for sMV E/e' and pMV E/e', respectively. No association between variables of RV function and different MMVD stage and severity of PH could be detected. Some relationships were found between echocardiographic variables of right and left ventricular function. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  7. Function Preservation After Conservative Resection and Radiotherapy for Soft-tissue Sarcoma of the Distal Extremity: Utility and Application of the Toronto Extremity Salvage Score (TESS).

    Cassidy, Richard J; Indelicato, Daniel J; Gibbs, Charles P; Scarborough, Mark T; Morris, Christopher G; Zlotecki, Robert A

    2016-12-01

    To evaluate outcomes after conservative resection and radiotherapy (RT) for soft-tissue sarcoma (STS) of the distal extremity, with assessment of functional quality of life using the validated Toronto Extremity Salvage Score (TESS) questionnaire and Common Terminology Criteria for Adverse Events (CTCAE), v4.0. Thirty-three patients with STS involving the hand/wrist (N=18) or foot/ankle (N=15) complex received adjuvant RT with conservative resection and were evaluated for local tumor control, survival, toxicities, and preservation of objective functional ability. Eight patients were treated with preoperative RT (median dose, 50.4 Gy) and 25 with postoperative RT (median dose, 61.8 Gy). Median follow-up was 11.5 years. Functional outcomes were measured using TESS; patients with amputations were excluded from the TESS analysis. Adverse events related to gait, limb edema, skin infection, wound complication, and wound dehiscence were assessed using the CTCAE. The 5- and 10-year local control rates were both 90%. The 10-year cause-specific, absolute, and distant metastasis-free survival rates were 97%, 87%, and 84%, respectively. Three patients had an amputation for reasons other than local recurrence or treatment complications and underwent amputation for patient preference. One third of the subjects (11/33 patients) were able to complete the TESS questionnaire; scores ranged from 88 to 100 (mean, 98.2). CTCAEv4 acute adverse events occurred in 2 cases: 1 patient had a grade 3 skin infection and 1 had a grade 2 wound complication of dehiscence. For management of distal extremity STS, the combination of adjuvant RT and conservative surgery achieves excellent local control and overall survival with few adverse events. In addition, through application of the TESS survey instrument, we have demonstrated that this treatment plan achieves robust functional preservation objectively and quantifiably.

  8. Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

    Yang, Tao; Liu, Shan; Wang, Chang-Hong; Tao, Yan-Yan; Zhou, Hua; Liu, Cheng-Hai

    2015-10-10

    Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging

    Behrens, Christopher B.; Langholz, Juliane H.; Eiler, Jessika; Jenewein, Raphael; Fuchs, Konstantin; Alzen, Gerhard F.P.; Naehrlich, Lutz; Harth, Sebastian; Krombach, Gabriele A.

    2013-01-01

    Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD. (orig.)

  10. A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging

    Behrens, Christopher B.; Langholz, Juliane H.; Eiler, Jessika; Jenewein, Raphael; Fuchs, Konstantin; Alzen, Gerhard F.P. [University Hospital Giessen, Department of Pediatric Radiology, Giessen (Germany); Naehrlich, Lutz [University Hospital Giessen, Department of Pediatrics, Giessen (Germany); Harth, Sebastian; Krombach, Gabriele A. [University Hospital Giessen, Department of Radiology, Giessen (Germany)

    2013-03-15

    Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD. (orig.)

  11. Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

    El-Mas, Mahmoud M.; Helmy, Maged W.; Ali, Rabab M.; El-Gowelli, Hanan M.

    2015-01-01

    The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ET A /ET B ) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20 mg kg −1 day −1 , 10 days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renal perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ET A (increases) and ET B (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5 mg kg −1 day −1 ), celecoxib (10 mg kg −1 day −1 ) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ET A /ET B receptor expressions. Selective blockade of ET A receptors by atrasentan (5 mg kg −1 day −1 ) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ET B receptor blocker, 0.1 mg kg −1 day −1 ) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ET A downregulation and ET B upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen. - Highlights: • Chronic CSA causes hypertension and renal perivascular fibrosis in rats. • CSA increased and decreased renal ET A and ET B receptor expression, respectively. • CSA

  12. Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts.

    Wyman, Anne E; Noor, Zahid; Fishelevich, Rita; Lockatell, Virginia; Shah, Nirav G; Todd, Nevins W; Atamas, Sergei P

    2017-06-01

    Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

  13. Tight Skin 2 Mice Exhibit Delayed Wound Healing Caused by Increased Elastic Fibers in Fibrotic Skin.

    Long, Kristen B; Burgwin, Chelsea M; Huneke, Richard; Artlett, Carol M; Blankenhorn, Elizabeth P

    2014-09-01

    Rationale: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of human disease, including tight skin, excessive collagen deposition, alterations in the extracellular matrix (ECM), increased elastic fibers, and occurrence of antinuclear antibodies with age. A tight skin phenotype is observed by 2 weeks of age, but measurable skin fibrosis is only apparent at 10 weeks. We completed a series of wound healing experiments to determine how fibrosis affects wound healing in Tsk2/+ mice compared with their wild-type (WT) littermates. Method: We performed these experiments by introducing four 4 mm biopsy punched wounds on the back of each mouse, ventral of the midline, and observed wound healing over 10 days. Tsk2/+ mice showed significantly delayed wound healing and increased wound size compared with the WT littermates at both 5 and 10 weeks of age. We explored the potential sources of this response by wounding Tsk2/+ mice that were genetically deficient either for the NLRP3 inflammasome (a known fibrosis mediator), or for elastic fibers in the skin, using a fibulin-5 knockout. Conclusion: We found that the loss of elastic fibers restores normal wound healing in the Tsk2/+ mouse and that the loss of the NLRP3 inflammasome had no effect. We conclude that elastic fiber dysregulation is the primary cause of delayed wound healing in the Tsk2/+ mouse and therapies that promote collagen deposition in the tissue matrix in the absence of elastin deposition might be beneficial in promoting wound healing in SSc and other diseases.

  14. Pareto utility

    Ikefuji, M.; Laeven, R.J.A.; Magnus, J.R.; Muris, C.H.M.

    2013-01-01

    In searching for an appropriate utility function in the expected utility framework, we formulate four properties that we want the utility function to satisfy. We conduct a search for such a function, and we identify Pareto utility as a function satisfying all four desired properties. Pareto utility

  15. Quantitative Characterization of Collagen in the Fibrotic Capsule Surrounding Implanted Polymeric Microparticles through Second Harmonic Generation Imaging.

    Akilbekova, Dana; Bratlie, Kaitlin M

    2015-01-01

    The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variation in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively.

  16. Quantitative Characterization of Collagen in the Fibrotic Capsule Surrounding Implanted Polymeric Microparticles through Second Harmonic Generation Imaging.

    Dana Akilbekova

    Full Text Available The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variation in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively.

  17. Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction.

    Xu, Wenxuan; Lu, Chunfeng; Zhang, Feng; Shao, Jiangjuan; Yao, Shunyu; Zheng, Shizhong

    2017-01-01

    Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl 4 -caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl 4 -administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl 4 -induced liver injury. DHA also reduced CCl 4 -caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis. © 2016 Federation of European Biochemical Societies.

  18. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic scleroderma lung microenvironment and in bleomycin induced pulmonary fibrosis

    Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L.; Lam, TuKiet T.; Kanyo, Jean E.; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H.; Bai, Hanwen; Feghali-Bostwick, Carol A.; Gan, Ye; Peng, Xueyan; Moore, Meagan W.; White, Eric S.; Sava, Parid; Gonzalez, Anjelica L.; Cheng, Yuwei; Niklason, Laura E.; Herzog, Erica L.

    2017-01-01

    Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD. PMID:26749424

  19. Glycoprotein YKL-40 Levels in Plasma Are Associated with Fibrotic Changes on HRCT in Asbestos-Exposed Subjects

    Tuija Väänänen

    2017-01-01

    Full Text Available YKL-40 is a chitinase-like glycoprotein produced by alternatively activated macrophages that are associated with wound healing and fibrosis. Asbestosis is a chronic asbestos-induced lung disease, in which injury of epithelial cells and activation of alveolar macrophages lead to enhanced collagen production and fibrosis. We studied if YKL-40 is related to inflammation, fibrosis, and/or lung function in subjects exposed to asbestosis. Venous blood samples were collected from 85 men with moderate or heavy occupational asbestos exposure and from 28 healthy, age-matched controls. Levels of plasma YKL-40, CRP, IL-6, adipsin, and MMP-9 were measured with enzyme-linked immunosorbent assay (ELISA. Plasma YKL-40 levels were significantly higher in subjects with asbestosis (n=19 than in those with no fibrotic findings in HRCT following asbestos exposure (n=66 or in unexposed healthy controls. In asbestos-exposed subjects, plasma YKL-40 correlated negatively with lung function capacity parameters FVC (Pearson’s r −0.259, p=0.018 and FEV1 (Pearson’s r −0.240, p=0.028 and positively with CRP (Spearman’s rho 0.371, p<0.001, IL-6 (Spearman’s rho 0.314, p=0.003, adipsin (Spearman’s rho 0.459, p<0.001, and MMP-9 (Spearman’s rho 0.243, p=0.025. The present finding suggests YKL-40 as a biomarker associated with fibrosis and inflammation in asbestos-exposed subjects.

  20. 99mTc-3PRGD2 scintigraphy to stage liver fibrosis and evaluate reversal after fibrotic stimulus withdrawn

    Zhang, Xin; Guo, Qiyong; Shi, Yu; Xu, Weina; Yu, Shupeng; Yang, Zhiguang; Cao, Li; Liu, Changping; Zhao, Zhoushe; Xin, Jun

    2017-01-01

    Objective: Scintigraphy using 99mTc-3PRGD2 targeting integrin αvβ3 could assess activation of hepatic stellate cells (HSCs). Liver fibrogenesis is intimately associated with activation of HSCs, and the fibrolytic process is accompanied by the reduction of the activated HSCs. In this study, we aimed to evaluate the feasibility of this method to assess the severity of liver fibrosis and the reversal after the fibrotic stimulus withdrawal. Methods: Liver fibrosis of different stages was induced by thioacetamide (TAA) injection for 2, 4 and 6 weeks (n = 6 for each time point). Another 6 rats with 8-week TAA administration (the 8-week group) and 6 rats which were injected with TAA for 6 weeks, and then withdrawn of TAA for 2 weeks (spontaneous recovery rats, SRR) were designed. The ratios of radioactivity detected in the liver vs. the heart at 30 min post-injection of 99m Tc-3PRGD2 (L/H30 min ), the collagen proportionate area (CPA), the protein and mRNA levels of integrin α v , integrin β 3 were analyzed and compared among groups. Results: The Ishak stage scores of the livers in the control and 2, 4, 6-week groups increased when the TAA administration period was extended. L/H30 min increased with the upgrading of liver fibrosis and the differences between each pair of groups were statistically significant (p 30 min in the 8-week group was similar to that in the 6-week group (p > 0.05), but was significantly higher than that in the SRR group (p = 0.005). Conclusions: Scintigraphy using 99m Tc-3PRGD2 may provide a non-invasive method for grading liver fibrosis and assessing liver fibrosis reversal.

  1. CT manifestations of radiation-induced change in chest tissue

    Pagani, J.J.; Libshitz, H.I.

    1982-01-01

    The computed tomographic appearance of acute and chronic radiation change in the thorax is described. Acute radiation pneumonitis demonstrates patchy, confluent regions of increased pulmonary attenuation. Chronic changes include soft tissue density fibrotic changes that blend smoothly with the pleural surfaces and adjacent mediastinal structures. Also seen are bronchiectatic changes and distortion of normal intrathoracic anatomic relationships. Both the acute and chronic changes usually make linear lateral margins with adjacent aerated lung. Development of a discrete mass or focal cavitation after the radiation changes have become stable is suspect for recurrent tumor or infection

  2. Photobiomodulation therapy alleviates tissue fibroses associated with chronic Graft-Versus-Host Disease : Two case reports and putative anti-fibrotic roles of TGF-β

    Epstein, J.B.; Raber-Durlacher, J.E.; Huysmans, M.C.; Schoordijk, M.C.E.; Cheng, J.E.; Bensadoun, R.J.; Arany, P.R.

    2018-01-01

    Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

  3. Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-

    Epstein, Joel B.; Raber-Durlacher, Judith E.; Huysmans, Marie-Charlotte; Schoordijk, Maria C. E.; Cheng, Jerry E.; Bensadoun, Rene-Jean; Arany, Praveen R.

    2018-01-01

    Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

  4. Engineering Complex Tissues

    MIKOS, ANTONIOS G.; HERRING, SUSAN W.; OCHAREON, PANNEE; ELISSEEFF, JENNIFER; LU, HELEN H.; KANDEL, RITA; SCHOEN, FREDERICK J.; TONER, MEHMET; MOONEY, DAVID; ATALA, ANTHONY; VAN DYKE, MARK E.; KAPLAN, DAVID; VUNJAK-NOVAKOVIC, GORDANA

    2010-01-01

    This article summarizes the views expressed at the third session of the workshop “Tissue Engineering—The Next Generation,” which was devoted to the engineering of complex tissue structures. Antonios Mikos described the engineering of complex oral and craniofacial tissues as a “guided interplay” between biomaterial scaffolds, growth factors, and local cell populations toward the restoration of the original architecture and function of complex tissues. Susan Herring, reviewing osteogenesis and vasculogenesis, explained that the vascular arrangement precedes and dictates the architecture of the new bone, and proposed that engineering of osseous tissues might benefit from preconstruction of an appropriate vasculature. Jennifer Elisseeff explored the formation of complex tissue structures based on the example of stratified cartilage engineered using stem cells and hydrogels. Helen Lu discussed engineering of tissue interfaces, a problem critical for biological fixation of tendons and ligaments, and the development of a new generation of fixation devices. Rita Kandel discussed the challenges related to the re-creation of the cartilage-bone interface, in the context of tissue engineered joint repair. Frederick Schoen emphasized, in the context of heart valve engineering, the need for including the requirements derived from “adult biology” of tissue remodeling and establishing reliable early predictors of success or failure of tissue engineered implants. Mehmet Toner presented a review of biopreservation techniques and stressed that a new breakthrough in this field may be necessary to meet all the needs of tissue engineering. David Mooney described systems providing temporal and spatial regulation of growth factor availability, which may find utility in virtually all tissue engineering and regeneration applications, including directed in vitro and in vivo vascularization of tissues. Anthony Atala offered a clinician’s perspective for functional tissue

  5. Measurement of tissue viscoelasticity with ultrasound

    Greenleaf, J. F.; Alizad, A.

    2017-02-01

    Tissue properties such as elasticity and viscosity have been shown to be related to such tissue conditions as contraction, edema, fibrosis, and fat content among others. Magnetic Resonance Elastography has shown outstanding ability to measure the elasticity and in some cases the viscosity of tissues, especially in the liver, providing the ability to stage fibrotic liver disease similarly to biopsy. We discuss ultrasound methods of measuring elasticity and viscosity in tissues. Many of these methods are becoming widely available in the extant ultrasound machines distributed throughout the world. Some of the methods to be discussed are in the developmental stage. The advantages of the ultrasound methods are that the imaging instruments are widely available and that many of the viscoelastic measurements can be made during a short addition to the normal ultrasound examination time. In addition, the measurements can be made by ultrasound repetitively and quickly allowing evaluation of dynamic physiologic function in circumstances such as muscle contraction or artery relaxation. Measurement of viscoelastic tissue mechanical properties will become a consistent part of clinical ultrasound examinations in our opinion.

  6. Cathepsin-S degraded decorin are elevated in fibrotic lung disorders - development and biological validation of a new serum biomarker

    Kehlet, Stephanie Nina; Bager, C. L.; Willumsen, N.

    2017-01-01

    Background: Decorin is one of the most abundant proteoglycans of the extracellular matrix and is mainly secreted and deposited in the interstitial matrix by fibroblasts where it plays an important role in collagen turnover and tissue homeostasis. Degradation of decorin might disturb normal tissue...

  7. Anti-fibrotic effects of Cuscuta chinensis with in vitro hepatic stellate cells and a thioacetamide-induced experimental rat model.

    Kim, Jin Seoub; Koppula, Sushruta; Yum, Mun Jeong; Shin, Gwang Mo; Chae, Yun Jin; Hong, Seok Min; Lee, Jae Dong; Song, MinDong

    2017-12-01

    Cuscuta chinensis Lam. (Convolvulaceae) has been used as a traditional herbal remedy for treating liver and kidney disorders. Anti-fibrotic effects of C. chinensis extract (CCE) in cellular and experimental animal models were investigated. HSC-T6 cell viability, cell cycle and apoptosis were analysed using MTT assay, flow cytometry and Annexin V-FITC/PI staining techniques. Thioacetamide (TAA)-induced fibrosis model was established using Sprague Dawley rats (n = 10). Control, TAA, CCE 10 (TAA with CCE 10 mg/kg), CCE 100 (TAA with CCE 100 mg/kg) and silymarin (TAA with silymarin 50 mg/kg). Fibrosis was induced by TAA (200 mg/kg, i.p.) twice per week for 13 weeks. CCE and silymarin were administered orally two times per week from the 7th to 13th week. Fibrotic related gene expression (α-SMA, Col1α1 and TGF-β1) was measured by RT-PCR. Serum biomarkers, glutathione (GSH) and hydroxyproline were estimated by spectrophotometer using commercial kits. CCE (0.05 and 0.1 mg/mL) and silymarin (0.05 mg/mL) treatment significantly (p < 0.01 and p < 0.001) induced apoptosis (11.56%, 17.52% for CCE; 16.50% for silymarin, respectively) in activated HSC-T6 cells, compared with control group (7.26%). Further, rat primary HSCs showed changes in morphology with CCE 0.1 mg/mL treatment. In in vivo studies, CCE (10 and 100 mg/kg) treatment ameliorated the TAA-induced altered levels of serum biomarkers, fibrotic related gene expression, GSH, hydroxyproline significantly (p < 0.05-0.001) and rescued the histopathological changes. CCE can be developed as a potential agent in the treatment of hepatofibrosis.

  8. Tissue response to intraperitoneal implants of polyethylene oxide-modified polyethylene terephthalate.

    Desai, N P; Hubbell, J A

    1992-01-01

    Polyethylene terephthalate films surface modified with polyethylene oxide of mol wt 18,500 g/mol (18.5 k) by a previously described technique, were implanted in the peritoneal cavity of mice, along with their respective untreated controls, for periods of 1-28 d. The implants were retrieved and examined for tissue reactivity and cellular adherence. The control polyethylene terephthalate surfaces showed an initial inflammatory reaction followed by an extensive fibrotic response with a mean thickness of 60 microns at 28 d. By contrast, polyethylene oxide-modified polyethylene terephthalate showed only a mild inflammatory response and no fibrotic encapsulation throughout the implantation period: at 28 d a cellular monolayer was observed. Apparently either the polyethylene oxide-modified surface was stimulating less inflammation, which was in turn stimulating less fibroblastic overgrowth, or the cellular adhesion to the polyethylene oxide-modified surface was too weak to support cellular multilayers.

  9. Epithelial-mesenchymal transition in tissue repair and fibrosis.

    Stone, Rivka C; Pastar, Irena; Ojeh, Nkemcho; Chen, Vivien; Liu, Sophia; Garzon, Karen I; Tomic-Canic, Marjana

    2016-09-01

    The epithelial-mesenchymal transition (EMT) describes the global process by which stationary epithelial cells undergo phenotypic changes, including the loss of cell-cell adhesion and apical-basal polarity, and acquire mesenchymal characteristics that confer migratory capacity. EMT and its converse, MET (mesenchymal-epithelial transition), are integral stages of many physiologic processes and, as such, are tightly coordinated by a host of molecular regulators. Converging lines of evidence have identified EMT as a component of cutaneous wound healing, during which otherwise stationary keratinocytes (the resident skin epithelial cells) migrate across the wound bed to restore the epidermal barrier. Moreover, EMT plays a role in the development of scarring and fibrosis, as the matrix-producing myofibroblasts arise from cells of the epithelial lineage in response to injury but are pathologically sustained instead of undergoing MET or apoptosis. In this review, we summarize the role of EMT in physiologic repair and pathologic fibrosis of tissues and organs. We conclude that further investigation into the contribution of EMT to the faulty repair of fibrotic wounds might identify components of EMT signaling as common therapeutic targets for impaired healing in many tissues. Graphical Abstract Model for injury-triggered EMT activation in physiologic wound repair (left) and fibrotic wound healing (right).

  10. Lung tissue remodeling in the acute respiratory distress syndrome

    Souza Alba Barros de

    2003-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro­liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patient?s prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.

  11. Multi-walled carbon nanotube-induced genotoxic, inflammatory and pro-fibrotic responses in mice: Investigating the mechanisms of pulmonary carcinogenesis

    Rahman, Luna; Jacobsen, Nicklas Raun; Aziz, Syed Abdul

    2017-01-01

    The International Agency for Research on Cancer has classified one type of multi-walled carbon nanotubes (MWCNTs) as possibly carcinogenic to humans. However, the underlying mechanisms of MWCNT- induced carcinogenicity are not known. In this study, the genotoxic, mutagenic, inflammatory, and fibr......The International Agency for Research on Cancer has classified one type of multi-walled carbon nanotubes (MWCNTs) as possibly carcinogenic to humans. However, the underlying mechanisms of MWCNT- induced carcinogenicity are not known. In this study, the genotoxic, mutagenic, inflammatory......, and fibrotic potential of MWCNTs were investigated. Muta™Mouse adult females were exposed to 36±6 or 109±18μg/mouse of Mitsui-7, or 26±2 or 78±5μg/mouse of NM-401, once a week for four consecutive weeks via intratracheal instillations, alongside vehicle-treated controls. Samples were collected 90days following...... extents. However, there was no evidence of DNA damage as measured by the comet assay following Mitsui-7 exposure, or increases in lacZ mutant frequency, for either MWCNTs. Increased p53 expression was observed in the fibrotic foci induced by both MWCNTs. Gene expression analysis revealed perturbations...

  12. ACVP-03: Novel CD4+ T Cell Specific Immunohistochemistry Detection and Analysis Utilizing Masking of Not-T Cell CD4 in Fixed Tissues from Virally Infected and Uninfected Specimens | Frederick National Laboratory for Cancer Research

    The Tissue Analysis Core (TAC) within the AIDS and Cancer Virus Program will process, embed, and perform microtomy on fixed tissue samples presented in ethanol. CD4 (DAB) and CD68/CD163 (FastRed) double immunohistochemistry will be performed, in whic

  13. A new nonlinear parameter in the developed strain-to-applied strain of the soft tissues and its application in ultrasound elasticity imaging.

    Xu, Jingping; Tripathy, Sakya; Rubin, Jonathan M; Stidham, Ryan W; Johnson, Laura A; Higgins, Peter D R; Kim, Kang

    2012-03-01

    Strain developed under quasi-static deformation has been mostly used in ultrasound elasticity imaging (UEI) to determine the stiffness change of tissues. However, the strain measure in UEI is often less sensitive to a subtle change of stiffness. This is particularly true for Crohn's disease where we have applied strain imaging to the differentiation of acutely inflamed bowel from chronically fibrotic bowel. In this study, a new nonlinear elastic parameter of the soft tissues is proposed to overcome this limit. The purpose of this study is to evaluate the newly proposed method and demonstrate its feasibility in the UEI. A nonlinear characteristic of soft tissues over a relatively large dynamic range of strain was investigated. A simplified tissue model based on a finite element (FE) analysis was integrated with a laboratory developed ultrasound radio-frequency (RF) signal synthesis program. Two-dimensional speckle tracking was applied to this model to simulate the nonlinear behavior of the strain developed in a target inclusion over the applied average strain to the surrounding tissues. A nonlinear empirical equation was formulated and optimized to best match the developed strain-to-applied strain relation obtained from the FE simulation. The proposed nonlinear equation was applied to in vivo measurements and nonlinear parameters were further empirically optimized. For an animal model, acute and chronic inflammatory bowel disease was induced in Lewis rats with trinitrobenzene sulfonic acid (TNBS)-ethanol treatments. After UEI, histopathology and direct mechanical measurements were performed on the excised tissues. The extracted nonlinear parameter from the developed strain-to-applied strain relation differentiated the three different tissue types with 1.96 ± 0.12 for normal, 1.50 ± 0.09 for the acutely inflamed and 1.03 ± 0.08 for the chronically fibrotic tissue. T-tests determined that the nonlinear parameters between normal, acutely inflamed and fibrotic tissue

  14. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling.

    Borkham-Kamphorst, Erawan; Schaffrath, Christian; Van de Leur, Eddy; Haas, Ute; Tihaa, Lidia; Meurer, Steffen K; Nevzorova, Yulia A; Liedtke, Christian; Weiskirchen, Ralf

    2014-05-01

    tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Estimating Utility

    Arndt, Channing; Simler, Kenneth R.

    2010-01-01

    A fundamental premise of absolute poverty lines is that they represent the same level of utility through time and space. Disturbingly, a series of recent studies in middle- and low-income economies show that even carefully derived poverty lines rarely satisfy this premise. This article proposes a......, with the current approach tending to systematically overestimate (underestimate) poverty in urban (rural) zones.......A fundamental premise of absolute poverty lines is that they represent the same level of utility through time and space. Disturbingly, a series of recent studies in middle- and low-income economies show that even carefully derived poverty lines rarely satisfy this premise. This article proposes...... an information-theoretic approach to estimating cost-of-basic-needs (CBN) poverty lines that are utility consistent. Applications to date illustrate that utility-consistent poverty measurements derived from the proposed approach and those derived from current CBN best practices often differ substantially...

  16. Tissue types (image)

    ... are 4 basic types of tissue: connective tissue, epithelial tissue, muscle tissue, and nervous tissue. Connective tissue supports ... binds them together (bone, blood, and lymph tissues). Epithelial tissue provides a covering (skin, the linings of the ...

  17. Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin.

    Jimenez-Sousa, Maria Angeles; Almansa, Raquel; de la Fuente, Concha; Caro-Paton, Agustín; Ruiz, Lourdes; Sanchez-Antolín, Gloria; Gonzalez, Jose Manuel; Aller, Rocio; Alcaide, Noelia; Largo, Pilar; Resino, Salvador; de Lejarazu, Raul Ortiz; Bermejo-Martin, Jesus F

    2010-06-01

    Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF

  18. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy

    Patrizia Pessina

    2015-06-01

    Full Text Available Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD, skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  19. Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo

    Ostrau, Christian; Huelsenbeck, Johannes; Herzog, Melanie; Schad, Arno; Torzewski, Michael; Lackner, Karl J.; Fritz, Gerhard

    2009-01-01

    Background and purpose: HMG-CoA-reductase inhibitors (statins) are widely used lipid-lowering drugs. Moreover, they have pleiotropic effects on cellular stress responses, proliferation and apoptosis in vitro. Here, we investigated whether lovastatin attenuates acute and subchronic ionizing radiation-induced normal tissue toxicity in vivo. Materials and methods: Four hours to 24 h after total body irradiation (6 Gy) of Balb/c mice, acute pro-inflammatory and pro-fibrotic responses were analyzed. To comprise subchronic radiation toxicity, mice were irradiated twice with 2.5 Gy and analyses were performed 3 weeks after the first radiation treatment. Molecular markers of inflammation and fibrosis as well as organ toxicities were measured. Results: Lovastatin attenuated IR-induced activation of NF-κB, mRNA expression of cell adhesion molecules and mRNA expression of pro-inflammatory and pro-fibrotic marker genes (i.e. TNFα, IL-6, TGFβ, CTGF, and type I and type III collagen) in a tissue- and time-dependent manner. γH2AX phosphorylation stimulated by IR was not affected by lovastatin, indicating that the statin has no major impact on the induction of DNA damage in vivo. Radiation-induced thrombopenia was significantly alleviated by lovastatin. Conclusions: Lovastatin inhibits both acute and subchronic IR-induced pro-inflammatory and pro-fibrotic responses and cell death in normal tissue in vivo. Therefore, lovastatin might be useful for selectively attenuating acute and subchronic normal tissue damage caused by radiotherapy.

  20. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

    Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.

    2016-04-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

  1. Control of Scar Tissue Formation in the Cornea: Strategies in Clinical and Corneal Tissue Engineering

    Samantha L. Wilson

    2012-09-01

    Full Text Available Corneal structure is highly organized and unified in architecture with structural and functional integration which mediates transparency and vision. Disease and injury are the second most common cause of blindness affecting over 10 million people worldwide. Ninety percent of blindness is permanent due to scarring and vascularization. Scarring caused via fibrotic cellular responses, heals the tissue, but fails to restore transparency. Controlling keratocyte activation and differentiation are key for the inhibition and prevention of fibrosis. Ophthalmic surgery techniques are continually developing to preserve and restore vision but corneal regression and scarring are often detrimental side effects and long term continuous follow up studies are lacking or discouraging. Appropriate corneal models may lead to a reduced need for corneal transplantation as presently there are insufficient numbers or suitable tissue to meet demand. Synthetic optical materials are under development for keratoprothesis although clinical use is limited due to implantation complications and high rejection rates. Tissue engineered corneas offer an alternative which more closely mimic the morphological, physiological and biomechanical properties of native corneas. However, replication of the native collagen fiber organization and retaining the phenotype of stromal cells which prevent scar-like tissue formation remains a challenge. Careful manipulation of culture environments are under investigation to determine a suitable environment that simulates native ECM organization and stimulates keratocyte migration and generation.

  2. Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties

    Beiert, Thomas; Tiyerili, Vedat; Knappe, Vincent

    2017-01-01

    Background Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial...... infarction (MI). Methods Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. Results RLX treatment significantly attenuated the increase in AF......-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant...

  3. Multiattribute Utility Theory without Expected Utility Foundations

    Stiggelbout, A.M.; Wakker, P.P.

    1995-01-01

    Methods for determining the form of utilities are needed for the implementation of utility theory in specific decisions. An important step forward was achieved when utility theorists characterized useful parametric families of utilities, and simplifying decompositions of multiattribute utilities.

  4. Multiattribute utility theory without expected utility foundations

    Wakker, P.P.; Miyamoto, J.

    1996-01-01

    Methods for determining the form of utilities are needed for the implementation of utility theory in specific decisions. An important step forward was achieved when utility theorists characterized useful parametric families of utilities, and simplifying decompositions of multiattribute utilities.

  5. Synthetic Phage for Tissue Regeneration

    So Young Yoo

    2014-01-01

    Full Text Available Controlling structural organization and signaling motif display is of great importance to design the functional tissue regenerating materials. Synthetic phage, genetically engineered M13 bacteriophage has been recently introduced as novel tissue regeneration materials to display a high density of cell-signaling peptides on their major coat proteins for tissue regeneration purposes. Structural advantages of their long-rod shape and monodispersity can be taken together to construct nanofibrous scaffolds which support cell proliferation and differentiation as well as direct orientation of their growth in two or three dimensions. This review demonstrated how functional synthetic phage is designed and subsequently utilized for tissue regeneration that offers potential cell therapy.

  6. Tissue Classification

    Van Leemput, Koen; Puonti, Oula

    2015-01-01

    Computational methods for automatically segmenting magnetic resonance images of the brain have seen tremendous advances in recent years. So-called tissue classification techniques, aimed at extracting the three main brain tissue classes (white matter, gray matter, and cerebrospinal fluid), are now...... well established. In their simplest form, these methods classify voxels independently based on their intensity alone, although much more sophisticated models are typically used in practice. This article aims to give an overview of often-used computational techniques for brain tissue classification...

  7. Utilities objectives

    Cousin, Y.; Fabian, H.U.

    1996-01-01

    The policy of French and german utilities is to make use of nuclear energy as a long term, competitive and environmentally friendly power supply. The world electricity generation is due to double within the next 30 years. In the next 20 to 30 years the necessity of nuclear energy will be broadly recognized. More than for most industries, to deal properly with nuclear energy requires the combination of a consistent political will, of a proper institutional framework, of strong and legitimate control authorities, of a sophisticated industry and of operators with skilled management and human resources. One of the major risk facing nuclear energy is the loss of competitiveness. This can be achieved only through the combination of an optimized design, a consistent standardization, a proper industrial partnership and a stable long term strategy. Although the existing plants in Western Europe are already very safe, the policy is clearly to enhance the safety of the next generation of nuclear plants which are designing today. The French and German utilities have chosen an evolutionary approach based on experience and proven technologies, with an enhanced defense in depth and an objective of easier operation and maintenance. The cost objective is to maintain and improve what has been achieved in the best existing power plants in both countries. This calls for rational choices and optimized design to meet the safety objectives, a strong standardization policy, short construction times, high availability and enough flexibility to enable optimization of the fuel cycle throughout the lifetime of the plants. The conceptual design phase has proven that the French and German teams from industry and from the utilities are able to pursue both the safety and the cost objectives, basing their decision on a rational approach which could be accepted by the safety authorities. (J.S.)

  8. Thorium utilization

    Trauger, D B [Oak Ridge National Lab., TN (USA)

    1978-01-01

    Some of the factors that provide incentive for the utilization of thorium in specific reactor types are explored and the constraints that stand in the way are pointed out. The properties of thorium and derived fuels are discussed, and test and reactor operating experience is reviewed. In addition, symbiotic systems of breeder and converter reactor are suggested as being particularly attractive systems for energy production. Throughout the discussion, the High-Temperature Gas-Cooled Reactor and Molten Salt Reactor are treated in some detail because they have been developed primarily for use with thorium fuel cycles.

  9. Japanese utilities' plutonium utilization program

    Matsuo, Yuichiro.

    1996-01-01

    Japan's 10 utility companies are working and will continue to work towards establishing a fully closed nuclear fuel cycle. The key goals of which are: (1) reprocessing spent fuel; (2) recycling recovered uranium and plutonium; and (3) commercializing fast breeder technology by around the year 2030. This course of action by the Japanese electric power industry is in full accordance with Japan's national policy outlined in the government's report ''The Long-Term Program for Research, Development, and Nuclear Energy,'' which was published in June 1994. The Japanese civilian nuclear program is a long-term program that looks into the 21st century and beyond. It is quite true that sustaining the recycling option for energy security and the global environment demands a large investment. For it to be accepted by the public, safety must be the highest priority and will be pursued at a great cost if necessary. In its history, Japan has learned that as technology advances, costs will come down. The Japanese utility industry will continue investment in technology without compromising safety until the recycling option becomes more competitive with other options. This effort will be equally applied to the development of the commercial FBRs. The Japanese utility industry is confident that Japan's stable policy and strong objective to develop competitive and peaceful technology will contribute to the global economy and the environment without increasing the threat of plutonium proliferation

  10. Multiattribute Utility Theory without Expected Utility Foundations

    J. Miyamoto (John); P.P. Wakker (Peter)

    1996-01-01

    textabstractMethods for determining the form of utilities are needed for the implementation of utility theory in specific decisions. An important step forward was achieved when utility theorists characterized useful parametric families of utilities and simplifying decompositions of multiattribute

  11. Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues.

    Nassari, Sonya; Duprez, Delphine; Fournier-Thibault, Claire

    2017-01-01

    Skeletal muscles belong to the musculoskeletal system, which is composed of bone, tendon, ligament and irregular connective tissue, and closely associated with motor nerves and blood vessels. The intrinsic molecular signals regulating myogenesis have been extensively investigated. However, muscle development, homeostasis and regeneration require interactions with surrounding tissues and the cellular and molecular aspects of this dialogue have not been completely elucidated. During development and adult life, myogenic cells are closely associated with the different types of connective tissue. Connective tissues are defined as specialized (bone and cartilage), dense regular (tendon and ligament) and dense irregular connective tissue. The role of connective tissue in muscle morphogenesis has been investigated, thanks to the identification of transcription factors that characterize the different types of connective tissues. Here, we review the development of the various connective tissues in the context of the musculoskeletal system and highlight their important role in delivering information necessary for correct muscle morphogenesis, from the early step of myoblast differentiation to the late stage of muscle maturation. Interactions between muscle and connective tissue are also critical in the adult during muscle regeneration, as impairment of the regenerative potential after injury or in neuromuscular diseases results in the progressive replacement of the muscle mass by fibrotic tissue. We conclude that bi-directional communication between muscle and connective tissue is critical for a correct assembly of the musculoskeletal system during development as well as to maintain its homeostasis in the adult.

  12. Regeneration of soft tissues is promoted by MMP1 treatment after digit amputation in mice.

    Xiaodong Mu

    Full Text Available The ratio of matrix metalloproteinases (MMPs to the tissue inhibitors of metalloproteinases (TIMPs in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.

  13. Detection of hydroxyapatite in calcified cardiovascular tissues.

    Lee, Jae Sam; Morrisett, Joel D; Tung, Ching-Hsuan

    2012-10-01

    The objective of this study is to develop a method for selective detection of the calcific (hydroxyapatite) component in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues ex vivo. This method uses a novel optical molecular imaging contrast dye, Cy-HABP-19, to target calcified cells and tissues. A peptide that mimics the binding affinity of osteocalcin was used to label hydroxyapatite in vitro and ex vivo. Morphological changes in vascular smooth muscle cells were evaluated at an early stage of the mineralization process induced by extrinsic stimuli, osteogenic factors and a magnetic suspension cell culture. Hydroxyapatite components were detected in monolayers of these cells in the presence of osteogenic factors and a magnetic suspension environment. Atherosclerotic plaque contains multiple components including lipidic, fibrotic, thrombotic, and calcific materials. Using optical imaging and the Cy-HABP-19 molecular imaging probe, we demonstrated that hydroxyapatite components could be selectively distinguished from various calcium salts in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues, carotid endarterectomy samples and aortic valves, ex vivo. Hydroxyapatite deposits in cardiovascular tissues were selectively detected in the early stage of the calcification process using our Cy-HABP-19 probe. This new probe makes it possible to study the earliest events associated with vascular hydroxyapatite deposition at the cellular and molecular levels. This target-selective molecular imaging probe approach holds high potential for revealing early pathophysiological changes, leading to progression, regression, or stabilization of cardiovascular diseases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Predictors of idiopathic pulmonary fibrosis in absence of radiologic honeycombing: A cross sectional analysis in ILD patients undergoing lung tissue sampling.

    Salisbury, Margaret L; Xia, Meng; Murray, Susan; Bartholmai, Brian J; Kazerooni, Ella A; Meldrum, Catherine A; Martinez, Fernando J; Flaherty, Kevin R

    2016-09-01

    Idiopathic pulmonary fibrosis (IPF) can be diagnosed confidently and non-invasively when clinical and computed tomography (CT) criteria are met. Many do not meet these criteria due to absence of CT honeycombing. We investigated predictors of IPF and combinations allowing accurate diagnosis in individuals without honeycombing. We utilized prospectively collected clinical and CT data from patients enrolled in the Lung Tissue Research Consortium. Included patients had no honeycombing, no connective tissue disease, underwent diagnostic lung biopsy, and had CT pattern consistent with fibrosing ILD (n = 200). Logistic regression identified clinical and CT variables predictive of IPF. The probability of IPF was assessed at various cut-points of important clinical and CT variables. A multivariable model adjusted for age and gender found increasingly extensive reticular densities (OR 2.93, CI 95% 1.55-5.56, p = 0.001) predicted IPF, while increasing ground glass densities predicted a diagnosis other than IPF (OR 0.55, CI 95% 0.34-0.89, p = 0.02). The model-based probability of IPF was 80% or greater in patients with age at least 60 years and extent of reticular density one-third or more of total lung volume; for patients meeting or exceeding these clinical thresholds the specificity for IPF is 96% (CI 95% 91-100%) with 21 of 134 (16%) biopsies avoided. In patients with suspected fibrotic ILD and absence of CT honeycombing, extent of reticular and ground glass densities predict a diagnosis of IPF. The probability of IPF exceeds 80% in subjects over age 60 years with one-third of total lung having reticular densities. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Radiation-induced enteropathy: Molecular basis of pentoxifylline–vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition

    Hamama, Saad; Gilbert-Sirieix, Marie; Vozenin, Marie-Catherine; Delanian, Sylvie

    2012-01-01

    Background: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline–vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. Methods: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline–vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-β1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. Results: Pentoxifylline–vitamin E combination induces regression of symptoms (SOMA) by −41% and −80% at 6 and 18 months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway. Conclusions: The anti-fibrotic effect of combined pentoxifylline–vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. It strengthens previous clinical data showing pentoxifylline–vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.

  16. Acid-base balance and cardiac index in SO2-bronchitic, papaine-emphysematous and paraquat-fibrotic rats after isoproterenol treatment.

    Vértes, K; Debreczeni, L A

    1990-01-01

    SO2-bronchitis, papaine-emphysema and paraquat fibrosis were induced in Wistar rats. Blood pressure, cardiac index, total peripheral resistance, arterial blood gas values, parameters of acid-base balance were determined. Effects of 0.1 and 0.3 microgram.-1.min-1 isoproterenol iv. infusion were examined. Morphologic alterations of the lungs were verified by histopathological examinations. All the parameters investigated were found to be normal in the control rats. The treated groups differed from the normal ones: an increased blood pressure was observed in emphysema and fibrosis. A decreased cardiac index was characteristic of chronic bronchitis, high cardiac index of emphysema, high TPR of bronchitis and arterial hypoxaemy of fibrosis. The groups reacted differently to beta adrenergic stimulation: in bronchitic and fibrotic rats the cardiac index was augmented, whereas in emphysematous ones the increase proved to be smaller. The effects of isoproterenol infusion can be related to the altered beta-receptor function in the various experimental pulmonary diseases.

  17. Utility training

    Villaros, P.E.; Luxo, Armando; Bruant, Jacques

    1977-01-01

    The study of operational training systems for electro-nuclear utilities may be conducted through two different approaches. A first analytical approach consists of determining, for each position of a given organization chart, the necessary qualifications required and the corresponding complementary training to be provided. This approach applies preferentially to existing classical systems which are converted to nuclear operation with objectives of minimum structural changes and conservation of maximum efficiency. A second synthetical approach consists of determining the specific characteristics of nuclear plant operation, then, of deducting the training contingencies and the optimized organization chart of the plant, while taking into account, at each step, the parameters linked to local conditions. This last approach is studied in some detail in the present paper, taking advantage of its better suitability to the problems raised at the first stage of an electro-nuclear program development. In this respect, the possibility offered by this apprach to coordinate the training system of a given nuclear power station personnel with the overall problem of developing a skilled industrial labor force in the country, may lead to reconsideration of some usual priorities in the economy of operation of the nuclear power plant

  18. [Human brown adipose tissue].

    Virtanen, Kirsi A; Nuutila, Pirjo

    2015-01-01

    Adult humans have heat-producing and energy-consuming brown adipose tissue in the clavicular region of the neck. There are two types of brown adipose cells, the so-called classic and beige adipose cells. Brown adipose cells produce heat by means of uncoupler protein 1 (UCP1) from fatty acids and sugar. By applying positron emission tomography (PET) measuring the utilization of sugar, the metabolism of brown fat has been shown to multiply in the cold, presumably influencing energy consumption. Active brown fat is most likely present in young adults, persons of normal weight and women, least likely in obese persons.

  19. TGF-β1 downregulates COX-2 expression leading to decrease of PGE2 production in human lung cancer A549 cells, which is involved in fibrotic response to TGF-β1.

    Erina Takai

    Full Text Available Transforming growth factor-ß1 (TGF-β1 is a multifunctional cytokine that is involved in various pathophysiological processes, including cancer progression and fibrotic disorders. Here, we show that treatment with TGF-β1 (5 ng/mL induced downregulation of cyclooxygenase-2 (COX-2, leading to reduced synthesis of prostaglandin E2 (PGE2, in human lung cancer A549 cells. Treatment of cells with specific inhibitors of COX-2 or PGE2 receptor resulted in growth inhibition, indicating that the COX-2/PGE2 pathway contributes to proliferation in an autocrine manner. TGF-β1 treatment induced growth inhibition, which was attenuated by exogenous PGE2. TGF-β1 is also a potent inducer of epithelial mesenchymal transition (EMT, a phenotype change in which epithelial cells differentiate into fibroblastoid cells. Supplementation with PGE2 or PGE2 receptor EP4 agonist PGE1-alcohol, as compared with EP1/3 agonist sulprostone, inhibited TGF-β1-induced expression of fibronectin and collagen I (extracellular matrix components. Exogenous PGE2 or PGE2 receptor agonists also suppressed actin remodeling induced by TGF-β1. These results suggest that PGE2 has an anti-fibrotic effect. We conclude that TGF-β1-induced downregulation of COX-2/PGE2 signaling is involved in facilitation of fibrotic EMT response in A549 cells.

  20. Identification of Two Novel Anti-Fibrotic Benzopyran Compounds Produced by Engineered Strains Derived from Streptomyces xiamenensis M1-94P that Originated from Deep-Sea Sediments

    Lei Feng

    2013-10-01

    Full Text Available The benzopyran compound obtained by cultivating a mangrove-derived strain, Streptomyces xiamenensis strain 318, shows multiple biological effects, including anti-fibrotic and anti-hypertrophic scar properties. To increase the diversity in the structures of the available benzopyrans, by means of biosynthesis, the strain was screened for spontaneous rifampicin resistance (Rif, and a mutated rpsL gene to confer streptomycin resistance (Str, was introduced into the S. xiamenensis strain M1-94P that originated from deep-sea sediments. Two new benzopyran derivatives, named xiamenmycin C (1 and D (2, were isolated from the crude extracts of a selected Str-Rif double mutant (M6 of M1-94P. The structures of 1 and 2 were identified by analyzing extensive spectroscopic data. Compounds 1 and 2 both inhibit the proliferation of human lung fibroblasts (WI26, and 1 exhibits better anti-fibrotic activity than xiamenmycin. Our study presents the novel bioactive compounds isolated from S. xiamenensis mutant strain M6 constructed by ribosome engineering, which could be a useful approach in the discovery of new anti-fibrotic compounds.

  1. Utilización del adhesivo tisular tisuacryl en Estomatología: Revisión bibliográfica Utilization of tisuacryl tissue adhesive in dentistry: Bibliographic review

    Mildres Barroso Palomino

    2005-12-01

    Full Text Available El trabajo presenta una revisión de la literatura nacional e internacional actualizada, así como experiencias realizadas en el campo de la Estomatología con los cianoacrilatos, haciendo énfasis en el adhesivo tisular tisuacryl , que es producido por el Centro de Biomateriales de la Universidad de La Habana. Se exponen resultados relevantes observados con su utilización como: sustituto de la sutura, apósito periodontal, en los autoinjertos gingivales, en el selle de alvéolos posextracción dentaria, en la toma de biopsias en la cavidad bucal y en el tratamiento de la estomatitis aftosa recurrente. Se detallan los avances logrados con esta terapia y la aceptación por parte de los pacientes que lo reciben.An updated review of the national and international literature, as well as the experiences obtained in the field of Stomatology with the cyanoacrylates are presented, making emphasis on the tisuacryl tissue adhesive, which is produced by the Center of Biomaterials of the University of Havana. The significant results attained with its use as a suture substitute and a periodontal dressing, and in the gingival autografts, the closure of the sockets after dental extraction, the taking of biopsies in the oral cavity, and the treatment of recurrent aphthous stomatitis, are exposed. The advances achieved with this therapy and the patient's acceptance are stressed.

  2. Proangiogenic scaffolds as functional templates for cardiac tissue engineering.

    Madden, Lauran R; Mortisen, Derek J; Sussman, Eric M; Dupras, Sarah K; Fugate, James A; Cuy, Janet L; Hauch, Kip D; Laflamme, Michael A; Murry, Charles E; Ratner, Buddy D

    2010-08-24

    We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30-40 microm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.

  3. Tissue irradiator

    Hungate, F.P.; Riemath, W.F.; Bunnell, L.R.

    1975-01-01

    A tissue irradiator is provided for the in-vivo irradiation of body tissue. The irradiator comprises a radiation source material contained and completely encapsulated within vitreous carbon. An embodiment for use as an in-vivo blood irradiator comprises a cylindrical body having an axial bore therethrough. A radioisotope is contained within a first portion of vitreous carbon cylindrically surrounding the axial bore, and a containment portion of vitreous carbon surrounds the radioisotope containing portion, the two portions of vitreous carbon being integrally formed as a single unit. Connecting means are provided at each end of the cylindrical body to permit connections to blood-carrying vessels and to provide for passage of blood through the bore. In a preferred embodiment, the radioisotope is thulium-170 which is present in the irradiator in the form of thulium oxide. A method of producing the preferred blood irradiator is also provided, whereby nonradioactive thulium-169 is dispersed within a polyfurfuryl alcohol resin which is carbonized and fired to form the integral vitreous carbon body and the device is activated by neutron bombardment of the thulium-169 to produce the beta-emitting thulium-170

  4. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.

    Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor; Wood, Tammara A; Christmann, Romy B; Farber, Harrison W; Lafyatis, Robert A; Denton, Christopher P; Hinchcliff, Monique E; Pioli, Patricia A; Mahoney, J Matthew; Whitfield, Michael L

    2017-03-23

    Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune

  5. ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis.

    Martins, Vanessa; Valença, Samuel S; Farias-Filho, Francisco A; Molinaro, Raphael; Simões, Rafael L; Ferreira, Tatiana P T; e Silva, Patrícia M R; Hogaboam, Cory M; Kunkel, Steven L; Fierro, Iolanda M; Canetti, Claudio; Benjamim, Claudia F

    2009-05-01

    Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (alpha-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-beta level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.

  6. Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts.

    Grove, Lisa M; Southern, Brian D; Jin, Tong H; White, Kimberly E; Paruchuri, Sailaja; Harel, Efrat; Wei, Ying; Rahaman, Shaik O; Gladson, Candece L; Ding, Qiang; Craik, Charles S; Chapman, Harold A; Olman, Mitchell A

    2014-05-02

    The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-linked membrane protein with no cytosolic domain that localizes to lipid raft microdomains. Our laboratory and others have documented that lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibit a hypermotile phenotype. This study was undertaken to elucidate the molecular mechanism whereby uPAR ligation with its cognate ligand, urokinase, induces a motile phenotype in human lung fibroblasts. We found that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) leads to enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Ligation of uPAR with the amino-terminal fragment recruited α5β1 integrin and the acylated form of the Src family kinase, Fyn, to lipid rafts. The biological consequences of this translocation were an increase in fibroblast motility and a switch of the integrin-initiated signal pathway for migration away from the lipid raft-independent focal adhesion kinase pathway and toward a lipid raft-dependent caveolin-Fyn-Shc pathway. Furthermore, an integrin homologous peptide as well as an antibody that competes with β1 for uPAR binding have the ability to block this effect. In addition, its relative insensitivity to cholesterol depletion suggests that the interactions of α5β1 integrin and uPAR drive the translocation of α5β1 integrin-acylated Fyn signaling complexes into lipid rafts upon uPAR ligation through protein-protein interactions. This signal switch is a novel pathway leading to the hypermotile phenotype of IPF patient-derived fibroblasts, seen with uPAR ligation. This uPAR dependent, fibrotic matrix-selective, and profibrotic fibroblast phenotype may be amenable to targeted therapeutics designed to ameliorate IPF.

  7. CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease.

    Riser, Bruce L; Najmabadi, Feridoon; Perbal, Bernard; Peterson, Darryl R; Rambow, Jo Ann; Riser, Melisa L; Sukowski, Ernest; Yeger, Herman; Riser, Sarah C

    2009-05-01

    Fibrosis is a major cause of end-stage renal disease, and although initiation factors have been elucidated, uncertainty concerning the downstream pathways has hampered the development of anti-fibrotic therapies. CCN2 (CTGF) functions downstream of transforming growth factor (TGF)-beta, driving increased extracellular matrix (ECM) accumulation and fibrosis. We examined the possibility that CCN3 (NOV), another CCN family member with reported biological activities that differ from CCN2, might act as an endogenous negative regulator of ECM and fibrosis. We show that cultured rat mesangial cells express CCN3 mRNA and protein, and that TGF-beta treatment reduced CCN3 expression levels while increasing CCN2 and collagen type I activities. Conversely, either the addition of CCN3 or CCN3 overexpression produced a marked down-regulation of CCN2 followed by virtual blockade of both collagen type I transcription and its accumulation. This finding occurred in both growth-arrested and CCN3-transfected cells under normal growth conditions after TGF-beta treatment. These effects were not attributable to altered cellular proliferation as determined by cell cycle analysis, nor were they attributable to interference of Smad signaling as shown by analysis of phosphorylated Smad3 levels. In conclusion, both CCN2 and CCN3 appear to act in a yin/yang manner to regulate ECM metabolism. CCN3, acting downstream of TGF-beta to block CCN2 and the up-regulation of ECM, may therefore serve to naturally limit fibrosis in vivo and provide opportunities for novel, endogenous-based therapeutic treatments.

  8. Vaginal native tissue repair versus transvaginal mesh repair for apical prolapse: how utilizing different methods of analysis affects the estimated trade-off between reoperation for mesh exposure/erosion and reoperation for recurrent prolapse.

    Dieter, Alexis A; Willis-Gray, Marcella G; Weidner, Alison C; Visco, Anthony G; Myers, Evan R

    2015-05-01

    Informed decision-making about optimal surgical repair of apical prolapse with vaginal native tissue (NT) versus transvaginal mesh (TVM) requires understanding the balance between the potential "harm" of mesh-related complications and the potential "benefit" of reducing prolapse recurrence. Synthesis of data from observational studies is required and the current literature shows that the average follow-up for NT repair is significantly longer than for TVM repair. We examined this harm/benefit balance. We hypothesized that using different methods of analysis to incorporate follow-up time would affect the balance of outcomes. We used a Markov state transition model to estimate the cumulative 24-month probabilities of reoperation for mesh exposure/erosion or for recurrent prolapse after either NT or TVM repair. We used four different analytic approaches to estimate probability distributions ranging from simple pooled proportions to a random effects meta-analysis using study-specific events per patient-time. As variability in follow-up time was accounted for better, the balance of outcomes became more uncertain. For TVM repair, the incremental ratio of number of operations for mesh exposure/erosion per single reoperation for recurrent prolapse prevented increased progressively from 1.4 to over 100 with more rigorous analysis methods. The most rigorous analysis showed a 70% probability that TVM would result in more operations for recurrent prolapse repair than NT. Based on the best available evidence, there is considerable uncertainty about the harm/benefit trade-off between NT and TVM for apical prolapse repair. Future studies should incorporate time-to-event analyses, with greater standardization of reporting, in order to better inform decision-making.

  9. Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo.

    Tower, R J; Campbell, G M; Müller, M; Glüer, C C; Tiwari, S

    2015-05-01

    The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in

  10. Effect-independent measures of tissue response to fractionated radiation

    Thames, H.D.

    1984-01-01

    Tissue repair factors are measures of sparing from dose fractionation, in the absence of proliferation. A desirable feature of any repair factor is that it be independent of the level of injury induced in the tissue, since otherwise the comparison of tissues on the basis of the factor would not be meaningful. The repair factors F/sub R/ and F/sub rec/ are increasing functions of D/sub 1/, and depend on level of skin reaction after fractionated radiation. By contrast, β/α is effect-independent as a measure of repair capacity in skin, gut, and bone marrow. For late fibrotic reactions in the kidney, there was an increase in β/α with increased levels of injury that was statistically insignificant. The halftime, T/sub 1/2/, for intracellular repair processes in tissues is a measure of repair kinetics. Effect-independence is defend for T/sub 1/2/ as independence from size of dose per fraction. T/sub 1/2/ is independent of fraction size in skin, gut, and spinal cord, and is longer (1.5 hours) in the late-reacting tissues (lung and spinal cord) than in those that react acutely (less than 1 hour), with skin as the exception (1.3 hours). Therefore, early and late-responding normal tissues may be distinguished in terms of both repair capacity and repair kinetics: repair is slower in late-responding tissues, which are also more sensitive to changes in dose fractionation

  11. Successful vitrification and autografting of baboon (Papio anubis) ovarian tissue.

    Amorim, Christiani A; Jacobs, Sophie; Devireddy, Ram V; Van Langendonckt, Anne; Vanacker, Julie; Jaeger, Jonathan; Luyckx, Valérie; Donnez, Jacques; Dolmans, Marie-Madeleine

    2013-08-01

    Can a vitrification protocol using an ethylene glycol/dimethyl sulphoxide-based solution and a cryopin successfully cryopreserve baboon ovarian tissue? Our results show that baboon ovarian tissue can be successfully cryopreserved with our vitrification protocol. Non-human primates have already been used as an animal model to test vitrification protocols for human ovarian tissue cryopreservation. Ovarian biopsies from five adult baboons were vitrified, warmed and autografted for 5 months. After grafting, follicle survival, growth and function and also the quality of stromal tissue were assessed histologically and by immunohistochemistry. The influence of the vitrification procedure on the cooling rate was evaluated by a computer model. After vitrification, warming and long-term grafting, follicles were able to grow and maintain their function, as illustrated by Ki67, anti-Müllerian hormone (AMH) and growth differentiation factor-9 (GDF-9) immunostaining. Corpora lutea were also observed, evidencing successful ovulation in all the animals. Stromal tissue quality did not appear to be negatively affected by our cryopreservation procedure, as demonstrated by vascularization and proportions of fibrotic areas, which were similar to those found in fresh ungrafted ovarian tissue. Despite our promising findings, before applying this technique in a clinical setting, we need to validate it by achieving pregnancies. In addition to encouraging results obtained with our vitrification procedure for non-human ovarian tissue, this study also showed, for the first time, expression of AMH and GDF-9 in ovarian follicles. This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (grant Télévie No. 7.4507.10, grant 3.4.590.08 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, Fondation St Luc, Foundation Against Cancer, and Department of Mechanical Engineering at Louisiana State University (support to Ram Devireddy), and

  12. Elevation of transforming growth factor beta (TGFbeta) and its downstream mediators in subcutaneous foreign body capsule tissue.

    Li, Allen G; Quinn, Matthew J; Siddiqui, Yasmin; Wood, Michael D; Federiuk, Isaac F; Duman, Heather M; Ward, W Kenneth

    2007-08-01

    Foreign body encapsulation represents a chronic fibrotic response and has been a major obstacle that reduces the useful life of implanted biomedical devices. The precise mechanism underlying such an encapsulation is still unknown. We hypothesized that, considering its central role in many other fibrotic conditions, transforming growth factor beta (TGFbeta) may play an important role during the formation of foreign body capsule (FBC). In the present study, we implanted mock sensors in rats subcutaneously and excised FBC samples at day 7, 21, and 48-55 postimplantation. The most abundant TGFbeta isoform in all tissues was TGFbeta1, which was expressed minimally in control tissue. The expression of both TGFbeta1 RNA and protein was significantly increased in FBC tissues at all time points, with the highest level in day 7 FBC. The number of cells stained for phosphorylated Smad2, an indication of activated TGFbeta signaling, paralleled the expression of TGFbeta. A similar dynamic change was also observed in the numbers of FBC myofibroblasts, which in response to TGFbeta, differentiate from quiescent fibroblasts and synthesize collagen. Type I collagen, the most prominent downstream target of TGFbeta in fibrosis, was found in abundance in the FBC, especially during the latter time periods. We suggest that TGFbeta plays an important role in the FBC formation. Inhibition of TGFbeta signaling could be a promising strategy in the prevention of FBC formation, thereby extending the useful life of subcutaneous implants.

  13. FOXO1 expression in keratinocytes promotes connective tissue healing

    Zhang, Chenying; Lim, Jason; Liu, Jian; Ponugoti, Bhaskar; Alsadun, Sarah; Tian, Chen; Vafa, Rameen; Graves, Dana T.

    2017-01-01

    Wound healing is complex and highly orchestrated. It is well appreciated that leukocytes, particularly macrophages, are essential for inducing the formation of new connective tissue, which requires the generation of signals that stimulate mesenchymal stem cells (MSC), myofibroblasts and fibroblasts. A key role for keratinocytes in this complex process has yet to be established. To this end, we investigated possible involvement of keratinocytes in connective tissue healing. By lineage-specific deletion of the forkhead box-O 1 (FOXO1) transcription factor, we demonstrate for the first time that keratinocytes regulate proliferation of fibroblasts and MSCs, formation of myofibroblasts and production of collagen matrix in wound healing. This stimulation is mediated by a FOXO1 induced TGFβ1/CTGF axis. The results provide direct evidence that epithelial cells play a key role in stimulating connective tissue healing through a FOXO1-dependent mechanism. Thus, FOXO1 and keratinocytes may be an important therapeutic target where healing is deficient or compromised by a fibrotic outcome. PMID:28220813

  14. Effect-independent measures of tissue responses to fractionated irradiation

    Thames, H.D. Jr.

    1984-01-01

    Tissue repair factors measure the sparing that can be achieved from dose fractionation in the absence of proliferation. Four repair factors are analysed in these terms: Fsub(R),Fsub(rec), the ratio of linear-quadratic survival model parameters β/α and the half-time Tsub(1/2) for intracellular repair processes. Theoretically, Fsub(R) and Fsub(rec) are increasing functions of D 1 , and thus depend on level of effect. This is confirmed by analysis of skin reactions after multifractionated radiation. By contrast, β/α is effect-independent as a measure of repair capacity in skin, gut, and bone marrow, tissues for which it is reasonable to assume that survival of identifiable target cells is the primary determinant of the endpoint. For a functional endpoint not clearly connected with the depletion of a specific target-cell population (late fibrotic reactions in the kidney), there was an increase in β/α with increased levels of injury, but this was statistically insignificant. Tsub(1/2) is independent of fraction size in skin, gut, and spinal cord, and is longer (1.5 hours) in the late-reacting tissues (lung and spinal cord) than in those that react acutely (Tsub(1/2) less than 1 hour), with skin as the exception (Tsub(1/2) approx. 1.3 hours). (author)

  15. Proteolytic processing of connective tissue growth factor in normal ocular tissues and during corneal wound healing.

    Robinson, Paulette M; Smith, Tyler S; Patel, Dilan; Dave, Meera; Lewin, Alfred S; Pi, Liya; Scott, Edward W; Tuli, Sonal S; Schultz, Gregory S

    2012-12-13

    Connective tissue growth factor (CTGF) is a fibrogenic cytokine that is up-regulated by TGF-β and mediates most key fibrotic actions of TGF-β, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. This study addresses the role of proteolytic processing of CTGF in human corneal fibroblasts (HCF) stimulated with TGF-β, normal ocular tissues and wounded corneas. Proteolytic processing of CTGF in HCF cultures, normal animal eyes, and excimer laser wounded rat corneas were examined by Western blot. The identity of a 21-kDa band was determined by tandem mass spectrometry, and possible alternative splice variants of CTGF were assessed by 5' Rapid Amplification of cDNA Ends (RACE). HCF stimulated by TGF-β contained full length 38-kDa CTGF and fragments of 25, 21, 18, and 13 kDa, while conditioned medium contained full length 38- and a 21-kDa fragment of CTGF that contained the middle "hinge" region of CTGF. Fragmentation of recombinant CTGF incubated in HCF extracts was blocked by the aspartate protease inhibitor, pepstatin. Normal mouse, rat, and rabbit whole eyes and rabbit ocular tissues contained abundant amounts of C-terminal 25- and 21-kDa fragments and trace amounts of 38-kDa CTGF, although no alternative transcripts were detected. All forms of CTGF (38, 25, and 21 kDa) were detected during healing of excimer ablated rat corneas, peaking on day 11. Proteolytic processing of 38-kDa CTGF occurs during corneal wound healing, which may have important implications in regulation of corneal scar formation.

  16. Mouse genetic approaches applied to the normal tissue radiation response

    Haston, Christina K.

    2012-01-01

    The varying responses of inbred mouse models to radiation exposure present a unique opportunity to dissect the genetic basis of radiation sensitivity and tissue injury. Such studies are complementary to human association studies as they permit both the analysis of clinical features of disease, and of specific variants associated with its presentation, in a controlled environment. Herein I review how animal models are studied to identify specific genetic variants influencing predisposition to radiation-induced traits. Among these radiation-induced responses are documented strain differences in repair of DNA damage and in extent of tissue injury (in the lung, skin, and intestine) which form the base for genetic investigations. For example, radiation-induced DNA damage is consistently greater in tissues from BALB/cJ mice, than the levels in C57BL/6J mice, suggesting there may be an inherent DNA damage level per strain. Regarding tissue injury, strain specific inflammatory and fibrotic phenotypes have been documented for principally, C57BL/6 C3H and A/J mice but a correlation among responses such that knowledge of the radiation injury in one tissue informs of the response in another is not evident. Strategies to identify genetic differences contributing to a trait based on inbred strain differences, which include linkage analysis and the evaluation of recombinant congenic (RC) strains, are presented, with a focus on the lung response to irradiation which is the only radiation-induced tissue injury mapped to date. Such approaches are needed to reveal genetic differences in susceptibility to radiation injury, and also to provide a context for the effects of specific genetic variation uncovered in anticipated clinical association studies. In summary, mouse models can be studied to uncover heritable variation predisposing to specific radiation responses, and such variations may point to pathways of importance to phenotype development in the clinic.

  17. 25-Hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway

    Ichikawa, Tomohiro [Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8509 (Japan); Sugiura, Hisatoshi, E-mail: sugiura@rm.med.tohoku.ac.jp [Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574 (Japan); Koarai, Akira; Kikuchi, Takashi; Hiramatsu, Masataka; Kawabata, Hiroki; Akamatsu, Keiichiro; Hirano, Tsunahiko; Nakanishi, Masanori; Matsunaga, Kazuto; Minakata, Yoshiaki [Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8509 (Japan); Ichinose, Masakazu [Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574 (Japan)

    2013-05-01

    Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblasts (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-β{sub 1} production (P<0.01) and a neutralizing anti-TGF-β antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-β{sub 1} release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-β dependent pathway.

  18. TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.

    Qi, Yu; Jiang, Dongsheng; Sindrilaru, Anca; Stegemann, Agatha; Schatz, Susanne; Treiber, Nicolai; Rojewski, Markus; Schrezenmeier, Hubert; Vander Beken, Seppe; Wlaschek, Meinhard; Böhm, Markus; Seitz, Andreas; Scholz, Natalie; Dürselen, Lutz; Brinckmann, Jürgen; Ignatius, Anita; Scharffetter-Kochanek, Karin

    2014-02-01

    Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-α (TNF-α)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mφ or following injection into wound margins suppressed the release of TNF-α from activated Mφ and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-β1 (TGF-β1)/TGF-β3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mφ activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.

  19. The effect of keratinocytes on the biomechanical characteristics and pore microstructure of tissue engineered skin using deep dermal fibroblasts.

    Varkey, Mathew; Ding, Jie; Tredget, Edward E

    2014-12-01

    Fibrosis affects most organs, it results in replacement of normal parenchymal tissue with collagen-rich extracellular matrix, which compromises tissue architecture and ultimately causes loss of function of the affected organ. Biochemical pathways that contribute to fibrosis have been extensively studied, but the role of biomechanical signaling in fibrosis is not clearly understood. In this study, we assessed the effect keratinocytes have on the biomechanical characteristics and pore microstructure of tissue engineered skin made with superficial or deep dermal fibroblasts in order to determine any biomaterial-mediated anti-fibrotic influences on tissue engineered skin. Tissue engineered skin with deep dermal fibroblasts and keratinocytes were found to be less stiff and contracted and had reduced number of myofibroblasts and lower expression of matrix crosslinking factors compared to matrices with deep fibroblasts alone. However, there were no such differences between tissue engineered skin with superficial fibroblasts and keratinocytes and matrices with superficial fibroblasts alone. Also, tissue engineered skin with deep fibroblasts and keratinocytes had smaller pores compared to those with superficial fibroblasts and keratinocytes; pore size of tissue engineered skin with deep fibroblasts and keratinocytes were not different from those matrices with deep fibroblasts alone. A better understanding of biomechanical characteristics and pore microstructure of tissue engineered skin may prove beneficial in promoting normal wound healing over pathologic healing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Fell-Muir lecture: connective tissue growth factor (CCN2) – a pernicious and pleiotropic player in the development of kidney fibrosis

    Mason, Roger M

    2013-01-01

    Connective tissue growth factor (CTGF, CCN2) is a member of the CCN family of matricellular proteins. It interacts with many other proteins, including plasma membrane proteins, modulating cell function. It is expressed at low levels in normal adult kidney cells but is increased in kidney diseases, playing important roles in inflammation and in the development of glomerular and interstitial fibrosis in chronic disease. This review reports the evidence for its expression in human and animal models of chronic kidney disease and summarizes data showing that anti-CTGF therapy can successfully attenuate fibrotic changes in several such models, suggesting that therapies targeting CTGF and events downstream of it in renal cells may be useful for the treatment of human kidney fibrosis. Connective tissue growth factor stimulates the development of fibrosis in the kidney in many ways including activating cells to increase extracellular matrix synthesis, inducing cell cycle arrest and hypertrophy, and prolonging survival of activated cells. The relationship between CTGF and the pro-fibrotic factor TGFβ is examined and mechanisms by which CTGF promotes signalling by the latter are discussed. No specific cellular receptors for CTGF have been discovered but it interacts with and activates several plasma membrane proteins including low-density lipoprotein receptor-related protein (LRP)-1, LRP-6, tropomyosin-related kinase A, integrins and heparan sulphate proteoglycans. Intracellular signalling and downstream events triggered by such interactions are reviewed. Finally, the relationships between CTGF and several anti-fibrotic factors, such as bone morphogenetic factor-4 (BMP4), BMP7, hepatocyte growth factor, CCN3 and Oncostatin M, are discussed. These may determine whether injured tissue heals or progresses to fibrosis. PMID:23110747

  1. Engineered Biomaterials to Enhance Stem Cell-Based Cardiac Tissue Engineering and Therapy.

    Hasan, Anwarul; Waters, Renae; Roula, Boustany; Dana, Rahbani; Yara, Seif; Alexandre, Toubia; Paul, Arghya

    2016-07-01

    Cardiovascular disease is a leading cause of death worldwide. Since adult cardiac cells are limited in their proliferation, cardiac tissue with dead or damaged cardiac cells downstream of the occluded vessel does not regenerate after myocardial infarction. The cardiac tissue is then replaced with nonfunctional fibrotic scar tissue rather than new cardiac cells, which leaves the heart weak. The limited proliferation ability of host cardiac cells has motivated investigators to research the potential cardiac regenerative ability of stem cells. Considerable progress has been made in this endeavor. However, the optimum type of stem cells along with the most suitable matrix-material and cellular microenvironmental cues are yet to be identified or agreed upon. This review presents an overview of various types of biofunctional materials and biomaterial matrices, which in combination with stem cells, have shown promises for cardiac tissue replacement and reinforcement. Engineered biomaterials also have applications in cardiac tissue engineering, in which tissue constructs are developed in vitro by combining stem cells and biomaterial scaffolds for drug screening or eventual implantation. This review highlights the benefits of using biomaterials in conjunction with stem cells to repair damaged myocardium and give a brief description of the properties of these biomaterials that make them such valuable tools to the field. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Epithelial-Mesenchymal Transition in Tissue Repair and Fibrosis

    Stone, Rivka C.; Pastar, Irena; Ojeh, Nkemcho; Chen, Vivien; Liu, Sophia; Garzon, Karen I.; Tomic-Canic, Marjana

    2016-01-01

    Epithelial-mesenchymal transition (EMT) describes the global process by which stationary epithelial cells undergo phenotypic changes, including loss of cell-cell adhesion and apical-basal polarity, and acquire mesenchymal characteristics which confer migratory capacity. EMT and its converse, MET (mesenchymal-to-epithelial transition), are integral stages of many physiologic processes, and as such are tightly coordinated by a host of molecular regulators. Converging lines of evidence have identified EMT as a component of cutaneous wound healing, during which otherwise stationary keratinocytes - the resident skin epithelial cells - migrate across the wound bed to restore the epidermal barrier. Moreover, EMT also plays a role in the development of scarring and fibrosis, as the matrix-producing myofibroblast arises from cells of epithelial lineage in response to injury but is pathologically sustained instead of undergoing MET or apoptosis. In this review, we summarize the role of EMT in physiologic repair and pathologic fibrosis of tissues and organs. We conclude that further investigation into the contribution of EMT to the impaired repair of fibrotic wounds may identify components of EMT signaling as common therapeutic targets for impaired healing in many tissues. PMID:27461257

  3. Mixed Connective Tissue Disease

    Mixed connective tissue disease Overview Mixed connective tissue disease has signs and symptoms of a combination of disorders — primarily lupus, scleroderma and polymyositis. For this reason, mixed connective tissue disease ...

  4. Undifferentiated Connective Tissue Disease

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... by Barbara Goldstein, MD (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  5. Soft Tissue Sarcoma

    ... muscles, tendons, fat, and blood vessels. Soft tissue sarcoma is a cancer of these soft tissues. There ... have certain genetic diseases. Doctors diagnose soft tissue sarcomas with a biopsy. Treatments include surgery to remove ...

  6. Cancerous tissue mapping from random lasing emission spectra

    Polson, R C; Vardeny, Z V

    2010-01-01

    Random lasing emission spectra have been collected from both healthy and cancerous tissues. The two types of tissue with optical gain have different light scattering properties as obtained from an average power Fourier transform of their random lasing emission spectra. The difference in the power Fourier transform leads to a contrast between cancerous and benign tissues, which is utilized for tissue mapping of healthy and cancerous regions of patients

  7. Arming drug carriers to disable the Hepatic Stellate Cell : the targeted delivery of apoptosis-inducing drugs to the fibrotic liver

    Hagens, Werner Ivo

    2006-01-01

    Chronic liver damage of various origins (e.g. viral hepatitis; chronic intoxication by alcohol, chemicals or drugs; Wilson’s disease) can eventually lead to liver cirrhosis, the end stage of liver fibrosis. This process is characterized by the accumulation of excessive amounts of scar tissue within

  8. Biomarkers in Scleroderma: Progressing from Association to Clinical Utility.

    Ligon, Colin; Hummers, Laura K

    2016-03-01

    Scleroderma is a heterogenous disease characterized by autoimmunity, a characteristic vasculopathy, and often widely varying extents of deep organ fibrosis. Recent advances in the understanding of scleroderma's evolution have improved the ability to identify subgroups of patients with similar prognosis in order to improve risk stratification, enrich clinical trials for patients likely to benefit from specific therapies, and identify promising therapeutic targets for intervention. High-throughput technologies have recently identified fibrotic and inflammatory effectors in scleroderma that exhibit strong prognostic ability and may be tied to disease evolution. Increasingly, the use of collections of assayed circulating proteins and patterns of gene expression in tissue has replaced single-marker investigations in understanding the evolution of scleroderma and in objectively characterizing disease extent. Lastly, identification of shared patterns of disease evolution has allowed classification of patients into latent disease subtypes, which may allow rapid clinical prognostication and targeted management in both clinical and research settings. The concept of biomarkers in scleroderma is expanding to include nontraditional measures of aggregate protein signatures and disease evolution. This review examines the recent advances in biomarkers with a focus on those approaches poised to guide prospective management or themselves serve as quantitative surrogate disease outcomes.

  9. Expanded polytetrafluoroethylene membrane alters tissue response to implanted Ahmed glaucoma valve.

    DeCroos, Francis Char; Ahmad, Sameer; Kondo, Yuji; Chow, Jessica; Mordes, Daniel; Lee, Maria Regina; Asrani, Sanjay; Allingham, R Rand; Olbrich, Kevin C; Klitzman, Bruce

    2009-07-01

    Long-term intraocular pressure control by glaucoma drainage implants is compromised by the formation of an avascular fibrous capsule that surrounds the glaucoma implant and increases aqueous outflow resistance. It is possible to alter this fibrotic tissue reaction and produce a more vascularized and potentially more permeable capsule around implanted devices by enclosing them in a porous membrane. Ahmed glaucoma implants modified with an outer 5-microm pore size membrane (termed porous retrofitted implant with modified enclosure or PRIME-Ahmed) and unmodified glaucoma implants were implanted into paired rabbit eyes. After 6 weeks, the devices were explanted and subject to histological analysis. A tissue response containing minimal vascularization, negligible immune response, and a thick fibrous capsule surrounded the unmodified Ahmed glaucoma implant. In comparison, the tissue response around the PRIME-Ahmed demonstrated a thinner fibrous capsule (46.4 +/- 10.8 microm for PRIME-Ahmed versus 94.9 +/- 21.2 microm for control, p vascularized near the tissue-material interface. A prominent chronic inflammatory response was noted as well. Encapsulating the aqueous outflow pathway with a porous membrane produces a more vascular tissue response and thinner fibrous capsule compared with a standard glaucoma implant plate. Enhanced vascularity and a thinner fibrous capsule may reduce aqueous outflow resistance and improve long-term glaucoma implant performance.

  10. Modeling the Human Scarred Heart In Vitro: Toward New Tissue Engineered Models.

    Deddens, Janine C; Sadeghi, Amir Hossein; Hjortnaes, Jesper; van Laake, Linda W; Buijsrogge, Marc; Doevendans, Pieter A; Khademhosseini, Ali; Sluijter, Joost P G

    2017-02-01

    Cardiac remodeling is critical for effective tissue healing, however, excessive production and deposition of extracellular matrix components contribute to scarring and failing of the heart. Despite the fact that novel therapies have emerged, there are still no lifelong solutions for this problem. An urgent need exists to improve the understanding of adverse cardiac remodeling in order to develop new therapeutic interventions that will prevent, reverse, or regenerate the fibrotic changes in the failing heart. With recent advances in both disease biology and cardiac tissue engineering, the translation of fundamental laboratory research toward the treatment of chronic heart failure patients becomes a more realistic option. Here, the current understanding of cardiac fibrosis and the great potential of tissue engineering are presented. Approaches using hydrogel-based tissue engineered heart constructs are discussed to contemplate key challenges for modeling tissue engineered cardiac fibrosis and to provide a future outlook for preclinical and clinical applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Entrez Programming Utilities

    U.S. Department of Health & Human Services — The Entrez Programming Utilities (E-utilities) are a set of eight server-side programs that provide a stable interface into the Entrez query and database system at...

  12. Preoperative chemotherapy of bone and soft tissue sarcomas. Evaluation with dynamic MR imaging

    Ando, Yoko; Fukatsu, Hiroshi; Isomura, Takayuki; Itoh, Shigeki; Ishigaki, Takeo; Yamamura, Shigeki; Sugiura, Hideshi; Satoh, Keiji.

    1995-01-01

    Dynamic MR imaging and conventional angiography were performed in eleven patients with musculoskeletal malignant tumors before and after preoperative chemotherapy in order to evaluate its effect. Dynamic MRI was obtained with GRASS (TR/TE/FA=50/10-13/30) or SE (TR/TE=150-350/20). Although resected specimen in one case of osteosarcoma had the necrotic ratio of more than 90%, it had marked early enhancement in dynamic MRI, and microscopic examination revealed fibrotic necrosis with many capillaries. In soft tissue sarcomas with hemorrhage and/or cystic change, dynamic MRI findings did not necessarily correlate with the chemotherapy effect. Dynamic MRI was more useful than angiography because of its ability to show tumor vascularity and of its non-invasiveness. (author)

  13. Curcumin inhibits TGF-β1-induced connective tissue growth factor expression through the interruption of Smad2 signaling in human gingival fibroblasts.

    Chen, Jung-Tsu; Wang, Chen-Ying; Chen, Min-Huey

    2018-01-13

    Many fibrotic processes are associated with an increased level of transforming growth factor-β1 (TGF-β1). TGF-β1 can increase synthesis of matrix proteins and enhance secretion of protease inhibitors, resulting in matrix accumulation. Connective tissue growth factor (CTGF) is a downstream profibrotic effector of TGF-β1 and is associated with the fibrosis in several human organs. Curcumin has been applied to reduce matrix accumulation in fibrotic diseases. This study was aimed to evaluate whether curcumin could suppress TGF-β1-induced CTGF expression and its related signaling pathway involving in this inhibitory action in primary human gingival fibroblasts. The differences in CTGF expression among three types of gingival overgrowth and normal gingival tissues were assessed by immunohistochemistry. Gingival fibroblast viability in cultured media with different concentrations of curcumin was studied by MTT assay. The effect of curcumin on TGF-β1-induced CTGF expression in primary human gingival fibroblasts was examined by immunoblotting. Moreover, the proteins involved in TGF-β1 signaling pathways including TGF-β1 receptors and Smad2 were also analyzed by immunoblotting. CTGF was highly expressed in fibroblasts, epithelial cells and some of endothelial cells, smooth muscle cells, and inflammatory cells in phenytoin-induced gingival overgrowth tissues rather than in those of hereditary and inflammatory gingival overgrowth tissues. Moreover, CTGF expression in the epithelial and connective tissue layers was higher in phenytoin-induced gingival overgrowth tissues than in normal gingival tissues. Curcumin was nontoxic and could reduce TGF-β1-induced CTGF expression by attenuating the phosphorylation and nuclear translocation of Smad2. Curcumin can suppress TGF-β1-induced CTGF expression through the interruption of Smad2 signaling. Copyright © 2018. Published by Elsevier B.V.

  14. Cell-based and biomaterial approaches to connective tissue repair

    Stalling, Simone Suzette

    Connective tissue injuries of skin, tendon and ligament, heal by a reparative process in adults, filling the wound site with fibrotic, disorganized scar tissue that poorly reflects normal tissue architecture or function. Conversely, fetal skin and tendon have been shown to heal scarlessly. Complete regeneration is not intrinsically ubiquitous to all fetal tissues; fetal diaphragmatic and gastrointestinal injuries form scars. In vivo studies suggest that the presence of fetal fibroblasts is essential for scarless healing. In the orthopaedic setting, adult anterior cruciate ligament (ACL) heals poorly; however, little is known about the regenerative capacity of fetal ACL or fetal ACL fibroblasts. We characterized in vitro wound healing properties of fetal and adult ACL fibroblasts demonstrating that fetal ACL fibroblasts migrate faster and elaborate greater quantities of type I collagen, suggesting the healing potential of the fetal ACL may not be intrinsically poor. Similar to fetal ACL fibroblasts, fetal dermal fibroblasts also exhibit robust cellular properties. We investigated the age-dependent effects of dermal fibroblasts on tendon-to-bone healing in rat supraspinatus tendon injuries, a reparative injury model. We hypothesized delivery of fetal dermal fibroblasts would increase tissue organization and mechanical properties in comparison to adult dermal fibroblasts. However, at 1 and 8 weeks, the presence of dermal fibroblasts, either adult or fetal, had no significant effect on tissue histology or mechanical properties. There was a decreasing trend in cross-sectional area of repaired tendons treated with fetal dermal fibroblasts in comparison to adult, but this finding was not significant in comparison to controls. Finally, we synthesized a novel polysaccharide, methacrylated methylcellulose (MA-MC), and fabricated hydrogels using a well-established photopolymerization technique. We characterized the physical and mechanical properties of MA-MC hydrogels in

  15. Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis.

    Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin; St Croix, Brad; Bonventre, Joseph V; Olsen, Bjorn R

    2015-03-01

    It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2. Copyright © 2014 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  16. Plant Tissue Culture

    Admin

    Plant tissue culture is a technique of culturing plant cells, tissues and organs on ... working methods (Box 2) and discovery of the need for B vita- mins and auxins for ... Kotte (Germany) reported some success with growing isolated root tips.

  17. Breast reconstruction - natural tissue

    ... flap; TRAM; Latissimus muscle flap with a breast implant; DIEP flap; DIEAP flap; Gluteal free flap; Transverse upper gracilis flap; TUG; Mastectomy - breast reconstruction with natural tissue; Breast cancer - breast reconstruction with natural tissue

  18. FRD tissue archive

    National Oceanic and Atmospheric Administration, Department of Commerce — The fishery genetics tissue collection has over 80,000 tissues stored in 95% ethanol representing fishes and invertebrates collected globally but with a focus on the...

  19. Tissue banking in australia.

    Ireland, Lynette; McKelvie, Helen

    2003-01-01

    The legal structure for the regulation of tissue banking has existed for many years. In Australia, the donation of human tissue is regulated by legislation in each of the eight States and Territories. These substantially uniform Acts were passed in the late 1970's and early 1980's, based on model legislation and underpinned by the concept of consensual giving. However, it was not until the early 1990's that tissue banking came under the notice of regulatory authorities. Since then the Australian Government has moved quickly to oversee the tissue banking sector in Australia. Banked human tissue has been deemed to be a therapeutic good under the Therapeutic Goods Act 1989, and tissue banks are required to be licensed by the Therapeutic Goods Administration and are audited for compliance with the Code of Good Manufacturing Practice- Human Blood and Tissues. In addition, tissue banks must comply with a myriad of other standards, guidelines and recommendations.

  20. Breast Cancer Tissue Repository

    Iglehart, J

    1997-01-01

    The Breast Tissue Repository at Duke enters its fourth year of finding. The purpose of the Repository at Duke is to provide substantial quantities of frozen tissue for explorative molecular studies...

  1. Automated ISS Flight Utilities

    Offermann, Jan Tuzlic

    2016-01-01

    EVADES output. As mentioned above, GEnEVADOSE makes extensive use of ROOT version 6, the data analysis framework developed at the European Organization for Nuclear Research (CERN), and the code is written to the C++11 standard (as are the other projects). My second project is the Automated Mission Reference Exposure Utility (AMREU).Unlike GEnEVADOSE, AMREU is a combination of three frameworks written in both Python and C++, also making use of ROOT (and PyROOT). Run as a combination of daily and weekly cron jobs, these macros query the SRAG database system to determine the active ISS missions, and query minute-by-minute radiation dose information from ISS-TEPC (Tissue Equivalent Proportional Counter), one of the radiation detectors onboard the ISS. Using this information, AMREU creates a corrected data set of daily radiation doses, addressing situations where TEPC may be offline or locked up by correcting doses for days with less than 95% live time (the total amount time the instrument acquires data) by averaging the past 7 days. As not all errors may be automatically detectable, AMREU also allows for manual corrections, checking an updated plaintext file each time it runs. With the corrected data, AMREU generates cumulative dose plots for each mission, and uses a Python script to generate a flight note file (.docx format) containing these plots, as well as information sections to be filled in and modified by the space weather environment officers with information specific to the week. AMREU is set up to run without requiring any user input, and it automatically archives old flight notes and information files for missions that are no longer active. My other projects involve cleaning up a large data set from the Charged Particle Directional Spectrometer (CPDS), joining together many different data sets in order to clean up information in SRAG SQL databases, and developing other automated utilities for displaying information on active solar regions, that may be used by the

  2. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.

    Molofsky, Ari B; Savage, Adam K; Locksley, Richard M

    2015-06-16

    Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells, and CD8(+) T cells. Here, we highlight the regulation and function of IL-33 and ST2 and review their roles in homeostasis, damage, and inflammation, suggesting a conceptual framework for future studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Long-term follow-up of bronchus-associated lymphoid tissue lymphomas (BALTOMA)

    Gaffke, G.; Jost, D.; Stroszcynski, C.; Puls, R.; Schlecht, I.; Felix, R.; Ludwig, W.D.; Hosten, N.

    2002-01-01

    Purpose: The purpose of this work was to describe the findings and the long term follow up of pathologically confirmed bronchus-associated lymphoid tissue lymphoma (BALTOMA) in 6 patients. Methods: CT examinations and conventional radiological examinations were reviewed and compared to describe typical radiological findings and patterns of pulmonary manifestations. It were described the number of lesions and characteristics like presence of airspace consolidation, ground-glass attenuation, bubble-like radio-lucencies, air bronchogram, bronchial dilatation, Infiltration and the long term behaviour of the manifestations. Results: Lesions with a positive air bronchogram, no infiltration of extrapulmonary tissue or extrapulmonary manifestations were revealed as typical findings. Only a slow or no progression of disease was shown in most patients over a term of up to twelve years. Conclusions: The lymphoma of the bronchus-associated lymphoid tissue of the lung is a rare tumor. A positive air bronchogram, a multiplicity of disease, bilateral lesions, a fibrotic transformation of the lung tissue and no growth or only a slow groth over al long term of observation are typical radiological findings. (orig.) [de

  4. Development of tissue bank

    R P Narayan

    2012-01-01

    Full Text Available The history of tissue banking is as old as the use of skin grafting for resurfacing of burn wounds. Beneficial effects of tissue grafts led to wide spread use of auto and allograft for management of varied clinical conditions like skin wounds, bone defects following trauma or tumor ablation. Availability of adequate amount of tissues at the time of requirement was the biggest challenge that forced clinicians to find out techniques to preserve the living tissue for prolonged period of time for later use and thus the foundation of tissue banking was started in early twentieth century. Harvesting, processing, storage and transportation of human tissues for clinical use is the major activity of tissue banks. Low temperature storage of processed tissue is the best preservation technique at present. Tissue banking organization is a very complex system and needs high technical expertise and skilled personnel for proper functioning in a dedicated facility. A small lapse/deviation from the established protocol leads to loss of precious tissues and or harm to recipients as well as the risk of transmission of deadly diseases and tumors. Strict tissue transplant acts and stringent regulations help to streamline the whole process of tissue banking safe for recipients and to community as whole.

  5. Connective Tissue Disorders

    ... of connective tissue. Over 200 disorders that impact connective tissue. There are different types: Genetic disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta Autoimmune disorders, such as lupus and scleroderma Cancers, like some types of soft tissue sarcoma Each ...

  6. Tanshinon IIA injection accelerates tissue expansion by reducing the formation of the fibrous capsule.

    Yu, Qingxiong; Sheng, Lingling; Yang, Mei; Zhu, Ming; Huang, Xiaolu; Li, Qingfeng

    2014-01-01

    The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR), which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA) has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and transforming growth factor-β (TGF-β) were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.

  7. Tanshinon IIA injection accelerates tissue expansion by reducing the formation of the fibrous capsule.

    Qingxiong Yu

    Full Text Available The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR, which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6 and interleukin-1β (IL-1β and transforming growth factor-β (TGF-β were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.

  8. The role of cyclosporine A on the periodontal tissues

    Mallappa Jayasheela

    2013-01-01

    Conclusion: CsA targets the periodontal tissues (gingiva, alveolar bone and cementum in different pattern. Its role in cementogenesis can be utilized for periodontal regeneration, if its local application is testified and verified in the future animal studies.

  9. US utility partnerships

    Worthington, B.

    1995-01-01

    Activities of the United States Energy Association were reviewed, as well as the manner in which its members are benefitting from the Association's programs. The principal cooperative program set up is the Utility Partnership Program, which was described. Through this program the Association is matching US companies, both electric utilities and gas utilities, with counterparts in Eastern Europe or the former Soviet Union. So far, about 25 partnerships were signed, e.g. in the Czech Republic, in Kazakhstan, in Poland, and in Slovakia. It was estimated that the return to the United States from the investments made by the American government in these Utility Partnership Programs has been well over 100-fold

  10. Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses.

    Morris, Aaron H; Mahal, Rajwant S; Udell, Jillian; Wu, Michelle; Kyriakides, Themis R

    2017-10-01

    Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Cell and Tissue Engineering

    2012-01-01

    “Cell and Tissue Engineering” introduces the principles and new approaches in cell and tissue engineering. It includes both the fundamentals and the current trends in cell and tissue engineering, in a way useful both to a novice and an expert in the field. The book is composed of 13 chapters all of which are written by the leading experts. It is organized to gradually assemble an insight in cell and tissue function starting form a molecular nano-level, extending to a cellular micro-level and finishing at the tissue macro-level. In specific, biological, physiological, biophysical, biochemical, medical, and engineering aspects are covered from the standpoint of the development of functional substitutes of biological tissues for potential clinical use. Topics in the area of cell engineering include cell membrane biophysics, structure and function of the cytoskeleton, cell-extracellular matrix interactions, and mechanotransduction. In the area of tissue engineering the focus is on the in vitro cultivation of ...

  12. X-rays utilization

    Rebigan, F.

    1979-03-01

    The modality of X-ray utilization in different activities and economy is given. One presents firstly quantities and units used in radiation dosimetry and other fields. One gives the generation of X-rays, their properties as well as the elements of radiation protection. The utilization characteristics of these radiations in different fields are finally given. (author)

  13. The role of mechanical loading in ligament tissue engineering.

    Benhardt, Hugh A; Cosgriff-Hernandez, Elizabeth M

    2009-12-01

    Tissue-engineered ligaments have received growing interest as a promising alternative for ligament reconstruction when traditional transplants are unavailable or fail. Mechanical stimulation was recently identified as a critical component in engineering load-bearing tissues. It is well established that living tissue responds to altered loads through endogenous changes in cellular behavior, tissue organization, and bulk mechanical properties. Without the appropriate biomechanical cues, new tissue formation lacks the necessary collagenous organization and alignment for sufficient load-bearing capacity. Therefore, tissue engineers utilize mechanical conditioning to guide tissue remodeling and improve the performance of ligament grafts. This review provides a comparative analysis of the response of ligament and tendon fibroblasts to mechanical loading in current bioreactor studies. The differential effect of mechanical stimulation on cellular processes such as protease production, matrix protein synthesis, and cell proliferation is examined in the context of tissue engineering design.

  14. Imaging the hard/soft tissue interface.

    Bannerman, Alistair; Paxton, Jennifer Z; Grover, Liam M

    2014-03-01

    Interfaces between different tissues play an essential role in the biomechanics of native tissues and their recapitulation is now recognized as critical to function. As a consequence, imaging the hard/soft tissue interface has become increasingly important in the area of tissue engineering. Particularly as several biotechnology based products have made it onto the market or are close to human trials and an understanding of their function and development is essential. A range of imaging modalities have been developed that allow a wealth of information on the morphological and physical properties of samples to be obtained non-destructively in vivo or via destructive means. This review summarizes the use of a selection of imaging modalities on interfaces to date considering the strengths and weaknesses of each. We will also consider techniques which have not yet been utilized to their full potential or are likely to play a role in future work in the area.

  15. Engineering Musculoskeletal Tissue Interfaces

    Ece Bayrak

    2018-04-01

    Full Text Available Tissue engineering aims to bring together biomaterials, cells, and signaling molecules within properly designed microenvironments in order to create viable treatment options for the lost or malfunctioning tissues. Design and production of scaffolds and cell-laden grafts that mimic the complex structural and functional features of tissues are among the most important elements of tissue engineering strategy. Although all tissues have their own complex structure, an even more complex case in terms of engineering a proper carrier material is encountered at the tissue interfaces, where two distinct tissues come together. The interfaces in the body can be examined in four categories; cartilage-bone and ligament-bone interfaces at the knee and the spine, tendon-bone interfaces at the shoulder and the feet, and muscle-tendon interface at the skeletal system. These interfaces are seen mainly at the soft-to-hard tissue transitions and they are especially susceptible to injury and tear due to the biomechanical inconsistency between these tissues where high strain fields are present. Therefore, engineering the musculoskeletal tissue interfaces remain a challenge. This review focuses on recent advancements in strategies for musculoskeletal interface engineering using different biomaterial-based platforms and surface modification techniques.

  16. THE ANTI-FIBROTIC ACTIONS OF RELAXIN ARE MEDIATED THROUGH A NO-sGC-cGMP-DEPENDENT PATHWAY IN RENAL MYOFIBROBLASTS IN VITRO AND ENHANCED BY THE NO DONOR, DIETHYLAMINE NONOATE

    Chao eWang

    2016-03-01

    Full Text Available INTRODUCTION: The anti-fibrotic hormone, relaxin, has been inferred to disrupt TGF-beta1/Smad2 phosphorylation (pSmad2 signal transduction and promote collagen-degrading gelatinase activity via a nitric oxide (NO-dependent pathway. Here, we determined the extent to which NO, soluble guanylate cyclase (sGC and cyclic guanosine monophosphate (cGMP were directly involved in the anti-fibrotic actions of relaxin using a selective NO scavenger and sGC inhibitor, and comparing and combining relaxin’s effects with that of an NO donor. METHODS AND RESULTS: Primary renal cortical myofibroblasts isolated from injured rat kidneys were treated with human recombinant relaxin (RLX; 16.8nM, the NO donor, diethylamine NONOate (DEA/NO; 0.5-5uM or the combined effects of RLX (16.8nM and DEA/NO (5uM over 72 hours. The effects of RLX (16.8nM and DEA/NO (5uM were also evaluated in the presence of the NO scavenger, hydroxocobalamin (HXC; 100uM or sGC inhibitor, ODQ (5uM over 72 hours. Furthermore, the effects of RLX (30nM, DEA/NO (5uM and RLX (30nM+DEA/NO (5uM on cGMP levels were directly measured, in the presence or absence of ODQ (5uM. Changes in matrix metalloproteinase (MMP-2, MMP-9 (cell media, pSmad2 and α-smooth muscle actin (α-SMA; a measure myofibroblast differentiation (cell layer were assessed by gelatin zymography and Western blotting, respectively. At the highest concentration tested, both RLX and DEA/NO promoted MMP-2 and MMP-9 levels by 25-33%, while inhibiting pSmad2 and α-SMA expression by up to 50% (all p<0.05 vs untreated and vehicle-treated cells. However, 5uM of DEA/NO was required to produce the effects seen with 16.8nM of RLX over 72 hours. The anti-fibrotic effects of RLX or DEA/NO alone were completely abrogated by HXC and ODQ (both p<0.01 vs RLX alone or DEA/NO alone, but were significantly enhanced when added in combination (all p<0.05 vs RLX alone. Additionally, the direct cGMP-promoting effects of RLX, DEA/NO and RLX+DEA/NO (which all

  17. Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III.

    Blok, J L; Spoo, J R; Leeman, F W J; Jonkman, M F; Horváth, B

    2015-02-01

    Surgery is the only curative treatment for removal of the persistent sinus tracts in the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of the affected tissue by wide excision is currently regarded as the preferred surgical technique in these cases. However, relatively large amounts of healthy tissue are removed with this method and suitable skin-tissue-saving techniques aiming at creating less-extensive surgical defects are therefore needed in severe HS. We describe a skin-tissue-saving surgical technique for HS Hurley stage II-III disease: the Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure. In contrast to wide excisions that generally reach into the deep subcutaneous fat, the fat is maximally spared with the STEEP procedure by performing successive tangential excisions of lesional tissue until the epithelialized bottom of the sinus tracts has been reached. From here, secondary intention healing can occur. In addition, fibrotic tissue is completely removed in the same manner as this also serves as a source of recurrence. This tissue-sparing technique results in low recurrence rates, high patient satisfaction with relatively short healing times and favourable cosmetic outcomes without contractures. © 2014 European Academy of Dermatology and Venereology.

  18. DNA from keratinous tissue

    Bengtsson, Camilla F.; Olsen, Maja E.; Brandt, Luise Ørsted

    2011-01-01

    Keratinous tissues such as nail, hair, horn, scales and feather have been used as a source of DNA for over 20 years. Particular benefits of such tissues include the ease with which they can be sampled, the relative stability of DNA in such tissues once sampled, and, in the context of ancient...... genetic analyses, the fact that sampling generally causes minimal visual damage to valuable specimens. Even when freshly sampled, however, the DNA quantity and quality in the fully keratinized parts of such tissues is extremely poor in comparison to other tissues such as blood and muscle – although little...... systematic research has been undertaken to characterize how such degradation may relate to sample source. In this review paper we present the current understanding of the quality and limitations of DNA in two key keratinous tissues, nail and hair. The findings indicate that although some fragments of nuclear...

  19. Utility portfolio diversification

    Griffes, P.H.

    1990-01-01

    This paper discusses portfolio analysis as a method to evaluate utility supply decisions. Specifically a utility is assumed to increase the value of its portfolio of assets whenever it invests in a new supply technology. This increase in value occurs because the new asset either enhances the return or diversifies the risks of the firm's portfolio of assets. This evaluation method is applied to two supply innovations in the electric utility industry: jointly-owned generating plants and supply contracts with independent power producers (IPPs)

  20. Assessment of tissue viability by polarization spectroscopy

    Nilsson, G.; Anderson, C.; Henricson, J.; Leahy, M.; O'Doherty, J.; Sjöberg, F.

    2008-09-01

    A new and versatile method for tissue viability imaging based on polarization spectroscopy of blood in superficial tissue structures such as the skin is presented in this paper. Linearly polarized light in the visible wavelength region is partly reflected directly by the skin surface and partly diffusely backscattered from the dermal tissue matrix. Most of the directly reflected light preserves its polarization state while the light returning from the deeper tissue layers is depolarized. By the use of a polarization filter positioned in front of a sensitive CCD-array, the light directly reflected from the tissue surface is blocked, while the depolarized light returning from the deeper tissue layers reaches the detector array. By separating the colour planes of the detected image, spectroscopic information about the amount of red blood cells (RBCs) in the microvascular network of the tissue under investigation can be derived. A theory that utilizes the differences in light absorption of RBCs and bloodless tissue in the red and green wavelength region forms the basis of an algorithm for displaying a colour coded map of the RBC distribution in a tissue. Using a fluid model, a linear relationship (cc. = 0.99) between RBC concentration and the output signal was demonstrated within the physiological range 0-4%. In-vivo evaluation using transepidermal application of acetylcholine by the way of iontophoresis displayed the heterogeneity pattern of the vasodilatation produced by the vasoactive agent. Applications of this novel technology are likely to be found in drug and skin care product development as well as in the assessment of skin irritation and tissue repair processes and even ultimately in a clinic case situation.

  1. Tissue engineering in dentistry.

    Abou Neel, Ensanya Ali; Chrzanowski, Wojciech; Salih, Vehid M; Kim, Hae-Won; Knowles, Jonathan C

    2014-08-01

    of this review is to inform practitioners with the most updated information on tissue engineering and its potential applications in dentistry. The authors used "PUBMED" to find relevant literature written in English and published from the beginning of tissue engineering until today. A combination of keywords was used as the search terms e.g., "tissue engineering", "approaches", "strategies" "dentistry", "dental stem cells", "dentino-pulp complex", "guided tissue regeneration", "whole tooth", "TMJ", "condyle", "salivary glands", and "oral mucosa". Abstracts and full text articles were used to identify causes of craniofacial tissue loss, different approaches for craniofacial reconstructions, how the tissue engineering emerges, different strategies of tissue engineering, biomaterials employed for this purpose, the major attempts to engineer different dental structures, finally challenges and future of tissue engineering in dentistry. Only those articles that dealt with the tissue engineering in dentistry were selected. There have been a recent surge in guided tissue engineering methods to manage periodontal diseases beyond the traditional approaches. However, the predictable reconstruction of the innate organisation and function of whole teeth as well as their periodontal structures remains challenging. Despite some limited progress and minor successes, there remain distinct and important challenges in the development of reproducible and clinically safe approaches for oral tissue repair and regeneration. Clearly, there is a convincing body of evidence which confirms the need for this type of treatment, and public health data worldwide indicates a more than adequate patient resource. The future of these therapies involving more biological approaches and the use of dental tissue stem cells is promising and advancing. Also there may be a significant interest of their application and wider potential to treat disorders beyond the craniofacial region. Considering the

  2. Biomaterials for Tissue Engineering

    Lee, Esther J.; Kasper, F. Kurtis; Mikos, Antonios G.

    2013-01-01

    Biomaterials serve as an integral component of tissue engineering. They are designed to provide architectural framework reminiscent of native extracellular matrix in order to encourage cell growth and eventual tissue regeneration. Bone and cartilage represent two distinct tissues with varying compositional and mechanical properties. Despite these differences, both meet at the osteochondral interface. This article presents an overview of current biomaterials employed in bone and cartilage applications, discusses some design considerations, and alludes to future prospects within this field of research. PMID:23820768

  3. Glutathione turnover in 14 rat tissues

    Potter, D.W.; Tran, T.

    1990-01-01

    GSH is a tripeptide found in all tissues and is important in maintaining cellular redox status. First-order rate constants for GSH turnover were determined for various tissues of Fischer male rats. Animals were administered [ 35 S]Cys by tail vein injection and GSH turnover was estimated by the decrease in GSH specific activity following incorporation of Cys, 1-102 hr after administration. Tissue nonprotein sulfhydryls (NPSH) were detected by Ellman's assay and compared with GSH and Cys concentrations determined by HPLC with electrochemical detection. [ 35 S]GSH was analyzed by HPLC equipped with a flow-through radioactivity detector. Although total GSH and Cys were usually slightly lower than NPSH concentrations for the tissues examined, both assay systems gave comparable results. An exception was the glandular stomach which had approximately 2-fold higher NPSH. Liver and kidney had rapid turnover rates with GSH half-lives between 2-5 hr, while heart and skeletal muscle tissue had half-lives of 80-90 hr. Turnover in the blood was slowest, with a half-life of 170 hr. Gastrointestinal tract tissues were shown to have intermediate turnover rates of the following order: glandular stomach > duodenum = small intestine = caecum = large intestine = colon > forestomach. GSH half-life in lung and skin was approximately 45 hr. These studies indicate that tissues utilize GSH at markedly different rates

  4. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins.

    Halper, Jaroslava; Kjaer, Michael

    2014-01-01

    -elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide a scaffold for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.

  5. MSIS Drug Utilization Datamart

    U.S. Department of Health & Human Services — This page provides background needed to take advantage of the capabilities of the MSIS Drug Utilization Datamart. This mart allows the user to develop high-level...

  6. Utility franchises reconsidered

    Weidner, B.

    1981-11-01

    It is easier to obtain a public utility franchise than one for a fast food store because companies like Burger King value the profit share and control available with a franchise arrangement. The investor-owned utilities (IOUs) in Chicago and elsewhere gets little financial or regulatory benefit, although they do have an alternative because the franchise can be taken over by the city with a one-year notice. As IOUs evolved, the annual franchise fee has been incorporated into the rate in a move that taxes ratepayers and maximizes profits. Cities that found franchising unsatisfactory are looking for ways to terminate the franchise and finance a takeover, but limited-term and indeterminate franchises may offer a better mechanism when public needs and utility aims diverge. A directory lists franchised utilities by state and comments on their legal status. (DCK)

  7. Chemical Search Web Utility

    U.S. Environmental Protection Agency — The Chemical Search Web Utility is an intuitive web application that allows the public to easily find the chemical that they are interested in using, and which...

  8. Utility requirements for HTGRs

    Nicholls, D.R.

    1997-01-01

    Eskom, the state utility of South Africa, is currently evaluating the technical and economic feasibility of the helium cooled Pebble Bed Modular Reactor with a closed cycle gas turbine power conversion system for future power generating additions to its electric system. This paper provides an overview of the Eskom system including the needs of the utility for future generation capacity and the key performance requirements necessary for incorporation of this gas cooled reactor plant. (author)

  9. Utility, games, and narratives

    Fioretti, Guido

    2009-01-01

    This paper provides a general overview of theories and tools to model individual and collective decision-making. In particular, stress is laid on the interaction of several decision-makers. A substantial part of this paper is devoted to utility maximization and its application to collective decision-making, Game Theory. However, the pitfalls of utility maximization are thoroughly discussed, and the radically alternative approach of viewing decision-making as constructing narratives is pre...

  10. Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions

    Monument, Michael J.; Hart, David A.; Salo, Paul T.; Befus, A. Dean; Hildebrand, Kevin A.

    2015-01-01

    Significance: The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. Recent Advances: As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell-myofibroblast signaling pathway. Critical Issues: The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Future Directions: Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies. PMID:25785237

  11. Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.

    Alves, Michele Joana; Figuerêdo, Raquel Galvão; Azevedo, Flavia Figueiredo; Cavallaro, Diego Alexandre; Neto, Nelson Inácio Pinto; Lima, Joanna Darck Carola; Matos-Neto, Emidio; Radloff, Katrin; Riccardi, Daniela Mendes; Camargo, Rodolfo Gonzalez; De Alcântara, Paulo Sérgio Martins; Otoch, José Pinhata; Junior, Miguel Luiz Batista; Seelaender, Marília

    2017-03-14

    Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients. After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay. There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas

  12. Utility requirements for fusion

    Vondrasek, R.J.

    1982-02-01

    This report describes work done and results obtained during performance of Task 1 of a study of Utility Requirements and Criteria for Fusion Options. The work consisted of developing a list of utility requirements for fusion optics containing definition of the requirements and showing their relative importance to the utility industry. The project team members developed a preliminary list which was refined by discussions and literature searches. The refined list was recast as a questionnaire which was sent to a substantial portion of the utility industry in this country. Forty-three questionnaire recipients responded including thirty-two utilities. A workshop was held to develop a revised requirements list using the survey responses as a major input. The list prepared by the workshop was further refined by a panel consisting of vice presidents of the three project team firms. The results of the study indicate that in addition to considering the cost of energy for a power plant, utilities consider twenty-three other requirements. Four of the requirements were judged to be vital to plant acceptability: Plant Capital Cost, Financial Liability, Plant Safety and Licensability

  13. Can tissues be owned?

    2013-06-17

    Jun 17, 2013 ... Regulations Regarding Rendering of Clinical Forensic Medicine ... 1 Special Interest Research Group on Biotechnology and Medical Law of the College of Law, University of ... persons for the following medical and dental purposes: ... tissue to the international market were taking tissue without consent.

  14. Neural tissue-spheres

    Andersen, Rikke K; Johansen, Mathias; Blaabjerg, Morten

    2007-01-01

    By combining new and established protocols we have developed a procedure for isolation and propagation of neural precursor cells from the forebrain subventricular zone (SVZ) of newborn rats. Small tissue blocks of the SVZ were dissected and propagated en bloc as free-floating neural tissue...... content, thus allowing experimental studies of neural precursor cells and their niche...

  15. Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

    Hyosang Kim

    2017-01-01

    Full Text Available Endoplasmic reticulum (ER stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1 hemeoxygenase-1 (HO-1/thioredoxin pathway. Renal tubular cells, tunicamycin (TM-induced ER stress, and unilateral ureteral obstruction (UUO mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78 and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α, through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor. Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

  16. Viscoelastic Properties of Human Tracheal Tissues.

    Safshekan, Farzaneh; Tafazzoli-Shadpour, Mohammad; Abdouss, Majid; Shadmehr, Mohammad B

    2017-01-01

    The physiological performance of trachea is highly dependent on its mechanical behavior, and therefore, the mechanical properties of its components. Mechanical characterization of trachea is key to succeed in new treatments such as tissue engineering, which requires the utilization of scaffolds which are mechanically compatible with the native human trachea. In this study, after isolating human trachea samples from brain-dead cases and proper storage, we assessed the viscoelastic properties of tracheal cartilage, smooth muscle, and connective tissue based on stress relaxation tests (at 5% and 10% strains for cartilage and 20%, 30%, and 40% for smooth muscle and connective tissue). After investigation of viscoelastic linearity, constitutive models including Prony series for linear viscoelasticity and quasi-linear viscoelastic, modified superposition, and Schapery models for nonlinear viscoelasticity were fitted to the experimental data to find the best model for each tissue. We also investigated the effect of age on the viscoelastic behavior of tracheal tissues. Based on the results, all three tissues exhibited a (nonsignificant) decrease in relaxation rate with increasing the strain, indicating viscoelastic nonlinearity which was most evident for cartilage and with the least effect for connective tissue. The three-term Prony model was selected for describing the linear viscoelasticity. Among different models, the modified superposition model was best able to capture the relaxation behavior of the three tracheal components. We observed a general (but not significant) stiffening of tracheal cartilage and connective tissue with aging. No change in the stress relaxation percentage with aging was observed. The results of this study may be useful in the design and fabrication of tracheal tissue engineering scaffolds.

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

    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.

  18. Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors

    Aakhus Svend

    2010-01-01

    Full Text Available Abstract Background Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2 is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease. Methods Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation. Results Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3. Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR. Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3. There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p Conclusions Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.

  19. Measurement of utility.

    Thavorncharoensap, Montarat

    2014-05-01

    The Quality Adjusted Life Year (QALY) is the most widely recommended health outcome measure for use in economic evaluations. The QALY gives a value to the effect of a given health intervention in terms of both quantity and quality. QALYs are calculated by multiplying the duration of time spent in a given health state, in years, by the quality of life weighted, known as utility. Utility can range from 0 (the worst health state-the equivalent of death) to 1 (the best health state-full health). This paper provides an overview of the various methods that can be used to measure utility and outlines the recommended protocol for measuring utility, as described in the Guidelines for Health Technology Assessment in Thailand (second edition). The recommendations are as follows: Wherever possible, primary data collection using EQ-5D-3L in patients using Thai value sets generated from the general public should be used. Where the EQ-5D-3L is considered inappropriate, other methods such as Standard gamble (SG), Time-trade-off (TTO), Visual analogue scale (VAS), Health Utilities Index (HUI), SF-6D, or Quality of well being (QWB) can be used. However, justification and full details on the chosen instrument should always be provided.

  20. Ontology-based, Tissue MicroArray oriented, image centered tissue bank

    Viti Federica

    2008-04-01

    Full Text Available Abstract Background Tissue MicroArray technique is becoming increasingly important in pathology for the validation of experimental data from transcriptomic analysis. This approach produces many images which need to be properly managed, if possible with an infrastructure able to support tissue sharing between institutes. Moreover, the available frameworks oriented to Tissue MicroArray provide good storage for clinical patient, sample treatment and block construction information, but their utility is limited by the lack of data integration with biomolecular information. Results In this work we propose a Tissue MicroArray web oriented system to support researchers in managing bio-samples and, through the use of ontologies, enables tissue sharing aimed at the design of Tissue MicroArray experiments and results evaluation. Indeed, our system provides ontological description both for pre-analysis tissue images and for post-process analysis image results, which is crucial for information exchange. Moreover, working on well-defined terms it is then possible to query web resources for literature articles to integrate both pathology and bioinformatics data. Conclusions Using this system, users associate an ontology-based description to each image uploaded into the database and also integrate results with the ontological description of biosequences identified in every tissue. Moreover, it is possible to integrate the ontological description provided by the user with a full compliant gene ontology definition, enabling statistical studies about correlation between the analyzed pathology and the most commonly related biological processes.

  1. Electric utility report '80

    Anon.

    1980-01-01

    A collection of brief atricles describes the trends and developments in Canada's electric utilities for the 1980's. Generating stations planned or under construction are listed. The trends in technology discused at a recent Canadian Electrical Association meeting are summarized in such areas as turbine stability control, power line vibration control, system reliability, substations and transformer specifications. Developments in nuclear generation are discussed and compared on the world scale where Japan, for example, has the world's largest nuclear program. Progress on fusion is discussed. In Canada the electric utilities are receiving the support of the comprehensive nuclear R and D program of Atomic Energy of Canada Ltd. New innovations in utility technology such as street lighting contactors, superconductive fault limiters and demand profile analyzers are discussed. (T.I.)

  2. Utility planning for decommissioning

    Williams, D.H.

    1982-01-01

    Though the biggest impact on a utility of nuclear power plant decommissioning may occur many years from now, procrastination of efforts to be prepared for that time is unwarranted. Foresight put into action through planning can significantly affect that impact. Financial planning can assure the recovery of decommissioning costs in a manner equitable to customers. Decision-making planning can minimize adverse affects of current decisions on later decommissioning impacts and prepare a utility to be equipped to make later decommissioning decisions. Technological knowledge base planning can support all other planning aspects for decommissioning and prepare a utility for decommissioning decisions. Informed project planning can ward off potentially significant pitfalls during decommissioning and optimize the effectiveness of the actual decommissioning efforts

  3. Markets: green utilities

    Wood, Elisa

    2006-01-01

    Publicly owned utilities have consistently led the United States in the rate of customer participation in green power programmes. The US has about 2000 community and state-owned utilities, which serve 43 million customers and account for about 16.6% of kilowatt-hour sales to consumers. In all, public power is responsible for about 10% of the nation's installed electric capacity. Investor owned utilities account for 39%, with the remainder of the nation's power mostly from independent power generators. Although IOUs have almost four times as much electric capacity as public power, they edge out public power by only a small margin when it comes to renewable capacity. IOUs are responsible for 24,577.5 MW of renewable capacity, compared to the 21,338 MW installed by public power. The reasons discussed by the author range from small town advantage to clean and cheap power. (Author)

  4. Traction force microscopy of engineered cardiac tissues.

    Pasqualini, Francesco Silvio; Agarwal, Ashutosh; O'Connor, Blakely Bussie; Liu, Qihan; Sheehy, Sean P; Parker, Kevin Kit

    2018-01-01

    Cardiac tissue development and pathology have been shown to depend sensitively on microenvironmental mechanical factors, such as extracellular matrix stiffness, in both in vivo and in vitro systems. We present a novel quantitative approach to assess cardiac structure and function by extending the classical traction force microscopy technique to tissue-level preparations. Using this system, we investigated the relationship between contractile proficiency and metabolism in neonate rat ventricular myocytes (NRVM) cultured on gels with stiffness mimicking soft immature (1 kPa), normal healthy (13 kPa), and stiff diseased (90 kPa) cardiac microenvironments. We found that tissues engineered on the softest gels generated the least amount of stress and had the smallest work output. Conversely, cardiomyocytes in tissues engineered on healthy- and disease-mimicking gels generated significantly higher stresses, with the maximal contractile work measured in NRVM engineered on gels of normal stiffness. Interestingly, although tissues on soft gels exhibited poor stress generation and work production, their basal metabolic respiration rate was significantly more elevated than in other groups, suggesting a highly ineffective coupling between energy production and contractile work output. Our novel platform can thus be utilized to quantitatively assess the mechanotransduction pathways that initiate tissue-level structural and functional remodeling in response to substrate stiffness.

  5. Octopus: LLL's computing utility

    Anon.

    1978-01-01

    The Laboratory's Octopus network constitutes one of the greatest concentrations of computing power in the world. This power derives from the network's organization as well as from the size and capability of its computers, storage media, input/output devices, and communication channels. Being in a network enables these facilities to work together to form a unified computing utility that is accessible on demand directly from the users' offices. This computing utility has made a major contribution to the pace of research and development at the Laboratory; an adequate rate of progress in research could not be achieved without it. 4 figures

  6. Nondestructive measurement of esophageal biaxial mechanical properties utilizing sonometry

    Aho, Johnathon M.; Qiang, Bo; Wigle, Dennis A.; Tschumperlin, Daniel J.; Urban, Matthew W.

    2016-07-01

    Malignant esophageal pathology typically requires resection of the esophagus and reconstruction to restore foregut continuity. Reconstruction options are limited and morbid. The esophagus represents a useful target for tissue engineering strategies based on relative simplicity in comparison to other organs. The ideal tissue engineered conduit would have sufficient and ideally matched mechanical tolerances to native esophageal tissue. Current methods for mechanical testing of esophageal tissues both in vivo and ex vivo are typically destructive, alter tissue conformation, ignore anisotropy, or are not able to be performed in fluid media. The aim of this study was to investigate biomechanical properties of swine esophageal tissues through nondestructive testing utilizing sonometry ex vivo. This method allows for biomechanical determination of tissue properties, particularly longitudinal and circumferential moduli and strain energy functions. The relative contribution of mucosal-submucosal layers and muscular layers are compared to composite esophagi. Swine thoracic esophageal tissues (n  =  15) were tested by pressure loading using a continuous pressure pump system to generate stress. Preconditioning of tissue was performed by pressure loading with the pump system and pre-straining the tissue to in vivo length before data was recorded. Sonometry using piezocrystals was utilized to determine longitudinal and circumferential strain on five composite esophagi. Similarly, five mucosa-submucosal and five muscular layers from thoracic esophagi were tested independently. This work on esophageal tissues is consistent with reported uniaxial and biaxial mechanical testing and reported results using strain energy theory and also provides high resolution displacements, preserves native architectural structure and allows assessment of biomechanical properties in fluid media. This method may be of use to characterize mechanical properties of tissue engineered esophageal

  7. Quantitative characterization of viscoelastic behavior in tissue-mimicking phantoms and ex vivo animal tissues.

    Ashkan Maccabi

    Full Text Available Viscoelasticity of soft tissue is often related to pathology, and therefore, has become an important diagnostic indicator in the clinical assessment of suspect tissue. Surgeons, particularly within head and neck subsites, typically use palpation techniques for intra-operative tumor detection. This detection method, however, is highly subjective and often fails to detect small or deep abnormalities. Vibroacoustography (VA and similar methods have previously been used to distinguish tissue with high-contrast, but a firm understanding of the main contrast mechanism has yet to be verified. The contributions of tissue mechanical properties in VA images have been difficult to verify given the limited literature on viscoelastic properties of various normal and diseased tissue. This paper aims to investigate viscoelasticity theory and present a detailed description of viscoelastic experimental results obtained in tissue-mimicking phantoms (TMPs and ex vivo tissues to verify the main contrast mechanism in VA and similar imaging modalities. A spherical-tip micro-indentation technique was employed with the Hertzian model to acquire absolute, quantitative, point measurements of the elastic modulus (E, long term shear modulus (η, and time constant (τ in homogeneous TMPs and ex vivo tissue in rat liver and porcine liver and gallbladder. Viscoelastic differences observed between porcine liver and gallbladder tissue suggest that imaging modalities which utilize the mechanical properties of tissue as a primary contrast mechanism can potentially be used to quantitatively differentiate between proximate organs in a clinical setting. These results may facilitate more accurate tissue modeling and add information not currently available to the field of systems characterization and biomedical research.

  8. Quantitative characterization of viscoelastic behavior in tissue-mimicking phantoms and ex vivo animal tissues.

    Maccabi, Ashkan; Shin, Andrew; Namiri, Nikan K; Bajwa, Neha; St John, Maie; Taylor, Zachary D; Grundfest, Warren; Saddik, George N

    2018-01-01

    Viscoelasticity of soft tissue is often related to pathology, and therefore, has become an important diagnostic indicator in the clinical assessment of suspect tissue. Surgeons, particularly within head and neck subsites, typically use palpation techniques for intra-operative tumor detection. This detection method, however, is highly subjective and often fails to detect small or deep abnormalities. Vibroacoustography (VA) and similar methods have previously been used to distinguish tissue with high-contrast, but a firm understanding of the main contrast mechanism has yet to be verified. The contributions of tissue mechanical properties in VA images have been difficult to verify given the limited literature on viscoelastic properties of various normal and diseased tissue. This paper aims to investigate viscoelasticity theory and present a detailed description of viscoelastic experimental results obtained in tissue-mimicking phantoms (TMPs) and ex vivo tissues to verify the main contrast mechanism in VA and similar imaging modalities. A spherical-tip micro-indentation technique was employed with the Hertzian model to acquire absolute, quantitative, point measurements of the elastic modulus (E), long term shear modulus (η), and time constant (τ) in homogeneous TMPs and ex vivo tissue in rat liver and porcine liver and gallbladder. Viscoelastic differences observed between porcine liver and gallbladder tissue suggest that imaging modalities which utilize the mechanical properties of tissue as a primary contrast mechanism can potentially be used to quantitatively differentiate between proximate organs in a clinical setting. These results may facilitate more accurate tissue modeling and add information not currently available to the field of systems characterization and biomedical research.

  9. Tissue banking and clinical research on radiation and ethylene oxide sterilization of tissue grafts

    Pe Khin

    1987-06-01

    The research works carried out in Rangoon, Burma under the Agency supported project RC4420/RB have dealt with an elucidation of the radiation interaction(s) with the species of biomolecules such as proteins, lipids, collagens, connective tissues present in the cleaned and freeze-dried non-viable tissue grafts. Radiation as a cool process furthermore effectively helps to destroy the microbial bioburden as the undesirable contaminants which may associate the tissue grafts. Radiation also concomitantly helps to suppress the tissue-specific immunogenicity. All these attributes of radiation induced effects have proved successful towards the development of a sterilization process. A series of non-viable tissue grafts, such as bone, nerve, fascia, dura, cartilage, chorion-amnion (as dressings in burn wounds) and tympanic membrane have been successfully attempted in Burma and many more possibilities seem to still remain unexplored. Radiation sterilization modality has proved as a blessing for the promotion of clinical surgical applications of tissue allografts in the corrective/reconstructive surgery on the disability cases due to diseases which accompany tissue losses. The investigator in Burma has reported on the case histories where freeze dried radiation sterilized tissue allografts have been successfully used in the osteogenic inductions (bone grafts); midear tympanoplasty; partial recovery of nerve sensation throught nerve allografts; rapid healing of high degree burn wounds through the use of amnion dressings. Besides, there have been a widespread surgical use of radiation sterilized dura and fascia as allografts. A national tissue banking facility has been established in Burma surrounding the processing and clinical utilization of tissue allografts which has involved over ten hospital centres throughout the country. Radiation induced effects on the biomolecules of clinical significance in the tissue grafts have been researched to help gain insight into a better

  10. Peptide-Based Materials for Cartilage Tissue Regeneration.

    Hastar, Nurcan; Arslan, Elif; Guler, Mustafa O; Tekinay, Ayse B

    2017-01-01

    Cartilaginous tissue requires structural and metabolic support after traumatic or chronic injuries because of its limited capacity for regeneration. However, current techniques for cartilage regeneration are either invasive or ineffective for long-term repair. Developing alternative approaches to regenerate cartilage tissue is needed. Therefore, versatile scaffolds formed by biomaterials are promising tools for cartilage regeneration. Bioactive scaffolds further enhance the utility in a broad range of applications including the treatment of major cartilage defects. This chapter provides an overview of cartilage tissue, tissue defects, and the methods used for regeneration, with emphasis on peptide scaffold materials that can be used to supplement or replace current medical treatment options.

  11. Dobutamine Stress Echocardiography and Tissue Synchronization Imaging

    Tas, Hakan; Gundogdu, Fuat; Gurlertop, Yekta; Karakelleoglu, Sule

    2008-01-01

    Dobutamine stress echocardiography has emerged as a reliable method for the diagnosis of coronary artery disease and the management of its treatment. Several studies have shown that that this technique works with 80–85% accuracy in comparison with other imaging methods. There are few studies aimed at developing the clinical utility of dobutamine stress echocardiography for the evaluation of normal and abnormal segments that result from dobutamine stress with Tissue Synchronization Imaging. PMID:25610034

  12. Activation of the connective tissue growth factor (CTGF-transforming growth factor β 1 (TGF-β 1 axis in hepatitis C virus-expressing hepatocytes.

    Tirumuru Nagaraja

    Full Text Available BACKGROUND: The pro-fibrogenic cytokine connective tissue growth factor (CTGF plays an important role in the development and progression of fibrosis in many organ systems, including liver. However, its role in the pathogenesis of hepatitis C virus (HCV-induced liver fibrosis remains unclear. METHODS: In the present study, we assessed CTGF expression in HCV-infected hepatocytes using replicon cells containing full-length HCV genotype 1 and the infectious HCV clone JFH1 (HCV genotype 2 by real-time PCR, Western blot analysis and confocal microscopy. We evaluated transforming growth factor β1 (TGF-β1 as a key upstream mediator of CTGF production using neutralizing antibodies and shRNAs. We also determined the signaling molecules involved in CTGF production using various immunological techniques. RESULTS: We demonstrated an enhanced expression of CTGF in two independent models of HCV infection. We also demonstrated that HCV induced CTGF expression in a TGF-β1-dependent manner. Further dissection of the molecular mechanisms revealed that CTGF production was mediated through sequential activation of MAPkinase and Smad-dependent pathways. Finally, to determine whether CTGF regulates fibrosis, we showed that shRNA-mediated knock-down of CTGF resulted in reduced expression of fibrotic markers in HCV replicon cells. CONCLUSION: Our studies demonstrate a central role for CTGF expression in HCV-induced liver fibrosis and highlight the potential value of developing CTGF-based anti-fibrotic therapies to counter HCV-induced liver damage.

  13. Electric utilities in Illinois

    1978-01-01

    Although the conference dealt specifically with concerns of the electric utilities in Illinois, the issues were dealt with in the national context as well. A separate abstract was prepared for each of the 5 sections of this proceeding. A total of 25 papers were presented. Section titles are: Forecasting, Planning and Siting, Reliability, Rates and Financing, and Future Developments.

  14. Male Adolescent Contraceptive Utilization.

    Finkel, Madelon Lubin; Finkel, David J.

    1978-01-01

    The contraceptive utilization of a sample of sexually active, urban, high school males (Black, Hispanic, and White) was examined by anonymous questionnaire. Contraceptive use was haphazard, but White males tended to be more effective contraceptors than the other two groups. Reasons for nonuse were also studied. (Author/SJL)

  15. "Utilizing" signal detection theory.

    Lynn, Spencer K; Barrett, Lisa Feldman

    2014-09-01

    What do inferring what a person is thinking or feeling, judging a defendant's guilt, and navigating a dimly lit room have in common? They involve perceptual uncertainty (e.g., a scowling face might indicate anger or concentration, for which different responses are appropriate) and behavioral risk (e.g., a cost to making the wrong response). Signal detection theory describes these types of decisions. In this tutorial, we show how incorporating the economic concept of utility allows signal detection theory to serve as a model of optimal decision making, going beyond its common use as an analytic method. This utility approach to signal detection theory clarifies otherwise enigmatic influences of perceptual uncertainty on measures of decision-making performance (accuracy and optimality) and on behavior (an inverse relationship between bias magnitude and sensitivity optimizes utility). A "utilized" signal detection theory offers the possibility of expanding the phenomena that can be understood within a decision-making framework. © The Author(s) 2014.

  16. Imaging of human breast tissue using polarization sensitive optical coherence tomography

    Verma, Y.; Gautam, M.; Divakar Rao, K.; Swami, M. K.; Gupta, P. K.

    2011-12-01

    We report a study on the use of polarization sensitive optical coherence tomography (PSOCT) for discriminating malignant (invasive ductal carcinoma), benign (fibroadenoma) and normal (adipocytes) breast tissue sites. The results show that while conventional OCT, that utilizes only the intensity of light back-scattered from tissue microstructures, is able to discriminate breast tissues as normal (adipocytes) and abnormal (malignant and benign) tissues, PS-OCT helps in discriminating between malignant and benign tissue sites also. The estimated values of birefringence obtained from the PSOCT imaging show that benign breast tissue samples have significantly higher birefringence as compared to the malignant tissue samples.

  17. Synovial tissue research

    Orr, Carl; Sousa, Elsa; Boyle, David L

    2017-01-01

    The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable...... easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly...... diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis...

  18. Optical tomography of tissues

    Zimnyakov, D A; Tuchin, Valerii V

    2002-01-01

    Methods of optical tomography of biological tissues are considered, which include pulse-modulation and frequency-modulation tomography, diffusion tomography with the use of cw radiation sources, optical coherent tomography, speckle-correlation tomography of nonstationary media, and optoacoustic tomography. The method for controlling the optical properties of tissues is studied from the point of view of increasing a probing depth in optical coherent tomography. The modern state and prospects of the development of optical tomography are discussed. (review)

  19. Non-invasive measurement and imaging of tissue iron oxide nanoparticle concentrations in vivo using proton relaxometry

    St Pierre, T G; Clark, P R; Chua-anusorn, W; Fleming, A; Pardoe, H; Jeffrey, G P; Olynyk, J K; Pootrakul, P; Jones, S; Moroz, P

    2005-01-01

    Magnetic nanoparticles and microparticles can be found in biological tissues for a variety of reasons including pathological deposition of biogenic particles, administration of synthetic particles for scientific or clinical reasons, and the inclusion of biogenic magnetic particles for the sensing of the geomagnetic field. In applied magnetic fields, the magnetisation of tissue protons can be manipulated with radiofrequency radiation such that the macroscopic magnetisation of the protons precesses freely in the plane perpendicular to the applied static field. The presence of magnetic particles within tissue enhances the rate of dephasing of proton precession with higher concentrations of particles resulting in higher dephasing rates. Magnetic resonance imaging instruments can be used to measure and image the rate of decay of spin echo recoverable proton transverse magnetisation (R 2 ) within tissues enabling the measurement and imaging of magnetic particle concentrations with the aid of suitable calibration curves. Applications include the non-invasive measurement of liver iron concentrations in iron-overload disorders and measurement and imaging of magnetic particle concentrations used in magnetic hyperthermia therapy. Future applications may include the tracking of magnetically labelled drugs or biomolecules and the measurement of fibrotic liver damage

  20. An acellular biologic scaffold does not regenerate appreciable de novo muscle tissue in rat models of volumetric muscle loss injury.

    Aurora, Amit; Roe, Janet L; Corona, Benjamin T; Walters, Thomas J

    2015-10-01

    Extracellular matrix (ECM) derived scaffolds continue to be investigated for the treatment of volumetric muscle loss (VML) injuries. Clinically, ECM scaffolds have been used for lower extremity VML repair; in particular, MatriStem™, a porcine urinary bladder matrix (UBM), has shown improved functional outcomes and vascularization, but limited myogenesis. However, efficacy of the scaffold for the repair of traumatic muscle injuries has not been examined systematically. In this study, we demonstrate that the porcine UBM scaffold when used to repair a rodent gastrocnemius musculotendinous junction (MTJ) and tibialis anterior (TA) VML injury does not support muscle tissue regeneration. In the MTJ model, the scaffold was completely resorbed without tissue remodeling, suggesting that the scaffold may not be suitable for the clinical repair of muscle-tendon injuries. In the TA VML injury, the scaffold remodeled into a fibrotic tissue and showed functional improvement, but not due to muscle fiber regeneration. The inclusion of physical rehabilitation also did not improve functional response or tissue remodeling. We conclude that the porcine UBM scaffold when used to treat VML injuries may hasten the functional recovery through the mechanism of scaffold mediated functional fibrosis. Thus for appreciable muscle regeneration, repair strategies that incorporate myogenic cells, vasculogenic accelerant and a myoconductive scaffold need to be developed. Published by Elsevier Ltd.

  1. Percutaneous window chamber method for chronic intravital microscopy of sensor-tissue interactions.

    Koschwanez, Heidi E; Klitzman, Bruce; Reichert, W Monty

    2008-11-01

    A dorsal, two-sided skin-fold window chamber model was employed previously by Gough in glucose sensor research to characterize poorly understood physiological factors affecting sensor performance. We have extended this work by developing a percutaneous one-sided window chamber model for the rodent dorsum that offers both a larger subcutaneous area and a less restrictive tissue space than previous animal models. A surgical procedure for implanting a sensor into the subcutis beneath an acrylic window (15 mm diameter) is presented. Methods to quantify changes in the microvascular network and red blood cell perfusion around the sensors using noninvasive intravital microscopy and laser Doppler flowmetry are described. The feasibility of combining interstitial glucose monitoring from an implanted sensor with intravital fluorescence microscopy was explored using a bolus injection of fluorescein and dextrose to observe real-time mass transport of a small molecule at the sensor-tissue interface. The percutaneous window chamber provides an excellent model for assessing the influence of different sensor modifications, such as surface morphologies, on neovascularization using real-time monitoring of the microvascular network and tissue perfusion. However, the tissue response to an implanted sensor was variable, and some sensors migrated entirely out of the field of view and could not be observed adequately. A percutaneous optical window provides direct, real-time images of the development and dynamics of microvascular networks, microvessel patency, and fibrotic encapsulation at the tissue-sensor interface. Additionally, observing microvessels following combined bolus injections of a fluorescent dye and glucose in the local sensor environment demonstrated a valuable technique to visualize mass transport at the sensor surface.

  2. Effect of anesthesia on glucose production and utilization in rats

    Penicaud, L.; Ferre, P.; Kande, J.; Leturque, A.; Issad, T.; Girard, J.

    1987-01-01

    This study was undertaken to determine the effects of pentobarbital anesthesia (50 mg/kg ip) on glucose kinetics and individual tissue glucose utilization in vivo, in chronically catheterized rats. Glucose turnover studies were carried out using [3- 3 H] glucose as tracer. A transient hyperglycemia and an increased glucose production were observed 3 min after induction of anesthesia. However, 40 min after induction of anesthesia, glycemia returned to the level observed in awake animals, whereas glucose turnover was decreased by 30% as compared with unanesthetized rats. These results are discussed with regard to the variations observed in plasma insulin, glucagon, and catecholamine levels. Glucose utilization by individual tissues was studied by the 2-[1- 3 H] deoxyglucose technique. A four- to fivefold decrease in glucose utilization was observed in postural muscles (soleus and adductor longus), while in other nonpostural muscles (epitrochlearis, tibialis anterior, extensor digitorum longus, and diaphragm) and other tissues (white and brown adipose tissues) anesthesia did not modify the rate of glucose utilization. A decrease in glucose utilization was also observed in the brain

  3. Diffuse reflectance spectroscopy for optical soft tissue differentiation as remote feedback control for tissue-specific laser surgery.

    Stelzle, Florian; Tangermann-Gerk, Katja; Adler, Werner; Zam, Azhar; Schmidt, Michael; Douplik, Alexandre; Nkenke, Emeka

    2010-04-01

    Laser surgery does not provide haptic feedback for operating layer-by-layer and thereby preserving vulnerable anatomical structures like nerve tissue or blood vessels. Diffuse reflectance spectra can facilitate remote optical tissue differentiation. It is the aim of the study to use this technique on soft tissue samples, to set a technological basis for a remote optical feedback system for tissue-specific laser surgery. Diffuse reflectance spectra (wavelength range: 350-650 nm) of ex vivo types of soft tissue (a total of 10,800 spectra) of the midfacial region of domestic pigs were remotely measured under reduced environmental light conditions and analyzed in order to differentiate between skin, mucosa, muscle, subcutaneous fat, and nerve tissue. We performed a principal components (PC) analysis (PCA) to reduce the number of variables. Linear discriminant analysis (LDA) was utilized for classification. For the tissue differentiation, we calculated the specificity and sensitivity by receiver operating characteristic (ROC) analysis and the area under curve (AUC). Six PCs were found to be adequate for tissue differentiation with diffuse reflectance spectra using LDA. All of the types of soft tissue could be differentiated with high specificity and sensitivity. Only the tissue pairs nervous tissue/fatty tissue and nervous tissue/mucosa showed a decline of differentiation due to bio-structural similarity. However, both of these tissue pairs could still be differentiated with a specificity and sensitivity of more than 90%. Analyzing diffuse reflectance spectroscopy with PCA and LDA allows for remote differentiation of biological tissue. Considering the limitations of the ex vivo conditions, the obtained results are promising and set a basis for the further development of a feedback system for tissue-specific laser surgery. (c) 2010 Wiley-Liss, Inc.

  4. [Biofabrication: new approaches for tissue regeneration].

    Horch, Raymund E; Weigand, Annika; Wajant, Harald; Groll, Jürgen; Boccaccini, Aldo R; Arkudas, Andreas

    2018-04-01

    The advent of Tissue Engineering (TE) in the early 1990ies was fostered by the increasing need for functional tissue and organ replacement. Classical TE was based on the combination of carrier matrices, cells and growth factors to reconstitute lost or damaged tissue and organs. Despite considerable results in vitro and in experimental settings the lack of early vascularization has hampered its translation into daily clinical practice so far. A new field of research, called "biofabrication" utilizing latest 3D printing technologies aims at hierarchically and spatially incorporating different cells, biomaterials and molecules into a matrix to alleviate a directed maturation of artificial tissue. A literature research of the relevant publications regarding biofabrication and bioprinting was performed using the PubMed data base. Relevant papers were selected and evaluated with secondary analysis of specific citations on the bioprinting techniques. 180 relevant papers containing the key words were identified and evaluated. Basic principles into the developing field of bioprinting technology could be discerned. Key elements comprise the high-throughput assembly of cells and the fabrication of complex and functional hierarchically organized tissue constructs. Five relevant technological principles for bioprinting were identified, such as stereolithography, extrusion-based printing, laser-assisted printing, inkjet-based printing and nano-bioprinting. The different technical methods of 3D printing were found to be associated with various positive but also negative effects on cells and proteins during the printing process. Research efforts in this field obviously aim towards the development of optimizing the so called bioinks and the printing technologies. This review details the evolution of the classical methods of TE in Regenerative Medicine into the evolving field of biofabrication by bioprinting. The advantages of 3D bioprinting over traditional tissue engineering

  5. Biomass ash utilization

    Bristol, D.R.; Noel, D.J.; O`Brien, B. [HYDRA-CO Operations, Inc., Syracuse, NY (United States); Parker, B. [US Energy Corp., Fort Fairfield, ME (United States)

    1993-12-31

    This paper demonstrates that with careful analysis of ash from multiple biomass and waste wood fired power plants that most of the ash can serve a useful purpose. Some applications require higher levels of consistency than others. Examples of ash spreading for agricultural purposes as a lime supplement for soil enhancement in Maine and North Carolina, as well as a roadbase material in Maine are discussed. Use of ash as a horticultural additive is explored, as well as in composting as a filtering media and as cover material for landfills. The ash utilization is evaluated in a framework of environmental responsibility, regulations, handling and cost. Depending on the chemical and physical properties of the biomass derived fly ash and bottom ash, it can be used in one or more applications. Developing a program that utilizes ash produced in biomass facilities is environmentally and socially sound and can be financially attractive.

  6. Utilization of research reactors

    1962-01-01

    About 200 research reactors are now in operation in different parts of the world, and at least 70 such facilities, which are in advanced stages of planning and construction, should be critical within the next two or three years. In the process of this development a multitude of problems are being encountered in formulating and carrying out programs for the proper utilization of these facilities, especially in countries which have just begun or are starting their atomic energy work. An opportunity for scientific personnel from different Member States to discuss research reactor problems was given at an international symposium on the Programing and Utilization of Research Reactors organized by the Agency almost immediately after the General Conference session. Two hundred scientists from 35 countries, as well as from the European Nuclear Energy Agency and EURATOM, attended the meeting which was held in Vienna from 16 to 21 October 1961

  7. Health care utilization

    Jacobsen, Christian Bøtcher; Andersen, Lotte Bøgh; Serritzlew, Søren

    An important task in governing health services is to control costs. The literatures on both costcontainment and supplier induced demand focus on the effects of economic incentives on health care costs, but insights from these literatures have never been integrated. This paper asks how economic cost...... containment measures affect the utilization of health services, and how these measures interact with the number of patients per provider. Based on very valid register data, this is investigated for 9.556 Danish physiotherapists between 2001 and 2008. We find that higher (relative) fees for a given service...... make health professionals provide more of this service to each patient, but that lower user payment (unexpectedly) does not necessarily mean higher total cost or a stronger association between the number of patients per supplier and the health care utilization. This implies that incentives...

  8. Industrial coal utilization

    None

    1979-01-01

    The effects of the National Energy Act on the use of coal in US industrial and utility power plants are considered. Innovative methods of using coal in an environmentally acceptable way are discussed: furnace types, fluidized-bed combustion, coal-oil-mixtures, coal firing in kilns and combustion of synthetic gas and liquid fuels. Fuel use in various industries is discussed with trends brought about by uncertain availability and price of natural gas and fuel oils: steel, chemical, cement, pulp and paper, glass and bricks. The symposium on Industrial Coal Utilization was sponsored by the US DOE, Pittsburgh Energy Technology Center, April 3 to 4, 1979. Twenty-one papers have been entered individually into the EDB. (LTN)

  9. Utility customer issues

    Downey, W.H.

    1997-01-01

    Customer issues affected by the restructuring of the $250 billion US electric power industry were discussed. In the past the industry's vertically integrated utilities conducted their business in protected geographic markets. With deregulation and greater competition, that industry structure will change. This presentation highlighted the strategies that Unicom is using to react to the restructuring of the electric power industry. The underlying principle is for the utility to reinvent itself to change its market orientation and focus on customer services, such as reliability, responsiveness, custom tailored solutions, and guaranteed savings over time. Attempting to become total energy providers and delivering integrated solutions to meet the needs of large industrial and commercial consumers, intensive market research, improved service and installation, and sophisticated customer retention initiatives will also have to be high on the agenda

  10. A simple indentation device for measuring micrometer-scale tissue stiffness

    Levental, I; Levental, K R; Janmey, P A [Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104 (United States); Klein, E A; Assoian, R [Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Miller, R T [Departments of Medicine and Physiology, Louis Stokes VAMC, Cleveland, OH (United States); Wells, R G, E-mail: janmey@mail.med.upenn.ed [Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 (United States)

    2010-05-19

    Mechanical properties of cells and extracellular matrices are critical determinants of function in contexts including oncogenic transformation, neuronal synapse formation, hepatic fibrosis and stem cell differentiation. The size and heterogeneity of biological specimens and the importance of measuring their mechanical properties under conditions that resemble their environments in vivo present a challenge for quantitative measurement. Centimeter-scale tissue samples can be measured by commercial instruments, whereas properties at the subcellular (nm) scale are accessible by atomic force microscopy, optical trapping, or magnetic bead microrheometry; however many tissues are heterogeneous on a length scale between micrometers and millimeters which is not accessible to most current instrumentation. The device described here combines two commercially available technologies, a micronewton resolution force probe and a micromanipulator for probing soft biological samples at sub-millimeter spatial resolution. Several applications of the device are described. These include the first measurement of the stiffness of an intact, isolated mouse glomerulus, quantification of the inner wall stiffness of healthy and diseased mouse aortas, and evaluation of the lateral heterogeneity in the stiffness of mouse mammary glands and rat livers with correlation of this heterogeneity with malignant or fibrotic pathology as evaluated by histology.

  11. External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site.

    Chin, Michael S; Lujan-Hernandez, Jorge; Babchenko, Oksana; Bannon, Elizabeth; Perry, Dylan J; Chappell, Ava G; Lo, Yuan-Chyuan; Fitzgerald, Thomas J; Lalikos, Janice F

    2016-05-01

    External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. Twenty-four SKH1-E mice received 50 Gy of β-radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at -25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors' mouse model. Further studies are needed to assess these changes in fat graft retention.

  12. Role of the utility

    Bellin, A.

    1986-03-01

    It is common to say that a nuclear programme needs basic infrastructures such as an appropriate educational system, governmental organizations for regulation, decision and inspection, engineering organizations for design and implementation, industrial infrastructures for manufacturing, erection and commissioning, operation organizations for running and maintaining power plants. This schematic organization is not sufficient to succeed in a nuclear programme: one has to consider very carefully the attribution of responsibilities. It appears, that, among all the different systems which exist in the world for the organization of a nuclear project, it is always the utility which bears the overall responsibility for the implementation of the project. It defines objectives such as production capacity, schedule, price; it takes part in the definition of a national policy for energy supply, for the choice of a type of reactor, for the implementation of a national nuclear industry; it selects sites and conducts feasibility studies including a preliminary project; it participates in the definition of organization charts and selects contractors; it calls for and obtains authorizations from regulatory bodies; it manages the project, coordinates contractors and permanently ensures that goals are attained as regards safety, quality, schedule, costs. The French utility has directly taken charge of all these basic responsibilities and this is commonly considered as a major reason of the success of the French nuclear programme. Depending on its capacities, the utility may delegate some of these responsibilities - mainly concerning engineering and project management - to experienced firms. Nevertheless, one has to remember that the utility bears the final responsibility and that it is probably the organization most fully aware of the fact that the final goal is not the construction of a nuclear power station but the production of nuclear electricity in the best and safest conditions

  13. Reactor utilization, Annex A

    Martinc, R.; Stanic, A.

    1984-01-01

    Reactor was operated until August 1984 due to prohibition issued by the Ministry since the reactor does not have the emergency cooling system nor special filters in the ventilation system yet. This means that the operation plan was fulfilled by 69%. This annex includes detailed tables containing data about utilization of reactor experimental channels, irradiated samples, as well as interruptions of operation. Detailed data about reactor power during this period are shown as well

  14. Electric utilities in 2007

    Hyman, L.S. [Smith Barney Inc., New York, NY (United States)

    1998-10-01

    A century ago--in the year J.J. Thomson discovered the electron--electricity, gas and traction companies battled for markets, and corrupt city councils demanded their fair share of the take. One tycoon became so disgusted with the confusion and dishonesty that he decided to bribe the legislature to set up an honest, state-run regulatory agency that would bring order to chaos. But he was found out. The scandal set back the cause of regulation until 1907, the year in which the electric washing machine and the vacuum cleaner were invented. By then, electricity sales had septupled from 1897 levels, and three states had established utility regulation. In the coming decade, 1997 to 2007, the utility business could undergo similar dramatic change, but it will move toward less regulation and more competition during a period of slow growth. Management will have to work harder to achieve success, however, because much of the profits will have to come not from a growing market but from the pockets of competitors. By 2007, electricity will constitute a component of a larger energy and utility services industry that sells electricity, natural gas and possibly water, propane and telecommunications. Customized service will meet the needs of consumers of all sizes. The dominant firm in the industry, the virtual utility, may look more like a financial organization or a mass marketer than the traditional converter of raw material to energy. Emphasis on market-based pricing should lead to more efficient use of resources. If the process works right, the consumer wins.

  15. Utilization of biogas

    Walsh, J L; Ross, C C; Smith, M S; Harper, S R [Georgia Tech Research Corp., Atlanta, GA (USA)

    1989-01-01

    A comprehensive study of the systems and equipment required to convert biogas into useful thermal and/or electrical energy was conducted, and the results published in the Handbook on Biogas Utilization (Walsh et al., Georgia Institute of Technology, Atlanta, GA, 1988). The physical, chemical and combustion characteristics of biogas, and the impact of these characteristics on both new and modified combustion equipment, were considered. The study also included consideration of auxiliary equipment for biogas collection, clean-up, compression and storage. (author).

  16. UTILITY OF SIMPLIFIED LABANOTATION

    Maria del Pilar Naranjo

    2016-02-01

    Full Text Available After using simplified Labanotation as a didactic tool for some years, the author can conclude that it accomplishes at least three main functions: efficiency of rehearsing time, social recognition and broadening of the choreographic consciousness of the dancer. The doubts of the dancing community about the issue of ‘to write or not to write’ are highly determined by the contexts and their own choreographic evolution, but the utility of Labanotation, as a tool for knowledge, is undeniable.

  17. Quantification of differences in the effective atomic numbers of healthy and cancerous tissues: A discussion in the context of diagnostics and dosimetry

    Taylor, M. L. [School of Applied Sciences and Health Innovation Research Institute, RMIT University, Melbourne 3000 (Australia); Physical Sciences, Peter MacCallum Cancer Centre, East Melbourne 3001 (Australia) and Medical Physics, WBRC, Alfred Hospital, Melbourne 3000 (Australia)

    2012-09-15

    Purpose: There are a range of genetic and nongenetic factors influencing the elemental composition of different human tissues. The elemental composition of cancerous tissues frequently differs from healthy tissue of the same organ, particularly in high-Z trace element concentrations. For this reason, one could suggest that this may be exploited in diagnostics and perhaps even influence dosimetry. Methods: In this work, for the first time, effective atomic numbers are computed for common cancerous and healthy tissues using a robust, energy-dependent approach between 10 keV and 100 MeV. These are then quantitatively compared within the context of diagnostics and dosimetry. Results: Differences between effective atomic numbers of healthy and diseased tissues are found to be typically less than 10%. Fibrotic tissues and calcifications of the breast exhibit substantial (tens to hundreds of percent) differences to healthy tissue. Expectedly, differences are most pronounced in the photoelectric regime and consequently most relevant for kV imaging/therapy and radionuclides with prominent low-energy peaks. Cancerous tissue of the testes and stomach have lower effective atomic numbers than corresponding healthy tissues, while diseased tissues of the other organ sites typically have higher values. Conclusions: As dose calculation approaches improve in accuracy, there may be an argument for the explicit inclusion of pathologies. This is more the case for breast, penile, prostate, nasopharyngeal, and stomach cancer, less so for testicular and kidney cancer. The calculated data suggest dual-energy computed tomography could potentially improve lesion identification in the aforementioned organs (with the exception of testicular cancer), with most import in breast imaging. Ultimately, however, the differences are very small. It is likely that the assumption of a generic 'tissue ramp' in planning will be sufficient for the foreseeable future, and that the Z differences do

  18. Quantification of differences in the effective atomic numbers of healthy and cancerous tissues: A discussion in the context of diagnostics and dosimetry

    Taylor, M. L.

    2012-01-01

    Purpose: There are a range of genetic and nongenetic factors influencing the elemental composition of different human tissues. The elemental composition of cancerous tissues frequently differs from healthy tissue of the same organ, particularly in high-Z trace element concentrations. For this reason, one could suggest that this may be exploited in diagnostics and perhaps even influence dosimetry. Methods: In this work, for the first time, effective atomic numbers are computed for common cancerous and healthy tissues using a robust, energy-dependent approach between 10 keV and 100 MeV. These are then quantitatively compared within the context of diagnostics and dosimetry. Results: Differences between effective atomic numbers of healthy and diseased tissues are found to be typically less than 10%. Fibrotic tissues and calcifications of the breast exhibit substantial (tens to hundreds of percent) differences to healthy tissue. Expectedly, differences are most pronounced in the photoelectric regime and consequently most relevant for kV imaging/therapy and radionuclides with prominent low-energy peaks. Cancerous tissue of the testes and stomach have lower effective atomic numbers than corresponding healthy tissues, while diseased tissues of the other organ sites typically have higher values. Conclusions: As dose calculation approaches improve in accuracy, there may be an argument for the explicit inclusion of pathologies. This is more the case for breast, penile, prostate, nasopharyngeal, and stomach cancer, less so for testicular and kidney cancer. The calculated data suggest dual-energy computed tomography could potentially improve lesion identification in the aforementioned organs (with the exception of testicular cancer), with most import in breast imaging. Ultimately, however, the differences are very small. It is likely that the assumption of a generic “tissue ramp” in planning will be sufficient for the foreseeable future, and that the Z differences do not

  19. Clean energy utilization technology

    Honma, Takuya

    1992-01-01

    The technical development of clean energy including the utilization of solar energy was begun in 1973 at the time of the oil crisis, and about 20 years elapsed. Also in Japan, the electric power buying system by electric power companies for solar light electric power and wind electric power has been started in 1992, namely their value as a merchandise was recognized. As for these two technologies, the works of making the international standards and JIS were begun. The range of clean energy or natural energy is wide, and its kinds are many. The utilization of solar heat and the electric power generation utilizing waves, tide and geotherm already reached the stage of practical use. Generally in order to practically use new energy, the problem of price must be solved, but the price is largely dependent on the degree of spread. Also the reliability, durability and safety must be ensured, and the easiness of use, effectiveness and trouble-saving maintenance and operation are required. For the purpose, it is important to packaging those skillfully in a system. The cases of intelligent natural energy systems are shown. Solar light and wind electric power generation systems and the technology of transporting clean energy are described. (K.I.)

  20. [Connective tissue and inflammation].

    Jakab, Lajos

    2014-03-23

    The author summarizes the structure of the connective tissues, the increasing motion of the constituents, which determine the role in establishing the structure and function of that. The structure and function of the connective tissue are related to each other in the resting as well as inflammatory states. It is emphasized that cellular events in the connective tissue are part of the defence of the organism, the localisation of the damage and, if possible, the maintenance of restitutio ad integrum. The organism responds to damage with inflammation, the non specific immune response, as well as specific, adaptive immunity. These processes are located in the connective tissue. Sterile and pathogenic inflammation are relatively similar processes, but inevitable differences are present, too. Sialic acids and glycoproteins containing sialic acids have important roles, and the role of Siglecs is also highlighted. Also, similarities and differences in damages caused by pathogens and sterile agents are briefly summarized. In addition, the roles of adhesion molecules linked to each other, and the whole event of inflammatory processes are presented. When considering practical consequences it is stressed that the structure (building up) of the organism and the defending function of inflammation both have fundamental importance. Inflammation has a crucial role in maintaining the integrity and the unimpaired somato-psychological state of the organism. Thus, inflammation serves as a tool of organism identical with the natural immune response, inseparably connected with the specific, adaptive immune response. The main events of the inflammatory processes take place in the connective tissue.

  1. Autopsy Tissue Program

    Fox, T.; Tietjen, G.

    1979-01-01

    The Autopsy Tissue Program was begun in 1960. To date, tissues on 900 or more persons in 7 geographic regions have been collected and analyzed for plutonium content. The tissues generally consist of lung, liver, kidney, lymph, bone, and gonadal tissue for each individual. The original objective of the program was to determine the level of plutonium in human tissues due solely to fall-out from weapons testing. The baseline thus established was to be used to evaluate future changes. From the first, this program was beset with chemical and statistical difficulties. Many factors whose effects were not recognized and not planned for were found later to be important. Privacy and ethical considerations hindered the gathering of adequate data. Since the chemists were looking for amounts of plutonium very close to background, possible contamination was a very real problem. Widely used chemical techniques introduced a host of statistical problems. The difficulties encountered touch on areas common to large data sets, unusual outlier detection methods, minimum detection limits, problems with Aliquot sizes, and time-trends in the data. The conclusions point out areas to which the biologists will have to devote much more careful attention than was believed

  2. Morphology of urethral tissues

    Müller, Bert; Schulz, Georg; Herzen, Julia; Mushkolaj, Shpend; Bormann, Therese; Beckmann, Felix; Püschel, Klaus

    2010-09-01

    Micro computed tomography has been developed to a powerful technique for the characterization of hard and soft human and animal tissues. Soft tissues including the urethra, however, are difficult to be analyzed, since the microstructures of interest exhibit X-ray absorption values very similar to the surroundings. Selective staining using highly absorbing species is a widely used approach, but associated with significant tissue modification. Alternatively, one can suitably embed the soft tissue, which requires the exchange of water. Therefore, the more recently developed phase contrast modes providing much better contrast of low X-ray absorbing species are especially accommodating in soft tissue characterization. The present communication deals with the morphological characterization of sheep, pig and human urethras on the micrometer scale taking advantage of micro computed tomography in absorption and phase contrast modes. The performance of grating-based tomography is demonstrated for freshly explanted male and female urethras in saline solution. The micro-morphology of the urethra is important to understand how the muscles close the urethra to reach continence. As the number of incontinent patients is steadily increasing, the function under static and, more important, under stress conditions has to be uncovered for the realization of artificial urinary sphincters, which needs sophisticated, biologically inspired concepts to become nature analogue.

  3. Recombinant protein scaffolds for tissue engineering

    Werkmeister, Jerome A; Ramshaw, John A M

    2012-01-01

    New biological materials for tissue engineering are now being developed using common genetic engineering capabilities to clone and express a variety of genetic elements that allow cost-effective purification and scaffold fabrication from these recombinant proteins, peptides or from chimeric combinations of these. The field is limitless as long as the gene sequences are known. The utility is dependent on the ease, product yield and adaptability of these protein products to the biomedical field. The development of recombinant proteins as scaffolds, while still an emerging technology with respect to commercial products, is scientifically superior to current use of natural materials or synthetic polymer scaffolds, in terms of designing specific structures with desired degrees of biological complexities and motifs. In the field of tissue engineering, next generation scaffolds will be the key to directing appropriate tissue regeneration. The initial period of biodegradable synthetic scaffolds that provided shape and mechanical integrity, but no biological information, is phasing out. The era of protein scaffolds offers distinct advantages, particularly with the combination of powerful tools of molecular biology. These include, for example, the production of human proteins of uniform quality that are free of infectious agents and the ability to make suitable quantities of proteins that are found in low quantity or are hard to isolate from tissue. For the particular needs of tissue engineering scaffolds, fibrous proteins like collagens, elastin, silks and combinations of these offer further advantages of natural well-defined structural scaffolds as well as endless possibilities of controlling functionality by genetic manipulation. (topical review)

  4. Market research for electric utilities

    Shippee, G.

    1999-01-01

    Marketing research is increasing in importance as utilities become more marketing oriented. Marketing research managers need to maintain autonomy from the marketing director or ad agency and make sure their work is relevant to the utility's operation. This article will outline a model marketing research program for an electric utility. While a utility may not conduct each and every type of research described, the programs presented offer a smorgasbord of activities which successful electric utility marketers often use or have access to

  5. Skeletal muscle connective tissue

    Brüggemann, Dagmar Adeline

    in the structure of fibrous collagen and myofibers at high-resolution. The results demonstrate that the collagen composition in the extra cellular matrix of Gadus morhua fish muscle is much more complex than previously anticipated, as it contains type III, IV, V  and VI collagen in addition to type I. The vascular....... Consequently, functional structures, ensuring "tissue maintenance" must form a major role of connective tissue, in addition that is to the force transmitting structures one typically finds in muscle. Vascular structures have also been shown to change their mechanical properties with age and it has been shown...

  6. Biomimetic Materials and Fabrication Approaches for Bone Tissue Engineering.

    Kim, Hwan D; Amirthalingam, Sivashanmugam; Kim, Seunghyun L; Lee, Seunghun S; Rangasamy, Jayakumar; Hwang, Nathaniel S

    2017-12-01

    Various strategies have been explored to overcome critically sized bone defects via bone tissue engineering approaches that incorporate biomimetic scaffolds. Biomimetic scaffolds may provide a novel platform for phenotypically stable tissue formation and stem cell differentiation. In recent years, osteoinductive and inorganic biomimetic scaffold materials have been optimized to offer an osteo-friendly microenvironment for the osteogenic commitment of stem cells. Furthermore, scaffold structures with a microarchitecture design similar to native bone tissue are necessary for successful bone tissue regeneration. For this reason, various methods for fabricating 3D porous structures have been developed. Innovative techniques, such as 3D printing methods, are currently being utilized for optimal host stem cell infiltration, vascularization, nutrient transfer, and stem cell differentiation. In this progress report, biomimetic materials and fabrication approaches that are currently being utilized for biomimetic scaffold design are reviewed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Biomimetic material strategies for cardiac tissue engineering

    Prabhakaran, Molamma P.; Venugopal, J.; Kai, Dan; Ramakrishna, Seeram

    2011-01-01

    Cardiovascular disease precedes many serious complications including myocardial infarction (MI) and it remains a major problem for the global community. Adult mammalian heart has limited ability to regenerate and compensate for the loss of cardiomyocytes. Restoration of cardiac function by replacement of diseased myocardium with functional cardiomyocytes is an intriguing strategy because it offers a potential cure for MI. Biomaterials are fabricated in nanometer scale dimensions by combining the chemical, biological, mechanical and electrical aspects of material for potential tissue engineering (TE) applications. Synthetic polymers offer advantageous in their ability to tailor the mechanical properties, and natural polymers offer cell recognition sites necessary for cell, adhesion and proliferation. Cardiac tissue engineering (TE) aim for the development of a bioengineered construct that can provide physical support to the damaged cardiac tissue by replacing certain functions of the damaged extracellular matrix and prevent adverse cardiac remodeling and dysfunction after MI. Electrospun nanofibers are applied as heart muscle patches, while hydrogels serve as a platform for controlled delivery of growth factors, prevent mechanical complications and assist in cell recruitment. This article reviews the applications of different natural and synthetic polymeric materials utilized as cardiac patches, injectables or 3D constructs for cardiac TE. Smart organization of nanoscale assemblies with synergistic approaches of utilizing nanofibers and hydrogels could further advance the field of cardiac tissue engineering. Rapid innovations in biomedical engineering and cell biology will bring about new insights in the development of optimal scaffolds and methods to create tissue constructs with relevant contractile properties and electrical integration to replace or substitute the diseased myocardium.

  8. Biomimetic material strategies for cardiac tissue engineering

    Prabhakaran, Molamma P., E-mail: nnimpp@nus.edu.sg [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore); Venugopal, J. [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore); Kai, Dan [NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore (Singapore); Ramakrishna, Seeram [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore)

    2011-04-08

    Cardiovascular disease precedes many serious complications including myocardial infarction (MI) and it remains a major problem for the global community. Adult mammalian heart has limited ability to regenerate and compensate for the loss of cardiomyocytes. Restoration of cardiac function by replacement of diseased myocardium with functional cardiomyocytes is an intriguing strategy because it offers a potential cure for MI. Biomaterials are fabricated in nanometer scale dimensions by combining the chemical, biological, mechanical and electrical aspects of material for potential tissue engineering (TE) applications. Synthetic polymers offer advantageous in their ability to tailor the mechanical properties, and natural polymers offer cell recognition sites necessary for cell, adhesion and proliferation. Cardiac tissue engineering (TE) aim for the development of a bioengineered construct that can provide physical support to the damaged cardiac tissue by replacing certain functions of the damaged extracellular matrix and prevent adverse cardiac remodeling and dysfunction after MI. Electrospun nanofibers are applied as heart muscle patches, while hydrogels serve as a platform for controlled delivery of growth factors, prevent mechanical complications and assist in cell recruitment. This article reviews the applications of different natural and synthetic polymeric materials utilized as cardiac patches, injectables or 3D constructs for cardiac TE. Smart organization of nanoscale assemblies with synergistic approaches of utilizing nanofibers and hydrogels could further advance the field of cardiac tissue engineering. Rapid innovations in biomedical engineering and cell biology will bring about new insights in the development of optimal scaffolds and methods to create tissue constructs with relevant contractile properties and electrical integration to replace or substitute the diseased myocardium.

  9. Time Functions as Utilities

    Minguzzi, E.

    2010-09-01

    Every time function on spacetime gives a (continuous) total preordering of the spacetime events which respects the notion of causal precedence. The problem of the existence of a (semi-)time function on spacetime and the problem of recovering the causal structure starting from the set of time functions are studied. It is pointed out that these problems have an analog in the field of microeconomics known as utility theory. In a chronological spacetime the semi-time functions correspond to the utilities for the chronological relation, while in a K-causal (stably causal) spacetime the time functions correspond to the utilities for the K + relation (Seifert’s relation). By exploiting this analogy, we are able to import some mathematical results, most notably Peleg’s and Levin’s theorems, to the spacetime framework. As a consequence, we prove that a K-causal (i.e. stably causal) spacetime admits a time function and that the time or temporal functions can be used to recover the K + (or Seifert) relation which indeed turns out to be the intersection of the time or temporal orderings. This result tells us in which circumstances it is possible to recover the chronological or causal relation starting from the set of time or temporal functions allowed by the spacetime. Moreover, it is proved that a chronological spacetime in which the closure of the causal relation is transitive (for instance a reflective spacetime) admits a semi-time function. Along the way a new proof avoiding smoothing techniques is given that the existence of a time function implies stable causality, and a new short proof of the equivalence between K-causality and stable causality is given which takes advantage of Levin’s theorem and smoothing techniques.

  10. Electricity utilities: Nuclear sector

    Brosche, D.

    1992-01-01

    The safe and economic operation of nuclear power plants requires an appropriate infrastructure on the part of the operator as well as a high level of technical quality of the plants and of qualification of the personnel. Added to this are a variety of services rendered by specialist firms. The Bayernwerk utility, with plants of its own, has played a major role in the development of nuclear power in the Federal Republic of Germany. The importance of nuclear power to this firm is reflected in the pattern of its electricity sources and in the composition of its power plants. (orig.) [de

  11. Reactor utilization, Part 1

    Martinc, R.; Stanic, A.

    1981-01-01

    The reactor operating plan for 1981 was subject to the needs of testing operation with the 80% enriched fuel and was fulfilled on the whole. This annex includes data about reactor operation, review of shorter interruptions due to demands of the experiments, data about safety shutdowns caused by power cuts. Period of operation at low power levels was used mostly for activation analyses, and the operation at higher power levels were used for testing and regular isotope production. Detailed data about samples activation are included as well as utilization of the reactor as neutron source and the operating plan for 1982 [sr

  12. Energy utilization in Canada

    Klassen, J.

    1976-04-01

    The situation of the energy supply of Canada is characterized by its geographic location and by the dispersal of the energy consumers over a wide area. At present, the energy supply leaving the successful CANDU nuclear energy programme out of account, is based mainly on crude oil, natural gas, and electricity as well as on coal imported from the USA. The targets of Canadian enery policies and energy research are stated as follows: a) Reducing and optimizing energy consumption, b) introducing district heating, and c) utilizing the extensive local coal deposits. (GG) [de

  13. Managing the nuclear utility

    Williams, J.W. Jr.

    1985-01-01

    The Florida Power and Light Company (FP and L) is the fifth largest investor-owned utility in the country. The success of nuclear power generation at the St. Lucie Units 1 and 2 and Turkey Point Units 3 and 4 has resulted from a continuing management commitment to the nuclear program. The management of the power plants rely strongly on teamwork for most large projects and activities whether they entail plant operation, construction, or maintenance. Various examples of how teamwork has been used to realize the successful completion of projects or solutions to problems are given

  14. Tribal Utility Feasibility Study

    Engel, R. A.; Zoellick, J. J.

    2007-06-30

    The Schatz Energy Research Center (SERC) assisted the Yurok Tribe in investigating the feasibility of creating a permanent energy services program for the Tribe. The original purpose of the DOE grant that funded this project was to determine the feasibility of creating a full-blown Yurok Tribal electric utility to buy and sell electric power and own and maintain all electric power infrastructure on the Reservation. The original project consultant found this opportunity to be infeasible for the Tribe. When SERC took over as project consultant, we took a different approach. We explored opportunities for the Tribe to develop its own renewable energy resources for use on the Reservation and/or off-Reservation sales as a means of generating revenue for the Tribe. We also looked at ways the Tribe can provide energy services to its members and how to fund such efforts. We identified opportunities for the development of renewable energy resources and energy services on the Yurok Reservation that fall into five basic categories: • Demand-side management – This refers to efforts to reduce energy use through energy efficiency and conservation measures. • Off-grid, facility and household scale renewable energy systems – These systems can provide electricity to individual homes and Tribal facilities in areas of the Reservation that do not currently have access to the electric utility grid. • Village scale, micro-grid renewable energy systems - These are larger scale systems that can provide electricity to interconnected groups of homes and Tribal facilities in areas of the Reservation that do not have access to the conventional electric grid. This will require the development of miniature electric grids to serve these interconnected facilities. • Medium to large scale renewable energy development for sale to the grid – In areas where viable renewable energy resources exist and there is access to the conventional electric utility grid, these resources can be

  15. Social group utility maximization

    Gong, Xiaowen; Yang, Lei; Zhang, Junshan

    2014-01-01

    This SpringerBrief explains how to leverage mobile users' social relationships to improve the interactions of mobile devices in mobile networks. It develops a social group utility maximization (SGUM) framework that captures diverse social ties of mobile users and diverse physical coupling of mobile devices. Key topics include random access control, power control, spectrum access, and location privacy.This brief also investigates SGUM-based power control game and random access control game, for which it establishes the socially-aware Nash equilibrium (SNE). It then examines the critical SGUM-b

  16. Bone morphogenetic protein 2 and decorin expression in old fracture fragments and surrounding tissues.

    Han, X G; Wang, D K; Gao, F; Liu, R H; Bi, Z G

    2015-09-21

    Bone morphogenetic protein 2 (BMP-2) can promote fracture healing. Although the complex role BMP-2 in bone formation is increasingly understood, the role of endogenous BMP-2 in nonunion remains unclear. Decorin (DCN) can promote the formation of bone matrix and calcium deposition to control bone morphogenesis. In this study, tissue composition and expression of BMP-2 and DCN were detected in different parts of old fracture zones to explore inherent anti-fibrotic ability and osteogenesis. Twenty-three patients were selected, including eight cases of delayed union and 15 cases of nonunion. Average duration of delayed union or nonunion was 15 months. Fracture fragments and surrounding tissues, including bone grafts, marrow cavity contents, and sticking scars, were categorically sampled during surgery. Through observation and histological testing, component comparisons were made between fracture fragments and surrounding tissue. The expression levels of DCN and BMP-2 in different tissues were detected by immunohistochemical staining and real-time polymerase chain reaction. The expression of DCN and BMP- 2 in different parts of the nonunion area showed that, compared with bone graft and marrow cavity contents, sticking scars had the highest expression of BMP-2. Compared with the marrow cavity contents and sticking scars, bone grafts had the highest expression of DCN. The low antifibrotic and osteogenic activity of the nonunion area was associated with non-co-expression of BMP-2 and DCN. Therefore, the co-injection of osteogenic factor BMP and DCN into the nonunion area can improve the induction of bone formation and enhance the conversion of the old scar, thereby achieving better nonunion treatment.

  17. Failure in cartilaginous tissues

    Huyghe, J.M.R.J.; Talen-Jongeneelen, C.J.M.; Schroeder, Y.; Kraaijeveld, F.; Borst, de R.; Baaijens, F.P.T.

    2007-01-01

    Cartilaginous tissues high load bearing capacity is explained by osmotic prestressing putting the collagen fiber reinforcement under tension and the proteoglycan gel under compression. The osmotic forces are boosted by a further 50 % by the affinity of the collagen with the aquous solution. The high

  18. Connective tissue activation. XVII

    Weiss, J.J.; Donakowski, C.; Anderson, B.; Meyers, S.; Castor, C.W.

    1980-01-01

    The platelet-derived connective tissue activating peptide (CTAP-III) has been shown to be an important factor stimulating the metabolism and proliferation of human connective tissue cell strains, including synovial tissue cells. The quantities of CTAP-III affecting the cellular changes and the amounts in various biologic fluids and tissues are small. The objectives of this study were to develop a radioimmunoassay (RIA) for CTAP-III and to ascertain the specificities of the anti-CTAP-III sera reagents. The antisera were shown not to cross-react with a number of polypeptide hormones. However, two other platelet proteins β-thromboglobulin and low affinity platelet factor-4, competed equally as well as CTAP-III for anti-CTAP-III antibodies in the RIA system. Thus, the three platelet proteins are similar or identical with respect to those portions of the molecules constituting the reactive antigenic determinants. The levels of material in normal human platelet-free plasma that inhibited anti-CTAP-III- 125 I-CTAP-III complex formation were determined to be 34+-13 (S.D.) ng/ml. (Auth.)

  19. Soft Tissue Extramedullary Plasmacytoma

    Fernando Ruiz Santiago

    2010-01-01

    Full Text Available We present the uncommon case of a subcutaneous fascia-based extramedullary plasmacytoma in the leg, which was confirmed by the pathology report and followed up until its remission. We report the differential diagnosis with other more common soft tissue masses. Imaging findings are nonspecific but are important to determine the tumour extension and to plan the biopsy.

  20. Neoproteoglycans in tissue engineering

    Weyers, Amanda; Linhardt, Robert J.

    2014-01-01

    Proteoglycans, comprised of a core protein to which glycosaminoglycan chains are covalently linked, are an important structural and functional family of macromolecules found in the extracellular matrix. Advances in our understanding of biological interactions have lead to a greater appreciation for the need to design tissue engineering scaffolds that incorporate mimetics of key extracellular matrix components. A variety of synthetic and semisynthetic molecules and polymers have been examined by tissue engineers that serve as structural, chemical and biological replacements for proteoglycans. These proteoglycan mimetics have been referred to as neoproteoglycans and serve as functional and therapeutic replacements for natural proteoglycans that are often unavailable for tissue engineering studies. Although neoproteoglycans have important limitations, such as limited signaling ability and biocompatibility, they have shown promise in replacing the natural activity of proteoglycans through cell and protein binding interactions. This review focuses on the recent in vivo and in vitro tissue engineering applications of three basic types of neoproteoglycan structures, protein–glycosaminoglycan conjugates, nano-glycosaminoglycan composites and polymer–glycosaminoglycan complexes. PMID:23399318

  1. Sensing in tissue bioreactors

    Rolfe, P.

    2006-03-01

    Specialized sensing and measurement instruments are under development to aid the controlled culture of cells in bioreactors for the fabrication of biological tissues. Precisely defined physical and chemical conditions are needed for the correct culture of the many cell-tissue types now being studied, including chondrocytes (cartilage), vascular endothelial cells and smooth muscle cells (blood vessels), fibroblasts, hepatocytes (liver) and receptor neurones. Cell and tissue culture processes are dynamic and therefore, optimal control requires monitoring of the key process variables. Chemical and physical sensing is approached in this paper with the aim of enabling automatic optimal control, based on classical cell growth models, to be achieved. Non-invasive sensing is performed via the bioreactor wall, invasive sensing with probes placed inside the cell culture chamber and indirect monitoring using analysis within a shunt or a sampling chamber. Electroanalytical and photonics-based systems are described. Chemical sensing for gases, ions, metabolites, certain hormones and proteins, is under development. Spectroscopic analysis of the culture medium is used for measurement of glucose and for proteins that are markers of cell biosynthetic behaviour. Optical interrogation of cells and tissues is also investigated for structural analysis based on scatter.

  2. Geothermal Resource Utilization

    Lienau, Paul J.

    1998-01-03

    Man has utilized the natural heat of the earth for centuries. Worldwide direct use of geothermal currently amounts to about 7,000 MWt, as compared to 1,500 MWe, now being used for the generation of electricity. Since the early 1970s, dwindling domestic reservoirs of oil and gas, continued price escalation of oil on the world market and environmental concerns associated with coal and nuclear energy have created a growing interest in the use of geothermal energy in the United States. The Department of Energy goals for hydrothermal resources utilization in the United States, expressed in barrels of oil equivalent, is 50 to 90 million bbl/yr by 1985 and 350 to 900 million bbl/yr by the year 2000. This relatively clean and highly versatile resource is now being used in a multitude of diverse applications (e.g., space heating and cooling, vegetable dehydration, agriculture, aquaculture, light manufacturing), and other applications requiring a reliable and economic source of heat.

  3. Utilization of coalbed methane

    Gustavson, J.B. [Gustavson Associates Inc., Boulder, CO (United States)

    1996-02-01

    Substantial progress has been made in capturing coalbed methane (CBM gas), which constitutes a valuable source of clean burning energy. It is of importance to study the various potential uses of coalbed methane and to understand the various technologies required, as well as their economics and any institutional constraints. In industrialised countries, the uses of coalbed methane are almost solely dependent on microeconomics; coalbed methane must compete for a market against natural gas and other energy sources - and frequently, coalbed methane is not competitive against other energy sources. In developing countries, on the other hand, particularly where other sources of energy are in short supply, coalbed methane economics yield positive results. Here, constraints to development of CBM utilization are mainly lack of technology and investment capital. Sociological aspects such as attitude and cultural habits, may also have a strong negative influence. This paper outlines the economics of coalbed methane utilization, particularly its competition with natural gas, and touches upon the many different uses to which coalbed methane may be applied. 24 refs., 4 figs.

  4. Degradable polymers for tissue engineering

    van Dijkhuizen-Radersma, Riemke; Moroni, Lorenzo; van Apeldoorn, Aart A.; Zhang, Zheng; Grijpma, Dirk W.; van Blitterswijk, Clemens A.

    2008-01-01

    This chapter elaborates the degradable polymers for tissue engineering and their required scaffold material in tissue engineering. It recognizes the examples of degradable polymers broadly used in tissue engineering. Tissue engineering is the persuasion of the body to heal itself through the

  5. Advances of mesenchymal stem cells derived from bone marrow and dental tissue in craniofacial tissue engineering.

    Yang, Maobin; Zhang, Hongming; Gangolli, Riddhi

    2014-05-01

    Bone and dental tissues in craniofacial region work as an important aesthetic and functional unit. Reconstruction of craniofacial tissue defects is highly expected to ensure patients to maintain good quality of life. Tissue engineering and regenerative medicine have been developed in the last two decades, and been advanced with the stem cell technology. Bone marrow derived mesenchymal stem cells are one of the most extensively studied post-natal stem cell population, and are widely utilized in cell-based therapy. Dental tissue derived mesenchymal stem cells are a relatively new stem cell population that isolated from various dental tissues. These cells can undergo multilineage differentiation including osteogenic and odontogenic differentiation, thus provide an alternative source of mesenchymal stem cells for tissue engineering. In this review, we discuss the important issues in mesenchymal stem cell biology including the origin and functions of mesenchymal stem cells, compare the properties of these two types of mesenchymal cells, update recent basic research and clinic applications in this field, and address important future challenges.

  6. Transforming growth factor-β1/Smad/connective tissue growth factor axis: The main pathway in radiation-induced fibrosis of osteoradionecrosis?

    Qian Wei Zhuang

    2013-01-01

    Full Text Available Introduction: Osteoradionecrosis (ORN of the mandible is a serious complication following radiation therapy for malignancies of the head and neck. Radiation-induced fibrosis (RIF is a new theory that accounts for the damage to normal tissues after radiotherapy, and the radiation-induced fibroatrophic mechanism includes the free-radical formation, endothelial dysfunction, inflammation, microvascular thrombosis, fibrosis and remodeling, and finally bone and tissue necrosis. The Hypothesis: Previous studies revealed that transforming growth factor-β1 (TGF-β1 is the master switch cytokine responsible for the regulation of fibroblast proliferation and differentiation that result in RIF. Among the targets of TGF-β1, connective tissue growth factor (CTGF is a downstream mediator through the Smad3/4 pathway and plays an important role in connective tissue homeostasis and fibroblast proliferation. Studies have proved that the TGF-β1/Smad/CTGF signaling pathway is involved in the RIF of soft tissues, so the authors put forward a hypothesis that the TGF-β1/Smad/CTGF axis is also the main pathway in RIF of ORN. Evaluation of the Hypothesis: The validation of our hypothesis may provide new insights for better understanding the pathogenesis of ORN and open new perspectives for anti-fibrotic therapies, and pioneer novel approaches to treat ORN.

  7. Utilities in UNIX

    Perez, L.

    2002-01-01

    This manual goes to the users with some or much experience in the unix operating system. In such manner that they can get more efficiency using the unix of the most vendors. Include the majority of UNIX commands, shell built-in functions to create scripts, and a brief explication of the variables in several environments. In addition, other products are included, more and more integrated in the most of the unix operating systems. For example: the scanning and processing language awk, the print server LPRng, GNU Utilities, batch subsystem, etc. The manual was initially based in an specific unix. But it and been written for use of the most unix that exist: Tru64 unix, aix, iris, hpux. solaris y linux. In this way, many examples in the chapter had been included. The purpose of this manual is to provide an UNIX reference for advanced users in any of the unix operating systems family. (Author)

  8. Hydrogen and energy utilities

    Hustadt, Daniel [Vattenfall Europe Innovation GmbH (Germany)

    2010-07-01

    Renewable electricity generation plays one major role with the biggest share being wind energy. At the end of the year 2009 a wind power plant capacity of around 26 GW was installed in Germany. Several outlooks come to the conclusion that this capacity can be doubled in ten years (compare Figure 1). Additionally the German government has set a target of 26 GW installed off-shore capacity in North and Baltic Sea until 2030. At Vattenfall only a minor percentage of the electricity production comes from wind power today. This share will be increased up to 12% until 2030 following Vattenfall's strategy 'Making Electricity Clean'. This rapid development of wind power offers several opportunities but also means some challenges to Utilities. (orig.)

  9. Utility prudency issues

    Charnoff, G.

    1986-01-01

    The conventional legal standard of prudence found in the common law of public utility regulation precludes a judgment about past decisions based on present knowledge of whether the decisions proved in time to have been right or wrong. The proper inquiry is not whether every management decision proved to be correct. Rather, the proper inquiry as stated by the New York Public Service Commission in Re Consolidated Edison Co. of New York, Inc. is ...whether the company's conduct was reasonable at the time, under all of the circumstances, considering that the company had to solve its problems prospectively.... The exercise of prudence does not guarantee performance on schedule or within budget, or the making of correct decisions, when judged after the fact. But it does require or involve the exercise of reasoned decision making within a framework of reasonably available alternatives

  10. Energy utilities and the Internet

    2000-01-01

    The chances for energy utilities in the Netherlands to present themselves on the Internet are briefly outlined. It appears that other businesses are ahead of the Dutch utilities in offering electronic services with respect to energy

  11. Reptile Soft Tissue Surgery.

    Di Girolamo, Nicola; Mans, Christoph

    2016-01-01

    The surgical approach to reptiles can be challenging. Reptiles have unique physiologic, anatomic, and pathologic differences. This may result in frustrating surgical experiences. However, recent investigations provided novel, less invasive, surgical techniques. The purpose of this review was to describe the technical aspects behind soft tissue surgical techniques that have been used in reptiles, so as to provide a general guideline for veterinarians working with reptiles. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Ligament Tissue Engineering

    Khan, Wasim Sardar

    2016-01-01

    Ligaments are commonly injured in the knee joint, and have a poor capacity for healing due to their relative avascularity. Ligament reconstruction is well established for injuries such as anterior cruciate ligament rupture, however the use of autografts and allografts for ligament reconstruction are associated with complications, and outcomes are variable. Ligament tissue engineering using stem cells, growth factors and scaffolds is a novel technique that has the potential to provide an unlim...

  13. Subcutaneous adipose tissue classification

    A. Sbarbati

    2010-11-01

    Full Text Available The developments in the technologies based on the use of autologous adipose tissue attracted attention to minor depots as possible sampling areas. Some of those depots have never been studied in detail. The present study was performed on subcutaneous adipose depots sampled in different areas with the aim of explaining their morphology, particularly as far as regards stem niches. The results demonstrated that three different types of white adipose tissue (WAT can be differentiated on the basis of structural and ultrastructural features: deposit WAT (dWAT, structural WAT (sWAT and fibrous WAT (fWAT. dWAT can be found essentially in large fatty depots in the abdominal area (periumbilical. In the dWAT, cells are tightly packed and linked by a weak net of isolated collagen fibers. Collagenic components are very poor, cells are large and few blood vessels are present. The deep portion appears more fibrous then the superficial one. The microcirculation is formed by thin walled capillaries with rare stem niches. Reinforcement pericyte elements are rarely evident. The sWAT is more stromal; it is located in some areas in the limbs and in the hips. The stroma is fairly well represented, with a good vascularity and adequate staminality. Cells are wrapped by a basket of collagen fibers. The fatty depots of the knees and of the trochanteric areas have quite loose meshes. The fWAT has a noteworthy fibrous component and can be found in areas where a severe mechanic stress occurs. Adipocytes have an individual thick fibrous shell. In conclusion, the present study demonstrates evident differences among subcutaneous WAT deposits, thus suggesting that in regenerative procedures based on autologous adipose tissues the sampling area should not be randomly chosen, but it should be oriented by evidence based evaluations. The structural peculiarities of the sWAT, and particularly of its microcirculation, suggest that it could represent a privileged source for

  14. The plant tissue culture

    Crocomo, O.J.; Sharp, W.R.

    1973-01-01

    Progress in the field of plant tissue culture at the Plant Biochemistry Sector, Centro de Energia na Agricultura (CENA), Piracicaba, S.P., Brazil, pertains to the simplification of development in 'Phaseolus vulgaris' by dividing the organism into its component organs, tissues, and cells and the maintenance of these components on defined culture media 'in vitro'. This achievement has set the stage for probing the basis for the stability of the differentiated states and/or the reentry of mature differentiated cells into the mitotic cell cycle and their subsequent redifferentiation. Data from such studies at the cytological and biochemical level have been invaluable in the elucidation of the control mechanisms responsible for expression of the cellular phenotype. Unlimited possibilities exist for the application of tissue culture in the vegetative propagation of 'Phaseolus' and other important cultivars in providing genocopies or a large scale and/or readily obtaining plantlets from haploid cell lines or from protoplast (wall-less cells) hybridization products following genetic manipulation. These tools are being applied in this laboratory for the development and selection of high protein synthesizing 'Phaseolus' cultivars

  15. Cardiac tissue engineering

    MILICA RADISIC

    2005-03-01

    Full Text Available We hypothesized that clinically sized (1-5 mm thick,compact cardiac constructs containing physiologically high density of viable cells (~108 cells/cm3 can be engineered in vitro by using biomimetic culture systems capable of providing oxygen transport and electrical stimulation, designed to mimic those in native heart. This hypothesis was tested by culturing rat heart cells on polymer scaffolds, either with perfusion of culture medium (physiologic interstitial velocity, supplementation of perfluorocarbons, or with electrical stimulation (continuous application of biphasic pulses, 2 ms, 5 V, 1 Hz. Tissue constructs cultured without perfusion or electrical stimulation served as controls. Medium perfusion and addition of perfluorocarbons resulted in compact, thick constructs containing physiologic density of viable, electromechanically coupled cells, in contrast to control constructs which had only a ~100 mm thick peripheral region with functionally connected cells. Electrical stimulation of cultured constructs resulted in markedly improved contractile properties, increased amounts of cardiac proteins, and remarkably well developed ultrastructure (similar to that of native heart as compared to non-stimulated controls. We discuss here the state of the art of cardiac tissue engineering, in light of the biomimetic approach that reproduces in vitro some of the conditions present during normal tissue development.

  16. Atomically resolved tissue integration.

    Karlsson, Johan; Sundell, Gustav; Thuvander, Mattias; Andersson, Martin

    2014-08-13

    In the field of biomedical technology, a critical aspect is the ability to control and understand the integration of an implantable device in living tissue. Despite the technical advances in the development of biomaterials, the elaborate interplay encompassing materials science and biology on the atomic level is not very well understood. Within implantology, anchoring a biomaterial device into bone tissue is termed osseointegration. In the most accepted theory, osseointegration is defined as an interfacial bonding between implant and bone; however, there is lack of experimental evidence to confirm this. Here we show that atom probe tomography can be used to study the implant-tissue interaction, allowing for three-dimensional atomic mapping of the interface region. Interestingly, our analyses demonstrated that direct contact between Ca atoms and the implanted titanium oxide surface is formed without the presence of a protein interlayer, which means that a pure inorganic interface is created, hence giving experimental support to the current theory of osseointegration. We foresee that this result will be of importance in the development of future biomaterials as well as in the design of in vitro evaluation techniques.

  17. Microwave Tissue Ablation: Biophysics, Technology and Applications

    2010-01-01

    Microwave ablation is an emerging treatment option for many cancers, cardiac arrhythmias and other medical conditions. During treatment, microwaves are applied directly to tissues to produce rapid temperature elevations sufficient to produce immediate coagulative necrosis. The engineering design criteria for each application differ, with individual consideration for factors such as desired ablation zone size, treatment duration, and procedural invasiveness. Recent technological developments in applicator cooling, power control and system optimization for specific applications promise to increase the utilization of microwave ablation in the future. This article will review the basic biophysics of microwave tissue heating, provide an overview of the design and operation of current equipment, and outline areas for future research for microwave ablation. PMID:21175404

  18. Necrotizing Soft Tissue Infection

    Sahil Aggarwal, BS

    2018-04-01

    Full Text Available History of present illness: A 71-year-old woman with a history of metastatic ovarian cancer presented with sudden onset, rapidly progressing painful rash in the genital region and lower abdominal wall. She was febrile to 103°F, heart rate was 114 beats per minute, and respiratory rate was 24 per minute. Her exam was notable for a toxic-appearing female with extensive areas of erythema, tenderness, and induration to her lower abdomen, intertriginous areas, and perineum with intermittent segments of crepitus without hemorrhagic bullae or skin breakdown. Significant findings: Computed tomography (CT of the abdominal and pelvis with intravenous (IV contrast revealed inflammatory changes, including gas and fluid collections within the ventral abdominal wall extending to the vulva, consistent with a necrotizing soft tissue infection. Discussion: Necrotizing fasciitis is a serious infection of the skin and soft tissues that requires an early diagnosis to reduce morbidity and mortality. Classified into several subtypes based on the type of microbial infection, necrotizing fasciitis can rapidly progress to septic shock or death if left untreated.1 Diagnosing necrotizing fasciitis requires a high index of suspicion based on patient risk factors, presentation, and exam findings. Definitive treatment involves prompt surgical exploration and debridement coupled with IV antibiotics.2,3 Clinical characteristics such as swelling, disproportionate pain, erythema, crepitus, and necrotic tissue should be a guide to further diagnostic tests.4 Unfortunately, lab values such as white blood cell count and lactate imaging studies have high sensitivity but low specificity, making the diagnosis of necrotizing fasciitis still largely a clinical one.4,5 CT is a reliable method to exclude the diagnosis of necrotizing soft tissue infections (sensitivity of 100%, but is only moderately reliable in correctly identifying such infections (specificity of 81%.5 Given the emergent

  19. YEAR 2 BIOMASS UTILIZATION

    Christopher J. Zygarlicke

    2004-11-01

    This Energy & Environmental Research Center (EERC) Year 2 Biomass Utilization Final Technical Report summarizes multiple projects in biopower or bioenergy, transportation biofuels, and bioproducts. A prototype of a novel advanced power system, termed the high-temperature air furnace (HITAF), was tested for performance while converting biomass and coal blends to energy. Three biomass fuels--wood residue or hog fuel, corn stover, and switchgrass--and Wyoming subbituminous coal were acquired for combustion tests in the 3-million-Btu/hr system. Blend levels were 20% biomass--80% coal on a heat basis. Hog fuel was prepared for the upcoming combustion test by air-drying and processing through a hammer mill and screen. A K-Tron biomass feeder capable of operating in both gravimetric and volumetric modes was selected as the HITAF feed system. Two oxide dispersion-strengthened (ODS) alloys that would be used in the HITAF high-temperature heat exchanger were tested for slag corrosion rates. An alumina layer formed on one particular alloy, which was more corrosion-resistant than a chromia layer that formed on the other alloy. Research activities were completed in the development of an atmospheric pressure, fluidized-bed pyrolysis-type system called the controlled spontaneous reactor (CSR), which is used to process and condition biomass. Tree trimmings were physically and chemically altered by the CSR process, resulting in a fuel that was very suitable for feeding into a coal combustion or gasification system with little or no feed system modifications required. Experimental procedures were successful for producing hydrogen from biomass using the bacteria Thermotoga, a deep-ocean thermal vent organism. Analytical procedures for hydrogen were evaluated, a gas chromatography (GC) method was derived for measuring hydrogen yields, and adaptation culturing and protocols for mutagenesis were initiated to better develop strains that can use biomass cellulose. Fly ash derived from

  20. Periodontics--tissue engineering and the future.

    Douglass, Gordon L

    2005-03-01

    Periodontics has a long history of utilizing advances in science to expand and improve periodontal therapies. Recently the American Academy of Periodontology published the findings of the Contemporary Science Workshop, which conducted state-of-the-art evidence-based reviews of current and emerging areas in periodontics. The findings of this workshop provide the basis for an evidence-based approach to periodontal therapy. While the workshop evaluated all areas of periodontics, it is in the area of tissue engineering that the most exciting advances are becoming a reality.

  1. Soft tissue expansion before vertical ridge augmentation: Inflatable silicone balloons or self-filling osmotic tissue expanders?

    Prasad Vijayrao Dhadse

    2014-01-01

    Full Text Available Recent advances in periodontal plastic surgical procedures allow the clinician to reconstruct deficient alveolar ridges in more predictable ways than previously possible. Placement of implant/s in resorbed ridges poses numerous challenges to the clinician for successful esthetic and functional rehabilitation. The reconstruction frequently utilizes one or combination of periodontal plastic surgical procedures in conjunction with autogenous bone grafting, allogenic bone block grafting, ridge split techniques, distraction osteogenesis, or guided bone regeneration (GBR for most predictable outcomes. Current surgical modalities used in reconstruction of alveolar ridge (horizontal and/or vertical component often involve the need of flap transfer. Moreover, there is compromise in tissue integrity and color match owing to different surgical site and the tissue utilized is insufficient in quantity leading to post surgical graft exposition and/or loss of grafted bone. Soft tissue expansion (STE by implantation of inflatable silicone balloon or self filling osmotic tissue expanders before reconstructive surgery can overcome these disadvantages and certainly holds a promise for effective method for generation of soft tissue thereby achieving predictable augmentation of deficient alveolar ridges for the implant success. This article focuses and compares these distinct tissue expanders for their clinical efficacy of achieving excess tissue that predominantly seems to be prerequisite for ridge augmentation which can be reasonably followed by successful placement of endosseous fixtures.

  2. Biomaterials for tissue engineering applications.

    Keane, Timothy J; Badylak, Stephen F

    2014-06-01

    With advancements in biological and engineering sciences, the definition of an ideal biomaterial has evolved over the past 50 years from a substance that is inert to one that has select bioinductive properties and integrates well with adjacent host tissue. Biomaterials are a fundamental component of tissue engineering, which aims to replace diseased, damaged, or missing tissue with reconstructed functional tissue. Most biomaterials are less than satisfactory for pediatric patients because the scaffold must adapt to the growth and development of the surrounding tissues and organs over time. The pediatric community, therefore, provides a distinct challenge for the tissue engineering community. Copyright © 2014. Published by Elsevier Inc.

  3. National Utility Rate Database: Preprint

    Ong, S.; McKeel, R.

    2012-08-01

    When modeling solar energy technologies and other distributed energy systems, using high-quality expansive electricity rates is essential. The National Renewable Energy Laboratory (NREL) developed a utility rate platform for entering, storing, updating, and accessing a large collection of utility rates from around the United States. This utility rate platform lives on the Open Energy Information (OpenEI) website, OpenEI.org, allowing the data to be programmatically accessed from a web browser, using an application programming interface (API). The semantic-based utility rate platform currently has record of 1,885 utility rates and covers over 85% of the electricity consumption in the United States.

  4. Utility service entrance in boreholes

    1987-08-01

    This study evaluates alternatives for utility service entrances to the repository. We determined the requirements for a repository utility supply. These requirements were defined as safety, maintainability, flexibility, reliability, cost efficiency, voltage regulation, and simplicity of operation. The study showed that repository shafts can best satisfy all requirements for location of the utility supply without the use of borehole penetrations into the repository. It is recommended that the shafts be utilized for utility distribution to the repository, and that the current NWTS program position to minimize the number of boreholes penetrating the repository horizon be maintained. 42 refs., 2 figs., 3 tabs

  5. Utility application of simulation software

    Sudduth, A.L.

    1986-01-01

    The purpose of this paper is to discuss dynamic system simulation from the perspective of a successful utility user. In it, four aspects of the issue of utility use of simulation will be addressed: (1) What simulation software is available to utilities which can be of practical assistance with a modest investment in staff and training. (2) To what specific problems can utilities apply the technique of simulation and achieve reasonably cost effective results. (3) What the advantages are of in-house dynamic simulation capability, as opposed to depending on NSSS vendors or consultants. (4) What the prospects are for wider use of dynamic simulation in the utility industry

  6. Market research for electric utilities

    Shippee, G.

    1999-12-01

    Marketing research is increasing in importance as utilities become more marketing oriented. Marketing research managers need to maintain autonomy from the marketing director or ad agency and make sure their work is relevant to the utility's operation. This article will outline a model marketing research program for an electric utility. While a utility may not conduct each and every type of research described, the programs presented offer a smorgasbord of activities which successful electric utility marketers often use or have access to.

  7. Utilization management in anatomic pathology.

    Lewandrowski, Kent; Black-Schaffer, Steven

    2014-01-01

    There is relatively little published literature concerning utilization management in anatomic pathology. Nonetheless there are many utilization management opportunities that currently exist and are well recognized. Some of these impact only the cost structure within the pathology department itself whereas others reduce charges for third party payers. Utilization management may result in medical legal liabilities for breaching the standard of care. For this reason it will be important for pathology professional societies to develop national utilization guidelines to assist individual practices in implementing a medically sound approach to utilization management. © 2013.

  8. SYMPAL: utilities guide

    Simpson, J.A.; Sublet, J.-Ch.

    1997-02-01

    The processing code SYMPAL is used to perform the data treatment for creating a new version of the European Activation File (EAF). The entire process is handled by different modules of the code in a sequential and orderly manner. The modular code system accesses, translates and processes cross section data from a wide variety of libraries and calculations with nuclear model codes. Two major data bases are accessed and merged so as to create a new library version. The Master Data File (MDF) contains the original cross section data extracted, unmodified but reformatted, from numerous sources. The Master Parameter File (MPF) contains a compilation of all physical information necessary to renormalise, split and internally validate any particular type of cross section. The combination of these two files generates a new activation library in pointwise and various groupwise formats. The SYMPAL utilities guide describes a set of programs developed to handle certain aspects of the procedure done outside of the main processing tasks. These include counting, translating, selecting and plotting data streams. Special printing and plotting procedures have been written to handle the large amounts of information present in activation libraries. (author)

  9. Gnuastro: GNU Astronomy Utilities

    Akhlaghi, Mohammad

    2018-01-01

    Gnuastro (GNU Astronomy Utilities) manipulates and analyzes astronomical data. It is an official GNU package of a large collection of programs and C/C++ library functions. Command-line programs perform arithmetic operations on images, convert FITS images to common types like JPG or PDF, convolve an image with a given kernel or matching of kernels, perform cosmological calculations, crop parts of large images (possibly in multiple files), manipulate FITS extensions and keywords, and perform statistical operations. In addition, it contains programs to make catalogs from detection maps, add noise, make mock profiles with a variety of radial functions using monte-carlo integration for their centers, match catalogs, and detect objects in an image among many other operations. The command-line programs share the same basic command-line user interface for the comfort of both the users and developers. Gnuastro is written to comply fully with the GNU coding standards and integrates well with all Unix-like operating systems. This enables astronomers to expect a fully familiar experience in the source code, building, installing and command-line user interaction that they have seen in all the other GNU software that they use. Gnuastro's extensive library is included for users who want to build their own unique programs.

  10. Knowledge-based utility

    Chwalowski, M.

    1997-01-01

    This presentation provides industry examples of successful marketing practices by companies facing deregulation and competition. The common thread through the examples is that long term survival of today's utility structure is dependent on the strategic role of knowledge. As opposed to regulated monopolies which usually own huge physical assets and have very little intelligence about their customers, unregulated enterprises tend to be knowledge-based, characterized by higher market value than book value. A knowledge-based enterprise gathers data, creates information and develops knowledge by leveraging it as a competitive weapon. It institutionalizes human knowledge as a corporate asset for use over and over again by the use of databases, computer networks, patents, billing, collection and customer services (BCCS), branded interfaces and management capabilities. Activities to become knowledge-based such as replacing inventory/fixed assets with information about material usage to reduce expenditure and achieve more efficient operations, and by focusing on integration and value-adding delivery capabilities, were reviewed

  11. Gas utilization technologies

    Biljetina, R.

    1994-01-01

    One of the constant challenges facing the research community is the identification of technology needs 5 to 15 years from now. A look back into history indicates that the forces driving natural gas research have changed from decade to decade. In the 1970s research was driven by concerns for adequate supply; in the 1980s research was aimed at creating new markets for natural gas. What then are the driving forces for the 1990s? Recent reports from the natural gas industry have helped define a new direction driven primarily by market demand for natural gas. A study prepared by the Interstate Natural Gas Association of America Foundation entitled ''Survey of Natural Research, Development, and Demonstration RD ampersand D Priorities'' indicated that in the 1990s the highest research priority should be for natural gas utilization and that technology development efforts should not only address efficiency and cost, but environmental and regulatory issues as well. This study and others, such as the report by the American Gas Association (A.G.A.) entitled ''Strategic Vision for Natural Gas Through the Year 2000,'' clearly identify the market sectors driving today's technology development needs. The biggest driver is the power generation market followed by the industrial, transportation, appliance, and gas cooling markets. This is best illustrated by the GRI 1994 Baseline Projection on market growth in various sectors between the year 1992 and 2010. This paper highlights some of the recent technology developments in each one of these sectors

  12. Fuel manufacturing and utilization

    2005-01-01

    The efficient utilisation of nuclear fuel requires manufacturing facilities capable of making advanced fuel types, with appropriate quality control. Once made, the use of such fuels requires a proper understanding of their behaviour in the reactor environment, so that safe operation for the design life can be achieved. The International Atomic Energy Agency supports Member States to improve in-pile fuel performance and management of materials; and to develop advanced fuel technologies for ensuring reliability and economic efficiency of the nuclear fuel cycle. It provides assistance to Member States to support fuel-manufacturing capability, including quality assurance techniques, optimization of manufacturing parameters and radiation protection. The IAEA supports the development fuel modelling expertise in Member States, covering both normal operation and postulated and severe accident conditions. It provides information and support for the operation of Nuclear Power Plant to ensure that the environment and water chemistry is appropriate for fuel operation. The IAEA supports fuel failure investigations, including equipment for failed fuel detection and for post-irradiation examination and inspection, as well as fuel repair, it provides information and support research into the basic properties of fuel materials, including UO 2 , MOX and zirconium alloys. It further offers guidance on the relationship with back-end requirement (interim storage, transport, reprocessing, disposal), fuel utilization and management, MOX fuels, alternative fuels and advanced fuel technology

  13. Extraction of low molecular weight RNA from Citrus trifolita tissues ...

    We employed a simple and quick method involving trizol for total RNA extraction from citrus tissues, then generation of LMW RNA using 4M LiCl, which have been successfully utilized in studies in our laboratory. Compared with traditional methods, this method is less expensive and produced high RNA yields while avoiding ...

  14. A review of rapid prototyping techniques for tissue engineering purposes

    Peltola, Sanna M.; Melchels, Ferry P. W.; Grijpma, Dirk W.; Kellomaki, Minna

    2008-01-01

    Rapid prototyping (RP) is a common name for several techniques, which read in data from computer-aided design (CAD) drawings and manufacture automatically three-dimensional objects layer-by-layer according to the virtual design. The utilization of RP in tissue engineering enables the production of

  15. Soft tissue sparganosis

    Park, Ki Soon; Lee, Yul; Chung, Soo Young; Park, Choong Ki; Lee, Kwan Sup [Hallym University College of Medicine, Seoul (Korea, Republic of); Cho, In Hwan; Suh, Hyoung Sim [Daelin S. Mary' s Hospital, Seoul (Korea, Republic of)

    1993-11-15

    Sparganosis is a rare tissue-parasitic infestation caused by a plerocercoid tapeworm larva(sparganum), genus Spirometra. The most common clinical presentation of sparganosis is a palpable subcutaneous mass or masses. Fifteen simple radiographs and 10 ultrasosnograms of 17 patients with operatively verified subcutaneous sparganosis were retrospectively analyzed to find its radiologic characteristics for preoperative diagnosis of sparganosis. The location of the subcutaneous sparganosis were lower extremity, abdominal wall, breast, inguinal region and scrotum in order of frequency. The simple radiographs showed linear or elongated calcification with or without nodular elongated shaped soft tissue mass shadows in 8 patients, soft tissue mass shadow only in 2 patients and lateral abdominal wall thickening in 1 patient. But no specific findings was noted in 4 patients with small abdominal and inguinal masses. We could classify the subcutaneous sparganosis by ultrasound into 2 types: one is long band-like hypoechoic structures, corresponding to the subcutaneous tunnel-like tracks formed by migration of sparganum larva and the order is elongated or ovoid hyperechoic nodules, representing granulomas. Long band-like hypoechoic structures within or associated with mixed echoic granulomatous masses were noted in 6 patients and elongated or ovoid hypoechoic mass or masses were noted in 4 patients. In conclusion, sparganosis should be considered when these radiologic findings-irregular linear calcifications on simple radiograph and long band-like hypoechoic structures on ultrasonography, corresponding to the subcutaneous tunnel-like tracks formed by migration of sparganum larva are noted in the patients who have subcutaneous palpable mass or masses. And radiologic examination especially ultrasonography is very helpful to diagnose sparganosis.

  16. Extracellular matrix hydrogels from decellularized tissues: Structure and function.

    Saldin, Lindsey T; Cramer, Madeline C; Velankar, Sachin S; White, Lisa J; Badylak, Stephen F

    2017-02-01

    Extracellular matrix (ECM) bioscaffolds prepared from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clinical applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biological signals retained from the native source tissue. The present review describes the utility, formation, and physical and biological characterization of ECM hydrogels. Two examples of clinical application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clinical translation of ECM hydrogels are discussed. More than 70 papers have been published on extracellular matrix (ECM) hydrogels created from source tissue in almost every organ system. The present manuscript represents a review of ECM hydrogels and attempts to identify structure-function relationships that influence the tissue remodeling outcomes and gaps in the understanding thereof. There is a Phase 1 clinical trial now in progress for an ECM hydrogel. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  17. Microsurgical Composite Tissue Transplantation

    Serafin, Donald; Georgiade, Nicholas G.

    1978-01-01

    Since 1974, 69 patients with extensive defects have undergone reconstruction by microsurgical composite tissue transplantation. Using this method, donor composite tissue is isolated on its blood supply, removed to a distant recipient site, and the continuity of blood flow re-established by microvascular anastomoses. In this series, 56 patients (81%) were completely successful. There have been eight (12%) failures, primarily in the extremities. There have been five (7%) partial successes, (i.e., a microvascular flap in which a portion was lost requiring a secondary procedure such as a split thickness graft). In those patients with a severely injured lower extremity, the failure rate was the greatest. Most of these were arterial (six of seven). These failures occurred early in the series and were thought to be related to a severely damaged recipient vasculature. This problem has been circumvented by an autogenous interpositional vein graft, permitting more mobility of flap placement. In the upper extremity, all but one case were successful. Early motion was permitted, preventing joint capsular contractures and loss of function. Twenty-three cases in the head and neck region were successful (one partial success). This included two composite rib grafts to the mandible. Prolonged delays in reconstruction following extirpation of a malignancy were avoided. A rapid return to society following complete reconstruction was ensured. Nine patients presented for reconstruction of the breast and thorax following radical mastectomy. All were successfully reconstructed with this new technique except one patient. Its many advantages include immediate reconstruction without delayed procedures and no secondary deformity of the donor site. Healthy, well vascularized tissue can now be transferred to a previously irradiated area with no tissue loss. This new method offers many advantages to older methods of reconstruction. Length of hospital stay and immobilization are reduced. The

  18. Butyltin Compounds in Tissues.

    1986-01-01

    accumulate tin in their tissues (Dooley & Homer. 1983). Whether the toxic tributyltin (Bu 3 Sn) is accumulated as such or whether the various marine organisms...did not appear to have reached an equilibrium after 60 days of exposure: while fish appeared to be able to deal with tributyltin fairly efficiently...Depuration of tributyltin in oysters occurred at 5 percent/day to give a calculated half-life of about 2 weeks. AcO51.on. For I;, + I - INSPECTED~ is

  19. Soft tissue anchor systems.

    Yu, G V; Chang, T; White, J M

    1994-04-01

    The concept of soft tissue attachment and reattachment has been addressed over the years through a variety of surgical techniques. This includes tendons and ligaments that have been detached both surgically and traumatically from their osseous origins or insertions. This study is designed to provide the reader with a comprehensive overview of current commercially available devices. Detailed descriptions of the various devices are provided along with a discussion of the advantages and disadvantages of each. Their application and use in reconstructive foot and ankle surgery are also discussed.

  20. Tissue bank: Sri Lanka

    2003-01-01

    Human degenerative diseases and congenital defects are common throughout the world. Many people suffer also from burns, fractures and nerve damage resulting from traumatic accidents and outbreaks of violence which occur all too frequently, especially in poorer countries. Far too many people are impaired for life because they have no access to treatment or simply cannot afford it. The Department of Technical Co-operation is sponsoring a programme, with technical support from the Division of Nuclear Medicine, to improve facilities at the Sri Lanka Tissue Bank. (IAEA)

  1. Heritable Disorders of Connective Tissue

    ... Home Health Topics English Español Heritable Disorders of Connective Tissue Basics In-Depth Download Download EPUB Download PDF ... they? Points To Remember About Heritable Disorders of Connective Tissue There are more than 200 heritable disorders that ...

  2. Random lasing in human tissues

    Polson, Randal C.; Vardeny, Z. Valy

    2004-01-01

    A random collection of scatterers in a gain medium can produce coherent laser emission lines dubbed 'random lasing'. We show that biological tissues, including human tissues, can support coherent random lasing when infiltrated with a concentrated laser dye solution. To extract a typical random resonator size within the tissue we average the power Fourier transform of random laser spectra collected from many excitation locations in the tissue; we verified this procedure by a computer simulation. Surprisingly, we found that malignant tissues show many more laser lines compared to healthy tissues taken from the same organ. Consequently, the obtained typical random resonator was found to be different for healthy and cancerous tissues, and this may lead to a technique for separating malignant from healthy tissues for diagnostic imaging

  3. Liesegang rings in tissue. How to distinguish Liesegang rings from the giant kidney worm, Dioctophyma renale.

    Tuur, S M; Nelson, A M; Gibson, D W; Neafie, R C; Johnson, F B; Mostofi, F K; Connor, D H

    1987-08-01

    Liesegang rings (LRs) are periodic precipitation zones from supersaturated solutions in colloidal systems. They are formed by a process that involves an interplay of diffusion, nucleation, flocculation or precipitation, and supersaturation. Examples include LRs of calcium carbonate in oölitic limestone (in nature), LRs of silver chromate in gelatin (in vitro), and LRs of glycoprotein in pulmonary corpora amylacea (in vivo). Here we describe LRs in lesions from 29 patients--mostly lesions of the kidney, synovium, conjunctiva, and eyelid. The LRs formed in cysts, or in fibrotic, inflamed, or necrotic tissue. The LRs in this study varied greatly in shape and size, measuring 7-800 microns. Special stains and energy-dispersive radiographic analysis or scanning electron microscopy revealed that some LRs contained calcium, iron (hemosiderin), silicon, and sulfur. Some pathologists have mistaken LRs for eggs, larvae, or adults of the giant kidney worm, Dioctophyma renale. D. renale is a large blood-red nematode that infects a variety of fish-eating mammals, especially mink. Fourteen documented infections of humans have been recorded, usually with adult worms expelled from the urethra. The adult worms are probably the largest helminth to parasitize humans. Eggs of D. renale are constant in size (60-80 microns X 39-47 microns), contain an embryo, and have characteristic sculpturing of the shell. Liesegang rings should not be mistaken for eggs, larvae, or adults of D. renale, or for any other helminth.

  4. ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney

    Scharpfenecker, Marion; Floot, Ben; Korlaar, Regina; Russell, Nicola S.; Stewart, Fiona A.

    2011-01-01

    Background and Purpose: Activin receptor-like kinase 1 (ALK1) is a transforming growth factor β (TGF-β) receptor, which is mainly expressed in endothelial cells regulating proliferation and migration in vitro and angiogenesis in vivo. Endothelial cells also express the co-receptor endoglin, which modulates ALK1 effects on endothelial cells. Our previous studies showed that mice with reduced endoglin levels develop less irradiation-induced vascular damage and fibrosis, caused by an impaired inflammatory response. This study was aimed at investigating the role of ALK1 in late radiation toxicity. Material and Methods: Kidneys of ALK +/+ and ALK1 +/- mice were irradiated with 14 Gy. Mice were sacrificed at 10, 20, and 30 weeks after irradiation and gene expression and protein levels were analyzed. Results: Compared to wild type littermates, ALK1 +/- mice developed less inflammation and fibrosis at 20 weeks after irradiation, but displayed an increase in pro-inflammatory and pro-fibrotic gene expression at 30 weeks. In addition, ALK1 +/- mice showed superior vascular integrity at 10 and 20 weeks after irradiation which deteriorated at 30 weeks coinciding with changes in the VEGF pathway. Conclusions: ALK1 +/- mice develop a delayed normal tissue response by modulating the inflammatory response and growth factor expression after irradiation.

  5. E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.

    Kusminski, Christine M; Gallardo-Montejano, Violeta I; Wang, Zhao V; Hegde, Vijay; Bickel, Perry E; Dhurandhar, Nikhil V; Scherer, Philipp E

    2015-10-01

    Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism. We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes. Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events. We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

  6. Facility Utilization Reports - FAA Aviation Information Utilization Reports

    Department of Transportation — Provides: (1) Space management and planning, including area calculations, tracking space by organization and employee, and monitoring space utilization information....

  7. Utility Computing: Reality and Beyond

    Ivanov, Ivan I.

    Utility Computing is not a new concept. It involves organizing and providing a wide range of computing-related services as public utilities. Much like water, gas, electricity and telecommunications, the concept of computing as public utility was announced in 1955. Utility Computing remained a concept for near 50 years. Now some models and forms of Utility Computing are emerging such as storage and server virtualization, grid computing, and automated provisioning. Recent trends in Utility Computing as a complex technology involve business procedures that could profoundly transform the nature of companies' IT services, organizational IT strategies and technology infrastructure, and business models. In the ultimate Utility Computing models, organizations will be able to acquire as much IT services as they need, whenever and wherever they need them. Based on networked businesses and new secure online applications, Utility Computing would facilitate "agility-integration" of IT resources and services within and between virtual companies. With the application of Utility Computing there could be concealment of the complexity of IT, reduction of operational expenses, and converting of IT costs to variable `on-demand' services. How far should technology, business and society go to adopt Utility Computing forms, modes and models?

  8. Increased expression of Interleukin-13 and connective tissue growth factor, and their potential roles during foreign body encapsulation of subcutaneous implants.

    Ward, W Kenneth; Li, Allen G; Siddiqui, Yasmin; Federiuk, Isaac F; Wang, Xiao-Jing

    2008-01-01

    The purpose of this study was to better understand whether interleukin-13 (IL-13) and connective tissue growth factor (CTGF) are highly expressed during foreign body encapsulation of subcutaneous devices. Mock biosensors were implanted into rats for three lengths of time (7-, 21- and 48-55 days) to address different stages of the foreign body response. Using quantitative real-time PCR and immunofluorescence, the expression of IL13, CTGF, collagen 1, decorin and fibronectin were measured in this tissue. IL-13, a product of Th2 cells, was highly expressed at all time points, with greatest expression at day 21. The IL-13 expression was paralleled by increased presence of T-cells at all time points. CTGF was also found to be more highly expressed in foreign body tissue than in controls. Collagen and decorin were highly expressed at the middle and later stages. Given the increased expression of IL-13 and CTGF in foreign body tissue, and their roles in other fibrotic disorders, these cytokines may well contribute to the formation of the foreign body capsule. Since the peak gene expression of IL-13 occurred later than the previously-reported TGFbeta expression peak, IL-13 is probably not the major stimulus to TGFbeta expression during foreign body encapsulation and may contribute to fibrosis independently.

  9. Neutron RBE for normal tissues

    Field, S.B.; Hornsey, S.

    1979-01-01

    RBE for various normal tissues is considered as a function of neutron dose per fraction. Results from a variety of centres are reviewed. It is shown that RBE is dependent on neutron energy and is tissue dependent, but is not specially high for the more critical tissues or for damage occurring late after irradiation. (author)

  10. Repair kinetics in tissues

    Thames, H.D.

    1989-01-01

    Monoexponential repair kinetics is based on the assumption of a single, dose-independent rate of repair of sublethal injury in the target cells for tissue injury after exposure to ionizing radiation. Descriptions of the available data based on this assumption have proved fairly successful for both acutely responding (skin, lip mucosa, gut) and late-responding (lung, spinal cord) normal tissues. There are indications of biphasic exponential repair in both categories, however. Unfortunately, the data usually lack sufficient resolution to permit unambiguous determination of the repair rates. There are also indications that repair kinetics may depend on the size of the dose. The data are conflicting on this account, however, with suggestions of both faster and slower repair after larger doses. Indeed, experiments that have been explicitly designed to test this hypothesis show either no effect (gut, spinal cord), faster repair after higher doses (lung, kidney), or slower repair after higher doses (skin). Monoexponential repair appears to be a fairly accurate description that provides an approximation to a more complicated picture, the elucidation of whose details will, however, require very careful and extensive experimental study. (author). 30 refs.; 1 fig

  11. Peripheral tissue oximetry

    Hyttel-Sorensen, Simon; Hessel, Trine Witzner; Greisen, Gorm

    2014-01-01

    Estimation of regional tissue oxygenation (rStO2) by near infrared spectroscopy enables non-invasive end-organ oxygen balance monitoring and could be a valuable tool in intensive care. However, the diverse absolute values and dynamics of different devices, and overall poor repeatability of measur......Estimation of regional tissue oxygenation (rStO2) by near infrared spectroscopy enables non-invasive end-organ oxygen balance monitoring and could be a valuable tool in intensive care. However, the diverse absolute values and dynamics of different devices, and overall poor repeatability......, and response to changing oxygenation by the down slope of rStO2 during vascular occlusion in the respective arm. 10 healthy adults, 21-29 years old, with double skinfolds on the forearm less than 10 mm participated. The median rStO2 was 70.7% (interquartile range (IQR) 7.7%), 68.4% (IQR 8.4%), and 64.6% (IQR 4...

  12. Localization of IAA transporting tissue by tissue printing and autoradiography

    Mee-Rye Cha; Evans, M.L.; Hangarter, R.P.

    1991-01-01

    Tissue printing on nitrocellulose membranes provides a useful technique for visualizing anatomical details of tissue morphology of cut ends of stem segments. Basal ends of Coleus stem and corn coleoptile segments that were transporting 14 C-IAA were gently blotted onto DEAE-nitrocellulose for several minutes to allow 14 C-IAA to efflux from the tissue. Because of the anion exchange properties of DEAE-nitrocellulose the 14 C-IAA remains on the membrane at the point it leaves the transporting tissue. Autoradiography of the DEAE membrane allowed indirect visualization of the tissues preferentially involved in auxin transport. The authors observed that polar transport through the stem segments occurred primarily through or in association with vascular tissues. However, in Coleus stems, substantial amounts of the label appeared to move through the tissue by diffusion as well as by active transport

  13. Alteration of gene expression profile in Niemann-Pick type C mice correlates with tissue damage and oxidative stress.

    Mary C Vázquez

    Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild-type control (Npc1(+/+; WT and homozygous-mutant (Npc1(-/-; NPC mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice. CONCLUSIONS/SIGNIFICANCE: In NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress

  14. Three-dimensional bioprinting in tissue engineering and regenerative medicine.

    Gao, Guifang; Cui, Xiaofeng

    2016-02-01

    With the advances of stem cell research, development of intelligent biomaterials and three-dimensional biofabrication strategies, highly mimicked tissue or organs can be engineered. Among all the biofabrication approaches, bioprinting based on inkjet printing technology has the promises to deliver and create biomimicked tissue with high throughput, digital control, and the capacity of single cell manipulation. Therefore, this enabling technology has great potential in regenerative medicine and translational applications. The most current advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review, including vasculature, muscle, cartilage, and bone. In addition, the benign side effect of bioprinting to the printed mammalian cells can be utilized for gene or drug delivery, which can be achieved conveniently during precise cell placement for tissue construction. With layer-by-layer assembly, three-dimensional tissues with complex structures can be printed using converted medical images. Therefore, bioprinting based on thermal inkjet is so far the most optimal solution to engineer vascular system to the thick and complex tissues. Collectively, bioprinting has great potential and broad applications in tissue engineering and regenerative medicine. The future advances of bioprinting include the integration of different printing mechanisms to engineer biphasic or triphasic tissues with optimized scaffolds and further understanding of stem cell biology.

  15. Privatization of municipal electrical utilities

    Carr, J.

    1998-01-01

    The challenges and special issues which arise through the sale of a municipal electric utility were discussed. The recent sales of two utilities, the Kentville Electric Commission in Nova Scotia and Cornwall Electric in Ontario, were used as examples to show how the sale of an electric utility differs from the sale of most business enterprises. Municipal utilities are integral parts of the communities they serve which introduces several complexities into the sale. Factors that require special attention in the sale of the utilities, including electricity rates, local accountability, treatment of employees and local economic development, and the need for a comprehensive communication program to deal with the substantial public interest that sale of a municipal utility will engender, were reviewed

  16. Mox fuel utilization in ATR

    下村 和生; 川太 徳夫

    1987-01-01

    ATR, a heavy-water moderated boiling-light-water cooled reactor developed in Japan, is a unique reactor with out-standing flexibility regarding nuclear fuel utilization, because it has superior properties concerning the utilization of plutonium, recovered uranium and depleted uranium. The development of this type of reactor is expected to contribute both to the stable supply of energy and to the establishment of plutonium utilization in Japan. Much effort has been and will be made on the deve...

  17. Utility deregulation and AMR technology

    Moore, G.

    1991-01-01

    This article reviews the effects of deregulation on other utilities and services and examines how the electric utilities can avoid the worst of these effects and capitalize of the best aspects of competition in achieving marketing excellence. The article presents deregulation as a customer service and underscores the need for utilities to learn to compete aggressively and intelligently and provide additional services available through technology such as automated meter reading

  18. Subjective expected utility without preferences

    Bouyssou , Denis; Marchant , Thierry

    2011-01-01

    This paper proposes a theory of subjective expected utility based on primitives only involving the fact that an act can be judged either "attractive" or "unattractive". We give conditions implying that there are a utility function on the set of consequences and a probability distribution on the set of states such that attractive acts have a subjective expected utility above some threshold. The numerical representation that is obtained has strong uniqueness properties.

  19. VT Electric Utility Franchise Areas

    Vermont Center for Geographic Information — (Link to Metadata) ELCFRANCHISE includes Vermont's Electric Utility Franchise boundaries. It is a compilation of many data sources. The boundaries are approximate...

  20. Multiattribute Utility Theory, Intertemporal Utility and Correlation Aversion

    Andersen, Steffen; Harrison, Glenn W.; Lau, Morten

    2018-01-01

    Convenient assumptions about qualitative properties of the intertemporal utility function have generated counterintuitive implications for the relationship between atemporal risk aversion and the intertemporal elasticity of substitution. If the intertemporal utility function is additively separable...... aversion. Our results show that subjects are correlation averse over lotteries with intertemporal income profiles....

  1. The changing utility workforce and the evolution of utility design

    Saunders, A. [Autodesk Inc., (United States); Zeiss, G. [Autodesk Inc., (Canada)

    2008-07-01

    Electric utilities are experiencing an unprecedented workforce turnover as a wave of retirement approaches. The challenge for the industry is to mitigate the loss of industry knowledge and attract talented new designers and engineers. Utilities need to effectively transfer knowledge from an existing workforce with up to three decades of experience to their new hires who have very different skill levels as well as different expectations regarding design tools compared to their predecessors. Knowledge transfer from the retiring workforce to the new hires can be facilitated with rules-based design software. Easy-to-use design software with built-in validations can accelerate training. By investing in utility design software that incorporates the best elements of design processes from other industries, utilities can attract the new generation of engineers and designers to help utilities define new processes to upgrade existing infrastructure, bring online new distributed and renewable generation facilities, implement smart devices and meters, and improve customer service. 3 refs.

  2. Evaluation of thyroid tissue by Raman spectroscopy

    Teixeira, C. S. B.; Bitar, R. A.; Santos, A. B. O.; Kulcsar, M. A. V.; Friguglietti, C. U. M.; Martinho, H. S.; da Costa, R. B.; Martin, A. A.

    2010-02-01

    Thyroid gland is a small gland in the neck consisting of two lobes connected by an isthmus. Thyroid's main function is to produce the hormones thyroxine (T4), triiodothyronine (T3) and calcitonin. Thyroid disorders can disturb the production of these hormones, which will affect numerous processes within the body such as: regulating metabolism and increasing utilization of cholesterol, fats, proteins, and carbohydrates. The gland itself can also be injured; for example, neoplasias, which have been considered the most important, causing damage of to the gland and are difficult to diagnose. There are several types of thyroid cancer: Papillary, Follicular, Medullary, and Anaplastic. The occurrence rate, in general is between 4 and 7%; which is on the increase (30%), probably due to new technology that is able to find small thyroid cancers that may not have been found previously. The most common method used for thyroid diagnoses are: anamnesis, ultrasonography, and laboratory exams (Fine Needle Aspiration Biopsy- FNAB). However, the sensitivity of those test are rather poor, with a high rate of false-negative results, therefore there is an urgent need to develop new diagnostic techniques. Raman spectroscopy has been presented as a valuable tool for cancer diagnosis in many different tissues. In this work, 27 fragments of the thyroid were collected from 18 patients, comprising the following histologic groups: goitre adjacent tissue, goitre nodular tissue, follicular adenoma, follicular carcinoma, and papillary carcinoma. Spectral collection was done with a commercial FTRaman Spectrometer (Bruker RFS100/S) using a 1064 nm laser excitation and Ge detector. Principal Component Analysis, Cluster Analysis, and Linear Discriminant Analysis with cross-validation were applied as spectral classification algorithm. Comparing the goitre adjacent tissue with the goitre nodular region, an index of 58.3% of correct classification was obtained. Between goitre (nodular region and

  3. Tissue engineered tumor models.

    Ingram, M; Techy, G B; Ward, B R; Imam, S A; Atkinson, R; Ho, H; Taylor, C R

    2010-08-01

    Many research programs use well-characterized tumor cell lines as tumor models for in vitro studies. Because tumor cells grown as three-dimensional (3-D) structures have been shown to behave more like tumors in vivo than do cells growing in monolayer culture, a growing number of investigators now use tumor cell spheroids as models. Single cell type spheroids, however, do not model the stromal-epithelial interactions that have an important role in controlling tumor growth and development in vivo. We describe here a method for generating, reproducibly, more realistic 3-D tumor models that contain both stromal and malignant epithelial cells with an architecture that closely resembles that of tumor microlesions in vivo. Because they are so tissue-like we refer to them as tumor histoids. They can be generated reproducibly in substantial quantities. The bioreactor developed to generate histoid constructs is described and illustrated. It accommodates disposable culture chambers that have filled volumes of either 10 or 64 ml, each culture yielding on the order of 100 or 600 histoid particles, respectively. Each particle is a few tenths of a millimeter in diameter. Examples of histological sections of tumor histoids representing cancers of breast, prostate, colon, pancreas and urinary bladder are presented. Potential applications of tumor histoids include, but are not limited to, use as surrogate tumors for pre-screening anti-solid tumor pharmaceutical agents, as reference specimens for immunostaining in the surgical pathology laboratory and use in studies of invasive properties of cells or other aspects of tumor development and progression. Histoids containing nonmalignant cells also may have potential as "seeds" in tissue engineering. For drug testing, histoids probably will have to meet certain criteria of size and tumor cell content. Using a COPAS Plus flow cytometer, histoids containing fluorescent tumor cells were analyzed successfully and sorted using such criteria.

  4. Expressão eficiente do gene reporter beta-glucuronidase nos tecidos vasculares de batata (Solanum tuberosum L. utilizando de um promotor específico (BRA3 de Agrobacterium rhizogenes Efficient expression of beta-glucuronidase reporter gene in vascular tissue of potato (Solanum tuberosum L. utilizing a specific promoter (BRA3 from Agrobacterium rhizogenes

    Antonio Carlos Torres

    2003-06-01

    Full Text Available Promotores tecido-específico controlam a transcrição de genes em diferentes tecidos vegetais bem como em diferentes estádios de desenvolvimento da planta, levando à indução de distintos níveis de atividade transiente e/ou estável do gene. Tais promotores podem ser empregados para a expressão seletiva de genes de interesse. O promotor rol A de Agrobacterium rhizogenes, por exemplo, é floema-específico, sugerindo que possa ser empregado em estratégias de defesa de plantas que são infectadas por vírus com replicação restrita ao floema. A expressão do gene marcador da ß-glucuronidase (gus dirigido pelo promotor rol A (pBRA3 foi observada em plantas transgênicas de batata (cvs. Macaca e Baronesa. Entrenós e secções de folhas foram submetidos ao cocultivo com A. tumefaciens. A atividade do gene gus avaliada em brotações resistentes à canamicina não se restringiu ao floema (alto nível de expressão do gene, mas também se manifestou no xilema dos caules. As expressões transiente e estável são, no entanto, tecido-específicas, localizadas sobretudo no sistema vascular de entrenós e ausente em raízes e folhas. As plantas gus positivas foram micropropagadas, plantadas em casa de vegetação e avaliadas por PCR, utilizando-se 'primers' específicos para o gene npt II. Nenhuma alteração fenotípica foi observada em plantas transgênicas, em relação às não transformadas.Tissue-especific promoters allow the modulation of gene transcription in different tissue types as well as in different stages of plant development, leading different levels of transient and stable activity of the gene product. These promoters have been employed for selective gene expression. The Agrobacterium rhizogenes rol A gene promoter (BRA3 controls phloem-specific expression indicating that this promoter might have an important role in plant defense strategies against virus which replicated only in the phloem. The expression of

  5. Radioligand assay for biotin in liver tissues

    Rettenmaier, R.

    1979-01-01

    A radioligand assay for biotin in liver tissue is described. 3 H-biotin is used as tracer and avidin as binder. The biotin-loaded avidin is separated from free biotin on dextran-coated charcoal, which leaves the avidin-biotin complex in the supernatant liquid. Thus, the avidin-biotin complex can easily be utilized for determination of the radioactivity. Calibration with known additions of biotin in the range 0.25-8.0 ng per assay sample yields a linear logit-log plot. The biotin is extracted from liver tissues by enzymatic proteolysis with papain. This treatment is optimized to liberate the bound forms of the vitamin. Microbiological parallel assays with Lactobacillus plantarum were in good agreement with the radioligand assay giving a regression coefficient of 0.974(n=44). The coefficient of variation was found to be 4.2% in the range 500-1200 ng of biotin per g of liver tissue (n=46). The method is simple and reliable and allows the simultaneous analysis of a considerable number of samples. (Auth.)

  6. The broccoli (Brassica oleracea) phloem tissue proteome.

    Anstead, James A; Hartson, Steven D; Thompson, Gary A

    2013-11-07

    The transport of sugars, hormones, amino acids, proteins, sugar alcohols, and other organic compounds from the sites of synthesis to the sites of use or storage occurs through the conducting cells of the phloem. To better understand these processes a comprehensive understanding of the proteins involved is required. While a considerable amount of data has been obtained from proteomic analyses of phloem sap, this has mainly served to identify the soluble proteins that are translocated through the phloem network. In order to obtain more comprehensive proteomic data from phloem tissue we developed a simple dissection procedure to isolate phloem tissue from Brassica oleracea. The presence of a high density of phloem sieve elements was confirmed using light microscopy and fluorescently labeled sieve element-specific antibodies. To increase the depth of the proteomic analysis for membrane bound and associated proteins, soluble proteins were extracted first and subsequent extractions were carried out using two different detergents (SDS and CHAPSO). Across all three extractions almost four hundred proteins were identified and each extraction method added to the analysis demonstrating the utility of an approach combining several extraction protocols. The phloem was found to be enriched in proteins associated with biotic and abiotic stress responses and structural proteins. Subsequent expression analysis identified a number of genes that appear to be expressed exclusively or at very high levels in phloem tissue, including genes that are known to express specifically in the phloem as well as novel phloem genes.

  7. The tissue microarray OWL schema: An open-source tool for sharing tissue microarray data

    Hyunseok P Kang

    2010-01-01

    Full Text Available Background: Tissue microarrays (TMAs are enormously useful tools for translational research, but incompatibilities in database systems between various researchers and institutions prevent the efficient sharing of data that could help realize their full potential. Resource Description Framework (RDF provides a flexible method to represent knowledge in triples, which take the form Subject- Predicate-Object. All data resources are described using Uniform Resource Identifiers (URIs, which are global in scope. We present an OWL (Web Ontology Language schema that expands upon the TMA data exchange specification to address this issue and assist in data sharing and integration. Methods: A minimal OWL schema was designed containing only concepts specific to TMA experiments. More general data elements were incorporated from predefined ontologies such as the NCI thesaurus. URIs were assigned using the Linked Data format. Results: We present examples of files utilizing the schema and conversion of XML data (similar to the TMA DES to OWL. Conclusion: By utilizing predefined ontologies and global unique identifiers, this OWL schema provides a solution to the limitations of XML, which represents concepts defined in a localized setting. This will help increase the utilization of tissue resources, facilitating collaborative translational research efforts.

  8. Tissue preservation with mass spectroscopic analysis: Implications for cancer diagnostics.

    Hall, O Morgan; Peer, Cody J; Figg, William D

    2018-05-17

    Surgical intervention is a common treatment modality for localized cancer. Post-operative analysis involves evaluation of surgical margins to assess whether all malignant tissue has been resected because positive surgical margins lead to a greater likelihood of recurrence. Secondary treatments are utilized to minimize the negative effects of positive surgical margins. Recently, in Science Translational Medicine, Zhang et al describe a new mass spectroscopic technique that could potentially decrease the likelihood of positive surgical margins. Their nondestructive in vivo tissue sampling leads to a highly accurate and rapid cancer diagnosis with great precision between healthy and malignant tissue. This new tool has the potential to improve surgical margins and accelerate cancer diagnostics by analyzing biomolecular signatures of various tissues and diseases.

  9. The utility target market model

    Leng, G.J.; Martin, J.

    1994-01-01

    A new model (the Utility Target Market Model) is used to evaluate the economic benefits of photovoltaic (PV) power systems located at the electrical utility customer site. These distributed PV demand-side generation systems can be evaluated in a similar manner to other demand-side management technologies. The energy and capacity values of an actual PV system located in the service area of the New England Electrical System (NEES) are the two utility benefits evaluated. The annual stream of energy and capacity benefits calculated for the utility are converted to the installed cost per watt that the utility should be willing to invest to receive this benefit stream. Different discount rates are used to show the sensitivity of the allowable installed cost of the PV systems to a utility's average cost of capital. Capturing both the energy and capacity benefits of these relatively environmentally friendly distributed generators, NEES should be willing to invest in this technology when the installed cost per watt declines to ca $2.40 using NEES' rated cost of capital (8.78%). If a social discount rate of 3% is used, installation should be considered when installed cost approaches $4.70/W. Since recent installations in the Sacramento Municipal Utility District have cost between $7-8/W, cost-effective utility applications of PV are close. 22 refs., 1 fig., 2 tabs

  10. Empirical Specification of Utility Functions.

    Mellenbergh, Gideon J.

    Decision theory can be applied to four types of decision situations in education and psychology: (1) selection; (2) placement; (3) classification; and (4) mastery. For the application of the theory, a utility function must be specified. Usually the utility function is chosen on a priori grounds. In this paper methods for the empirical assessment…

  11. Xylose utilization in recombinant zymomonas

    Caimi, Perry G; McCole, Laura; Tao, Luan; Tomb, Jean-Francois; Viitanen, Paul V

    2014-03-25

    Xylose-utilizing Zymomonas strains studied were found to accumulate ribulose when grown in xylose-containing media. Engineering these strains to increase ribose-5-phosphate isomerase activity led to reduced ribulose accumulation, improved growth, improved xylose utilization, and increased ethanol production.

  12. A compendium of canine normal tissue gene expression.

    Joseph Briggs

    Full Text Available BACKGROUND: Our understanding of disease is increasingly informed by changes in gene expression between normal and abnormal tissues. The release of the canine genome sequence in 2005 provided an opportunity to better understand human health and disease using the dog as clinically relevant model. Accordingly, we now present the first genome-wide, canine normal tissue gene expression compendium with corresponding human cross-species analysis. METHODOLOGY/PRINCIPAL FINDINGS: The Affymetrix platform was utilized to catalogue gene expression signatures of 10 normal canine tissues including: liver, kidney, heart, lung, cerebrum, lymph node, spleen, jejunum, pancreas and skeletal muscle. The quality of the database was assessed in several ways. Organ defining gene sets were identified for each tissue and functional enrichment analysis revealed themes consistent with known physio-anatomic functions for each organ. In addition, a comparison of orthologous gene expression between matched canine and human normal tissues uncovered remarkable similarity. To demonstrate the utility of this dataset, novel canine gene annotations were established based on comparative analysis of dog and human tissue selective gene expression and manual curation of canine probeset mapping. Public access, using infrastructure identical to that currently in use for human normal tissues, has been established and allows for additional comparisons across species. CONCLUSIONS/SIGNIFICANCE: These data advance our understanding of the canine genome through a comprehensive analysis of gene expression in a diverse set of tissues, contributing to improved functional annotation that has been lacking. Importantly, it will be used to inform future studies of disease in the dog as a model for human translational research and provides a novel resource to the community at large.

  13. Spaceflight bioreactor studies of cells and tissues.

    Freed, Lisa E; Vunjak-Novakovic, Gordana

    2002-01-01

    Studies of the fundamental role of gravity in the development and function of biological organisms are a central component of the human exploration of space. Microgravity affects numerous physical phenomena relevant to biological research, including the hydrostatic pressure in fluid filled vesicles, sedimentation of organelles, and buoyancy-driven convection of flow and heat. These physical phenomena can in turn directly and indirectly affect cellular morphology, metabolism, locomotion, secretion of extracellular matrix and soluble signals, and assembly into functional tissues. Studies aimed at distinguishing specific effects of gravity on biological systems require the ability to: (i) control and systematically vary gravity, e.g. by utilizing the microgravity environment of space in conjunction with an in-flight centrifuge; and (ii) maintain constant all other factors in the immediate environment, including in particular concentrations and exchange rates of biochemical species and hydrodynamic shear. The latter criteria imply the need for gravity-independent mechanisms to provide for mass transport between the cells and their environment. Available flight hardware has largely determined the experimental design and scientific objectives of spaceflight cell and tissue culture studies carried out to date. Simple culture vessels have yielded important quantitative data, and helped establish in vitro models of cell locomotion, growth and differentiation in various mammalian cell types including embryonic lung cells [6], lymphocytes [2,8], and renal cells [7,31]. Studies done using bacterial cells established the first correlations between gravity-dependent factors such as cell settling velocity and diffusional distance and the respective cell responses [12]. The development of advanced bioreactors for microgravity cell and tissue culture and for tissue engineering has benefited both research areas and provided relevant in vitro model systems for studies of astronaut

  14. Hualapai Tribal Utility Development Project

    Hualapai Tribal Nation

    2008-05-25

    The first phase of the Hualapai Tribal Utility Development Project (Project) studied the feasibility of establishing a tribally operated utility to provide electric service to tribal customers at Grand Canyon West (see objective 1 below). The project was successful in completing the analysis of the energy production from the solar power systems at Grand Canyon West and developing a financial model, based on rates to be charged to Grand Canyon West customers connected to the solar systems, that would provide sufficient revenue for a Tribal Utility Authority to operate and maintain those systems. The objective to establish a central power grid over which the TUA would have authority and responsibility had to be modified because the construction schedule of GCW facilities, specifically the new air terminal, did not match up with the construction schedule for the solar power system. Therefore, two distributed systems were constructed instead of one central system with a high voltage distribution network. The Hualapai Tribal Council has not taken the action necessary to establish the Tribal Utility Authority that could be responsible for the electric service at GCW. The creation of a Tribal Utility Authority (TUA) was the subject of the second objective of the project. The second phase of the project examined the feasibility and strategy for establishing a tribal utility to serve the remainder of the Hualapai Reservation and the feasibility of including wind energy from a tribal wind generator in the energy resource portfolio of the tribal utility (see objective 2 below). It is currently unknown when the Tribal Council will consider the implementation of the results of the study. Objective 1 - Develop the basic organizational structure and operational strategy for a tribally controlled utility to operate at the Tribe’s tourism enterprise district, Grand Canyon West. Coordinate the development of the Tribal Utility structure with the development of the Grand Canyon

  15. Tritium metabolism in rat tissues

    Takeda, H.

    1982-01-01

    As part of a series of studies designed to evaluate the relative radiotoxicity of various tritiated compounds, metabolism of tritium in rat tissues was studied after administration of tritiated water, leucine, thymidine, and glucose. The distribution and retention of tritium varied widely, depending on the chemical compound administered. Tritium introduced as tritiated water behaved essentially as body water and became uniformly distributed among the tissues. However, tritium administered as organic compounds resulted in relatively high incorporation into tissue constituents other than water, and its distribution differed among the various tissues. Moreover, the excretion rate of tritium from tissues was slower for tritiated organic compounds than for tritiated water. Administrationof tritiated organic compounds results in higher radiation doses to the tissues than does administration of tritiated water. Among the tritiated compounds examined, for equal radioactivity administered, leucine gave the highest radiation dose, followed in turn by thymidine, glucose, and water. (author)

  16. Bioprinting for Neural Tissue Engineering.

    Knowlton, Stephanie; Anand, Shivesh; Shah, Twisha; Tasoglu, Savas

    2018-01-01

    Bioprinting is a method by which a cell-encapsulating bioink is patterned to create complex tissue architectures. Given the potential impact of this technology on neural research, we review the current state-of-the-art approaches for bioprinting neural tissues. While 2D neural cultures are ubiquitous for studying neural cells, 3D cultures can more accurately replicate the microenvironment of neural tissues. By bioprinting neuronal constructs, one can precisely control the microenvironment by specifically formulating the bioink for neural tissues, and by spatially patterning cell types and scaffold properties in three dimensions. We review a range of bioprinted neural tissue models and discuss how they can be used to observe how neurons behave, understand disease processes, develop new therapies and, ultimately, design replacement tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Computational Modeling in Tissue Engineering

    2013-01-01

    One of the major challenges in tissue engineering is the translation of biological knowledge on complex cell and tissue behavior into a predictive and robust engineering process. Mastering this complexity is an essential step towards clinical applications of tissue engineering. This volume discusses computational modeling tools that allow studying the biological complexity in a more quantitative way. More specifically, computational tools can help in:  (i) quantifying and optimizing the tissue engineering product, e.g. by adapting scaffold design to optimize micro-environmental signals or by adapting selection criteria to improve homogeneity of the selected cell population; (ii) quantifying and optimizing the tissue engineering process, e.g. by adapting bioreactor design to improve quality and quantity of the final product; and (iii) assessing the influence of the in vivo environment on the behavior of the tissue engineering product, e.g. by investigating vascular ingrowth. The book presents examples of each...

  18. Polyploidization in liver tissue.

    Gentric, Géraldine; Desdouets, Chantal

    2014-02-01

    Polyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and, therefore, possibly a gain of function; alternately, it can be associated with development of disease, such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division (endoreplication, mitotic slippage, or cytokinesis failure). Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs mainly during liver development, but also in adults with increasing age or because of cellular stress (eg, surgical resection, toxic exposure, or viral infections). This review will explore the mechanisms that lead to the development of polyploid cells, our current state of understanding of how polyploidization is regulated during liver growth, and its consequence on liver function. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  19. Soft tissue angiosarcomas

    Morales, P.H.; Lindberg, R.D.; Barkley, H.T.

    1981-12-01

    From 1949 to 1979, 12 patients with soft tissue angiosarcoma received radiotherapy (alone or in combination with other modalities of treatment) with curative intent at The University of Texas M.D. Anderson Hospital and Tumor Institute. The primary site was the head and neck in six patients (scalp, four; maxillary antrum, one; and oral tongue, one), the breast in four patients, and the thigh in two patients. All four patients with angiosarcoma of the scalp had advanced multifocal tumors, and two of them had clinically positive neck nodes. None of these tumors were controlled locally, and local recurrences occurred within and/or at a distance from the generous fields of irradiation. The remaining two patients with head and neck lesions had their disease controlled by surgery and postoperative irradiation. Three of the four angiosarcomas of the breast were primary cases which were treated by a combination of surgery (excisional biopsy, simple mastectomy, radical mastectomy) and postoperative irradiation. One patient also received adjuvant chemotherapy. The fourth patient was treated for scar recurrence after radical mastectomy. All four patients had their disease locally controlled, and two of them have survived over 5 years. The two patients with angiosarcoma of the thigh were treated by conservative surgical excision and postoperative irradiation. One patient had her disease controlled; the other had a local recurrence requiring hip disarticulation and subsequent hemipelvectomy for salvage.

  20. Extensive scarring induced by chronic intrathecal tubing augmented cord tissue damage and worsened functional recovery after rat spinal cord injury.

    Zhang, Shu-xin; Huang, Fengfa; Gates, Mary; White, Jason; Holmberg, Eric G

    2010-08-30

    Intrathecal infusion has been widely used to directly deliver drugs or neurotrophins to a lesion site following spinal cord injury. Evidence shows that intrathecal infusion is efficient for 7 days but is markedly reduced after 14 days, due to time dependent occlusion. In addition, extensive fibrotic scarring is commonly observed with intrathecal infusion. These anomalies need to be clearly elucidated in histology. In the present study, all adult Long-Evans rats received a 25 mm contusion injury on spinal cord T10 produced using the NYU impactor device. Immediately after injury, catheter tubing with an outer diameter of 0.38 mm was inserted through a small dural opening at L3 into the subdural space with the tubing tip positioned near the injury site. The tubing was connected to an Alzet mini pump, which was filled with saline solution and was placed subcutaneously. Injured rats without tubing served as control. Rats were behaviorally tested for 6 weeks using the BBB locomotor rating scale and histologically assessed for tissue scarring. Six weeks later, we found that the intrathecal tubing caused extensive scarring and inflammation, related to neutrophils, macrophages and plasma cells. The tubing's tip was occluded by scar tissue and inflammatory cells. The scar tissue surrounding the tubing consists of 20-70 layers of fibroblasts and densely compacted collagen fibers, seriously compressing and damaging the cord tissue. BBB scores of rats with intrathecal tubing were significantly lower than control rats (p<0.01) from 2 weeks after injury, implying serious impairment of functional recovery caused by the scarring. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  1. Epithelial-mesenchymal transition in keloid tissues and TGF-β1-induced hair follicle outer root sheath keratinocytes.

    Yan, Li; Cao, Rui; Wang, Lianzhao; Liu, Yuanbo; Pan, Bo; Yin, Yanhua; Lv, Xiaoyan; Zhuang, Qiang; Sun, Xuejian; Xiao, Ran

    2015-01-01

    Keloid is a skin fibrotic disease with the characteristics of recurrence and invasion, its pathogenesis still remains unrevealed. The epithelial-mesenchymal transition (EMT) is critical for wound healing, fibrosis, recurrence, and invasion of cancer. We sought to investigate the EMT in keloid and the mechanism through which the EMT regulates keloid formation. In keloid tissues, the expressions of EMT-associated markers and transforming growth factor (TGF)-β1/Smad3 signaling were examined by immunohistochemistry. In the keloid epidermis and dermal tissue, the expressions of genes related to the regulation of skin homeostasis, fibroblast growth factor receptor 2 (FGFR2) and p63, were analyzed using quantitative real-time polymerase chain reaction. The results showed that accompanying the loss of the epithelial marker E-cadherin and the gain of the mesenchymal markers fibroblast-specific protein 1 (FSP1) and vimentin in epithelial cells from epidermis and skin appendages, and in endothelial cells from dermal microvessels, enhanced TGF-β1 expression and Smad3 phosphorylation were noted in keloid tissues. Moreover, alternative splicing of the FGFR2 gene switched the predominantly expressed isoform from FGFR2-IIIb to -IIIc, concomitant with the decreased expression of ΔNp63 and TAp63, which changes might partially account for abnormal epidermis and appendages in keloids. In addition, we found that TGF-β1-induced hair follicle outer root sheath keratinocytes (ORSKs) and normal skin epithelial cells underwent EMT in vitro with ORSKs exhibiting more obvious EMT changes and more similar expression profiles for EMT-associated and skin homeostasis-related genes as in keloid tissues, suggesting that ORSKs might play crucial roles in the EMT in keloids. Our study provided insights into the molecular mechanisms mediating the EMT pathogenesis of keloids. © 2015 by the Wound Healing Society.

  2. Recent advances in hydrogels for cartilage tissue engineering.

    Vega, S L; Kwon, M Y; Burdick, J A

    2017-01-30

    Articular cartilage is a load-bearing tissue that lines the surface of bones in diarthrodial joints. Unfortunately, this avascular tissue has a limited capacity for intrinsic repair. Treatment options for articular cartilage defects include microfracture and arthroplasty; however, these strategies fail to generate tissue that adequately restores damaged cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. To date, a wide range of scaffolds and cell sources have emerged with a focus on recapitulating the microenvironments present during development or in adult tissue, in order to induce the formation of cartilaginous constructs with biochemical and mechanical properties of native tissue. Hydrogels have emerged as a promising scaffold due to the wide range of possible properties and the ability to entrap cells within the material. Towards improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Some of these advances include the development of improved network crosslinking (e.g. double-networks), new techniques to process hydrogels (e.g. 3D printing) and better incorporation of biological signals (e.g. controlled release). This review summarises these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

  3. Normal tissue complication probability (NTCP), the clinician,s perspective

    Yeoh, E.K.

    2011-01-01

    Full text: 3D radiation treatment planning has enabled dose distributions to be related to the volume of normal tissues irradiated. The dose volume histograms thus derived have been utilized to set NTCP dose constraints to facilitate optimization of treatment planning. However, it is not widely appreciated that a number of important variables other than DYH's which determine NTCP in the individual patient. These variables will be discussed under the headings of patient and treatment related as well as tumour related factors. Patient related factors include age, co-morbidities such as connective tissue disease and diabetes mellitus, previous tissue/organ damage, tissue architectural organization (parallel or serial), regional tissue/organ and individual tissue/organ radiosensitivities as well as the development of severe acute toxicity. Treatment related variables which need to be considered include dose per fraction (if not the conventional 1.8012.00 Gy/fraction, particularly for IMRT), number of fractions and total dose, dose rate (particularly if combined with brachytherapy) and concurrent chemotherapy or other biological dose modifiers. Tumour related factors which impact on NTCP include infiltration of normal tissue/organ usually at presentation leading to compromised function but also with recurrent disease after radiation therapy as well as variable tumour radiosensitivities between and within tumour types. Whilst evaluation of DYH data is a useful guide in the choice of treatment plan, the current state of knowledge requires the clinician to make an educated judgement based on a consideration of the other factors.

  4. Recent advances in hydrogels for cartilage tissue engineering

    SL Vega

    2017-01-01

    Full Text Available Articular cartilage is a load-bearing tissue that lines the surface of bones in diarthrodial joints. Unfortunately, this avascular tissue has a limited capacity for intrinsic repair. Treatment options for articular cartilage defects include microfracture and arthroplasty; however, these strategies fail to generate tissue that adequately restores damaged cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. To date, a wide range of scaffolds and cell sources have emerged with a focus on recapitulating the microenvironments present during development or in adult tissue, in order to induce the formation of cartilaginous constructs with biochemical and mechanical properties of native tissue. Hydrogels have emerged as a promising scaffold due to the wide range of possible properties and the ability to entrap cells within the material. Towards improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Some of these advances include the development of improved network crosslinking (e.g. double-networks, new techniques to process hydrogels (e.g. 3D printing and better incorporation of biological signals (e.g. controlled release. This review summarises these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

  5. Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice.

    Itai Spector

    Full Text Available INTRODUCTION: Stroma cells and extracellular matrix (ECM components provide the pivotal microenvironment for tumor development. The study aimed to evaluate the importance of the pancreatic stroma for tumor development. METHODS: Pancreatic tumor cells were implanted subcutaneously into green fluorescent protein transgenic mice, and stroma cells invading the tumors were identified through immunohistochemistry. Inhibition of tumor invasion by stroma cells was achieved with halofuginone, an inhibitor of TGFβ/Smad3 signaling, alone or in combination with chemotherapy. The origin of tumor ECM was evaluated with species-specific collagen I antibodies and in situ hybridization of collagen α1(I gene. Pancreatic fibrosis was induced by cerulean injection and tumors by spleen injection of pancreatic tumor cells. RESULTS: Inhibition of stroma cell infiltration and reduction of tumor ECM levels by halofuginone inhibited development of tumors derived from mouse and human pancreatic cancer cells. Halofuginone reduced the number only of stroma myofibroblasts expressing both contractile and collagen biosynthesis markers. Both stroma myofibroblasts and tumor cells generated ECM that contributes to tumor growth. Combination of treatments that inhibit stroma cell infiltration, cause apoptosis of myofibroblasts and inhibit Smad3 phosphorylation, with chemotherapy that increases tumor-cell apoptosis without affecting Smad3 phosphorylation was more efficacious than either treatment alone. More tumors developed in fibrotic than in normal pancreas, and prevention of tissue fibrosis greatly reduced tumor development. CONCLUSIONS: The utmost importance of tissue fibrosis and of stroma cells for tumor development presents potential new therapy targets, suggesting combination therapy against stroma and neoplastic cells as a treatment of choice.

  6. Development of carbon-11 labeled acryl amides for selective PET imaging of active tissue transglutaminase.

    van der Wildt, Berend; Wilhelmus, Micha M M; Bijkerk, Jonne; Haveman, Lizeth Y F; Kooijman, Esther J M; Schuit, Robert C; Bol, John G J M; Jongenelen, Cornelis A M; Lammertsma, Adriaan A; Drukarch, Benjamin; Windhorst, Albert D

    2016-04-01

    Tissue transglutaminase (TG2) is a ubiquitously expressed enzyme capable of forming metabolically and mechanically stable crosslinks between the γ-carboxamide of a glutamine acyl-acceptor substrate and the ε-amino functionality of a lysine acyl-donor substrate resulting in protein oligomers. High TG2 crosslinking activity has been implicated in the pathogenesis of various diseases including celiac disease, cancer and fibrotic and neurodegenerative diseases. Development of a PET tracer specific for active TG2 provides a novel tool to further investigate TG2 biology in vivo in disease states. Recently, potent irreversible active site TG2 inhibitors carrying an acrylamide warhead were synthesized and pharmacologically characterized. Three of these inhibitors, compound 1, 2 and 3, were successfully radiolabeled with carbon-11 on the acrylamide carbonyl position using a palladium mediated [(11)C]CO aminocarbonylation reaction. Ex vivo biodistribution and plasma stability were evaluated in healthy Wistar rats. Autoradiography was performed on MDA-MB-231 tumor sections. [(11)C]1, -2 and -3 were obtained in decay corrected radiochemical yields of 38-55%. Biodistribution showed low uptake in peripheral tissues, with the exception of liver and kidney. Low brain uptake of <0.05% ID/g was observed. Blood plasma analysis demonstrated that [(11)C]1 and [(11)C]2 were rapidly metabolized, whereas [(11)C]3 was metabolized at a more moderate rate (63.2 ± 6.8 and 28.7 ± 10.8% intact tracer after 15 and 45 min, respectively). Autoradiography with [(11)C]3 on MDA-MB-231 tumor sections showed selective and specific binding of the radiotracer to the active state of TG2. Taken together, these results identify [(11)C]3 as the most promising of the three compounds tested for development as PET radiotracer for the in vivo investigation of TG2 activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Dealing with the difficult utility

    Keats, D.E.; Sundquist, M.J.; Cross, J.P.

    1991-01-01

    STS HydroPower, Ltd. (STS) is an independent hydroelectric power developer involved in the full scope of hydroelectric activities. This includes the permitting, design, financing, turbine design and manufacturing, site construction and operation of small to mid-sized hydroelectric sites across the United States. At the present time, STS owns and operates nine sites in four states with a combined capacity of 20 megawatts. In dealing with the implementation of these sites, STS has dealt with five different utilities. In addition, in pursuing additional development opportunities throughout the United States, STS has had contact with numerous other utilities. During this time it would be fair to conclude that each of these utilities has exhibited its own personality with respect to dealing with independent developers. To the credit of the utility industry, the majority of these utilities have been helpful and supportive of independent projects, but a small number of utilities have approached projects from an initial and continuing adversarial position. The purpose of this paper is to examine those options and procedures available to the developer when a utility is encountered with a negative predisposition

  8. Tissue Harmonic Synthetic Aperture Imaging

    Rasmussen, Joachim

    The main purpose of this PhD project is to develop an ultrasonic method for tissue harmonic synthetic aperture imaging. The motivation is to advance the field of synthetic aperture imaging in ultrasound, which has shown great potentials in the clinic. Suggestions for synthetic aperture tissue...... system complexity compared to conventional synthetic aperture techniques. In this project, SASB is sought combined with a pulse inversion technique for 2nd harmonic tissue harmonic imaging. The advantages in tissue harmonic imaging (THI) are expected to further improve the image quality of SASB...

  9. Modeling collagen remodeling in tissue engineered cardiovascular tissues

    Soares, A.L.F.

    2012-01-01

    Commonly, heart valve replacements consist of non-living materials lacking the ability to grow, repair and remodel. Tissue engineering (TE) offers a promising alternative to these replacement strategies since it can overcome its disadvantages. The technique aims to create an autologous living tissue

  10. A utility perspective on BRC

    Farrell, B.

    1988-01-01

    The author is program manager for low-level radioactive waste (LLW) for the Utility Nuclear Waste Management Group (UNWMG), an activity funded by 45 utilities with nuclear power programs. The UNWMG represents the utility industry on high-level and low-level radioactive waste issues in legislative, regulatory, and technical proceedings, and therefore has a strong interest in the progress of below-regulatory-concern (BRC) regulations. The author addresses waste disposal volumes prior to discussing recent developments and status of BRC regulations

  11. Clinical management of soft tissue sarcomas

    Pinedo, H.M.; Verweij, J.

    1986-01-01

    This book is concerned with the clinical management of soft tissue sarcomas. Topics covered include: Radiotherapy; Pathology of soft tissue sarcomas; Surgical treatment of soft tissue sarcomas; and Chemotherapy in advanced soft tissue sarcomas

  12. Aging changes in organs - tissue - cells

    ... and structure to the skin and internal organs. Epithelial tissue provides a covering for deeper body layers. The ... such as the gastrointestinal system, are made of epithelial tissue. Muscle tissue includes three types of tissue: Striated ...

  13. Infiltration of plasma rich in growth factors enhances in vivo angiogenesis and improves reperfusion and tissue remodeling after severe hind limb ischemia.

    Anitua, Eduardo; Pelacho, Beatriz; Prado, Roberto; Aguirre, José Javier; Sánchez, Mikel; Padilla, Sabino; Aranguren, Xabier L; Abizanda, Gloria; Collantes, María; Hernandez, Milagros; Perez-Ruiz, Ana; Peñuelas, Ivan; Orive, Gorka; Prosper, Felipe

    2015-03-28

    PRGF is a platelet concentrate within a plasma suspension that forms an in situ-generated fibrin-matrix delivery system, releasing multiple growth factors and other bioactive molecules that play key roles in tissue regeneration. This study was aimed at exploring the angiogenic and myogenic effects of PRGF on in vitro endothelial cells (HUVEC) and skeletal myoblasts (hSkMb) as well as on in vivo mouse subcutaneously implanted matrigel and on limb muscles after a severe ischemia. Human PRGF was prepared and characterized. Both proliferative and anti-apoptotic responses to PRGF were assessed in vitro in HUVEC and hSkMb. In vivo murine matrigel plug assay was conducted to determine the angiogenic capacity of PRGF, whereas in vivo ischemic hind limb model was carried out to demonstrate PRGF-driven vascular and myogenic regeneration. Primary HUVEC and hSkMb incubated with PRGF showed a dose dependent proliferative and anti-apoptotic effect and the PRGF matrigel plugs triggered an early and significant sustained angiogenesis compared with the control group. Moreover, mice treated with PRGF intramuscular infiltrations displayed a substantial reperfusion enhancement at day 28 associated with a fibrotic tissue reduction. These findings suggest that PRGF-induced angiogenesis is functionally effective at expanding the perfusion capacity of the new vasculature and attenuating the endogenous tissue fibrosis after a severe-induced skeletal muscle ischemia. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Chitin Scaffolds in Tissue Engineering

    Jayakumar, Rangasamy; Chennazhi, Krishna Prasad; Srinivasan, Sowmya; Nair, Shantikumar V.; Furuike, Tetsuya; Tamura, Hiroshi

    2011-01-01

    Tissue engineering/regeneration is based on the hypothesis that healthy stem/progenitor cells either recruited or delivered to an injured site, can eventually regenerate lost or damaged tissue. Most of the researchers working in tissue engineering and regenerative technology attempt to create tissue replacements by culturing cells onto synthetic porous three-dimensional polymeric scaffolds, which is currently regarded as an ideal approach to enhance functional tissue regeneration by creating and maintaining channels that facilitate progenitor cell migration, proliferation and differentiation. The requirements that must be satisfied by such scaffolds include providing a space with the proper size, shape and porosity for tissue development and permitting cells from the surrounding tissue to migrate into the matrix. Recently, chitin scaffolds have been widely used in tissue engineering due to their non-toxic, biodegradable and biocompatible nature. The advantage of chitin as a tissue engineering biomaterial lies in that it can be easily processed into gel and scaffold forms for a variety of biomedical applications. Moreover, chitin has been shown to enhance some biological activities such as immunological, antibacterial, drug delivery and have been shown to promote better healing at a faster rate and exhibit greater compatibility with humans. This review provides an overview of the current status of tissue engineering/regenerative medicine research using chitin scaffolds for bone, cartilage and wound healing applications. We also outline the key challenges in this field and the most likely directions for future development and we hope that this review will be helpful to the researchers working in the field of tissue engineering and regenerative medicine. PMID:21673928

  15. [Cellular subcutaneous tissue. Anatomic observations].

    Marquart-Elbaz, C; Varnaison, E; Sick, H; Grosshans, E; Cribier, B

    2001-11-01

    We showed in a companion paper that the definition of the French "subcutaneous cellular tissue" considerably varied from the 18th to the end of the 20th centuries and has not yet reached a consensus. To address the anatomic reality of this "subcutaneous cellular tissue", we investigated the anatomic structures underlying the fat tissue in normal human skin. Sixty specimens were excised from the surface to the deep structures (bone, muscle, cartilage) on different body sites of 3 cadavers from the Institut d'Anatomie Normale de Strasbourg. Samples were paraffin-embedded, stained and analysed with a binocular microscope taking x 1 photographs. Specimens were also excised and fixed after subcutaneous injection of Indian ink, after mechanic tissue splitting and after performing artificial skin folds. The aspects of the deep parts of the skin greatly varied according to their anatomic localisation. Below the adipose tissue, we often found a lamellar fibrous layer which extended from the interlobular septa and contained horizontally distributed fat cells. No specific tissue below the hypodermis was observed. Artificial skin folds concerned either exclusively the dermis, when they were superficial or included the hypodermis, but no specific structure was apparent in the center of the fold. India ink diffused to the adipose tissue, mainly along the septa, but did not localise in a specific subcutaneous compartment. This study shows that the histologic aspects of the deep part of the skin depend mainly on the anatomic localisation. Skin is composed of epidermis, dermis and hypodermis and thus the hypodermis can not be considered as being "subcutaneous". A difficult to individualise, fibrous lamellar structure in continuity with the interlobular septa is often found under the fat lobules. This structure is a cleavage line, as is always the case with loose connective tissues, but belongs to the hypodermis (i.e. fat tissue). No specific tissue nor any virtual space was

  16. Soft tissue augmentation - Use of hyaluronic acid as dermal filler

    Vedamurthy Maya

    2004-11-01

    Full Text Available Soft tissue augmentation has revolutionized the treatment of the aging face. It is a technique in which a substance is injected under the skin. The concept of utilizing materials for soft tissue augmentation actually began around 1950 with the use of fluid silicone. Today we have a large armamentarium of implant materials to delay the tell tale signs of aging. Filling has replaced conventional surgery in facial rejuvenation. In this article, the emphasis will be on hyaluronic acid as this substance is easily available in India and ranks among the most widely used dermal fillers.

  17. Soft tissue augmentation - Use of hyaluronic acid as dermal filler

    Vedamurthy Maya

    2004-01-01

    Full Text Available Soft tissue augmentation has revolutionized the treatment of the aging face. It is a technique in which a substance is injected under the skin. The concept of utilizing materials for soft tissue augmentation actually began around 1950 with the use of fluid silicone. Today we have a large armamentarium of implant materials to delay the tell tale signs of aging. Filling has replaced conventional surgery in facial rejuvenation. In this article, the emphasis will be on hyaluronic acid as this substance is easily available in India and ranks among the most widely used dermal fillers.

  18. Optical spectroscopy for the detection of ischemic tissue injury

    Demos, Stavros [Livermore, CA; Fitzgerald, Jason [Sacramento, CA; Troppmann, Christoph [Sacramento, CA; Michalopoulou, Andromachi [Athens, GR

    2009-09-08

    An optical method and apparatus is utilized to quantify ischemic tissue and/or organ injury. Such a method and apparatus is non-invasive, non-traumatic, portable, and can make measurements in a matter of seconds. Moreover, such a method and apparatus can be realized through optical fiber probes, making it possible to take measurements of target organs deep within a patient's body. Such a technology provides a means of detecting and quantifying tissue injury in its early stages, before it is clinically apparent and before irreversible damage has occurred.

  19. Dose-dependent induction of transforming growth factor β (TGF-β) in the lung tissue of fibrosis-prone mice after thoracic irradiation

    Ruebe, Claudia E.; Uthe, Daniela; Schmid, Kurt W.; Richter, Klaus D.; Wessel, Jan; Schuck, Andreas; Willich, Norman; Ruebe, Christian

    2000-01-01

    Purpose: The lung is the major dose-limiting organ for radiotherapy of cancer in the thoracic region. The pathogenesis of radiation-induced lung injury at the molecular level is still unclear. Immediate cellular damage after irradiation is supposed to result in cytokine-mediated multicellular interactions with induction and progression of fibrotic tissue reactions. The purpose of this investigation was to evaluate the acute and long-term effects of radiation on the gene expression of transforming growth factor beta (TGF-β) in a model of lung injury using fibrosis-sensitive C57BL/6 mice. Methods and Materials: The thoraces of C57BL/6 mice were irradiated with 6 and 12 Gy, respectively. Treated and sham-irradiated control mice were sacrificed at times corresponding to the latent period (1, 3, 6, 12, 24, 48, 72 hours and 1 week postirradiation), the pneumonic phase (2, 4, 8, and 16 weeks postirradiation), and the beginning of the fibrotic phase (24 weeks postirradiation). The lung tissue from three different mice per dosage and time point was analyzed by a combination of polymerase chain reaction (PCR), immunohistochemistry, and light microscopy. The mRNA expression of TGF-β was quantified by competitive reverse transcriptase/polymerase chain reaction (RT-PCR); the cellular origin of the TGF-β protein was identified by immunohistochemical staining (alkaline phosphatase-anti-alkaline phosphatase [APAAP]). The cytokine expression on mRNA and protein level was correlated with the histopathological alterations. Results: Following thoracic irradiation with a single dose of 12 Gy, radiation-induced TGF-β release in lung tissue was appreciable already within the first hours (1, 3, and 6 hours postirradiation) and reached a significant increase after 12 hours; subsequently (48 hours, 72 hours, and 1 week postirradiation) the TGF-β expression declined to basal levels. At the beginning of the pneumonic phase, irradiation-mediated stimulation of TGF-β release reached

  20. Medicare Utilization for Part B

    U.S. Department of Health & Human Services — This link takes you to the Medicare utilization statistics for Part B (Supplementary Medical Insurance SMI) which includes the Medicare Part B Physician and Supplier...

  1. State Drug Utilization Data 2003

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  2. Decentralized method for utility regulation

    Loeb, M. (North Carolina State Univ., Raleigh); Magat, W.A.

    1979-10-01

    A new institutional arrangement for regulating utilities is suggested that minimizes the costs of natural monopolies. A mixture of regulation and franchising, the plan draws on the advantages of each and eliminates many of the problems. The proposal allows utilities to set their own price on the basis of demand and marginal-cost projections. Subsidies are provided by the regulatory agency if there is a consumer surplus. The system encourages the utility to select a competitive price and to produce only the amount of service needed. Operating efficiency is encouraged by rewarding cost reductions and discouraging cost overstatement at the rate review. The regulatory agency would not need to take action to bring price and marginal costs into equality. The franchise sale can be made by competitive bidding, in which the bidders would capitalize part or all of the subsidy or the regulatory agency could recover the subsidy in a lump-sum tax on the utility.

  3. State Drug Utilization Data 2011

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  4. Medicare Utilization for Part A

    U.S. Department of Health & Human Services — This link takes you to the Medicare utilization statistics for Part A (Hospital Insurance HI) which include the Medicare Ranking for all Short-Stay Hospitals by...

  5. Build Resilience at Your Utility

    CREAT allows users to evaluate potential impacts of climate change on their utility and to evaluate adaptation options to address them using both traditional risk assessment and scenario-based decision making.

  6. State Drug Utilization Data 2009

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  7. State Drug Utilization Data 2016

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  8. Growth of hydrocarbon utilizing microorganisms

    Bhosle, N.B.; Mavinkurve, S.

    Two isolates from marine mud having broad spectrum hydrocarbon utilizing profile were identified as Arthrobacter simplex and Candida tropicalis.Both the organisms grew exponentially on crude oil. The cell yield of the organisms was influenced...

  9. State Drug Utilization Data 2017

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  10. State Drug Utilization Data 1996

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  11. State Drug Utilization Data 2008

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  12. State Drug Utilization Data 1992

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  13. State Drug Utilization Data 1995

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  14. State Drug Utilization Data 1998

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  15. State Drug Utilization Data 2014

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  16. State Drug Utilization Data 2005

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  17. State Drug Utilization Data 2002

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  18. State Drug Utilization Data 2004

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  19. State Drug Utilization Data 1993

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  20. State Drug Utilization Data 2006

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...