In situ elasticity modulation with dynamic substrates to direct cell phenotype

PubMed Central

Kloxin, April M.; Benton, Julie A.; Anseth, Kristi S.

2009-01-01

Microenvironment elasticity influences critical cell functions such as differentiation, cytoskeletal organization, and process extension. Unfortunately, few materials allow elasticity modulation in real-time to probe its direct effect on these dynamic cellular processes. Here, a new approach is presented for the photochemical modulation of elasticity within the cell's microenvironment at any point in time. A photodegradable hydrogel was irradiated and degraded under cytocompatible conditions to generate a wide range of elastic moduli similar to soft tissues and characterized using rheometry and atomic force microscopy (AFM). The effect of the elastic modulus on valvular interstitial cell (VIC) activation into myofibroblasts was explored. In these studies, gradient samples were used to identify moduli that either promote or suppress VIC myofibroblastic activation. With this knowledge, VICs were cultured on a high modulus, activating hydrogel substrate, and uniquely, results show that decreasing the substrate modulus with irradiation reverses this activation, demonstrating that myofibroblasts can be de-activated solely by changing the modulus of the underlying substrate. This finding is important for the rational design of biomaterials for tissue regeneration and offers insight into fibrotic disease progression. These photodegradable hydrogels demonstrate the capability to both probe and direct cell function through dynamic changes in substrate elasticity. PMID:19788947

Manipulation of valve composition to elucidate the role of collagen in aortic valve calcification

PubMed Central

2014-01-01

Background Extracellular matrix (ECM) disarray is found in calcific aortic valvular disease (CAVD), yet much remains to be learned about the role of individual ECM components in valvular interstitial cell (VIC) function and dysfunction. Previous clinical analyses have shown that calcification is associated with decreased collagen content, while previous in vitro work has suggested that the presence of collagen attenuates the responsiveness of VICs to pro-calcific stimuli. The current study uses whole leaflet cultures to examine the contributions of endogenous collagen in regulating the phenotype and calcification of VICs. Methods A “top-down” approach was used to characterize changes in VIC phenotype in response to collagen alterations in the native 3D environment. Collagen-deficient leaflets were created via enzymatic treatment and cultured statically for six days in vitro. After culture, leaflets were harvested for analysis of DNA, proliferation, apoptosis, ECM composition, calcification, and gene/protein expression. Results In general, disruption of collagen was associated with increased expression of disease markers by VICs in whole organ leaflet culture. Compared to intact control leaflets, collagen-deficient leaflets demonstrated increased VIC proliferation and apoptosis, increased expression of disease-related markers such as alpha-smooth muscle actin, alkaline phosphatase, and osteocalcin, and an increase in calcification as evidenced by positive von Kossa staining. Conclusions These results indicate that disruption of the endogenous collagen structure in aortic valves is sufficient to stimulate pathological consequences in valve leaflet cultures, thereby highlighting the importance of collagen and the valve extracellular matrix in general in maintaining homeostasis of the valve phenotype. PMID:24581344

Inflammation Drives Retraction, Stiffening, and Nodule Formation via Cytoskeletal Machinery in a Three-Dimensional Culture Model of Aortic Stenosis.

PubMed

Lim, Jina; Ehsanipour, Arshia; Hsu, Jeffrey J; Lu, Jinxiu; Pedego, Taylor; Wu, Alexander; Walthers, Chris M; Demer, Linda L; Seidlits, Stephanie K; Tintut, Yin

2016-09-01

In calcific aortic valve disease, the valve cusps undergo retraction, stiffening, and nodular calcification. The inflammatory cytokine, tumor necrosis factor (TNF)-α, contributes to valve disease progression; however, the mechanisms of its actions on cusp retraction and stiffening are unclear. We investigated effects of TNF-α on murine aortic valvular interstitial cells (VICs) within three-dimensional, free-floating, compliant, collagen hydrogels, simulating their natural substrate and biomechanics. TNF-α increased retraction (percentage of diameter), stiffness, and formation of macroscopic, nodular structures with calcification in the VIC-laden hydrogels. The effects of TNF-α were attenuated by blebbistatin inhibition of myosin II-mediated cytoskeletal contraction. Inhibition of actin polymerization with cytochalasin-D, but not inhibition of Rho kinase with Y27632, blocked TNF-α-induced retraction in three-dimensional VIC hydrogels, suggesting that actin stress fibers mediate TNF-α-induced effects. In the hydrogels, inhibitors of NF-κB blocked TNF-α-induced retraction, whereas simultaneous inhibition of c-Jun N-terminal kinase was required to block TNF-α-induced stiffness. TNF-α also significantly increased collagen deposition, as visualized by Masson's trichrome staining, and up-regulated mRNA expression of discoidin domain receptor tyrosine kinase 2, fibronectin, and α-smooth muscle actin. In human aortic valves, calcified cusps were stiffer and had more collagen deposition than noncalcified cusps. These findings suggest that inflammation, through stimulation of cytoskeletal contractile activity, may be responsible for valvular cusp retraction, stiffening, and formation of calcified nodules. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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

Nagy, Edit, E-mail: edit.nagy@karolinska.se; Department of Cardiology, Karolinska University Hospital, Stockholm; Caidahl, Kenneth

Highlights: Black-Right-Pointing-Pointer Oxidative stress has been implicated in the pathomechanism of calcific aortic valve stenosis. Black-Right-Pointing-Pointer We assessed the transcript levels for PARP-1 (poly(ADP-ribose) polymerase), acts as a DNA damage nick sensor in stenotic valves. Black-Right-Pointing-Pointer Early stage of diseased tricuspid valves exhibited higher mRNA levels for PARP-1 compared to bicuspid valves. Black-Right-Pointing-Pointer The mRNA levels for PARP-1 inversely correlated with the clinical stenosis severity in tricuspid valves. Black-Right-Pointing-Pointer Our data demonstrated that DNA damage pathways might be associated with stenosis severity only in tricuspid valves. -- Abstract: Oxidative stress may contribute to the hemodynamic progression of aortic valve stenosis,more » and is associated with activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) 1. The aim of the present study was to assess the transcriptional profile and the topological distribution of PARP-1 in human aortic valves, and its relation to the stenosis severity. Human stenotic aortic valves were obtained from 46 patients undergoing aortic valve replacement surgery and used for mRNA extraction followed by quantitative real-time PCR to correlate the PARP-1 expression levels with the non invasive hemodynamic parameters quantifying the stenosis severity. Primary isolated valvular interstitial cells (VICs) were used to explore the effects of cytokines and leukotriene C{sub 4} (LTC{sub 4}) on valvular PARP-1 expression. The thickened areas of stenotic valves with tricuspid morphology expressed significantly higher levels of PARP-1 mRNA compared with the corresponding part of bicuspid valves (0.501 vs 0.243, P = 0.01). Furthermore, the quantitative gene expression levels of PARP-1 were inversely correlated with the aortic valve area (AVA) (r = -0.46, P = 0.0469) and AVA indexed for body surface area (BSA) (r = -0.498; P = 0.0298) only in tricuspid aortic valves. LTC{sub 4} (1 nM) significantly elevated the mRNA levels of PARP-1 by 2.38-fold in VICs. Taken together, these data suggest that valvular DNA-damage pathways may be associated with inflammation and the stenosis severity in tricuspid aortic valves.« less

Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis.

PubMed

Yao, Qingzhou; Song, Rui; Ao, Lihua; Cleveland, Joseph C; Fullerton, David A; Meng, Xianzhong

2017-06-01

Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 µg/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk-Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis. Copyright © 2017 the American Physiological Society.

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

Ohori, N.P.; Sciurba, F.C.; Owens, G.R.

We report four cases of giant-cell interstitial pneumonia that occurred in association with exposure to hard metals. All patients presented with chronic interstitial lung disease and had open-lung biopsies that revealed marked interstitial fibrosis, cellular interstitial infiltrates, and prominent intraalveolar macrophages as well as giant cells displaying cellular cannibalism. We also review the literature to determine the sensitivity and specificity of giant-cell interstitial pneumonia for hard-metal pneumoconiosis. Although hard-metal pneumoconiosis may take the form of usual interstitial pneumonia, desquamative interstitial pneumonia, and giant-cell interstitial pneumonia, the finding of giant-cell interstitial pneumonia is almost pathognomonic of hard-metal disease and should provokemore » an investigation of occupational exposure. 25 references.« less

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes

PubMed Central

Tae, Hyun-Jin; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2015-01-01

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/− mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2–4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6–14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS. PMID:26566724

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

PubMed

Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2016-01-15

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

Microfluidic approaches for the fabrication of gradient crosslinked networks based on poly(ethylene glycol) and hyperbranched polymers for manipulation of cell interactions

PubMed Central

Pedron, S; Peinado, C; Bosch, P; Benton, J A; Anseth, K S

2011-01-01

High-throughput methods allow rapid examination of parameter space to characterize materials and develop new polymeric formulations for biomaterials applications. One limitation is the difficulty of preparing libraries and performing high-throughput screening with conventional instrumentation and sample preparation. Here, we describe the fabrication of substrate materials with controlled gradients in composition by a rapid method of micromixing followed by a photopolymerization reaction. Specifically, poly(ethylene glycol) dimethacrylate was copolymerized with a hyperbranched multimethacrylate (P1000MA or H30MA) in a gradient manner. The extent of methacrylate conversion and the final network composition were determined by near-infrared spectroscopy, and mechanical properties were measured by nanoindentation. A relationship was observed between the elastic modulus and network crosslinking density. Roughness and hydrophilicity were increased on surfaces with a higher concentration of P1000MA. These results likely relate to a phase segregation process of the hyperbranched macromer that occurs during the photopolymerization reaction. On the other hand, the decrease in the final conversion in H30MA polymerization reactions was attributed to the lower termination rate as a consequence of the softening of the network. Valvular interstitial cell attachment was evaluated on these gradient substrates as a demonstration of studying cell morphology as a function of the local substrate properties. Data revealed that the presence of P1000MA affects cell–material interaction with a higher number of adhered cells and more cell spreading on gradient regions with a higher content of the multifunctional crosslinker. PMID:21105168

Deficiency of interstitial cells of Cajal in the small intestine of patients with Crohn's disease.

PubMed

Porcher, Christophe; Baldo, Marjolaine; Henry, Monique; Orsoni, Pierre; Julé, Yvon; Ward, Sean M

2002-01-01

Interstitial cells of Cajal are critical for the generation of electrical slow waves that regulate the phasic contractile activity of the tunica muscularis of the GI tract. Under certain pathophysiological conditions loss of interstitial cells of Cajal may play a role in the generation of certain motility disorders. The aim of the present study was to determine if there is an abnormality in the density or distribution of interstitial cells of Cajal from patients with Crohn's disease. Small intestines from control subjects and patients with Crohn's disease were examined using immunohistochemistry and antibodies against the Kit receptor, which is expressed in interstitial cells of Cajal within the tunica muscularis of the GI tract. The density and distribution of interstitial cells of Cajal were assessed in the longitudinal and circular muscle layers and in the myenteric and deep muscular plexus regions of Crohn's and control tissues. Tissues from Crohn's disease patients showed an almost complete abolition of interstitial cells of Cajal within the longitudinal and circular muscle layers and a significant reduction in numbers at the level of the myenteric and deep muscular plexuses. In tissues from Crohn's disease patients, the density of interstitial cells of Cajal was reduced throughout the tunica muscularis in comparison to control small intestines. The disturbance of intestinal motility that occurs in patients with Crohn's disease may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis.

Interstitial Cells: Regulators of Smooth Muscle Function

PubMed Central

Sanders, Kenton M.; Ward, Sean M.; Koh, Sang Don

2014-01-01

Smooth muscles are complex tissues containing a variety of cells in addition to muscle cells. Interstitial cells of mesenchymal origin interact with and form electrical connectivity with smooth muscle cells in many organs, and these cells provide important regulatory functions. For example, in the gastrointestinal tract, interstitial cells of Cajal (ICC) and PDGFRα+ cells have been described, in detail, and represent distinct classes of cells with unique ultrastructure, molecular phenotypes, and functions. Smooth muscle cells are electrically coupled to ICC and PDGFRα+ cells, forming an integrated unit called the SIP syncytium. SIP cells express a variety of receptors and ion channels, and conductance changes in any type of SIP cell affect the excitability and responses of the syncytium. SIP cells are known to provide pacemaker activity, propagation pathways for slow waves, transduction of inputs from motor neurons, and mechanosensitivity. Loss of interstitial cells has been associated with motor disorders of the gut. Interstitial cells are also found in a variety of other smooth muscles; however, in most cases, the physiological and pathophysiological roles for these cells have not been clearly defined. This review describes structural, functional, and molecular features of interstitial cells and discusses their contributions in determining the behaviors of smooth muscle tissues. PMID:24987007

Integrating valve-inspired design features into poly(ethylene glycol) hydrogel scaffolds for heart valve tissue engineering.

PubMed

Zhang, Xing; Xu, Bin; Puperi, Daniel S; Yonezawa, Aline L; Wu, Yan; Tseng, Hubert; Cuchiara, Maude L; West, Jennifer L; Grande-Allen, K Jane

2015-03-01

The development of advanced scaffolds that recapitulate the anisotropic mechanical behavior and biological functions of the extracellular matrix in leaflets would be transformative for heart valve tissue engineering. In this study, anisotropic mechanical properties were established in poly(ethylene glycol) (PEG) hydrogels by crosslinking stripes of 3.4 kDa PEG diacrylate (PEGDA) within 20 kDa PEGDA base hydrogels using a photolithographic patterning method. Varying the stripe width and spacing resulted in a tensile elastic modulus parallel to the stripes that was 4.1-6.8 times greater than that in the perpendicular direction, comparable to the degree of anisotropy between the circumferential and radial orientations in native valve leaflets. Biomimetic PEG-peptide hydrogels were prepared by tethering the cell-adhesive peptide RGDS and incorporating the collagenase-degradable peptide PQ (GGGPQG↓IWGQGK) into the polymer network. The specific amounts of RGDS and PEG-PQ within the resulting hydrogels influenced the elongation, de novo extracellular matrix deposition and hydrogel degradation behavior of encapsulated valvular interstitial cells (VICs). In addition, the morphology and activation of VICs grown atop PEG hydrogels could be modulated by controlling the concentration or micro-patterning profile of PEG-RGDS. These results are promising for the fabrication of PEG-based hydrogels using anatomically and biologically inspired scaffold design features for heart valve tissue engineering. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Understanding the structural features of symptomatic calcific aortic valve stenosis: A broad-spectrum clinico-pathologic study in 236 consecutive surgical cases.

PubMed

Galli, Daniela; Manuguerra, Roberta; Monaco, Rodolfo; Manotti, Laura; Goldoni, Matteo; Becchi, Gabriella; Carubbi, Cecilia; Vignali, Giulia; Cucurachi, Nicola; Gherli, Tiziano; Nicolini, Francesco; Lorusso, Roberto; Vitale, Marco; Corradi, Domenico

2017-02-01

With age, aortic valve cusps undergo varying degrees of sclerosis which, sometimes, can progress to calcific aortic valve stenosis (AVS). To perform a retrospective clinico-pathologic investigation in patients with calcific AVS. We characterized and graded the structural remodeling in 236 aortic valves (200 tricuspid and 36 bicuspid) from patients with calcific AVS (148 males; average 72years); possible relationships between general/clinical/echocardiographic characteristics and the histopathologic changes were explored. Twenty autopsy aortic valves served as controls. In 40 cases, we also tested the immunohistochemical expression of metalloproteinases and cytokines, and characterized the inflammatory infiltrate. In 5 cases, we cultured cusp stem cells and explored their potential to differentiate into osteoblasts/adipocytes. AVS cusps showed structural remodeling as severe fibrosis (100%), calcific nodules (100%), neoangiogenesis (81%), inflammation (71%), bone metaplasia with or without hematopoiesis (6% and 53%, respectively), adipose metaplasia (16%), and cartilaginous metaplasia (7%). At multivariate analysis, AVS degree and interventricular septum thickness were the only predictors of remodeling (barring inflammation). All the tested metalloproteinases (except MMP-13) and cytokines were expressed in AVS cusps. Inflammation mainly consisted of B and T lymphocytes (CD4+/CD8+ cell ratio 3:1) and plasma cells. AVS changes were mostly different from typical atherosclerosis. Cultured mesenchymal cusp stem cells could differentiate into osteoblasts/adipocytes. Structural remodeling in AVS is peculiar and considerable, and is related to the severity of the disease. However, the different newly formed tissues-where "valvular interstitial cells" play a key role-and their well-known slow turnover suggest a reverse structural remodeling improbable. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development of decellularized aortic valvular conduit coated by heparin-SDF-1α multilayer.

PubMed

Zhou, Jingxin; Ye, Xiaofeng; Wang, Zhe; Liu, Jun; Zhang, Busheng; Qiu, Jiapei; Sun, Yanjun; Li, Haiqing; Zhao, Qiang

2015-02-01

Decellularization can reduce the immune response to aortic valve allograft tissue, but the thrombogenicity and in vivo remolding of these grafts remain controversial. The aim of the present study was to modify the surface of decellularized valvular conduits with heparin-stromal cell-derived factor-1α (SDF-1α) polyelectrolyte multilayer film and to test the thrombogenicity and biocompatibility in vitro and recellularization in vivo. The donor aortic valvular conduits were decellularized with a combination of different detergents and were coated with heparin and SDF-1α alternately to form a polyelectrolyte multilayer. Platelet adhesion and lactate dehydrogenase assay were used to evaluate the antiplatelet property. The adhesion, growth, and migration of bone marrow stem cells (BMSCs) to the scaffolds were assessed. For in vivo studies, the grafts were anastomosed to the infrarenal aorta, without or with heparin and SDF-1α multilayer. Functional assessment was performed by Doppler echography and micro-computed tomography at 2-week and 4-week time points after implantation. Explanted grafts were examined histologically and by immunohistochemistry. In vitro studies demonstrated that the heparin-SDF-1α multilayer film improved hemocompatibility with respect to a substantial reduction of platelet adhesion. BMSCs also achieved better adhesion, proliferation, and migration on the modified graft. For in vivo studies, the grafts in both groups remained patent after 4 weeks, but it was demonstrated that the modified decellularized grafts had better self-endothelialization and recruitment of endothelial progenitor cells. These results indicate that heparin-SDF-1α multilayer film can be used to cover the decellularized aortic valvular graft to decrease platelet adhesion while precipitating regeneration of the decellularized aortic valve allograft in vivo. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

2013-01-01

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

The Significance of Interstitial Cells in Neurogastroenterology

PubMed Central

Blair, Peter J; Rhee, Poong-Lyul; Sanders, Kenton M; Ward, Sean M

2014-01-01

Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα+) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα+ cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract. PMID:24948131

The deep muscular plexus of the pig duodenum: a histochemical and ultrastructural study with special reference to the interstitial cells.

PubMed

Henry, M; Porcher, C; Julé, Y

1998-06-10

The aim of the present study was to describe the deep muscular plexus of the pig duodenum and to characterize its cellular components. Numerous nerve varicosities have been detected in the deep muscular plexus using anti-synaptophysin antibodies. Nerve fibres were also detected here in the outer circular muscle layer, whereas no nerve fibres were observed in the inner circular muscle layer. In the deep muscular plexus, nerve fibres projected to interstitial cells which were characterized at the ultrastructural level. The interstitial cells were of two kinds: the interstitial fibroblastic-like cells (FLC) and the interstitial dense cells (IDC), both of which were interposed between nerve fibres and smooth muscle cells. The FLC were characterized by their elongated bipolar shape, the lack of basal lamina, a well-developed endoplasmic reticulum, a Golgi apparatus, and intermediate filaments. They were closely apposed to axon terminals containing small clear synaptic vesicles and/or dense-cored vesicles. They were frequently connected to each other and to smooth muscle cells of the inner and outer circular layer by desmosomes and more rarely by gap junctions. The IDC are myoid-like cells. They had a stellate appearance and were characterized by a dense cell body, numerous caveolae, and a discontinuous basal lamina. The IDC were always closely apposed to nerve fibres and were connected to smooth muscle cells by desmosomes and small gap junctions. The present results show the unique pattern of cellular organization of the deep muscular plexus of the pig small intestine. They suggest that the interstitial cells in the deep muscular plexus are involved in the integration and transmission of nervous inputs from myenteric neurons to the inner and outer circular muscle layers. The clear-cut distinction observed here between the two types of interstitial cells (fibroblastic and myoid-like) suggests that the interstitial cells of each type may also be involved in some other specific activity, which still remains to be determined.

Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

PubMed Central

Liu, Qingdu; Binns, Thomas C.; Davidoff, Olena; Kapitsinou, Pinelopi P.; Pfaff, Andrew S.; Olauson, Hannes; Fogo, Agnes B.; Fong, Guo-Hua; Gross, Kenneth W.

2016-01-01

Renal peritubular interstitial fibroblast-like cells are critical for adult erythropoiesis, as they are the main source of erythropoietin (EPO). Hypoxia-inducible factor 2 (HIF-2) controls EPO synthesis in the kidney and liver and is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3, which function as cellular oxygen sensors. Renal interstitial cells with EPO-producing capacity are poorly characterized, and the role of the PHD/HIF-2 axis in renal EPO-producing cell (REPC) plasticity is unclear. Here we targeted the PHD/HIF-2/EPO axis in FOXD1 stroma-derived renal interstitial cells and examined the role of individual PHDs in REPC pool size regulation and renal EPO output. Renal interstitial cells with EPO-producing capacity were entirely derived from FOXD1-expressing stroma, and Phd2 inactivation alone induced renal Epo in a limited number of renal interstitial cells. EPO induction was submaximal, as hypoxia or pharmacologic PHD inhibition further increased the REPC fraction among Phd2–/– renal interstitial cells. Moreover, Phd1 and Phd3 were differentially expressed in renal interstitium, and heterozygous deficiency for Phd1 and Phd3 increased REPC numbers in Phd2–/– mice. We propose that FOXD1 lineage renal interstitial cells consist of distinct subpopulations that differ in their responsiveness to Phd2 inactivation and thus regulation of HIF-2 activity and EPO production under hypoxia or conditions of pharmacologic or genetic PHD inactivation. PMID:27088801

Mesenchymal stem cells from sternum: the type of heart disease, ischemic or valvular, does not influence the cell culture establishment and growth kinetics.

PubMed

Dias, Lucinara Dadda; Casali, Karina Rabello; Ghem, Carine; da Silva, Melissa Kristocheck; Sausen, Grasiele; Palma, Patrícia Bonini; Covas, Dimas Tadeu; Kalil, Renato A K; Schaan, Beatriz D; Nardi, Nance Beyer; Markoski, Melissa Medeiros

2017-07-25

In an attempt to increase the therapeutic potential for myocardial regeneration, there is a quest for new cell sources and types for cell therapy protocols. The pathophysiology of heart diseases may affect cellular characteristics and therapeutic results. To study the proliferative and differentiation potential of mesenchymal stem cells (MSC), isolated from bone marrow (BM) of sternum, we made a comparative analysis between samples of patients with ischemic (IHD) or non-ischemic valvular (VHD) heart diseases. We included patients with IHD (n = 42) or VHD (n = 20), with average age of 60 years and no differences in cardiovascular risk factors. BM samples were collected (16.4 ± 6 mL) and submitted to centrifugation with Ficoll-Paque, yielding 4.5 ± 1.5 × 10 7  cells/mL. Morphology, immunophenotype and differentiation ability had proven that the cultivated sternal BM cells had MSC features. The colony forming unit-fibroblast (CFU-F) frequency was similar between groups (p = 0.510), but VHD samples showed positive correlation to plated cells vs. CFU-F number (r = 0.499, p = 0.049). The MSC culture was established in 29% of collected samples, achieved passage 9, without significant difference in expansion kinetics between groups (p > 0.05). Dyslipidemia and the use of statins was associated with culture establishment for IHD patients (p = 0.049 and p = 0.006, respectively). Together, these results show that the sternum bone can be used as a source for MSC isolation, and that ischemic or valvular diseases do not influence the cellular yield, culture establishment or in vitro growth kinetics.

Reconstruction of the right ventricular outflow tract with a bovine jugular vein graft fixed with a naturally occurring crosslinking agent (genipin) in a canine model.

PubMed

Chang, Y; Tsai, C C; Liang, H C; Sung, H W

2001-12-01

This study was designed to evaluate a newly developed biologic valved conduit fixed with genipin used to reconstruct the right ventricular outflow tract in a canine model. Fresh bovine jugular veins with a retained native valve procured from a slaughterhouse were used as raw materials to fabricate the valved conduits. A naturally occurring crosslinking agent, genipin, was used to fix the procured jugular veins. The glutaraldehyde-fixed counterpart was used as a control. A canine model was used in the study. Echocardiography revealed that the motion of the valvular leaflets in both the glutaraldehyde- and genipin-fixed conduits was satisfactory. The transvalvular pressure gradients of both studied groups were minimal. No endothelium-like cells were observed on the luminal surface of the conduit and the valvular leaflet for the glutaraldehyde-fixed group throughout the entire course of the study. In contrast, endothelium-like cells were observed on the entire surface of the genipin-fixed valved conduit retrieved at 6 months postoperatively in all the cases studied. There was no evidence of luminal fibrous peel in any the valved conduits studied. Degradation of valvular leaflet in one of the glutaraldehyde-fixed conduits was observed. In this particular case, thrombus formation was also observed on the surface of the valvular leaflet. On the other hand, no apparent degradation or thrombus formation was observed on the surfaces of the genipin-fixed valvular leaflet and conduit. A significantly more severe inflammatory reaction was observed for the glutaraldehyde-fixed conduit than for its genipin-fixed counterpart throughout the entire course of the study. The calcium contents of the samples before implantation and those retrieved at distinct implantation duration were minimal for both the glutaraldehyde- and genipin-fixed tissues. Although further studies are necessary, the genipin-fixed valved conduit appears to have great potential in helping mitigate the complications observed in the commercially available conduits.

Arterial hypertension and hypertrophic pulmonary osteopathy associated with aortic valvular endocarditis in a dog.

PubMed

Vulgamott, J C; Clark, R G

1980-08-01

A 5-year-old spayed female Doberman Pinscher was referred for clinical evaluation following two acute episodes of lameness, lethargy, and respiratory dyspnea. The femoral pulse had a bounding "water-hammer" quality. Arterial blood pressures were 280 mm of Hg to greater than 300 mm of Hg during systole and approximately 40 mm of Hg during diastole. Systolic blood pressure was lowered to 210 mm of Hg, using prazosin. Radiography revealed extensive pulmonary interstitial markings and smooth subperiosteal expansions of the long bones indicative of hypertrophic pulmonary osteopathy. Despite symptomatic treatment, the dog's health gradually deteriorated, and it died 9 days after referral. Necropsy revealed vegetative endocarditis of the aortic valve. Insufficiency of the aortic valve was believed to be responsible for the systolic hypertension and the hypertrophic pulmonary osteopathy.

Innervation of the anterior byssal retractor muscle in Mytilus edulis L. II. Ultrastructure of the glio-interstitial cells.

PubMed

Gilloteaux, J

1975-08-27

Studies on the intrinsic innervation of the anterior byssal retractor muscle (ABRM) in Mytilus edulis L. were continued at the ultrastructural level. Electron micrographs show nerve processes ensheathed by glio-interstitial cells running between muscle fibers. The glio-interstitial cells may represent all the types of osmiophilic cells previously described by the light microscopic ZIO technique in the anterior byssal retractor muscle.

Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis.

PubMed

Moreso, F; Seron, D; O'Valle, F; Ibernon, M; Gomà, M; Hueso, M; Cruzado, J M; Bestard, O; Duarte, V; del Moral, R García; Grinyó, J M

2007-12-01

Patients with a protocol renal allograft biopsy simultaneously displaying interstitial fibrosis/tubular atrophy (IF/TA) and subclinical rejection (SCR) have a shortened graft survival than patients with a normal biopsy, or with a biopsy only displaying IF/TA or SCR. The poor outcome of these patients could be related with a more severe inflammation. We evaluate the immunophenotype of infiltrating cells in these diagnostic categories. Nonexhausted paraffin blocks from protocol biopsies done during the first year were stained with anti-CD45, CD3, CD20, CD68 and CD15 monoclonal antibodies. Glomerular and interstitial positive cells were counted. C4d deposition in peritubular capillaries was evaluated. Histological diagnoses were: normal (n = 80), SCR (n = 17), IF/TA (n = 42) and IF/TA + SCR (n = 17). Only interstitial CD20 positive cells were significantly increased in patients displaying IF/TA + SCR; normal (137 +/- 117), SCR (202 +/- 145), IF/TA (208 +/- 151) and IF/TA + SCR (307 +/- 180 cells/mm(2)), p < 0.01. The proportion of biopsies displaying C4d deposition was not different among groups. The upper tertile of CD20 positive interstitial cells was associated with a decreased death-censored graft survival (relative risk: 3.01, 95% confidence interval: 1.23-7.35; p = 0.015). These data suggest that B-cell interstitial infiltrates are associated with histological damage and outcome, but do not distinguish whether these infiltrates were the cause or the consequence of chronic tubulo-interstitial damage.

Alveolar epithelial cells undergo epithelial-mesenchymal transition in acute interstitial pneumonia: a case report

PubMed Central

2014-01-01

Background Acute interstitial pneumonia is a rare interstitial lung disease that rapidly progresses to respiratory failure or death. Several studies showed that myofibroblast plays an important role in the evolution of diffuse alveolar damage, which is the typical feature of acute interstitial pneumonia. However, no evidence exists whether alveolar epithelial cells are an additional source of myofibroblasts via epithelial-mesenchymal transition in acute interstitial pneumonia. Case presentation In this report, we present a case of acute interstitial pneumonia in a previously healthy 28-year-old non-smoking woman. Chest high-resolution computed tomography scan showed bilateral and diffusely ground-glass opacification. The biopsy was performed on the fifth day of her hospitalization, and results showed manifestation of acute exudative phase of diffuse alveolar damage characterized by hyaline membrane formation. On the basis of the preliminary diagnosis of acute interstitial pneumonia, high-dose glucocorticoid was used. However, this drug showed poor clinical response and could improve the patient’s symptoms only during the early phase. The patient eventually died of respiratory dysfunction. Histological findings in autopsy were consistent with the late form of acute interstitial pneumonia. Conclusions The results in this study revealed that alveolar epithelial cells underwent epithelial-mesenchymal transition and may be an important origin of myofibroblasts in the progression of acute interstitial pneumonia. Conducting research on the transformation of alveolar epithelial cells into myofibroblasts in the lung tissue of patients with acute interstitial pneumonia may be beneficial for the treatment of this disease. However, to our knowledge, no research has been conducted on this topic. PMID:24755111

[Effects of multidisciplinary blood management strategy on transfusion and outcomes in patients undergoing valvular heart surgery].

PubMed

Ji, Hongwen; Li, Zhiyuan; Sun, Hansong; Li, Lihuan; Long, Cun; Ma, Li; Chen, Lei; Wang, Wei; Hu, Shengshou

2014-02-25

To evaluate the effect of multidisciplinary blood management strategy in adults patients undergoing valvular heart surgery. A multidisciplinary patient blood management (PBM) strategy was instituted in Fuwai Hospital since January 2009. It includes Establishment of a multidisciplinary blood transfusion management team and designation of a coordinator; Enactment perioperative transfusion triggers (Hb < 80 g/L) for adults patients undergoing cardiac surgery; recommendation of antifibrinolytics, cell salvage, reduced cardiopulmonary bypass circuit; setting up Blood Consumption Announcement and Scoring System, which regularly publishes notifications of blood volume consumed per case, per single procedure and per surgeon. Clinical date before and after multidisciplinary patient blood management strategy will be presented. A total of 3 951 consecutive patients underwent Valvular Heart Surgery were analyzed. 1 713 cases were in pre-PBM group, and 2 238 cases were in post-PBM group. Both incidence and average units of allogeneic red blood cell transfusion perioperatively in post-PBM group were decreased (28.5% vs 75.3%, P = 0.000, and 1.2 U vs 4.0 U, P = 0.000). The postoperative length of stay in hospital and incidence of pneumonia were reduced in post-PBM group (8.2 d vs 10.5 d, P = 0.02, and 2.7% vs 3.5%, P = 0.04). The post-PBM group had lower in-hospital mortality (0.6% vs 1.2%, P = 0.000). Multidisciplinary patient blood management strategy significantly reduced blood transfusion, morbidity and mortality in patients underwent valvular heart surgery. It save plenty of blood resources.

Mechanics of Fluid-Filled Interstitial Gaps. II. Gap Characteristics in Xenopus Embryonic Ectoderm.

PubMed

Barua, Debanjan; Parent, Serge E; Winklbauer, Rudolf

2017-08-22

The ectoderm of the Xenopus embryo is permeated by a network of channels that appear in histological sections as interstitial gaps. We characterized this interstitial space by measuring gap sizes, angles formed between adjacent cells, and curvatures of cell surfaces at gaps. From these parameters, and from surface-tension values measured previously, we estimated the values of critical mechanical variables that determine gap sizes and shapes in the ectoderm, using a general model of interstitial gap mechanics. We concluded that gaps of 1-4 μm side length can be formed by the insertion of extracellular matrix fluid at three-cell junctions such that cell adhesion is locally disrupted and a tension difference between cell-cell contacts and the free cell surface at gaps of 0.003 mJ/m 2 is generated. Furthermore, a cell hydrostatic pressure of 16.8 ± 1.7 Pa and an interstitial pressure of 3.9 ± 3.6 Pa, relative to the central blastocoel cavity of the embryo, was found to be consistent with the observed gap size and shape distribution. Reduction of cell adhesion by the knockdown of C-cadherin increased gap volume while leaving intracellular and interstitial pressures essentially unchanged. In both normal and adhesion-reduced ectoderm, cortical tension of the free cell surfaces at gaps does not return to the high values characteristic of the free surface of the whole tissue. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma.

PubMed

Mizuno, Ryuichi; Asano, Koichiro; Mikami, Shuji; Nagata, Hirohiko; Kaneko, Gou; Oya, Mototsugu

2012-05-01

To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus. Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months. Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

Role of the testis interstitial compartment in spermatogonial stem cell function

PubMed Central

Potter, Sarah J.; DeFalco, Tony

2017-01-01

Male fertility is maintained through intricate cellular and molecular interactions that ensure spermatogonial stem cells (SSCs) proceed in a step-wise differentiation process through spermatogenesis and spermiogenesis to produce sperm. SSCs lie within the seminiferous tubule compartment, which provides a nurturing environment for the development of sperm. Cells outside of the tubules, such as interstitial and peritubular cells, also help direct SSC activity. This review focuses on interstitial (interstitial macrophages, Leydig cells, and vasculature) and peritubular (peritubular macrophages, peritubular myoid cells) cells and their role in regulating SSC self-renewal and differentiation in mammals. Leydig cells, the major steroidogenic cells in the testis, influence SSCs through secreted factors, such as insulin growth factor 1 (IGF1) and colony stimulating factor 1 (CSF1). Macrophages interact with SSCs through various potential mechanisms, such as CSF1 and retinoic acid (RA), to induce proliferation or differentiation of SSCs, respectively. Vasculature influences SSC dynamics through CSF1, vascular endothelial growth factor (VEGF), and regulating oxygen levels. Lastly, peritubular myoid cells produce one of the most well-known factors that is required for SSC self-renewal, glial cell line derived neurotrophic factor (GDNF), as well as CSF1. Overall, SSC interactions with interstitial and peritubular cells are critical for SSC function and are an important underlying factor promoting male fertility. PMID:28115580

Mechanics of Fluid-Filled Interstitial Gaps. I. Modeling Gaps in a Compact Tissue.

PubMed

Parent, Serge E; Barua, Debanjan; Winklbauer, Rudolf

2017-08-22

Fluid-filled interstitial gaps are a common feature of compact tissues held together by cell-cell adhesion. Although such gaps can in principle be the result of weak, incomplete cell attachment, adhesion is usually too strong for this to occur. Using a mechanical model of tissue cohesion, we show that, instead, a combination of local prevention of cell adhesion at three-cell junctions by fluidlike extracellular material and a reduction of cortical tension at the gap surface are sufficient to generate stable gaps. The size and shape of these interstitial gaps depends on the mechanical tensions between cells and at gap surfaces, and on the difference between intracellular and interstitial pressures that is related to the volume of the interstitial fluid. As a consequence of the dependence on tension/tension ratios, the presence of gaps does not depend on the absolute strength of cell adhesion, and similar gaps are predicted to occur in tissues of widely differing cohesion. Tissue mechanical parameters can also vary within and between cells of a given tissue, generating asymmetrical gaps. Within limits, these can be approximated by symmetrical gaps. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Therapeutic Effects of Human Amniotic Fluid-Derived Stem Cells on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

PubMed Central

Yin, Zhongcheng; Zhou, Xudong; Li, Xiaoju; Xiao, Aiguo

2013-01-01

Interstitial fibrosis is regarded as the main pathway for the progression of chronic kidney disease (CKD) and is often associated with severe renal dysfunction. Stem cell-based therapies may provide alternative approaches for the treatment of CKD. Human amniotic fluid-derived stem cells (hAFSCs) are a novel stem cell population, which exhibit both embryonic and mesenchymal stem cell characteristics. Herein, the present study investigated whether the transplantation of hAFSCs into renal tissues could improve renal interstitial fibrosis in a murine model of unilateral ureteral obstruction (UUO). We showed that hAFSCs provided a protective effect and alleviated interstitial fibrosis as reflected by an increase in microvascular density; additionally, hAFSCs treatment beneficially modulated protein levels of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1). Therefore, we hypothesize that hAFSCs could represent an alternative, readily available source of stem cells that can be applied for the treatment of renal interstitial fibrosis. PMID:23724119

Robust G2 pausing of adult stem cells in Hydra.

PubMed

Buzgariu, Wanda; Crescenzi, Marco; Galliot, Brigitte

2014-01-01

Hydra is a freshwater hydrozoan polyp that constantly renews its two tissue layers thanks to three distinct stem cell populations that cannot replace each other, epithelial ectodermal, epithelial endodermal, and multipotent interstitial. These adult stem cells, located in the central body column, exhibit different cycling paces, slow for the epithelial, fast for the interstitial. To monitor the changes in cell cycling in Hydra, we established a fast and efficient flow cytometry procedure, which we validated by confirming previous findings, as the Nocodazole-induced reversible arrest of cell cycling in G2/M, and the mitogenic signal provided by feeding. Then to dissect the cycling and differentiation behaviors of the interstitial stem cells, we used the AEP_cnnos1 and AEP_Icy1 transgenic lines that constitutively express GFP in this lineage. For the epithelial lineages we used the sf-1 strain that rapidly eliminates the fast cycling cells upon heat-shock and progressively becomes epithelial. This study evidences similar cycling patterns for the interstitial and epithelial stem cells, which all alternate between the G2 and S-phases traversing a minimal G1-phase. We also found interstitial progenitors with a shorter G2 that pause in G1/G0. At the animal extremities, most cells no longer cycle, the epithelial cells terminally differentiate in G2 and the interstitial progenitors in G1/G0. At the apical pole ~80% cells are post-mitotic differentiated cells, reflecting the higher density of neurons and nematocytes in this region. We discuss how the robust G2 pausing of stem cells, maintained over weeks of starvation, may contribute to regeneration. Copyright © 2014 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor in a ferret

PubMed Central

INOUE, Saki; YONEMARU, Kayoko; YANAI, Tokuma; SAKAI, Hiroki

2014-01-01

A 5-year-old male ferret presented with an enlarged canalicular testis in the left inguinal region. Microscopically, the enlarged testis consisted of a diffuse intimately admixed proliferation of c-kit-positive germ cell-like and Wilms tumor-1 protein-positive Sertoli cell-like components, but no Call-Exner body was detected. In addition, the compact proliferation of steroidogenic acute regulatory protein-intense positive interstitial cells was identified in a separate peripheral area of the mass. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as a mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor. PMID:25311985

Interstitial flows promote an amoeboid cell phenotype and motility of breast cancer cells

NASA Astrophysics Data System (ADS)

Tung, Chih-Kuan; Huang, Yu Ling; Zheng, Angela; Wu, Mingming

2015-03-01

Lymph nodes, the drainage systems for interstitial flows, are clinically known to be the first metastatic sites of many cancer types including breast and prostate cancers. Here, we demonstrate that breast cancer cell morphology and motility is modulated by interstitial flows in a cell-ECM adhesion dependent manner. The average aspect ratios of the cells are significantly lower (or are more amoeboid like) in the presence of the flow in comparison to the case when the flow is absent. The addition of exogenous adhesion molecules within the extracellular matrix (type I collagen) enhances the overall aspect ratio (or are more mesenchymal like) of the cell population. Using measured cell trajectories, we find that the persistence of the amoeboid cells (aspect ratio less than 2.0) is shorter than that of mesenchymal cells. However, the maximum speed of the amoeboid cells is larger than that of mesenchymal cells. Together these findings provide the novel insight that interstitial flows promote amoeboid cell morphology and motility and highlight the plasticity of tumor cell motility in response to its biophysical environment. Supported by NIH Grant R21CA138366.

The safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel in the treatment of non-small cell lung cancer patients with interstitial lung disease.

PubMed

Yasuda, Yuichiro; Hattori, Yoshihiro; Tohnai, Rie; Ito, Shoichi; Kawa, Yoshitaka; Kono, Yuko; Urata, Yoshiko; Nogami, Munenobu; Takenaka, Daisuke; Negoro, Shunichi; Satouchi, Miyako

2018-01-01

The optimal chemotherapy regimen for non-small cell lung cancer patients with interstitial lung disease is unclear. We therefore investigated the safety and efficacy of carboplatin plus nab-paclitaxel as a first-line regimen for non-small cell lung cancer in patients with interstitial lung disease. We retrospectively reviewed advanced non-small cell lung cancer patients with interstitial lung disease who received carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen at Hyogo Cancer Center between February 2013 and August 2016. interstitial lung disease was diagnosed according to the findings of pretreatment chest high-resolution computed tomography. Twelve patients were included (male, n = 11; female, n = 1). The overall response rate was 67% and the disease control rate was 100%. The median progression free survival was 5.1 months (95% CI: 2.9-8.3 months) and the median overall survival was 14.9 months (95% CI: 4.8-not reached). A chemotherapy-related acute exacerbation of interstitial lung disease was observed in one patient; the extent of this event was Grade 2. There were no treatment-related deaths. Carboplatin plus nab-paclitaxel, as a first-line chemotherapy regimen for non-small cell lung cancer, showed favorable efficacy and safety in patients with preexisting interstitial lung disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Modulation of invasive phenotype by interstitial pressure-driven convection in aggregates of human breast cancer cells.

PubMed

Tien, Joe; Truslow, James G; Nelson, Celeste M

2012-01-01

This paper reports the effect of elevated pressure on the invasive phenotype of patterned three-dimensional (3D) aggregates of MDA-MB-231 human breast cancer cells. We found that the directionality of the interstitial pressure profile altered the frequency of invasion by cells located at the surface of an aggregate. In particular, application of pressure at one end of an aggregate suppressed invasion at the opposite end. Experimental alteration of the configuration of cell aggregates and computational modeling of the resulting flow and solute concentration profiles revealed that elevated pressure inhibited invasion by altering the chemical composition of the interstitial fluid near the surface of the aggregate. Our data reveal a link between hydrostatic pressure, interstitial convection, and invasion.

Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

PubMed Central

2015-01-01

Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients. PMID:26560447

PURIFICATION OF RAT LEYDIG CELLS: INCREASED YIELDS AFTER UNIT-GRAVITY SEDIMENTATION OF COLLAGENASE-DISPERSED INTERSTITIAL CELLS

EPA Science Inventory

Abstract

Procedures for purification of Leydig cells have facilitated studies of their regulatory biology. A multistep procedure, that includes a filtration with nylon mesh (100 micron pore size) to separate interstitial cells from the seminiferous tubules, combining centr...

Chitosan fibers with improved biological and mechanical properties for tissue engineering applications.

PubMed

Albanna, Mohammad Z; Bou-Akl, Therese H; Blowytsky, Oksana; Walters, Henry L; Matthew, Howard W T

2013-04-01

The low mechanical properties of hydrogel materials such as chitosan hinder their broad utility for tissue engineering applications. Previous research efforts improved the mechanical properties of chitosan fiber through chemical and physical modifications; however, unfavorable toxicity effects on cells were reported. In this paper, we report the preparation of chitosan fibers with improved mechanical and biocompatibility properties. The structure-property relationships of extruded chitosan fibers were explored by varying acetic acid (AA) concentration, ammonia concentration, annealing temperature and degree of heparin crosslinking. Results showed that optimizing AA concentration to 2vol% improved fiber strength and stiffness by 2-fold. Extruding chitosan solution into 25wt% of ammonia solution reduced fiber diameters and improved fiber strength by 2-fold and stiffness by 3-fold, due to an increase in crystallinity as confirmed by XRD. Fiber annealing further reduced fiber diameter and improved fiber strength and stiffness as temperature increased. Chitosan fibers crosslinked with heparin had increased diameter but lower strength and stiffness properties and higher breaking strain values. When individual parameters were combined, further improvement in fiber mechanical properties was achieved. All mechanically improved fibers and heparin crosslinked fibers promoted valvular interstitial cells (VIC) attachment and growth over 10 day cultures. Our results demonstrate the ability to substantially improve the mechanical properties of chitosan fibers without adversely affecting their biological properties. The investigated treatments offer numerous advantages over previous physical/chemical modifications and thus are expected to expand the utility of chitosan fibers with tunable mechanical properties in various tissue engineering applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

Radiation damage and defect behavior in proton irradiated lithium-counterdoped n+p silicon solar cells

NASA Technical Reports Server (NTRS)

Stupica, John; Goradia, Chandra; Swartz, Clifford K.; Weinberg, Irving

1987-01-01

Two lithium-counterdoped n+p silicon solar cells with different lithium concentrations were irradiated by 10-MeV protons. Cell performance was measured as a function of fluence, and it was found that the cell with the highest concentration of lithium had the highest radiation resistance. Deep level transient spectroscopy which showed two deep level defects that were lithium related. Relating the defect energy levels obtained from this study with those from earlier work using 1-MeV electron irradiation shows no correlation of the defect energy levels. There is one marked similarity: the absence of the boron-interstitial-oxygen-interstitial defect. This consistency strengthens the belief that lithium interacts with oxygen to prevent the formation of the boron interstitial-oxygen interstitial defect. The results indicate that, in general, addition of lithium in small amounts to the p-base of a boron doped silicon solar cell such that the base remains p-type, tends to increase the radiation resistance of the cell.

Interstitial flow influences direction of tumor cell migration through competing mechanisms

PubMed Central

Polacheck, William J.; Charest, Joseph L.; Kamm, Roger D.

2011-01-01

Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. A microfluidic cell culture system was designed to apply stable pressure gradients and fluid flow and allow direct visualization of transient responses of cells seeded in a 3D collagen type I scaffold. We used this system to examine the effects of interstitial flow on cancer cell morphology and migration and to extend previous studies showing that interstitial flow increases the metastatic potential of MDA-MB-435S melanoma cells [Shields J, et al. (2007) Cancer Cell 11:526–538]. Using a breast carcinoma line (MDA-MB-231) we also observed cell migration along streamlines in the presence of flow; however, we further demonstrated that the strength of the flow as well as the cell density determined directional bias of migration along the streamline. In particular, we found that cells either at high seeding density or with the CCR-7 receptor inhibited migration against, rather than with the flow. We provide further evidence that CCR7-dependent autologous chemotaxis is the mechanism that leads to migration with the flow, but also demonstrate a competing CCR7-independent mechanism that causes migration against the flow. Data from experiments investigating the effects of cell concentration, interstitial flow rate, receptor activity, and focal adhesion kinase phosphorylation support our hypothesis that the competing stimulus is integrin mediated. This mechanism may play an important role in development of metastatic disease. PMID:21690404

Epimorphin expression in interstitial pneumonia

PubMed Central

Terasaki, Yasuhiro; Fukuda, Yuh; Suga, Moritaka; Ikeguchi, Naoki; Takeya, Motohiro

2005-01-01

Epimorphin modulates epithelial morphogenesis in embryonic mouse organs. We previously suggested that epimorphin contributes to repair of bleomycin-induced pulmonary fibrosis in mice via epithelium-mesenchyme interactions. To clarify the role of epimorphin in human lungs, we evaluated epimorphin expression and localization in normal lungs, lungs with nonspecific interstitial pneumonia (NSIP), and lungs with usual interstitial pneumonia (UIP); we also studied the effect of recombinant epimorphin on cultured human alveolar epithelial cells in vitro. Northern and Western blotting analyses revealed that epimorphin expression in NSIP samples were significantly higher than those in control lungs and lungs with UIP. Immunohistochemistry showed strong epimorphin expression in mesenchymal cells of early fibrotic lesions and localization of epimorphin protein on mesenchymal cells and extracellular matrix of early fibrotic lesions in the nonspecific interstitial pneumonia group. Double-labeled fluorescent images revealed expression of matrix metalloproteinase 2 in re-epithelialized cells overlying epimorphin-positive early fibrotic lesions. Immunohistochemistry and metalloproteinase activity assay demonstrated augmented expression of metalloproteinase induced by recombinant epimorphin in human alveolar epithelial cells. These findings suggest that epimorphin contributes to repair of pulmonary fibrosis in nonspecific interstitial pneumonia, perhaps partly by inducing expression of matrix metalloproteinase 2, which is an important proteolytic factor in lung remodeling. PMID:15651999

The evaluation of interstitial Cajal cells distribution in non-tumoral colon disorders.

PubMed

Becheanu, G; Manuc, M; Dumbravă, Mona; Herlea, V; Hortopan, Monica; Costache, Mariana

2008-01-01

Interstitial cells of Cajal (ICC) are pacemakers that generate electric waves recorded from the gut and are important for intestinal motility. The aim of the study was to evaluate the distribution of interstitial cells of Cajal in colon specimens from patients with idiopathic chronic pseudo-obstruction and other non-tumoral colon disorders as compared with samples from normal colon. The distribution pattern of ICC in the normal and pathological human colon was evaluated by immunohistochemistry using antibodies for CD117, CD34, and S-100. In two cases with intestinal chronic idiopathic pseudo-obstruction we found a diffuse or focal reducing number of Cajal cells, the loss of immunoreactivity for CD117 being correlated with loss of immunoreactivity for CD34 marker. Our study revealed that the number of interstitial cells of Cajal also decrease in colonic diverticular disease and Crohn disease (p<0.05), whereas the number of enteric neurones appears to be normal. These findings might explain some of the large bowel motor abnormalities known to occur in these disorders. Interstitial Cajal cells may play an important role in pathogenesis and staining for CD117 on transmural intestinal surgical biopsies could allow a more extensive diagnosis in evaluation of chronic intestinal pseudo-obstruction.

Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/Wv mutant mouse colon

PubMed Central

Tamada, Hiromi; Kiyama, Hiroshi

2015-01-01

Interstitial cells of Cajal (ICC) are mesenchymal cells that are distributed along the gastrointestinal tract and function as pacemaker cells or intermediary cells between nerves and smooth muscle cells. ICC express a receptor tyrosine kinase c-Kit, which is an established marker for ICC. The c-kit gene is allelic with the murine white-spotting locus (W), and some ICC subsets were reported to be missing in heterozygous mutant W/Wv mice carrying W and Wv mutated alleles. In this study, the characterization of interstitial cells in the subserosal layer of W/Wv mice was analyzed by immunohistochemistry and electron microscopy. In the proximal and distal colon of W/Wv mutant mice, no c-Kit-positive cells were detected in the subserosal layer by immunohistochemistry. By electron microscopy, the interstitial cells, which were characterized by the existence of caveolae, abundant mitochondria and gap junctions, were observed in the W/Wv mutant colon. The morphological characteristics were comparable to those of the multipolar c-Kit positive ICC seen in the subserosa of proximal and distal colon of wild-type mice. Fibroblasts were also located in the same layers, but the morphology of the fibroblasts was distinguishable from that of ICC in wild type mice or of ICC-like cells in W/Wv mutant mice. Collectively, it is concluded that c-Kit-negative interstitial cells showing a typical ICC ultrastructure exist in the proximal and distal colon of W/Wv mutant mice. PMID:26727725

Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/W(v) mutant mouse colon.

PubMed

Tamada, Hiromi; Kiyama, Hiroshi

2015-01-01

Interstitial cells of Cajal (ICC) are mesenchymal cells that are distributed along the gastrointestinal tract and function as pacemaker cells or intermediary cells between nerves and smooth muscle cells. ICC express a receptor tyrosine kinase c-Kit, which is an established marker for ICC. The c-kit gene is allelic with the murine white-spotting locus (W), and some ICC subsets were reported to be missing in heterozygous mutant W/W(v) mice carrying W and W(v) mutated alleles. In this study, the characterization of interstitial cells in the subserosal layer of W/W(v) mice was analyzed by immunohistochemistry and electron microscopy. In the proximal and distal colon of W/W(v) mutant mice, no c-Kit-positive cells were detected in the subserosal layer by immunohistochemistry. By electron microscopy, the interstitial cells, which were characterized by the existence of caveolae, abundant mitochondria and gap junctions, were observed in the W/W(v) mutant colon. The morphological characteristics were comparable to those of the multipolar c-Kit positive ICC seen in the subserosa of proximal and distal colon of wild-type mice. Fibroblasts were also located in the same layers, but the morphology of the fibroblasts was distinguishable from that of ICC in wild type mice or of ICC-like cells in W/W(v) mutant mice. Collectively, it is concluded that c-Kit-negative interstitial cells showing a typical ICC ultrastructure exist in the proximal and distal colon of W/W(v) mutant mice.

Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/Wv mutant mouse colon.

PubMed

Tamada, Hiromi; Kiyama, Hiroshi

2015-01-01

Interstitial cells of Cajal (ICC) are mesenchymal cells that are distributed along the gastrointestinal tract and function as pacemaker cells or intermediary cells between nerves and smooth muscle cells. ICC express a receptor tyrosine kinase c-Kit, which is an established marker for ICC. The c-kit gene is allelic with the murine white-spotting locus (W), and some ICC subsets were reported to be missing in heterozygous mutant W/Wv mice carrying W and Wv mutated alleles. In this study, the characterization of interstitial cells in the subserosal layer of W/Wv mice was analyzed by immunohistochemistry and electron microscopy. In the proximal and distal colon of W/Wv mutant mice, no c-Kit-positive cells were detected in the subserosal layer by immunohistochemistry. By electron microscopy, the interstitial cells, which were characterized by the existence of caveolae, abundant mitochondria and gap junctions, were observed in the W/Wv mutant colon.The morphological characteristics were comparable to those of the multipolar c-Kit positive ICC seen in the subserosa of proximal and distal colon of wild-type mice. Fibroblasts were also located in the same layers,but the morphology of the fibroblasts was distinguishable from that of ICC in wild type mice or of ICC-like cells in W/Wv mutant mice. Collectively, it is concluded that c-Kit-negative interstitial cells showing a typical ICC ultrastructure exist in the proximal and distal colon of W/Wv mutant mice.

Recent clinical trials in valvular heart disease.

PubMed

Kiss, Daniel; Anwaruddin, Saif

2017-07-01

With widespread adoption of transcatheter aortic valve replacement, there has been a change in the approach to management of valvular heart disease. New interest has taken hold in transcatheter therapies for valvular heart disease, as well as research into pathophysiology and progression of disease. Additionally, several key trials have further refined our understanding of surgical management of valvular heart disease. This review will elucidate recent clinical trial data leading to changes in practice. There have been several landmark trials expanding the indications for transcatheter aortic valve replacement. Additionally, although still early, trials are beginning to demonstrate the feasibility and safety of transcatheter mitral valves. Options for transcatheter management of right-sided valvular disease continue to evolve, and these are areas of active investigation. The emergence of novel therapies for valvular heart disease has expanded the management options available, allowing physicians to better individualize treatment of patients with valvular heart disease. This review will focus on the recent (within 2 years) trials in this field of interest.

Bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in non-small cell lung cancer.

PubMed

Sekimoto, Yasuhito; Kato, Motoyasu; Shukuya, Takehiko; Koyama, Ryo; Nagaoka, Tetsutaro; Takahashi, Kazuhisa

2016-04-01

Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor and a key drug for advanced non-small cell lung cancer. There are few reports describing bevacizumab-induced chronic interstitial pneumonia. A 62-year-old man with advanced non-small cell lung cancer was admitted to our hospital with dyspnea. He previously received four courses of carboplatin plus paclitaxel with bevacizumab combination therapy and thereafter received four courses of maintenance bevacizumab monotherapy. A chest-computed tomography scan on admission revealed diffuse ground glass opacity. He had not received any other drugs and did not have pneumonia. Thus, he was diagnosed with bevacizumab-induced chronic interstitial pneumonia and was treated with a high dose of corticosteroids. After steroid treatment, his dyspnea and radiological findings improved. This case report is the first description of bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in a patient with non-small cell lung cancer.

Proliferation and differentiation of brown adipocytes from interstitial cells during cold acclimation

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

Bukowiecki, L.J.; Geloeen, A.; Collet, A.J.

1986-06-01

The mechanisms of brown adipocyte proliferation and differentiation during cold acclimation (and/or adaptation to hyperphagia) have been studied by quantitative photonic radioautography. (/sup 3/H)thymidine was injected to warm-acclimated (25/sup 0/C) rats and to animals exposed to 5/sup 0/C for 2 days. Samples of interscapular brown adipose tissue were collected for quantitative analysis of mitotic frequencies at various periods of time (4 h-15 days) after the injection of (/sup 3/H)thymidine, the rats being maintained at the temperatures to which they were initially exposed. It was found that cold exposure for 2 days markedly enhanced mitotic activity in endothelial cells, interstitial cells,more » and brown preadipocytes rather than in fully differentiated brown adipocytes. The total tissue labeling index (percent of labeled nuclei) increased approx.70 times over control values. The authors now report that cellular labeling progressively increased in mature brown adipocytes during cold acclimation, whereas it correspondingly decreased in interstitial cells and brown preadipocytes. This indicates that the sequence of events for cellular differentiation is interstitial cells ..-->.. brown preadipocytes ..-->.. mature brown adipocytes. Remarkable, labeling frequency did not change in endothelial cells during cold acclimation demonstrating that these cells cannot be considered as progenitors of brown adipocytes. It is suggested that brown adipocyte proliferation and differentiation from interstitial cells represent the fundamental phenomena explaining the enhanced capacity of cold-acclimated and/or hyperphagic rats to respond calorigenically to catecholamines.« less

Sertoli Cell Wt1 Regulates Peritubular Myoid Cell and Fetal Leydig Cell Differentiation during Fetal Testis Development.

PubMed

Wen, Qing; Wang, Yuqian; Tang, Jixin; Cheng, C Yan; Liu, Yi-Xun

2016-01-01

Sertoli cells play a significant role in regulating fetal testis compartmentalization to generate testis cords and interstitium during development. The Sertoli cell Wilms' tumor 1 (Wt1) gene, which encodes ~24 zinc finger-containing transcription factors, is known to play a crucial role in fetal testis cord assembly and maintenance. However, whether Wt1 regulates fetal testis compartmentalization by modulating the development of peritubular myoid cells (PMCs) and/or fetal Leydig cells (FLCs) remains unknown. Using a Wt1-/flox; Amh-Cre mouse model by deleting Wt1 in Sertoli cells (Wt1SC-cKO) at embryonic day 14.5 (E14.5), Wt1 was found to regulate PMC and FLC development. Wt1 deletion in fetal testis Sertoli cells caused aberrant differentiation and proliferation of PMCs, FLCs and interstitial progenitor cells from embryo to newborn, leading to abnormal fetal testis interstitial development. Specifically, the expression of PMC marker genes α-Sma, Myh11 and Des, and interstitial progenitor cell marker gene Vcam1 were down-regulated, whereas FLC marker genes StAR, Cyp11a1, Cyp17a1 and Hsd3b1 were up-regulated, in neonatal Wt1SC-cKO testes. The ratio of PMC:FLC were also reduced in Wt1SC-cKO testes, concomitant with a down-regulation of Notch signaling molecules Jag 1, Notch 2, Notch 3, and Hes1 in neonatal Wt1SC-cKO testes, illustrating changes in the differentiation status of FLC from their interstitial progenitor cells during fetal testis development. In summary, Wt1 regulates the development of FLC and interstitial progenitor cell lineages through Notch signaling, and it also plays a role in PMC development. Collectively, these effects confer fetal testis compartmentalization.

Close association of vascular and valvular calcification and prognosis of patients on continuous ambulatory peritoneal dialysis.

PubMed

Gen, Shikou; Inoue, Tsutomu; Nodaira, Yuka; Ikeda, Naofumi; Kobayashi, Kazuhiro; Watanabe, Yusuke; Kanno, Yoshihiko; Nakamoto, Hidetomo; Suzuki, Hiromichi

2008-01-01

In the present study, we examined the association between vascular and valvular calcification and the prognosis of patients on continuous ambulatory peritoneal dialysis (CAPD). Data were collected from the records of patients introduced onto CAPD therapy during 1999 - 2006 at the Department of Nephrology, Saitama Medical University. At the start of CAPD, cardiac and vascular echography were used to examine 162 patients (average age: 56 +/- 5 years; 58 men, 104 women; 43 with and 119 without diabetes) for evaluation of vascular and valvular calcification. Both vascular and valvular calcification were found in 32 patients. Vascular calcification was found in 16, and valvular calcification in 11. Over 5 years, 11 patients suffered from cardiovascular disease (7 with stroke, 4 with myocardial infarction). All of these patients had vascular or valvular calcification at the start of CAPD therapy. We also used Cox hazard analysis to examine values for Ca, P, Ca x P, intact parathyroid hormone (iPTH), and lipids. None of these values were independent contributory factors for incidence of cardiovascular disease in patients on CAPD. These data suggest the importance of vascular and valvular echography to evaluate patients on CAPD, especially at the start of CAPD therapy. Vascular and valvular calcification are important factors for determining the prognosis of patients on CAPD.

Blood and interstitial flow in the hierarchical pore space architecture of bone tissue.

PubMed

Cowin, Stephen C; Cardoso, Luis

2015-03-18

There are two main types of fluid in bone tissue, blood and interstitial fluid. The chemical composition of these fluids varies with time and location in bone. Blood arrives through the arterial system containing oxygen and other nutrients and the blood components depart via the venous system containing less oxygen and reduced nutrition. Within the bone, as within other tissues, substances pass from the blood through the arterial walls into the interstitial fluid. The movement of the interstitial fluid carries these substances to the cells within the bone and, at the same time, carries off the waste materials from the cells. Bone tissue would not live without these fluid movements. The development of a model for poroelastic materials with hierarchical pore space architecture for the description of blood flow and interstitial fluid flow in living bone tissue is reviewed. The model is applied to the problem of determining the exchange of pore fluid between the vascular porosity and the lacunar-canalicular porosity in bone tissue due to cyclic mechanical loading and blood pressure. These results are basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells. Copyright © 2014 Elsevier Ltd. All rights reserved.

Blood and Interstitial flow in the hierarchical pore space architecture of bone tissue

PubMed Central

Cowin, Stephen C.; Cardoso, Luis

2015-01-01

There are two main types of fluid in bone tissue, blood and interstitial fluid. The chemical composition of these fluids varies with time and location in bone. Blood arrives through the arterial system containing oxygen and other nutrients and the blood components depart via the venous system containing less oxygen and reduced nutrition. Within the bone, as within other tissues, substances pass from the blood through the arterial walls into the interstitial fluid. The movement of the interstitial fluid carries these substances to the cells within the bone and, at the same time, carries off the waste materials from the cells. Bone tissue would not live without these fluid movements. The development of a model for poroelastic materials with hierarchical pore space architecture for the description of blood flow and interstitial fluid flow in living bone tissue is reviewed. The model is applied to the problem of determining the exchange of pore fluid between the vascular porosity and the lacunar-canalicular porosity in bone tissue due to cyclic mechanical loading and blood pressure. These results are basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells. PMID:25666410

Bilateral sertoli and interstitial cell tumours in abdominal testes of a goat with polled intersex syndrome (PIS).

PubMed

Canisso, I F; Coffee, L L; Ortved, K; Fubini, S L; Monteagudo, L V; Schlafer, D H; Gilbert, R O

2014-12-01

An 8-year-old, mixed breed, polled goat was presented for evaluation of male-like behaviour. Clinical findings included clitoromegaly, a heavily muscled neck, pronounced beard, and erect dorsal guard hairs, which are phenotypic characteristics commonly observed in intersex animals. Transrectal ultrasonography revealed the presence of two abdominal masses caudolateral to the uterine horns. Serum concentration of estradiol was elevated. Genetic evaluation was compatible with polled intersex syndrome defined by an XX karyotype without a Y chromosome or SRY gene. Based on gross and histologic evaluation, the abdominal masses were determined to be intra-abdominal testes, each of which was effaced by Sertoli cell and interstitial (Leydig) cell tumours. The Sertoli cell tumours (SCTs) represented two unique histologic patterns. Regardless of pattern, neoplastic Sertoli cells were consistently lipid laden and positive for vimentin. Interstitial cell tumours (ICTs) were negative for vimentin. Clinical and histopathologic findings suggest that prolonged exposure to steroids secreted by neoplastic Sertoli cells contributed to virilization. In addition, results from immunohistochemistry indicated that vimentin may be a valuable immunodiagnostic tool for differentiation between interstitial and Sertoli cell tumours in goats. © 2014 Blackwell Verlag GmbH.

The role of cardiac magnetic resonance in valvular heart disease.

PubMed

Lopez-Mattei, Juan C; Shah, Dipan J

2013-01-01

The prevalence of valvular heart disease is increasing as the population ages. In diagnosing individuals with valve disease, echocardiography is the primary imaging modality used by clinicians both for initial assessment and for longitudinal evaluation. However, in some cases cardiovascular magnetic resonance has become a viable alternative in that it can obtain imaging data in any plane prescribed by the scan operator, which makes it ideal for accurate investigation of all cardiac valves: aortic, mitral, pulmonic, and tricuspid. In addition, CMR for valve assessment is noninvasive, free of ionizing radiation, and in most instances does not require contrast administration. The objectives of a comprehensive CMR study for evaluating valvular heart disease are threefold: (1) to provide insight into the mechanism of the valvular lesion (via anatomic assessment), (2) to quantify the severity of the valvular lesion, and (3) to discern the consequences of the valvular lesion.

Histopathological Study of Left and Right Atria in Isolated Rheumatic Mitral Stenosis With and Without Atrial Fibrillation.

PubMed

Shenthar, Jayaprakash; Kalpana, Saligrama Ramegowda; Prabhu, Mukund A; Rai, Maneesh K; Nagashetty, Ravikumar Kalyani; Kamlapurkar, Giridhar

2016-09-01

Mitral stenosis (MS) has the highest incidence of atrial fibrillation (AF) in chronic rheumatic valvular disease. There are very few studies in isolated MS comparing histopathological changes in patients with sinus rhythm (SR) and AF. To analyze the histological changes associated with isolated MS and compare between changes in AF and SR. This was a prospective study in patients undergoing valve replacement surgery for symptomatic isolated MS who were divided into 2 groups, Group I AF (n = 13) and Group II SR (n = 10). Intra-operative biopsies performed from 5 different sites from both atria were analyzed for 10 histopathologic changes commonly associated with AF. On multivariate analysis, myocytolysis (odds ratio [OR]: 1.48, P = 0.05) was found to be associated with AF, whereas myocyte hypertrophy (OR: 0.21, P = 0.003), and glycogen deposition (OR: 0.43, P = 0.002) was associated with SR. Interstitial fibrosis the commonest change was uniformly distributed across both atria irrespective of the rhythm. In rheumatic MS, SR is associated with myocyte hypertrophy whereas AF is associated with myocytolysis. Endocardial inflammation is more common in left atrial appendage irrespective of rhythm. Interstitial fibrosis is seen in >90% of patients distributed in both the atria and is independent of the rhythm. Amyloid and Aschoff bodies are uncommon and the rest of the changes are uniformly distributed across both the atria. © 2016 Wiley Periodicals, Inc.

Carbon, oxygen and their interaction with intrinsic point defects in solar silicon ribbon material: A speculative approach

NASA Technical Reports Server (NTRS)

Goesele, U.; Ast, D. G.

1983-01-01

Some background information on intrinsic point defects is provided and on carbon and oxygen in silicon in so far as it may be relevant for the efficiency of solar cells fabricated from EFG ribbon material. The co-precipitation of carbon and oxygen and especially of carbon and silicon self interstitials are discussed. A simple model for the electrical activity of carbon-self-interstitial agglomerates is presented. The self-interstitial content of these agglomerates is assumed to determine their electrical activity and that both compressive stresses (high self-interstitial content) and tensile stresses (low self-interstitial content) give rise to electrical activity of the agglomerates. The self-interstitial content of these carbon-related agglomerates may be reduced by an appropriate high temperature treatment and enhanced by a supersaturation of self-interstitials generated during formation of the p-n junction of solar cells. Oxygen present in supersaturation in carbon-rich silicon may be induced to form SiO, precipitates by self-interstitials generated during phosphorus diffusion. It is proposed that the SiO2-Si interface of the precipates gives rise to a continuum of donor stables and that these interface states are responsible for at least part of the light inhancement effects observed in oxygen containing EFG silicon after phosphorus diffusion.

Congenital and Acquired Valvular Heart Disease in Pregnancy.

PubMed

Goldstein, Sarah A; Ward, Cary C

2017-08-24

The number of pregnancies complicated by valvular heart disease is increasing. This review describes the hemodynamic effects of clinically important valvular abnormalities during pregnancy and reviews current guideline-driven management strategies. Valvular heart disease in women of childbearing age is most commonly caused by congenital abnormalities and rheumatic heart disease. Regurgitant lesions are well tolerated, while stenotic lesions are associated with a higher risk of pregnancy-related complications. Management of symptomatic disease during pregnancy is primarily medical, with percutaneous interventions considered for refractory symptoms. Most guidelines addressing the management of valvular heart disease during pregnancy are based on case reports and observational studies. Additional investigation is required to further advance the care of this growing patient population.

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

PubMed

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

2018-05-01

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

Anderson-Fabry disease in heart failure.

PubMed

Akhtar, M M; Elliott, P M

2018-06-16

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry's disease is reported to be in the range of 1 in 40,000-117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system. Gb3 accumulation induces pathology via the release of pro-inflammatory cytokines, growth-promoting factors and by oxidative stress, resulting in myocardial extracellular matrix remodelling, left ventricular hypertrophy (LVH), vascular dysfunction and interstitial fibrosis. Cardiac involvement manifesting as ventricular hypertrophy, systolic and diastolic dysfunction, valvular abnormalities and conduction tissue disease is common in AFD and is associated with considerable cardiovascular morbidity and mortality from heart failure, sudden cardiac death and stroke-related death.

Cancer Cell Glycocalyx Mediates Mechanostransduction and Flow-Regulated Invasion

PubMed Central

Qazi, Henry; Palomino, Rocio; Shi, Zhong-Dong; Munn, Lance L.; Tarbell, John M.

2014-01-01

Mammalian cells are covered by a surface proteoglycan (glycocalyx) layer, and it is known that blood vessel-lining endothelial cells use the glycocalyx to sense and transduce the shearing forces of blood flow into intracellular signals. Tumor cells in vivo are exposed to forces from interstitial fluid flow that may affect metastatic potential but are not reproduced by most in vitro cell motility assays. We hypothesized that glycocalyx-mediated mechanotransduction of interstitial flow shear stress is an un-recognized factor that can significantly enhance metastatic cell motility and play a role in augmentation of invasion. Involvement of MMP levels, cell adhesion molecules (CD44, α3 integrin), and glycocalyx components (heparan sulfate and hyaluronan) were investigated in a cell/collagen gel suspension model designed to mimic the interstitial flow microenvironment. Physiologic levels of flow upregulated MMP levels and enhanced the motility of metastatic cells. Blocking the flow-enhanced expression of MMP actvity or adhesion molecules (CD44 and integrins) resulted in blocking the flow-enhanced migratory activity. The presence of a glycocalyx-like layer was verified around tumor cells, and the degradation of this layer by hyaluronidase and heparinase blocked the flow-regulated invasion. This study shows for the first time that interstitial flow enhancement of metastatic cell motility can be mediated by the cell surface glycocalyx – a potential target for therapeutics. PMID:24077103

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary.

PubMed

Lombardi, Leonardo Augusto; Simões, Ricardo Santos; Maganhin, Carla Cristina; Baracat, Maria Cândida Pinheiro; Silva-Sasso, Gisela Rodrigues; Florencio-Silva, Rinaldo; Soares, José Maria; Baracat, Edmund Chada

2014-07-01

to evaluate the immunohistochemical expression of proliferative, apoptotic and steroidogenic enzyme markers in the ovaries of rats with polycystic ovary syndrome (PCOS). twenty rats were divided into two groups: GCtrl - estrous phase, and PCOS - with polycystic ovaries. The GCtrl animals were subjected to a lighting period from 7 am to 7 pm, while the animals with PCOS group remained with continuous lighting for 60 days. Subsequently, the animals were anesthetized, the ovaries were removed and fixed in 10% formaldehyde, prior to paraffin embedding. Sections were stained using H.E. or subjected to immunohistochemical methods for the detection of Ki-67, cleaved caspase-3, CYP11A1, CYP17A1 and CYP19A1. The results were analyzed using Student's t-test (p < 0,05). morphological results showed evidence of interstitial cells originating from the inner theca cells of degenerating ovarian cysts in PCOS. Immunoexpression of Ki-67 was higher in the granulosa cells in GCtrl, and the theca interna cells in PCOS, while cleaved caspase-3 was higher in granulosa cells of ovarian cysts from PCOS and in the theca interna cells of GCtrl. Immunoreactivity of CYP11A1 in the theca interna, granulosa and interstitial cells was similar between the two groups, while CYP17A1 and CYP19A1 were higher in the granulosa and interstitial cells in the PCOS group. the results indicate that the interstitial cells are derived from the theca interna and that enzymatic changes occur in the theca interna and interstitial cells in ovaries of rats with PCOS, responsible for the high levels of androgens and estradiol.

Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

PubMed

Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

2014-01-01

To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

Single or group housing altered hormonal physiology and affected pituitary and interstitial cell kinetics

EPA Science Inventory

A significant negative correlation between testicular interstitial cell tumors and pituitary tumors in control male F344 rats has been reported associated with the number of animals per cage. Change in numbers of animals per cage may cause stress and increased serum corticosteroi...

COX2 Inhibition Reduces Aortic Valve Calcification In Vivo

PubMed Central

Wirrig, Elaine E.; Gomez, M. Victoria; Hinton, Robert B.; Yutzey, Katherine E.

2016-01-01

Objective Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects approximately 1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild type mice, increased expression of the gene encoding cyclooxygenase 2/COX2 (Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed. Approach and Results In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression. Conclusions COX2 expression is upregulated in CAVD and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo. PMID:25722432

Effects Of Continuous Argon Laser Irradiation On Canine And Autopsied Human Cardiac Tissue

NASA Astrophysics Data System (ADS)

Ben-Shachar, Giora; Sivakoff, Mark; Bernard, Steven L.; Dahms, Beverly B.; Riemenschneider, Thomas A.

1984-10-01

In eight human formalin preserved cardiac specimens, various cardiac and vascular obstructions were relieved by argon laser irradiation. Interatrial communication was also produced by a transar'rial approach in a live dog. In-vivo fresh canine cardiac tissues required power density of at feast 80, 90, and 110 watts/cm2 for vaporization of myocardial, vascular and valvular tissues respectively. The fiber tip to tissue distance (effective irradiation distance) for effective vaporization was less than I mm for vascular and valvular tissues and less than 4 mm for myocardium. Light microscopy showed four zones of histological damage common to all tissues - central crater surrounded by layers of charring, vacuolization and coagulation necorsis. Myocardium showed additionally a layer of normal appearing muscle cells (skip area) surrounded by a peripheral coagulation halo. Laser irradiation effects on valvular tissue showed the most lateral extension of coagulation necrosis. It is concluded that palliation and treatment of certain congenital heart defects by laser irradiation is anatomi-cally feasible and may be safe for in vivo application when low power output and short exposure time are used from a very short irradiation distance.

Atrioventricular valvular anomalies and their role in the etiopathogenesis of cardiorespiratory syndrome in farmed common foxes (Vulpes vulpes).

PubMed

Noszczyk-Nowak, Agnieszka; Piasecki, Tomasz; Cepiel, Alicja; Nowak, Marcin; Janus, Izabela; Pasławska, Urszula

2016-01-01

Cardiorespiratory syndrome of common foxes is associated with a mortality rate ranging from 2.1% to 20%. The aim of this study was to analyze the prevalence of cardiac abnormalities in common foxes (Vulpes vulpes) from Polish farms with a history of cardiorespiratory syndrome. The prevalence of cardiac abnormalities in common foxes from a Polish farm with a history of cardiorespiratory syndrome was assessed as well as morphological examination of 60 heart specimens from clinically healthy animals. In addition, 38 foxes were examined echocardiographically and subjected to postmortem examination. Atrioventricular valvular abnormalities were found in 57 out of the 98 (58%) analyzed hearts. The abnormalities of the mitral valve documented in more than 20% of the foxes in involved tendinous chords (completely lacking or shortened), papillary muscles and mitral cusps associated with both insufficiency and stenosis of the left atrioventricular orifice. Abnormalities of the tricuspid valve included significant shortening of the tendinous chords and thickening of the valve cusps with the impairment of their mobility. The results of the echocardiographic and postmortem examination were consistent in 79% of the cases. The specimens collected from animals with and without atrioventricular valvular anomalies did not differ significantly in terms of cardiomyocyte width, number of inflammatory cells, adipose tissue content and presence of polychromatic cardiomyocytes. Congenital atrioventricular valvular defects may be involved in the etiology of cardiorespiratory syndrome in common foxes, and echocardiography can be used as a measure of stock's health and a criterion for selection for mating.

Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells

PubMed Central

2016-01-01

Hydra continuously differentiates a sophisticated nervous system made of mechanosensory cells (nematocytes) and sensory–motor and ganglionic neurons from interstitial stem cells. However, this dynamic adult neurogenesis is dispensable for morphogenesis. Indeed animals depleted of their interstitial stem cells and interstitial progenitors lose their active behaviours but maintain their developmental fitness, and regenerate and bud when force-fed. To characterize the impact of the loss of neurogenesis in Hydra, we first performed transcriptomic profiling at five positions along the body axis. We found neurogenic genes predominantly expressed along the central body column, which contains stem cells and progenitors, and neurotransmission genes predominantly expressed at the extremities, where the nervous system is dense. Next, we performed transcriptomics on animals depleted of their interstitial cells by hydroxyurea, colchicine or heat-shock treatment. By crossing these results with cell-type-specific transcriptomics, we identified epithelial genes up-regulated upon loss of neurogenesis: transcription factors (Dlx, Dlx1, DMBX1/Manacle, Ets1, Gli3, KLF11, LMX1A, ZNF436, Shox1), epitheliopeptides (Arminins, PW peptide), neurosignalling components (CAMK1D, DDCl2, Inx1), ligand-ion channel receptors (CHRNA1, NaC7), G-Protein Coupled Receptors and FMRFRL. Hence epitheliomuscular cells seemingly enhance their sensing ability when neurogenesis is compromised. This unsuspected plasticity might reflect the extended multifunctionality of epithelial-like cells in early eumetazoan evolution. PMID:26598723

Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells.

PubMed

Wenger, Y; Buzgariu, W; Galliot, B

2016-01-05

Hydra continuously differentiates a sophisticated nervous system made of mechanosensory cells (nematocytes) and sensory-motor and ganglionic neurons from interstitial stem cells. However, this dynamic adult neurogenesis is dispensable for morphogenesis. Indeed animals depleted of their interstitial stem cells and interstitial progenitors lose their active behaviours but maintain their developmental fitness, and regenerate and bud when force-fed. To characterize the impact of the loss of neurogenesis in Hydra, we first performed transcriptomic profiling at five positions along the body axis. We found neurogenic genes predominantly expressed along the central body column, which contains stem cells and progenitors, and neurotransmission genes predominantly expressed at the extremities, where the nervous system is dense. Next, we performed transcriptomics on animals depleted of their interstitial cells by hydroxyurea, colchicine or heat-shock treatment. By crossing these results with cell-type-specific transcriptomics, we identified epithelial genes up-regulated upon loss of neurogenesis: transcription factors (Dlx, Dlx1, DMBX1/Manacle, Ets1, Gli3, KLF11, LMX1A, ZNF436, Shox1), epitheliopeptides (Arminins, PW peptide), neurosignalling components (CAMK1D, DDCl2, Inx1), ligand-ion channel receptors (CHRNA1, NaC7), G-Protein Coupled Receptors and FMRFRL. Hence epitheliomuscular cells seemingly enhance their sensing ability when neurogenesis is compromised. This unsuspected plasticity might reflect the extended multifunctionality of epithelial-like cells in early eumetazoan evolution. © 2015 The Authors.

The modern role of transoesophageal echocardiography in the assessment of valvular pathologies

PubMed Central

Bull, Sacha; Newton, James

2017-01-01

Despite significant advancements in the field of cardiovascular imaging, transoesophageal echocardiography remains the key imaging modality in the management of valvular pathologies. This paper provides echocardiographers with an overview of the modern role of TOE in the diagnosis and management of valvular disease. We describe how the introduction of 3D techniques has changed the detection and grading of valvular pathologies and concentrate on its role as a monitoring tool in interventional cardiology. In addition, we focus on the echocardiographic and Doppler techniques used in the assessment of prosthetic valves and provide guidance for the evaluation of prosthetic valves. Finally, we summarise quantitative methods used for the assessment of valvular stenosis and regurgitation and highlight the key areas where echocardiography remains superior over other novel imaging modalities. PMID:28096184

The modern role of transoesophageal echocardiography in the assessment of valvular pathologies.

PubMed

Wamil, Malgorzata; Bull, Sacha; Newton, James

2017-01-17

Despite significant advancements in the field of cardiovascular imaging, transoesophageal echocardiography remains the key imaging modality in the management of valvular pathologies. This paper provides echocardiographers with an overview of the modern role of TOE in the diagnosis and management of valvular disease. We describe how the introduction of 3D techniques has changed detection and grading of valvular pathologies and concentrate on its role as a monitoring tool in interventional cardiology. In addition, we focus on the echocardiographic and Doppler techniques used in the assessment of prosthetic valves, and provide guidance for evaluation of prosthetic valves. Finally, we summarise quantitative methods used for the assessment of valvular stenosis and regurgitation and highlight the key areas where echocardiography remains superior over other novel imaging modalities. © 2017 The authors.

Rheb/mTORC1 Signaling Promotes Kidney Fibroblast Activation and Fibrosis

PubMed Central

Jiang, Lei; Xu, Lingling; Mao, Junhua; Li, Jianzhong; Fang, Li; Zhou, Yang; Liu, Wei; He, Weichun; Zhao, Allan Zijian

2013-01-01

Ras homolog enriched in brain (Rheb) is a small GTPase that regulates cell growth, differentiation, and survival by upregulating mammalian target of rapamycin complex 1 (mTORC1) signaling. The role of Rheb/mTORC1 signaling in the activation of kidney fibroblasts and the development of kidney fibrosis remains largely unknown. In this study, we found that Rheb/mTORC1 signaling was activated in interstitial myofibroblasts from fibrotic kidneys. Treatment of rat kidney interstitial fibroblasts (NRK-49F cell line) with TGFβ1 also activated Rheb/mTORC1 signaling. Blocking Rheb/mTORC1 signaling with rapamycin or Rheb small interfering RNA abolished TGFβ1-induced fibroblast activation. In a transgenic mouse, ectopic expression of Rheb activated kidney fibroblasts. These Rheb transgenic mice exhibited increased activation of mTORC1 signaling in both kidney tubular and interstitial cells as well as progressive interstitial renal fibrosis; rapamycin inhibited these effects. Similarly, mice with fibroblast-specific deletion of Tsc1, a negative regulator of Rheb, exhibited activated mTORC1 signaling in kidney interstitial fibroblasts and increased renal fibrosis, both of which rapamycin abolished. Taken together, these results suggest that Rheb/mTORC1 signaling promotes the activation of kidney fibroblasts and contributes to the development of interstitial fibrosis, possibly providing a therapeutic target for progressive renal disease. PMID:23661807

Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

PubMed

Geng, Jie-jie; Zhang, Kui; Chen, Li-na; Miao, Jin-lin; Yao, Meng; Ren, Ying; Fu, Zhi-guang; Chen, Zhi-nan; Zhu, Ping

2014-09-01

Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1β, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Is the appearance of macrophages in pulmonary tissue related to time of asphyxia?

PubMed

Vacchiano, G; D'Armiento, F; Torino, R

2001-01-01

In order to connect the appearance of macrophages and giant cells in pulmonary tissue with the time of asphyxia the authors analyzed 50 asphyxiated human lungs paying their attention on the number of alveolar and interstitial macrophages and giant cells. They compared histological specimens of 25 asphixiated humans lungs following a slow asphyxia (30 min or more) with 25 histological specimens of asphyxiated human lungs following a rapid asphyxia (10-15 min). Alveolar and interstitial macrophages and giant cells per section, were considered and numbered. Controls were done on histological examination of traumatized lungs. In the pulmonary alveoli following on acute asphyxia there were 27.7+/-4.4 macrophages per section. Subjects dead after a slow asphyxiation showed 68.2+/-7.1 alveolar macrophages per section (p<0.001). Interstitial macrophages were also frequently present. No differences are detectable in the number of polynuclear giant cells between rapidly and slowly asphyxiated human lungs. The number of alveolar and interstitial macrophages per section can be considered as a further histological evidence of a slow asphyxia and can differentiate a slow asphyxia from an acute one.

A distinct type of cell in myocardium: interstitial Cajal-like cells (ICLCs)

PubMed Central

Kostin, S; Popescu, L M

2009-01-01

Abstract The existence of a novel type of interstitial cells in the heart, interstitial Cajal-like cells (ICLCs), had been described for the first time in 2005. Their identification was mainly based on ultrastructural criteria: very long (tens up to hundreds of micrometres) and moniliform prolongations, which are extremely thin (less than 0.2 μm), below the resolving power of light microscopy. Myocardial ICLCs were also identified by methylene-blue vital staining, silver impregnation, and immunoreactivity for CD 34, vimentin, CD117/c-kit, etc. Although a series of studies provided evidence for the existence of ICLCs in human atria and rat ventricles, further investigations in other laboratories, using additional techniques, are required to substantiate the consistency of these findings. Here we provide further evidence for the existence of ICLCs in human and mammalian hearts (by transmission and scanning electron microscopy, as well as confocal laser scanning microscopy). Noteworthy, we confirm that ICLCs communicate with neighbouring cells via shedding (micro)vesicles. Although these so-called ICLCs represent a distinct type of cells, different from classical interstitial cells of Cajal, or fibroblasts, their role(s) in myocardium remain(s) to be established. Several hypotheses are proposed: (i) adult stromal (mesenchymal) stem cells, which might participate in cardiac repair/remodelling; (ii) intercellular signalling (e.g. via shedding microvesicles); (iii) chemo-mechanical transducers and (iv) players in pacemaking and/or arrhytmogenesis, and so on. PMID:19183408

Interstitial inflammation in Alport syndrome.

PubMed

Jedlicka, Jan; Soleiman, Afschin; Draganovici, Dan; Mandelbaum, Jana; Ziegler, Urs; Regele, Heinz; Wüthrich, Rudolf P; Gross, Oliver; Anders, Hans-Joachim; Segerer, Stephan

2010-04-01

The Alport syndrome is a hereditary glomerular disease linked to structural abnormalities of collagen IV. In a mouse model of Alport syndrome, the interstitial lymphocyte influx was important for disease progression. CXCR3 is a chemokine receptor involved in lymphocyte recruitment to the kidney. We hypothesized that CXCR3-positive T cells might be involved in human Alport syndrome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded biopsies from 17 patients with Alport syndrome, 10 with immunoglobulin A (IgA) nephropathy, and 11 healthy donor kidneys. We investigated the expression of the alpha5 chain of collagen IV to confirm the morphologic diagnosis, the chemokine receptor CXCR3 and CD3-positive T cells. Alport syndrome biopsies demonstrated a complete loss of the alpha5 chain of collagen IV from the glomerular basement membrane and the morphologic features consistent with Alport syndrome on electron microscopy. A prominent number of CXCR3-positive cells were found in the tubulointerstitium. Most of the CXCR3-positive cells were CD3-positive T cells, demonstrated by double-labeling in selected biopsies. The number of CXCR3-positive cells in kidneys with Alport syndrome correlated with serum creatinine (P < .05) and with morphologic features of a progressive disease (eg, interstitial fibrosis, glomerulosclerosis, and tubular atrophy). The severity of interstitial CXCR3-positive cell influx was similar in Alport syndrome as compared to immunoglobulin A nephropathy. The noninflammatory glomerular lesion of Alport syndrome is associated with prominent interstitial accumulation of CD3- and CXCR3-positive lymphocytes. The degree of infiltration correlated with renal function. We speculate that targeting T lymphocytes, for example, by CXCR3 blocking agents, might be a novel approach to inhibit disease progression in patients with Alport syndrome. Copyright 2010 Elsevier Inc.

Teaching a changing paradigm in physiology: a historical perspective on gut interstitial cells.

PubMed

Drumm, Bernard T; Baker, Salah A

2017-03-01

The study and teaching of gastrointestinal (GI) physiology necessitates an understanding of the cellular basis of contractile and electrical coupling behaviors in the muscle layers that comprise the gut wall. Our knowledge of the cellular origin of GI motility has drastically changed over the last 100 yr. While the pacing and coordination of GI contraction was once thought to be solely attributable to smooth muscle cells, it is now widely accepted that the motility patterns observed in the GI tract exist as a result of a multicellular system, consisting of not only smooth muscle cells but also enteric neurons and distinct populations of specialized interstitial cells that all work in concert to ensure proper GI functions. In this historical perspective, we focus on the emerging role of interstitial cells in GI motility and examine the key discoveries and experiments that led to a major shift in a paradigm of GI physiology regarding the role of interstitial cells in modulating GI contractile patterns. A review of these now classic experiments and papers will enable students and educators to fully appreciate the complex, multicellular nature of GI muscles as well as impart lessons on how shifting paradigms in physiology are fueled by new technologies that lead to new emerging discoveries. Copyright © 2017 the American Physiological Society.

Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

PubMed

Avezum, Alvaro; Lopes, Renato D; Schulte, Phillip J; Lanas, Fernando; Gersh, Bernard J; Hanna, Michael; Pais, Prem; Erol, Cetin; Diaz, Rafael; Bahit, M Cecilia; Bartunek, Jozef; De Caterina, Raffaele; Goto, Shinya; Ruzyllo, Witold; Zhu, Jun; Granger, Christopher B; Alexander, John H

2015-08-25

Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10). More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. © 2015 American Heart Association, Inc.

Stroke prevention strategies in patients with atrial fibrillation and heart valve abnormalities: perceptions of 'valvular' atrial fibrillation: results of the European Heart Rhythm Association Survey.

PubMed

Potpara, Tatjana S; Lip, Gregory Y H; Larsen, Torben B; Madrid, Antonio; Dobreanu, Dan; Jędrzejczyk-Patej, Ewa; Dagres, Nikolaos

2016-10-01

The purpose of this European Heart Rhythm Association (EHRA) Survey was to assess the perceptions of 'valvular' atrial fibrillation (AF) and management of AF patients with various heart valve abnormalities in daily clinical practice in European electrophysiology (EP) centres. Questionnaire survey was sent via the Internet to the EHRA-EP Research Network Centres. Of the 52 responding centres, 42 (80.8%) were university hospitals. Choosing the most comprehensive definition of valvular AF, a total of 49 centres (94.2%) encountered a mechanical prosthetic heart valve and significant rheumatic mitral stenosis, 35 centres (67.3%) also considered bioprosthetic valves, and 25 centres (48.1%) included any significant valvular heart disease, requiring surgical repair in the definition of valvular AF. Only three centres (5.8%) would define valvular AF as the presence of any (even mild) valvular abnormality. None of the centres would use non-vitamin K antagonist oral anticoagulants (NOACs) in AF patients with mechanical prosthetic valves, only 5 centres (9.8%) would use NOACs in patients with significant mitral stenosis, 17 centres (32.7%) would consider the use of NOACs in patients with bioprosthetic valves, and 21 centres (41.2%) would use NOACs in patients with a non-recent transcatheter valve replacement/implantation, while 13 centres (25.5%) would never consider the use of NOACs in AF patients with even mild native heart valve abnormality. Our survey showed marked heterogeneity in the definition of valvular AF and thromboprophylactic treatments, with the use of variable NOACs in patients with valvular heart disease other than prosthetic heart valves or significant mitral stenosis, indicating that this term may be misleading and should not be used. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Replacement of the valvular prosthesis in a patient with a Bentall procedure.

PubMed

Panos, A L; Teoh, K T; Wilson, J K; Salerno, T A

1992-09-01

Patients who have had the Bentall-DeBono procedure using a composite conduit with a tissue valvular prosthesis pose a great challenge when problems develop with the tissue prosthesis. We herein report the surgical management of one such case, in which the valvular prosthesis was removed and replaced without replacement of the conduit.

T Cell Interstitial Migration: Motility Cues from the Inflamed Tissue for Micro- and Macro-Positioning.

PubMed

Gaylo, Alison; Schrock, Dillon C; Fernandes, Ninoshka R J; Fowell, Deborah J

2016-01-01

Effector T cells exit the inflamed vasculature into an environment shaped by tissue-specific structural configurations and inflammation-imposed extrinsic modifications. Once within interstitial spaces of non-lymphoid tissues, T cells migrate in an apparent random, non-directional, fashion. Efficient T cell scanning of the tissue environment is essential for successful location of infected target cells or encounter with antigen-presenting cells that activate the T cell's antimicrobial effector functions. The mechanisms of interstitial T cell motility and the environmental cues that may promote or hinder efficient tissue scanning are poorly understood. The extracellular matrix (ECM) appears to play an important scaffolding role in guidance of T cell migration and likely provides a platform for the display of chemotactic factors that may help to direct the positioning of T cells. Here, we discuss how intravital imaging has provided insight into the motility patterns and cellular machinery that facilitates T cell interstitial migration and the critical environmental factors that may optimize the efficiency of effector T cell scanning of the inflamed tissue. Specifically, we highlight the local micro-positioning cues T cells encounter as they migrate within inflamed tissues, from surrounding ECM and signaling molecules, as well as a requirement for appropriate long-range macro-positioning within distinct tissue compartments or at discrete foci of infection or tissue damage. The central nervous system (CNS) responds to injury and infection by extensively remodeling the ECM and with the de novo generation of a fibroblastic reticular network that likely influences T cell motility. We examine how inflammation-induced changes to the CNS landscape may regulate T cell tissue exploration and modulate function.

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

Nikula, K.J.; Swafford, D.S.; Hoover, M.D.

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2{sup k}) Mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro.more » Responses were similar in both strains of mice. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO{sub 4} in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease. 29 refs., 6 figs., 3 tabs.« less

Resveratrol Reduces Steroidogenesis in Rat Ovarian Theca-Interstitial Cells: The Role of Inhibition of Akt/PKB Signaling Pathway

PubMed Central

Ortega, Israel; Villanueva, Jesus A.; Wong, Donna H.; Cress, Amanda B.; Sokalska, Anna; Stanley, Scott D.

2012-01-01

Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1–10 μm), GGPP (30 μm), FPP (30 μm), nicotinamide (1 mm), and/or sirtinol (10 μm). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID:22719052

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

Chen, Wei-Yu, E-mail: wychen624@cgmh.org.tw; Chang, Ya-Jen; Su, Chia-Hao

Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneysmore » using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases. -- Highlights: •Interleukin (IL)-33 was upregulated in obstructed kidneys. •Interstitial myofibroblasts expressed IL-33 after UUO-induced renal injury. •Deficiency of IL33 reduced interstitial fibrosis and promoted tubular cell proliferation.« less

T Cell Interstitial Migration: Motility Cues from the Inflamed Tissue for Micro- and Macro-Positioning

PubMed Central

Gaylo, Alison; Schrock, Dillon C.; Fernandes, Ninoshka R. J.; Fowell, Deborah J.

2016-01-01

Effector T cells exit the inflamed vasculature into an environment shaped by tissue-specific structural configurations and inflammation-imposed extrinsic modifications. Once within interstitial spaces of non-lymphoid tissues, T cells migrate in an apparent random, non-directional, fashion. Efficient T cell scanning of the tissue environment is essential for successful location of infected target cells or encounter with antigen-presenting cells that activate the T cell’s antimicrobial effector functions. The mechanisms of interstitial T cell motility and the environmental cues that may promote or hinder efficient tissue scanning are poorly understood. The extracellular matrix (ECM) appears to play an important scaffolding role in guidance of T cell migration and likely provides a platform for the display of chemotactic factors that may help to direct the positioning of T cells. Here, we discuss how intravital imaging has provided insight into the motility patterns and cellular machinery that facilitates T cell interstitial migration and the critical environmental factors that may optimize the efficiency of effector T cell scanning of the inflamed tissue. Specifically, we highlight the local micro-positioning cues T cells encounter as they migrate within inflamed tissues, from surrounding ECM and signaling molecules, as well as a requirement for appropriate long-range macro-positioning within distinct tissue compartments or at discrete foci of infection or tissue damage. The central nervous system (CNS) responds to injury and infection by extensively remodeling the ECM and with the de novo generation of a fibroblastic reticular network that likely influences T cell motility. We examine how inflammation-induced changes to the CNS landscape may regulate T cell tissue exploration and modulate function. PMID:27790220

Ulcerative colitis: ultrastructure of interstitial cells in myenteric plexus.

PubMed

Rumessen, J J; Vanderwinden, J-M; Horn, T

2010-10-01

Interstitial cells of Cajal (ICC) are key regulatory cells in the gut. In the colon of patients with severe ulcerative colitis (UC), myenteric ICC had myoid ultrastructural features and were in close contact with nerve terminals. In all patients as opposed to controls, some ICC profiles showed degenerative changes, such as lipid droplets and irregular vacuoles. Nerve terminals often appeared swollen and empty. Glial cells, muscle cells, and fibroblast-like cells (FLC) showed no alterations. FLC enclosed macrophages (MLC), which were in close contact with naked axon terminals. The organization and cytological changes may be of pathophysiological significance in patients with UC.

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

Tabatowski, K.; Roggli, V.L.; Fulkerson, W.J.

A case of biopsy-proven giant cell interstitial pneumonia in a patient with occupational exposure to hard-metal dust is reported. Bronchial washings performed several days prior to open-lung biopsy yielded an almost exclusive population of nonpigmented alveolar macrophages and pleomorphic, phagocytic multinucleated giant cells. Microorganisms, viral inclusions in the giant cells, epithelioid histiocytes and well-formed granulomas were not seen. This cytologic picture strongly suggests the presence of giant cell interstitial pneumonia in a patient with restrictive lung disease, particularly when exposure to hard-metal dust is known or suspected. A specific diagnosis early in the course of the disease may facilitate removalmore » of the individual from the workplace and forestall the development of end-stage interstitial fibrosis. Additionally, the working environment may be modified to minimize inhalational exposure. Recognition of this entity by the cytopathologist may direct diagnostic efforts toward accurate histologic evaluation and the identification of particulates by microprobe analysis of either cellular or biopsy material.« less

Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms

PubMed Central

Miller, Jordan D.; Weiss, Robert M.; Heistad, Donald D.

2011-01-01

Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, non-osseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research. PMID:21617136

Electrode assembly for use in a solid polymer electrolyte fuel cell

DOEpatents

Raistrick, Ian D.

1989-01-01

A gas reaction fuel cell may be provided with a solid polymer electrolyte membrane. Porous gas diffusion electrodes are formed of carbon particles supporting a catalyst which is effective to enhance the gas reactions. The carbon particles define interstitial spaces exposing the catalyst on a large surface area of the carbon particles. A proton conducting material, such as a perfluorocarbon copolymer or ruthenium dioxide contacts the surface areas of the carbon particles adjacent the interstitial spaces. The proton conducting material enables protons produced by the gas reactions adjacent the supported catalyst to have a conductive path with the electrolyte membrane. The carbon particles provide a conductive path for electrons. A suitable electrode may be formed by dispersing a solution containing a proton conducting material over the surface of the electrode in a manner effective to coat carbon surfaces adjacent the interstitial spaces without impeding gas flow into the interstitial spaces.

New insights into canted spiro carbon interstitial in graphite

NASA Astrophysics Data System (ADS)

EL-Barbary, A. A.

2017-12-01

The self-interstitial carbon is the key to radiation damage in graphite moderator nuclear reactor, so an understanding of its behavior is essential for plant safety and maximized reactor lifetime. The density functional theory is applied on four different graphite unit cells, starting from of 64 carbon atoms up to 256 carbon atoms, using AIMPRO code to obtain the energetic, athermal and mechanical properties of carbon interstitial in graphite. This study presents first principles calculations of the energy of formation that prove its high barrier to athermal diffusion (1.1 eV) and the consequent large critical shear stress (39 eV-50 eV) necessary to shear graphite planes in its presence. Also, for the first time, the gamma surface of graphite in two dimensions is calculated and found to yield the critical shear stress for perfect graphite. Finally, in contrast to the extensive literature describing the interstitial of carbon in graphite as spiro interstitial, in this work the ground state of interstitial carbon is found to be canted spiro interstitial.

Valvular Abnormalities Detected by Echocardiography in 5-Year Survivors of Childhood Cancer: A Long-Term Follow-Up Study

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

Pal, Helena J. van der, E-mail: h.j.vanderpal@amc.uva.nl; Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam; Dijk, Irma W. van

Purpose: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). Methods and Materials: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD{sub 2}). Using multivariablemore » logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. Results: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD{sub 2}) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. Conclusions: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD{sub 2} to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS.« less

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans.

PubMed

Osman, Narin; Grande-Allen, K Jane; Ballinger, Mandy L; Getachew, Robel; Marasco, Silvana; O'Brien, Kevin D; Little, Peter J

2013-01-01

Calcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease. Diseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [(35)S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding. Classic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Haematological indices as predictors of atrial fibrillation following isolated coronary artery bypass grafting, valvular surgery, or combined procedures: a systematic review with meta-analysis.

PubMed

Weymann, Alexander; Ali-Hasan-Al-Saegh, Sadeq; Popov, Aron-Frederik; Sabashnikov, Anton; Mirhosseini, Seyed Jalil; Liu, Tong; Tse, Gary; Lotfaliani, Mohammadreza; Ghanei, Azam; Testa, Luca; D'Ascenzo, Fabrizio; Benedetto, Umberto; Dehghan, Hamidreza; Roever, Leonardo; Sá, Michel Pompeu Barros de Oliveira; Baker, William L; Yavuz, Senol; Zeriouh, Mohamed; Mashhour, Ahmed; Nombela-Franco, Luis; Jang, Jae-Sik; Meng, Lei; Gong, Mengqi; Deshmukh, Abhishek J; Palmerini, Tullio; Linde, Cecilia; Filipiak, Krzysztof J; Biondi-Zoccai, Giuseppe; Calkins, Hugh; Stone, Gregg W

2018-01-01

New postoperative atrial fibrillation (POAF) is one of the most critical and common complications after cardio¬vascular surgery precipitating early and late morbidities. Complete blood count (CBC) is an imperative blood test in clinical practice, routinely used in the examination of cardiovascular diseases. This systematic review with meta-analysis aimed to determine the strength of evidence for evaluating the association of haematological indices in CBC tests with atrial fibrillation following isolated coronary artery bypass graft (CABG), isolated valvular surgery, or a combination of these treatments. We conducted a meta-analysis of studies evaluating pre- and postoperative haematological indices in patients with POAF. A comprehensive subgroup analysis was performed to explore potential sources of heterogeneity. A literature search of all major databases retrieved 732 studies. After screening, 22 studies were analysed including a total of 6098 patients. Pooled analysis showed preoperative platelet count (PC) (weighted mean difference [WMD] = -7.07 × 109/L and p < 0.001), preoperative mean platelet volume (MPV) (WMD = 0.53 FL and p < 0.001), preoperative white blood cell count (WBC) (WMD = 0.130 × 109/L and p < 0.001), preoperative neutrophil-to-lymphocyte ratio (NLR) (WMD = 0.33 and p < 0.001), preoperative red blood cell distribution width (RDW) (WMD = 0.36% and p < 0.001), postoperative WBC (WMD = 1.36 × 109/L and p < 0.001), and postoperative NLR (WMD = 0.74 and p < 0.001) as associated factors with POAF. Haematological indices may predict the risk of POAF before surgery. These easily-performed tests should defi¬nitely be taken into account in patients undergoing isolated CABG, valvular surgery, or combined procedures.

Aortic insufficiency

MedlinePlus

... Heart valve - aortic regurgitation; Valvular disease - aortic regurgitation; AI - aortic insufficiency ... BA. Valvular heart disease. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. Philadelphia, PA: ...

Effectiveness of Combined Therapy with Pirfenidone and Erythromycin for Unclassifiable Interstitial Pneumonia Induced by HTLV-1-associated Bronchioloalveolar Disorder (HABA)

PubMed Central

Yokohori, Naoko; Sato, Akitoshi; Hasegawa, Mizue; Katsura, Hideki; Hiroshima, Kenzo; Takemura, Tamiko

2017-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus involved in the pathogenesis of adult T-cell leukemia (ATL) and HTVL-1-associated bronchioloalveolar disorder (HABA). The clinical and pathological findings of HABA have been characterized as either a diffuse panbronchiolitis (DPB) pattern or idiopathic interstitial pneumonia (IIP) pattern. Treatments for HABA include corticosteroids for the IIP pattern and erythromycin for the DPB pattern. We herein report a case of HABA-associated unclassifiable interstitial pneumonia that improved with combined therapy with pirfenidone and erythromycin. This is the first report on the effectiveness of combined therapy with pirfenidone and erythromycin for HABA. PMID:28050003

Giant-cell interstitial pneumonia in a gas station worker.

PubMed

Lee, S M; Moon, C H; Oh, Y B; Kim, H Y; Ahn, Y; Ko, E J; Joo, J E

1998-10-01

Giant-cell interstitial Pneumonia (GIP) is a very uncommon respiratory disease. The majority of cases of GIP are caused by exposure to cobalt, tungsten and other hard metals. In this report, we describe GIP in a patient who worked in gas station and dealt in propane gas vessels. He presented with clinical features of chronic interstitial lung disease and underwent an open lung biopsy that showed DIP-like reaction with large numbers of intra-alveolar macrophages and numerous large, multinucleated histiocytes which were admixed with the macrophages. Analysis of lung tissue for hard metals was done. Cobalt was the main component of detected hard metals. Corticosteroid therapy was started and he recovered fully.

Flow interactions with cells and tissues: cardiovascular flows and fluid-structure interactions. Sixth International Bio-Fluid Mechanics Symposium and Workshop, March 28-30, 2008, Pasadena, California.

PubMed

Friedman, Morton H; Krams, Rob; Chandran, Krishnan B

2010-03-01

Interactions between flow and biological cells and tissues are intrinsic to the circulatory, respiratory, digestive and genitourinary systems. In the circulatory system, an understanding of the complex interaction between the arterial wall (a living multi-component organ with anisotropic, nonlinear material properties) and blood (a shear-thinning fluid with 45% by volume consisting of red blood cells, platelets, and white blood cells) is vital to our understanding of the physiology of the human circulation and the etiology and development of arterial diseases, and to the design and development of prosthetic implants and tissue-engineered substitutes. Similarly, an understanding of the complex dynamics of flow past native human heart valves and the effect of that flow on the valvular tissue is necessary to elucidate the etiology of valvular diseases and in the design and development of valve replacements. In this paper we address the influence of biomechanical factors on the arterial circulation. The first part presents our current understanding of the impact of blood flow on the arterial wall at the cellular level and the relationship between flow-induced stresses and the etiology of atherosclerosis. The second part describes recent advances in the application of fluid-structure interaction analysis to arterial flows and the dynamics of heart valves.

Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis.

PubMed

Lei, P S; Lowichik, A; Allen, W; Mauch, T J

2000-12-01

A 17-year-old boy with juvenile rheumatoid arthritis presented with jaundice, confusion, hemolytic anemia, thrombocytopenia, and acute renal failure secondary to titer-confirmed acute Epstein-Barr virus (EBV). Renal biopsy specimen revealed interstitial nephritis with an inflammatory infiltrate composed of cytotoxic/suppressor T cells, and interstitial mononuclear cell nuclei expressed EBV encoded RNA-1 (EBER-1) mRNA. Methylprednisolone treatment resulted in rapid improvement.

The distribution of serum albumin in the rat testis, studied by electron microscope immunocytochemistry on ultrathin frozen sections.

PubMed

Christensen, A K; Komorowski, T E; Wilson, B; Ma, S F; Stevens, R W

1985-05-01

The distribution of serum albumin is of interest in the rat testis because this protein is the principal carrier for testosterone in the plasma and interstitial fluid of this species. We have localized extravascular serum albumin in the rat testis at the electron microscope level, using gold particle immunocytochemistry on ultrathin frozen sections of tissue fixed lightly by perfusion. The same localization was obtained with three different antisera. Preabsorption and normal rabbit serum controls were negative, and Western blots of testis extracts showed major activity only at the molecular weight of albumin. Serum albumin occurred in substantial concentration throughout extracellular space in the interstitial tissue, as well as in the space between the boundary layer and the base of the seminiferous epithelium. Immunoreactivity extended between Sertoli cells, as well as around spermatogonia and early primary spermatocytes (to stage 11), but did not traverse the Sertoli-Sertoli junctions that comprise the blood-testis barrier. Macrophages in the interstitial tissue showed some endocytic activity. If perfusion fixation was carried out in a manner that flushed most of the albumin from the interstitial space, then a layer of albumin remained on the surface of Leydig cells and many macrophages but was minimal or absent on the surface of other cell types that are normally in contact with albumin, such as Sertoli cells, spermatogonia, myoid cells, lymphatic endothelium, fibroblasts, or cells of blood vessels.

Renal myofibroblasts contract collagen I matrix lattices in vitro.

PubMed

Kelynack, K J; Hewitson, T D; Pedagogos, E; Nicholls, K M; Becker, G J

1999-01-01

Myofibroblasts, cells with both fibroblastic and smooth muscle cell features, have been implicated in renal scarring. In addition to synthetic properties, contractile features and integrin expression may allow myofibroblasts to rearrange and contract interstitial collagenous proteins. Myofibroblasts from normal rat kidneys were grown in cell-populated collagen lattices to measure cell generated contraction. Following detachment of cell populated collagen lattices, myofibroblasts progressively contracted collagen lattices, reducing lattice diameter by 42% at 24 h. Alignment of myofibroblasts, rearrangement of fibrils and beta(1) integrin expression were observed within lattices. We postulate that interstitial myofibroblasts contribute to renal scarring through manipulation of collagenous proteins. Copyright 1999 S. Karger AG, Basel

Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle.

PubMed

Tamaki, Tetsuro; Akatsuka, Akira; Ando, Kiyoshi; Nakamura, Yoshihiko; Matsuzawa, Hideyuki; Hotta, Tomomitsu; Roy, Roland R; Edgerton, V Reggie

2002-05-13

Putative myogenic and endothelial (myo-endothelial) cell progenitors were identified in the interstitial spaces of murine skeletal muscle by immunohistochemistry and immunoelectron microscopy using CD34 antigen. Enzymatically isolated cells were characterized by fluorescence-activated cell sorting on the basis of cell surface antigen expression, and were sorted as a CD34+ and CD45- fraction. Cells in this fraction were approximately 94% positive for Sca-1, and mostly negative (<3% positive) for CD14, 31, 49, 144, c-kit, and FLK-1. The CD34+/45- cells formed colonies in clonal cell cultures and colony-forming units displayed the potential to differentiate into adipocytes, endothelial, and myogenic cells. The CD34+/45- cells fully differentiated into vascular endothelial cells and skeletal muscle fibers in vivo after transplantation. Immediately after sorting, CD34+/45- cells expressed only c-met mRNA, and did not express any other myogenic cell-related markers such as MyoD, myf-5, myf-6, myogenin, M-cadherin, Pax-3, and Pax-7. However, after 3 d of culture, these cells expressed mRNA for all myogenic markers. CD34+/45- cells were distinct from satellite cells, as they expressed Bcrp1/ABCG2 gene mRNA (Zhou et al., 2001). These findings suggest that myo-endothelial progenitors reside in the interstitial spaces of mammalian skeletal muscles, and that they can potentially contribute to postnatal skeletal muscle growth.

MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM

PubMed Central

Bi, P.; Kuang, S.

2012-01-01

Stem cell niche plays a critical role in regulating the behavior and function of adult stem cells that underlie tissue growth, maintenance, and regeneration. In the skeletal muscle, stem cells, called satellite cells, contribute to postnatal muscle growth and hypertrophy, and thus, meat production in agricultural animals. Satellite cells are located adjacent to mature muscle fibers underneath a sheath of basal lamina. Microenvironmental signals from extracellular matrix mediated by the basal lamina and from the host myofiber both impinge on satellite cells to regulate their activity. Furthermore, several types of muscle interstitial cells, including intramuscular preadipocytes and connective tissue fibroblasts, have recently been shown to interact with satellite cells and actively regulate the growth and regeneration of postnatal skeletal muscles. From this regard, interstitial adipogenic cells are not only important for marbling and meat quality, but also represent an additional cellular component of the satellite cell niche. At the molecular level, these interstitial cells may interact with satellite cells through cell surface ligands, such as delta-like 1 homolog (Dlk1) protein whose overexpression is thought to be responsible for muscle hypertrophy in callipyge sheep. In fact, extracellular Dlk1 protein has been shown to promote the myogenic differentiation of satellite cells. Understanding the cellular and molecular mechanisms within the stem cell niche that regulate satellite cell differentiation and maintain muscle homeostasis may lead to promising approaches to optimizing muscle growth and composition, thus improving meat production and quality. PMID:22100594

Ulinastatin inhibits renal tubular epithelial apoptosis and interstitial fibrosis in rats with unilateral ureteral obstruction.

PubMed

Zhang, Qing-Fang

2017-12-01

The effect of ulinastatin (UTI) on renal tubular epithelial apoptosis and interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) was investigated. A total of 18 male Wistar rats were randomly divided into the following 3 groups: The Sham group (n=6), the UUO group (n=6), and the UTI group (n=6). In the UUO and UTI groups, the left ureter was ligated to establish a UUO model. Starting from day 1 after surgery, an intervention treatment was performed using normal saline (1 ml/kg/d) and UTI (40,000 unit/kg/d). On day 7 after surgery, 6 rats from each group were sacrificed. In the Sham group, the left ureter was only freed, not ligated; after 7 days of abdominal closure, all of the rats were sacrificed. Blood samples were collected prior to sacrificing the animals to measure the blood urea nitrogen (BUN) and serum creatinine (Scr). The incidence of renal interstitial lesions on the obstruction side was observed by hematoxylin and eosin, and Masson staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and immunohistochemical detection of apoptosis regulator Bax (Bax), apoptosis regulator Bcl‑2 (Bcl‑2) and caspase‑3 were performed to observe the presence of renal tubular epithelial cell apoptosis. The UTI did not have a significant influence on the mouse BUN and Scr levels in any of the groups (P>0.05). Compared with that in the Sham group, renal tissue injury in the UUO group was significantly aggravated with renal tubular dilation, epithelial cell atrophy, renal interstitial inflammatory cell infiltration and fibrous tissue hyperplasia (P<0.01). Furthermore, the renal tubular epithelial TUNEL+ cell number and Bax and caspase‑3 levels were increased, and the expression of Bcl‑2 was decreased (P<0.01). Following the UTI treatment, the renal interstitial injury at the obstruction side was significantly attenuated (P<0.05), the renal tubular epithelial TUNEL+ cell number, and Bax and caspase‑3 levels significantly decreased, and the expression of Bcl‑2 was restored (P<0.05). UTI inhibited renal tubular epithelial apoptosis and interstitial fibrosis in UUO rats.

Calcium responses in subserosal interstitial cells of the guinea-pig proximal colon.

PubMed

Tamada, H; Hashitani, H

2014-01-01

In the subserosal layer between the longitudinal muscle layer and mesothelium, heterogeneous populations of interstitial cells are distributed. As the distribution of nerve elements in this layer is sparse as compared with the nerve plexus layer or tunica muscularis, there may be unique communication among subserosal interstitial cells (SSICs). This study aimed to explore functional properties of SSICs. In subserosal preparations of the guinea-pig proximal colon, changes in intracellular Ca(2+) ([Ca(2+) ]i ) were visualized using Fluo-4 Ca(2+) imaging. Immunohistochemistry was also performed to identify the SSICs exhibiting Ca(2+) transients. A majority of SSICs responded to adenosine triphosphate (ATP, 10 μM) by increasing [Ca(2+) ]i , but remained quiescent during the application of acetylcholine (10 μM). ATP-induced Ca(2+) responses were mimicked by adenosine 5'-diphosphate (10 μM), MRS2365 (10 nM) but not α, β-methylene ATP (10 μM) or uridine triphosphate (10 μM), and could be reproduced in Ca(2+) -free solution, suggesting that ATP acts via P2Y receptors, most likely P2Y1 subtype, but not P2X receptors. Live staining of the same preparations after Ca(2+) imaging indicated the ATP-sensitive SSICs were not positive for c-Kit antibody, a specific marker for gastrointestinal interstitial cells of Cajal (ICC). Immunohistochemistry identified vimentin (mesenchymal cell marker)+/Kit- and SK3 (fibroblast-like cell (FLC) marker)+/Kit- cells that had a similar morphology to the ATP-sensitive SSICs in Ca(2+) imaging. A majority of the SSICs in the guinea-pig proximal colon, presumably FLC, are capable of responding to ATP and thus may contribute to smooth muscle relaxation upon stimulation with ATP released from non-neuronal cells. © 2013 John Wiley & Sons Ltd.

Immunophenotype of infiltrating cells in protocol renal allograft biopsies from tacrolimus-versus cyclosporine-treated patients.

PubMed

Serón, Daniel; O'Valle, Francisco; Moreso, Francesc; Gomà, Montse; Hueso, Miguel; Grinyó, Josep M; Garcia del Moral, Raimundo

2007-03-15

The prevalence of subclinical rejection is lower in patients receiving tacrolimus than in patients treated with cyclosporine. However, it is not known whether this difference is related to the modulation of a specific cell immunophenotype. We perform a two case-one control study in patients treated with tacrolimus (n=44) or cyclosporine (n=22) with a protocol biopsy performed at 4 to 6 months. Immunophenotype of infiltrating cells was evaluated with monoclonal antibodies directed against CD45 (all leukocytes), CD3 (T lymphocytes), CD68 (monocytes/macrophages), and CD20 (B lymphocytes) and expressed as interstitial positive cells/mm(2). The number of interstitial CD45 (290+/-209 vs. 696+/-560; P<0.01), CD3 (121+/-84 vs. 208+/-104; P<0.01), and CD68 (155+/-232 vs. 242+/-280; P<0.05) but not CD20 (137+/-119 vs. 197+/-154) positive cells was lower in tacrolimus-treated patients. T lymphocytes and macrophages interstitial infiltration was reduced in tacrolimus treated patients evaluated with protocol biopsies in comparison to cyclosporine-treated patients.

[Analysis of the prevalence and risk factors of preoperative angiography confirmed coronary artery stenosis in patients with degenerative valvular heart disease].

PubMed

Xu, Z J; Pan, J; Zhou, Q; Wang, D J

2017-10-24

Objective: To estimate the prevalence and the risk factors of preoperative coronary angiography (CAG) confirmed coronary stenosis in patients with degenerative valvular heart disease. Methods: A total of 491 patients who underwent screening CAG before valvular surgery due to degenerative valvular heart disease were enrolled from January 2011 to September 2014 in our hospital, and clinical data were analyzed. According to CAG results, patients were divided into positive CAG result (PCAG) group or negative CAG (NCAG) group. Positive CAG result was defined as stenosis ≥50% of the diameter of the left main coronary artery or stenosis ≥70% of the diameter of left anterior descending, left circumflex artery, and right coronary artery.Risk factors of positive CAG result were analyzed by multivariable logistic regression analysis, and Bootstrap method was used to verify the results. Results: There were 47(9.57%)degenerative valvular heart disease patients with PCAG. Patients were older ((68.0±7.6)years vs.(62.6±7.1)years, P <0.001) and the prevalence of typical angina was significantly higher (14.89%(7/47)vs. 2.03%(9/444), P <0.001)in PCAG group than in NCAG group. Multivariable logistic regression analysis showed that age ( OR =1.118, 95% CI 1.067-1.172, P <0.001), typical angina ( OR =8.970, 95% CI 2.963-27.154, P <0.001), and serum concentration of apolipoprotein B ( OR =20.311, 95% CI 4.774-86.416, P <0.001) were the independent risk factors of PCAG in degenerative valvular heart disease patients. Bootstrap method revealed satisfactory repeatability of multivariable logistic regression analysis results (age: OR =1.118, 95% CI 1.068-1.178, P =0.001; typical angina: OR =8.970, 95% CI 2.338-35.891, P =0.001; serum concentration of apolipoprotein B: OR =20.311, 95% CI 4.639-91.977, P =0.001). Conclusions: A low prevalence of PCAG before valvular surgery is observed in degenerative valvular heart disease patients in this patient cohort. Age, typical angina, and serum concentration of apolipoprotein B are independent risk factors of PCAG in this patient cohort.

Roles of CD34+ cells and ALK5 signaling in the reconstruction of seminiferous tubule-like structures in 3-D re-aggregate culture of dissociated cells from neonatal mouse testes.

PubMed

Abe, Shin-Ichi; Abe, Kazuko; Zhang, Jidong; Harada, Tomoaki; Mizumoto, Go; Oshikawa, Hiroki; Akiyama, Haruhiko; Shimamura, Kenji

2017-01-01

Tissue reconstruction in vitro can provide, if successful, a refined and simple system to analyze the underlying mechanisms that drive the morphogenesis and maintain the ordered structure. We have recently succeeded in reconstruction of seminiferous cord-like and tubule-like structures using 3-D re-aggregate culture of dissociated testicular cells. In testis formation, endothelial cells that migrated from mesonephroi to embryonic gonads have been shown to be critical for development of testis cords, but how endothelial cells contribute to testis cord formation remains unknown. To decipher the roles of endothelial and peritubular cells in the reconstruction of cord-like and tubule-like structures, we investigated the behavior of CD34+ endothelial and p75+ cells, and peritubular myoid cells (PTMCs) in 3-D re-aggregate cultures of testicular cells. The results showed that these 3 types of cells had the capacity of re-aggregation on their own and with each other, and of segregation into 3 layers in a re-aggregate, which were very similar to interstitial and peritubular tissues in vivo. Observation of behaviors of fluorescent Sertoli cells and other non-fluorescent types of cells using testes from Sox9-EGFP transgenic mice showed dynamic cell movement and segregation in re-aggregate cultures. Cultures of testicular cells deprived of interstitial and peritubular cells resulted in dysmorphic structures, but re-addition of them restored tubule-like structures. Purified CD34+ cells in culture differentiated into p75+ cells and PTMCs. These results indicate that CD34+ cells differentiate into p75+ cells, which then differentiate into PTMCs. TGFβ signaling inhibitors, SB431542 and ALK5i, disturbed the reconstruction of cord-like and tubule-like structures, and the latter compromised re-construction of interstitial-like and peritubular-like structures, as well as the proliferation of CD34+, p75+, PTMCs, and Sertoli cells, and their movement and differentiation. These results indicate that CD34+ cells and signaling through ALK5 play pivotal roles in the morphogenesis of interstitial-like, peritubular-like and cord-like structures.

Contribution of intravascular versus interstitial purines and nitric oxide in the regulation of exercise hyperaemia in humans

PubMed Central

Hellsten, Y; Nyberg, M; Mortensen, S P

2012-01-01

The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released into the skeletal muscle interstitium and in plasma in response to muscle contraction. Cellular sources of ATP and NO in plasma are erythrocytes and endothelial cells, whereas interstitial sources are skeletal muscle cells and endothelial cells. Adenosine originates primarily from extracellular degradation of ATP. During exercise the concentrations of ATP and adenosine increase markedly in the interstitium with smaller increases occurring in plasma, and thus the interstitial concentration during exercise is severalfold higher than in plasma. The concentration of NO metabolites (NOx) in interstitium and plasma does not change during exercise and is similar in the two compartments. Adenosine and NO have been shown to contribute to exercise hyperaemia whereas the role of ATP remains unclear due to lack of specific purinergic receptor blockers. The relative role of intravascular versus interstitial vasodilators is not known but evidence suggests that both compartments are important. In cardiovascular disease, a reduced capacity to form adenosine in the muscle interstitium may be a contributing factor in increased peripheral vascular resistance. PMID:22733661

Pericytes in kidney fibrosis.

PubMed

Ren, Shuyu; Duffield, Jeremy S

2013-07-01

Pericytes and perivascular fibroblasts have emerged as poorly appreciated yet extensive populations of mesenchymal cells in the kidney that play important roles in homeostasis and responses to injury. This review will update readers on the evolving understanding of the biology of these cells. Fate mapping has identified pericytes and perivascular fibroblasts as the major source of pathological fibrillar matrix-forming cells in interstitial kidney disease. In other organs similar cells have been described and independent fate mapping indicates that pericytes or perivascular cells are myofibroblast progenitors in multiple organs. Over the last year, new insights into the function of pericytes in kidney homeostasis has been uncovered and new molecular pathways that regulate detachment and their transdifferentiation into pathological myofibroblasts, including Wingless/Int, ephrin, transforming growth factor β, platelet derived growth factor, and Hedgehog signaling pathways, have been reported. In addition provocative studies indicate that microRNAs, which regulate posttranscriptional gene expression, may also play important roles in their transdifferentiation. Pericytes and perivascular fibroblasts are the major source of pathological collagen fiber-forming cells in interstitial kidney diseases. New avenues of research into their activation and differentiation has identified new drug candidates for the treatment of interstitial kidney disease.

Ultrastructural study of relationships between c-kit immunoreactive interstitial cells and other cellular elements in the human colon.

PubMed

Mazzia, C; Porcher, C; Julé, Y; Christen, M O; Henry, M

2000-05-01

C-kit immunocytochemistry was performed on ultrathin sections of human distal colon. Our attention was focused on relationships between c-kit immunoreactive interstitial cells (c-kit ICs) and muscular cells and nervous elements located in the external muscular layers of the colonic wall. C-kit ICs established membrane apposition with both nerve fibers and smooth muscle cells of, respectively, the longitudinal and circular muscle layers, the myenteric area, and the extremus submucosus plexus. C-kit ICs also surrounded the external submucosus plexus and established membrane appositions with nerve elements located inside the myenteric ganglia. These membrane appositions were observed either at the level of the c-kit IC bodies or at that of their cytoplasmic processes. In some cases, membrane appositions were observed concomitantly between the c-kit ICs, nerve fibers, and smooth muscle cells. In all the regions studied, the c-kit ICs were also found to be located in the close vicinity of blood vessels and to have established close contacts with non-immunoreactive fibroblast-like cells. The results of the present study shed essential light on the relationships of c-kit ICs with the neighboring muscle cells and nerve elements, and confirm that the intercalated c-kit ICs well fit with the so-called "interstitial cells of Cajal".

Smoking-related interstitial lung diseases.

PubMed

Caminati, A; Graziano, P; Sverzellati, N; Harari, S

2010-12-01

In pulmonary pathology, a wide spectrum of morphological changes is related to the consequences of smoking, and recognizing them on surgical specimens and on small transbronchial biopsies represents a challenge for the pathologist. Respiratory bronchiolitis, also referred to as smoker's bronchiolitis, is a common histologic feature found in the lung tissue of cigarette smokers. When identified as the sole histopathologic finding in the clinical setting of symptomatic interstitial lung disease, a diagnosis of respiratory bronchiolitis-interstitial lung disease is made. Since smoking is recognized to cause a variety of histologic patterns encompassing respiratory bronchiolitis, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia and pulmonary Langerhans cell hystiocytosis, smoking-related interstitial lung disease may be a useful concept to keep in mind for the pathologists. The relationship of smoking with each of these entities has been largely established on the basis of epidemiologic evidence. Although they have been retained as distinct and separate conditions in various classifications of interstitial lung diseases, these entities share a number of clinical, radiologic, and pathologic features suggesting that they represent a spectrum of patterns of interstitial lung disease occurring in predisposed individuals who smoke. Evaluation of histologic features, particularly in surgical lung biopsy samples, is important in making the distinction between these disorders. However, even after tissue biopsy, it may sometimes be difficult to clearly separate these entities. Recently, respiratory bronchiolitis-interstitial lung disease with fibrosis has been described and postulated that this is a smoking-related condition distinct from fibrotic non-specific interstitial pneumonia.

Comparison of valvular resistance, stroke work loss, and Gorlin valve area for quantification of aortic stenosis. An in vitro study in a pulsatile aortic flow model.

PubMed

Voelker, W; Reul, H; Nienhaus, G; Stelzer, T; Schmitz, B; Steegers, A; Karsch, K R

1995-02-15

Valvular resistance and stroke work loss have been proposed as alternative measures of stenotic valvular lesions that may be less flow dependent and, thus, superior over valve area calculations for the quantification of aortic stenosis. The present in vitro study was designed to compare the impacts of valvular resistance, stroke work loss, and Gorlin valve area as hemodynamic indexes of aortic stenosis. In a pulsatile aortic flow model, rigid stenotic orifices in varying sizes (0.5, 1.0, 1.5 and 2.0 cm2) and geometry were studied under different hemodynamic conditions. Ventricular and aortic pressures were measured to determine the mean systolic ventricular pressure (LVSPm) and the transstenotic pressure gradient (delta Pm). Transvalvular flow (Fm) was assessed with an electromagnetic flowmeter. Valvular resistance [VR = 1333.(delta Pm/Fm)] and stroke work loss [SWL = 100.(delta Pm/LVSPm)] were calculated and compared with aortic valve area [AVA = Fm/(50 square root of delta Pm)]. The measurements were performed for a large range of transvalvular flows. At low-flow states, flow augmentation (100-->200 mL/s) increased calculated valvular resistance between 21% (2.0 cm2 orifice) and 66% (0.5-cm2 orifice). Stroke work loss demonstrated an increase from 43% (2.0 cm2) to 100% (1.0 cm2). In contrast, Gorlin valve area revealed only a moderate change from 29% (2.0 cm2) to 5% (0.5 cm2). At physiological flow rates, increase in transvalvular flow (200-->300 mL/s) did not alter calculated Gorlin valve area, whereas valvular resistance and stroke work loss demonstrated a continuing increase. Our experimental results were adopted to interpret the results of three clinical studies in aortic stenosis. The flow-dependent increase of Gorlin valve area, which was found in the cited clinical studies, can be elucidated as true further opening of the stenotic valve but not as a calculation error due to the Gorlin formula. Within the physiological range of flow, calculated aortic valve area was less dependent on hemodynamic conditions than were valvular resistance and stroke work loss, which varied as a function of flow. Thus, for the assessment of the severity of aortic stenosis, the Gorlin valve area is superior over valvular resistance and stroke work loss, which must be indexed for flow to adequately quantify the hemodynamic severity of the obstruction.

Phosphatidylserine-exposing blood cells and microparticles induce procoagulant activity in non-valvular atrial fibrillation.

PubMed

Wang, Lixiu; Bi, Yayan; Yu, Muxin; Li, Tao; Tong, Dongxia; Yang, Xiaoyan; Zhang, Cong; Guo, Li; Wang, Chunxu; Kou, Yan; Dong, Zengxiang; Novakovic, Valerie A; Tian, Ye; Kou, Junjie; Shammas, Masood A; Shi, Jialan

2018-05-01

The definitive role of phosphatidylserine (PS) in the prothrombotic state of non-valvular atrial fibrillation (NVAF) remains unclear. Our objectives were to study the PS exposure on blood cells and microparticles (MPs) in NVAF, and evaluate their procoagulant activity (PCA). NVAF patients without (n = 60) and with left atrial thrombi (n = 18) and controls (n = 36) were included in our study. Exposed PS was analyzed with flow cytometry and confocal microscopy. PCA was evaluated using clotting time, factor Xa (FXa), thrombin and fibrin formation. PS + blood cells and MPs were significantly higher in NVAF patients without and with left atrial thrombi (both P < 0.01) than in controls. Patients with left atrial thrombi showed increased PS + platelets, neutrophils, erythrocytes and MPs compared with patients without thrombi (all P < 0.05). Moreover, in patients with left atrial thrombi, MPs primarily originated from platelets (56.1%) followed by leukocytes (21.9%, including MPs from neutrophils, monocytes and lymphocytes), erythrocytes (12.2%) and endothelial cells (8.9%). Additionally, PS + blood cells and MPs contributed to markedly shortened coagulation time and dramatically increased FXa/thrombin/fibrin (all P < 0.001) generation in both NVAF groups. Furthermore, blockade of exposed PS on blood cells and MPs with lactadherin inhibited PCA by approximately 80%. Lastly, we found that the amount of PS + platelets and MPs was positively correlated with thrombus diameter (all p < 0.005). Our results suggest that exposed PS on blood cells and MPs play a procoagulant role in NVAF patients. Blockade of PS prior to thrombus formation might be a novel therapeutic approach in these patients. Copyright © 2018 Elsevier B.V. All rights reserved.

A relationship between proteinuria and acute tubulointerstitial disease in rats with experimental nephrotic syndrome

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

Eddy, A.A.; McCulloch, L.; Liu, E.

1991-05-01

The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereasmore » ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.« less

Structural effects in the interstitial solid solution system (La,Ce)(Fe,Si)13Cx-H: Correlation with hydrogenation kinetics

NASA Astrophysics Data System (ADS)

Hai, X.; Porcher, F.; Mayer, C.; Miraglia, S.

2018-02-01

Steady state and in-situ neutron powder diffraction on selected compositions of the magneto-caloric (La,Ce)(Fe,Si)13CxHy compounds has been used to locate the sites accommodated by the interstitial species and to reveal the structural modifications (breathing) that occur upon metal substitution and/or interstitial insertion. The latter type of measurement in which the sequential filling of interstitial sites is followed allows one to extract some useful hydrogenation kinetics data. This structural investigation has allowed to precise the deformations undergone by the complex metallic alloys La(Fe,Si)13 when subjected to light interstitial insertion or rare earth substitution at the cation site of the NaZn13-structure type. We attempt to correlate hydrogenation kinetics variations (depression or enhancement of the hydrogen absorption rate) with a particular inhomogeneous cell variation (breathing) and bonding of the NaZn13 structure-type.

Anode for a secondary, high-temperature electrochemical cell

DOEpatents

Vissers, Donald R.; Tani, Benjamin S.

1976-01-01

A high-temperature, secondary electrochemical cell includes an anode containing lithium, an electrolyte containing lithium ions and a cathode containing a chalcogen material such as sulfur or a metallic sulfide. The anode includes a porous substrate formed of, for instance, a compacted mass of entangled metallic fibers providing interstitial crevices for receiving molten lithium metal. The surfaces of the interstitial crevices are provided with a coating of cobalt metal to enhance the retention of the molten lithium metal within the substrate.

Hydrogen Passivation of Interstitial Zn Defects in Heteroepitaxial InP Cell Structures and Influence on Device Characteristics

NASA Technical Reports Server (NTRS)

Ringel, S. A.; Chatterjee, B.

2004-01-01

Hydrogen passivation of heteroepitaxial InP solar cells is of recent interest for deactivation of dislocations and other defects caused by the cell/substrate lattice mismatch that currently limit the photovoltaic performance of these devices. In this paper we present strong evidence that, in addition to direct hydrogen-dislocation interactions, hydrogen forms complexes with the high concentration of interstitial Zn defects present within the p(+) Zn-doped emitter of MOCVD-grown heteroepitaxial InP devices, resulting in a dramatic increase of the forward bias turn-on voltage by as much as 280 mV, from 680 mV to 960 mV. This shift is reproducible and thermally reversible and no such effect is observed for either n(+)p structures or homoepitaxial p(+)n structures grown under identical conditions. A combination of photoluminescence (PL), electrochemical C-V dopant profiling, SIMS and I-V measurements were performed on a set of samples having undergone a matrix of hydrogenation and post-hydrogenation annealing conditions to investigate the source of this voltage enhancement and confirm the expected role of interstitial Zn and hydrogen. A precise correlation between all measurements is demonstrated which indicates that Zn interstitials within the p(+) emitter and their interaction with hydrogen are indeed responsible for this device behavior.

Percutaneous fiber optic angioscopy of the left ventricle in patients with rheumatic valvular disease

NASA Astrophysics Data System (ADS)

Hirose, Junichi; Oshima, Tomomitsu; Fujimori, Yoshiharu; Uchida, Yasumi

1993-05-01

Recent advances in fiberoptic technology enabled us to observe percutaneously the cardiac chambers and valves. We examined left ventricular luminal and valvular changes by percutaneous fiberoptic angioscopy in patients with rheumatic valvular disease. Six patients with echocardiographic rheumatic changes in the mitral valves, underwent angioscopy during routine cardiac catheterization. The fiberscope 4.2 F in diameter, and the guiding catheter 9 F in external diameter with an inflatable balloon around the distal most tip were used for angioscopy. The left ventricular endocardial surface was diffusely white in color or white and brown in mosaic fashion. Echocardiography and angiography had low sensitivity for detecting the changes of the left ventricular luminal surface. Whitish changes which were observed by angioscopy were not related to the indices derived from echocardiography and angiography. The results indicate the possibility of percutaneous angioscopy in detecting left ventricular luminal changes in patients with rheumatic valvular disease.

3-compartment talaporfin sodium pharmacokinetic model by optimization using fluorescence measurement data from canine skin to estimate the concentration in interstitial space

NASA Astrophysics Data System (ADS)

Uno, Yuko; Ogawa, Emiyu; Aiyoshi, Eitaro; Arai, Tsunenori

2018-02-01

We constructed the 3-compartment talaporfin sodium pharmacokinetic model for canine by an optimization using the fluorescence measurement data from canine skin to estimate the concentration in the interstitial space. It is difficult to construct the 3-compartment model consisted of plasma, interstitial space, and cell because there is a lack of the dynamic information. Therefore, we proposed the methodology to construct the 3-compartment model using the measured talaporfin sodium skin fluorescence change considering originated tissue part by a histological observation. In a canine animal experiment, the talaporfin sodium concentration time history in plasma was measured by a spectrophotometer with a prepared calibration curve. The time history of talaporfin sodium Q-band fluorescence on left femoral skin of a beagle dog excited by talaporfin sodium Soret-band of 409 nm was measured in vivo by our previously constructed measurement system. The measured skin fluorescence was classified to its source, that is, specific ratio of plasma, interstitial space, and cell. We represented differential rate equations of the talaporfin sodium concentration in plasma, interstitial space, cell. The specific ratios and a converting constant to obtain absolute value of skin concentration were arranged. Minimizing the squared error of the difference between the measured fluorescence data and calculated concentration by the conjugate gradient method in MATLAB, the rate constants in the 3-compartment model were determined. The accuracy of the fitting operation was confirmed with determination coefficient of 0.98. We could construct the 3-compartment pharmacokinetic model for canine using the measured talaporfin sodium fluorescence change from canine skin.

Overview of the cellular and molecular basis of kidney fibrosis

PubMed Central

Eddy, Allison A

2014-01-01

The common pathogenetic pathway of progressive injury in patients with chronic kidney disease (CKD) is epitomized as normal kidney parenchymal destruction due to scarring (fibrosis). Understanding the fundamental pathways that lead to renal fibrosis is essential in order to develop better therapeutic options for human CKD. Although complex, four cellular responses are pivotal. (1) An interstitial inflammatory response that has multiple consequences—some harmful and others healing. (2) The appearance of a unique interstitial cell population of myofibroblasts, primarily derived from kidney stromal cells (fibroblasts and pericytes), that are the primary source of the various extracellular matrix proteins that form interstitial scars. (3) Tubular epithelial cells that have variable and time-dependent roles as early responders to injury and later as victims of fibrosis due to the loss of their regenerative abilities. (4) Loss of interstitial capillary integrity that compromises oxygen delivery and leads to a vicious cascade of hypoxia–oxidant stress that accentuates injury and fibrosis. In the absence of adequate angiogenic responses, a healthy interstitial capillary network is not maintained. The fibrotic ‘scar' that typifies CKD is an interesting consortium of multifunctional macromolecules that not only change in composition and structure over time, but can be degraded via extracellular and intracellular proteases. Although transforming growth factor beta appears to be the primary driver of kidney fibrosis, a vast array of additional molecules may have modulating roles. The importance of genetic and epigenetic factors is increasingly appreciated. An intriguing but incompletely understood cardiorenal syndrome underlies the high morbidity and mortality rates that develop in association with progressive kidney fibrosis. PMID:25401038

SYNERGISTIC EFFECTS of CYCLIC TENSION and TRANSFORMING GROWTH FACTOR-β1 on the AORTIC VALVE MYOFIBROBLAST

PubMed Central

Merryman, W. David; Lukoff, Howard D.; Long, Rebecca A.; Engelmayr, George C.; Hopkins, Richard A.; Sacks, Michael S.

2007-01-01

Background Phenotypically, the aortic valve interstitial cell (AVIC) is a dynamic myofibroblast, appearing contractile and activated in times of development, disease, and remodeling. The precise mechanism of phenotypic modulation is unclear, but it is speculated that both biomechanical and biochemical factors are influential. Therefore, we hypothesized that isolated and combined treatments of cyclic tension and TGF-β1 would alter the phenotype and subsequent collagen biosynthesis of AVICs in situ. Methods and Results Porcine aortic valve leaflets received 7 and 14 day treatments of 15% cyclic stretch (Tension), 0.5 ng/ml TGF-β1 (TGF), 15% cyclic stretch and 0.5 ng/ml TGF-β1 (Tension+TGF), or neither mechanical nor cytokine stimuli (Null). Tissues were homogenized and assayed for AVIC phenotype (smooth muscle α-actin (SMA)) and collagen biosynthesis (via heat shock protein 47 (Hsp47) which was further verified with type I collagen C-terminal propeptide (CICP)). At both 7 and 14 days, SMA, Hsp47, and CICP quantities were significantly greater (p<0.001) in the Tension+TGF group compared to all other groups. Additionally, Tension alone appeared to maintain SMA and Hsp47 levels that were measured at day 0, while TGF alone elicited an increase in SMA and Hsp47 compared to day 0 levels. Null treatment revealed diminished proteins at both time points. Conclusions Elevated TGF-β1 levels, in the presence of cyclic mechanical tension, resulted in synergistic increases in the contractile and biosynthetic proteins in AVICs. Since cyclic mechanical stimuli can never be relieved in vivo, the presence of TGF-β1 (possibly from infiltrating macrophages) may result in overly biosynthetic AVICs, leading to altered ECM architecture, compromised valve function, and ultimately degenerative valvular disease. PMID:17868877

Computational Modeling of 3D Tumor Growth and Angiogenesis for Chemotherapy Evaluation

PubMed Central

Tang, Lei; van de Ven, Anne L.; Guo, Dongmin; Andasari, Vivi; Cristini, Vittorio; Li, King C.; Zhou, Xiaobo

2014-01-01

Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID:24404145

Assessment of trans-aortic pressure gradient using a coronary pressure wire in patients with mechanical aortic and mitral valve prostheses.

PubMed

Kherada, Nisharahmed; Brenes, Juan Carlos; Kini, Annapoorna S; Dangas, George D

2017-03-15

Accurate evaluation of trans-aortic valvular pressure gradients is challenging in cases where dual mechanical aortic and mitral valve prostheses are present. Non-invasive Doppler echocardiographic imaging has its limitations due to multiple geometric assumptions. Invasive measurement of trans-valvular gradients with cardiac catheterization can provide further information in patients with two mechanical valves, where simultaneous pressure measurements in the left ventricle and ascending aorta must be obtained. Obtaining access to the left ventricle via the mitral valve after a trans-septal puncture is not feasible in the case of a concomitant mechanical mitral valve, whereas left ventricular apical puncture technique is associated with high procedural risks. Retrograde crossing of a bileaflet mechanical aortic prosthesis with standard catheters is associated with the risk of catheter entrapment and acute valvular regurgitation. In these cases, the assessment of trans-valvular gradients using a 0.014˝ diameter coronary pressure wire technique has been described in a few case reports. We present the case of a 76-year-old female with rheumatic valvular heart disease who underwent mechanical aortic and mitral valve replacement in the past. She presented with decompensated heart failure and echocardiographic findings suggestive of elevated pressure gradient across the mechanical aortic valve prosthesis. The use of a high-fidelity 0.014˝ diameter coronary pressure guidewire resulted in the detection of a normal trans-valvular pressure gradient across the mechanical aortic valve. This avoided a high-risk third redo valve surgery in our patient. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Heart valve disease associated with treatment with ergot-derived dopamine agonists: a clinical and echocardiographic study of patients with Parkinson's disease.

PubMed

Rasmussen, V G; Poulsen, S H; Dupont, E; Østergaard, K; Safikhany, G; Egeblad, H

2008-01-01

To elucidate the association between treatment with ergot-derived dopamine agonists (EDDA) and valvular abnormalities amongst patients with idiopathic Parkinson's disease (IPD) and secondly, to analyse the yield of clinical screening for valvular heart disease. A cross-sectional controlled study. The cohort of IPD patients treated in the outpatient clinic, Department of Neurology, Aarhus University Hospital, Denmark. A total of 138 IPD patients [median age 64 (39-87) years, 62% men] treated with either EDDA (n = 85) or non-EDDA (n = 53) for at least 6 months. Interventions. Patients were screened for valvular heart disease by clinical means and by examiner-blinded echocardiography. Main outcome measure was valvular regurgitation revealed by echocardiography. Severe aortic regurgitation (n = 4) or moderate aortic (n = 12), mitral (n = 3) or tricuspidal valve regurgitation (n = 5) was found in 22 EDDA patients (25.9%). Two patients had coexistent moderate mitral and tricuspid valvular regurgitation. Two non-EDDA patients had moderate valve insufficiency (3.8%, P < 0.05). The adjusted relative risk for at least moderate valve insufficiency in the EDDA patients was 7.2% (P < 0.05). The sensitivity of detecting at least moderate valvular disease by cardiac murmur, dyspnoea, or the heart failure marker NT-proBNP (natriuretic peptide) was 62% for the neurologists and 93% for the cardiologist but with equally low specificity (30-35%). EDDA was associated with a clinically important and statistically significant risk of at least moderate valve regurgitation. Clinical screening for valve disease was inadequate and it seems advisable to offer EDDA patients control with echocardiography.

New transmitters and new targets in the autonomic nervous system.

PubMed

Barajas-López, C; Huizinga, J D

1993-12-01

Several recent findings have made research into the autonomic nervous system even more exciting, such as the revelation that nitric oxide is a major neurotransmitter, the delineation of the physiological roles for purines and vasoactive intestinal peptide, and the discovery that the interstitial cells of Cajal are major target cells for enteric innervation. Nitric oxide is probably the major neurotransmitter evoking inhibitory junction potentials in smooth muscle. ATP is a mediator of non-adrenergic non-cholinergic enteric innervation, as well as being a fast neurotransmitter in peripheral and autonomic neuro-neuronal synapses. The interactions between enteric nerves and both immune cells and interstitial cells of Cajal (as pacemaker cells of gut smooth muscle) are forcing a rethink of many aspects of gut physiology.

Immunohistochemical and ultrastructural characteristics of interstitial cells of Cajal in the rabbit duodenum. Presence of a single cilium

PubMed Central

Junquera, Concepción; Martínez-Ciriano, Carmen; Castiella, Tomás; Serrano, Pedro; Azanza, María Jesús; Ramón y Cajal Junquera, Santiago

2007-01-01

Abstract Santiago Ramón y Cajal discovered a new type of cell related to the myenteric plexus and also to the smooth muscle cells of the circular muscle layer of the intestine. Based on their morphology, relationships and staining characteristics, he considered these cells as primitive neurons. One century later, despite major improvements in cell biology, the interstitial cells of Cajal (ICCs) are still controversial for many researchers. The aim of study was to perform an immunohistochemical and ultrastructural characterization of the ICCs in the rabbit duo-denum. We have found interstitial cells that are positive for c-Kit, CD34 and nestin and are also positive for Ki67 protein, tightly associated with somatic cell proliferation. By means of electron microscopy, we describe ICCs around enteric ganglia. They present triangular or spindle forms and a very voluminous nucleus with scarce per-inuclear chromatin surrounded by a thin perinuclear cytoplasm that expands with long cytoplasmic processes. ICC processes penetrate among the smooth muscle cells and couple with the processes of other ICCs located in the connective tissue of the circular muscle layer and establish a three-dimensional network. Intercellular con-tacts by means of gap-like junctions are frequent. ICCs also establish gap-like junctions with smooth muscle cells. We also observe a population of interstitial cells of stellate morphology in the connective tissue that sur-rounds the muscle bundles in the circular muscle layer, usually close to nervous trunks. These cells establish different types of contacts with the muscle cells around them. In addition, the presence of a single cilium show-ing a structure 9 + 0 in an ICC is demonstrated for the first time. In conclusion, we report positive staining c-kit, CD34, nestin and Ki 67. ICCs fulfilled the usual transmission electron microscopy (TEM) criteria. A new ultrastructural characteristic of at least some ICCs is demonstrated: the presence of a single cilium. Some populations of ICCs in the rabbit duodenum present certain immunohistochemical and ultrastructural characteristics that often are present in progenitor cells. PMID:17760839

Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults.

PubMed

Wilson, Carole L; Gough, Peter J; Chang, Cindy A; Chan, Christina K; Frey, Jeremy M; Liu, Yonggang; Braun, Kathleen R; Chin, Michael T; Wight, Thomas N; Raines, Elaine W

2013-01-01

Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[Modern Views on Children's Interstitial Lung Disease].

PubMed

Boĭtsova, E V; Beliashova, M A; Ovsiannikov, D Iu

2015-01-01

Interstitial lung diseases (ILD, diffuse lung diseases) are a heterogeneous group of diseases in which a pathological process primarily involved alveoli and perialveolar interstitium, resulting in impaired gas exchange, restrictive changes of lung ventilation function and diffuse interstitial changes detectable by X-ray. Children's interstitial lung diseases is an topical problem ofpediatricpulmonoogy. The article presents current information about classification, epidemiology, clinical presentation, diagnostics, treatment and prognosis of these rare diseases. The article describes the differences in the structure, pathogenesis, detection of various histological changes in children's ILD compared with adult patients with ILD. Authors cite an instance of registers pediatric patients with ILD. The clinical semiotics of ILD, the possible results of objective research, the frequency of symptoms, the features of medical history, the changes detected on chest X-rays, CT semiotics described in detail. Particular attention was paid to interstitial lung diseases, occurring mainly in newborns and children during the first two years of life, such as congenital deficiencies of surfactant proteins, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis. The diagnostic program for children's ILD, therapy options are presented in this article.

Characterization of the Tumor Secretome from Tumor Interstitial Fluid (TIF).

PubMed

Gromov, Pavel; Gromova, Irina

2016-01-01

Tumor interstitial fluid (TIF) surrounds and perfuses bodily tumorigenic tissues and cells, and can accumulate by-products of tumors and stromal cells in a relatively local space. Interstitial fluid offers several important advantages for biomarker and therapeutic target discovery, especially for cancer. Here, we describe the most currently accepted method for recovering TIF from tumor and nonmalignant tissues that was initially performed using breast cancer tissue. TIF recovery is achieved by passive extraction of fluid from small, surgically dissected tissue specimens in phosphate-buffered saline. We also present protocols for hematoxylin and eosin (H&E) staining of snap-frozen and formalin-fixed, paraffin-embedded (FFPE) tumor sections and for proteomic profiling of TIF and matched tumor samples by high-resolution two-dimensional gel electrophoresis (2D-PAGE) to enable comparative analysis of tumor secretome and paired tumor tissue.

Human bone perivascular niche-on-a-chip for studying metastatic colonization.

PubMed

Marturano-Kruik, Alessandro; Nava, Michele Maria; Yeager, Keith; Chramiec, Alan; Hao, Luke; Robinson, Samuel; Guo, Edward; Raimondi, Manuela Teresa; Vunjak-Novakovic, Gordana

2018-02-06

Eight out of 10 breast cancer patients die within 5 years after the primary tumor has spread to the bones. Tumor cells disseminated from the breast roam the vasculature, colonizing perivascular niches around blood capillaries. Slow flows support the niche maintenance by driving the oxygen, nutrients, and signaling factors from the blood into the interstitial tissue, while extracellular matrix, endothelial cells, and mesenchymal stem cells regulate metastatic homing. Here, we show the feasibility of developing a perfused bone perivascular niche-on-a-chip to investigate the progression and drug resistance of breast cancer cells colonizing the bone. The model is a functional human triculture with stable vascular networks within a 3D native bone matrix cultured on a microfluidic chip. Providing the niche-on-a-chip with controlled flow velocities, shear stresses, and oxygen gradients, we established a long-lasting, self-assembled vascular network without supplementation of angiogenic factors. We further show that human bone marrow-derived mesenchymal stem cells, which have undergone phenotypical transition toward perivascular cell lineages, support the formation of capillary-like structures lining the vascular lumen. Finally, breast cancer cells exposed to interstitial flow within the bone perivascular niche-on-a-chip persist in a slow-proliferative state associated with increased drug resistance. We propose that the bone perivascular niche-on-a-chip with interstitial flow promotes the formation of stable vasculature and mediates cancer cell colonization.

Carcinoid heart disease: Diagnosis and management.

PubMed

Luis, Sushil A; Pellikka, Patricia A

2016-01-01

Hedinger syndrome refers to carcinoid valvular heart disease. The disease is believed to be triggered by vasoactive substances that result in valvular fibrosis. It classically occurs in patients with metastatic carcinoid and preferentially involves the right sided cardiac valves. Affected valves become thickened and retracted, exhibiting regurgitation and sometimes, stenosis. Echocardiography is recommended in patients with carcinoid syndrome and a follow up study is advisable in those who develop a murmur or other symptoms or signs of valvular heart disease. For appropriately selected patients, valve replacement surgery appears to improve outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Organization of testicular interstitial tissue of an Australian rodent, the spinifex hopping mouse, Notomys alexis.

PubMed

Peirce, E J; Breed, W G

1990-05-01

The organization of testicular interstitial tissue of the spinifex hopping mouse, Notomys alexis differs from that of other rodents. It comprises between 10.3% and 17.3% (average 15.0%) of the total testicular volume, and is variable in its organization both at different locations within the testis of the one animal and among different individuals. Abundant, closely packed Leydig cells are usually present; however, in some regions large, thick-walled blood vessels and extensive peritubular lymphatic spaces, often lacking an endothelium adjacent to the Leydig cells, are also prominent. The Leydig cells in contact with the large blood vessels and lymphatics, unlike those in regions where lymph is sparse, are not densely packed and sometimes contain numerous lipid droplets. Ultrastructure of Leydig cells is typical of steroid-producing cells; however, mitochondria are often extremely large, unusual in shape or bizarrely arranged in relation to one another. Also electron-dense bodies displaying a paracrystalline-like internal structure of parallel, electron-dense filaments arranged in a lattice pattern occur in the cytoplasm of many cells. The significance of these unusual ultrastructural features and the organization of the interstitial tissue remain to be determined conclusively, but may relate to steroid synthesis, secretion and uptake.

Hyperandrogenism from an ovarian interstitial-cell tumor in an alpaca.

PubMed

Gilbert, Rosanne; Kutzler, Michelle; Valentine, Beth A; Semevolos, Stacy

2006-11-01

An 8-year-old intact female Huacaya alpaca (Lama pacos) was presented for recent development of male behavior. Serum testosterone concentration was determined to be 969.1 pg/ml by using radioimmunoassay, while the range in 33 healthy female adult intact alpacas was 11.7-62.1 pg/ml. An ovarian mass was suspected, and an exploratory laparotomy was performed. A tan mass was present on the left ovary. Histologically, the mass was composed of closely packed, plump, polygonal cells with central round nuclei with granular chromatin and abundant eosinophilic finely granular to vesiculate cytoplasm. An ovarian benign interstitial (Leydig) cell tumor was diagnosed.

[Estimation of pulmonary hypertension in lung and valvular heart diseases by perfusion lung scintigraphy].

PubMed

Fujii, T; Tanaka, M; Yazaki, Y; Kitabayashi, H; Koizumi, T; Kubo, K; Sekiguchi, M; Yano, K

1999-06-01

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

Effect of secondary penicillin prophylaxis on valvular changes in patients with rheumatic heart disease in Far North Queensland.

PubMed

Haran, Shankar; Crane, Natalie; Kazi, Saniya; Axford-Haines, Louise; White, Andrew

2018-04-01

To determine the effect of secondary penicillin prophylaxis on echocardiographic diagnosed valvular changes in patients with rheumatic heart disease or history of acute rheumatic fever in the Townsville Health district. Patients with known were identified from the North Queensland register, serial echocardiogram results and number of secondary penicillin prophylaxis doses received in 2014 were collated. Descriptive statistics were utilised. Townsville Hospital and outreach clinics within the Townsville Health catchment zone. All patients diagnosed with acute rheumatic fever or rheumatic heart disease between 2010 and October 2013 who had serial echocardiograms prior to and post commencement of secondary penicillin prophylaxis were included. All patients were of Aboriginal or Torres Strait Islander descent. Progression of echocardiographic valvular changes and association with secondary penicillin prophylaxis compliance. Compliance with secondary penicillin prophylaxis among the study population was a secondary outcome measure. Twenty-three patients were recruited. Only those patients who were compliant with secondary penicillin prophylaxis had any improvement in valvular changes on echocardiogram. Four of six patients without any baseline valvular involvement developed new valvular changes. Seventy percent of patients received >75% of secondary penicillin prophylaxis doses. This small study of patients in Townsville suggests that with good secondary penicillin prophylaxis compliance there is regression of some cardiac lesions over time in people with rheumatic heart disease. Furthermore the natural history of acute rheumatic fever in the Indigenous population is progressive requiring strict adherence to secondary penicillin prophylaxis. Prospective studies or use of data from the nationwide RHD register and standardised reporting of cardiac echocardiograms will provide more robust evidence. © 2017 National Rural Health Alliance Inc.

Parameters indicative of persistence of valvular pathology at initial diagnosis in acute rheumatic carditis: the role of albumin and CD19 expression.

PubMed

Oner, Taliha; Ozdemir, Rahmi; Genc, Dildar Bahar; Kucuk, Mehmet; Karadeniz, Cem; Demirpence, Savas; Yilmazer, Murat Muhtar; Mese, Timur; Tavli, Vedide; Genel, Ferah

The aim of this study is to define the predictors of chronic carditis in patients with acute rheumatic carditis (ARC). Patients diagnosed with ARC between May 2010 and May 2011 were included in the study. Echocardiography, electrocardiography, lymphocyte subset analysis, acute phase reactants, plasma albumin levels, and antistreptolysin-O (ASO) tests were performed at initial presentation. The echocardiographic assessments were repeated at the sixth month of follow-up. The patients were divided into two groups according to persistence of valvular pathology at 6th month as Group 1 and Group 2, and all clinical and laboratory parameters at admission were compared between two groups of valvular involvement. During the one-year study period, 22 patients had valvular disease. Seventeen (77.2%) patients showed regression in valvular pathology. An initial mild regurgitation disappeared in eight patients (36.3%). Among seven (31.8%) patients with moderate regurgitation initially, the regurgitation disappeared in three, and four patients improved to mild regurgitation. Two patients with a severe regurgitation initially improved to moderate regurgitation (9.1%). In five (22.8%) patients, the grade of regurgitation [moderate regurgitation in one (4.6%), and severe regurgitation in 4 (18.2%)] remained unchanged. The albumin level was significantly lower at diagnosis in Group 2 (2.6±0.48g/dL). Lymphocyte subset analysis showed a significant decrease in the CD8 percentage and a significant increase in CD19 percentage at diagnosis in Group 2 compared to Group 1. The blood albumin level and the percentage of CD8 and CD19 (+) lymphocytes at diagnosis may help to predict chronic valvular disease risk in patients with acute rheumatic carditis. Copyright © 2016. Published by Elsevier Editora Ltda.

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

PubMed

Kaul, A M K; Goparaju, S; Dvorina, N; Iida, S; Keslar, K S; de la Motte, C A; Valujskikh, A; Fairchild, R L; Baldwin, W M

2015-02-01

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

A review of recent advances in the assessment of bone porosity, permeability, and interstitial fluid flow

PubMed Central

Cardoso, Luis; Fritton, Susannah P.; Gailani, Gaffar; Benalla, Mohammed; Cowin, Stephen C.

2012-01-01

This contribution reviews recent research performed to assess the porosity and permeability of bone tissue with the objective of understanding interstitial fluid movement. Bone tissue mechanotransduction is considered to occur due to the passage of interstitial pore fluid adjacent to dendritic cell structures in the lacunar-canalicular porosity. The movement of interstitial fluid is also necessary for the nutrition of osteocytes. This review will focus on four topics related to improved assessment of bone interstitial fluid flow. First, the advantages and limitations of imaging technologies to visualize bone porosities and architecture at several length scales are summarized. Second, recent efforts to measure the vascular porosity and lacunar-canalicular microarchitecture are discussed. Third, studies associated with the measurement and estimation of the fluid pressure and permeability in the vascular and lacunar-canalicular domains are summarized. Fourth, the development of recent models to represent the interchange of fluids between the bone porosities is described. PMID:23174418

Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension.

PubMed

Topilsky, Yan; Khanna, Amber; Le Tourneau, Thierry; Park, Soon; Michelena, Hector; Suri, Rakesh; Mahoney, Douglas W; Enriquez-Sarano, Maurice

2012-05-01

Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms. Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown. To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure ≥50 mm Hg), we analyzed 1161 patients with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140 PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and Id-FTR were also matched for TR effective-regurgitant-orifice (ERO). Id-FTR valvular alterations (versus controls) were largest annular area (3.53±0.6 versus 2.74±0.4 cm(2), P<0.0001) and lowest valvular/annular coverage ratio (1.06±0.1 versus 1.45±0.2, P<0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but excessive valve tenting height (0.8±0.3 versus 0.35±0.1 cm, P<0.0001). Valvular changes were linked to specific RV changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO ≥40 mm(2)), changes specific to each FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced. Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical deformation does not cause notable valvular tenting. Conversely, PHTN-FTR is determined by valvular tethering with tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important in considering surgical correction in FTR.

Generation and Long-term Maintenance of Nerve-free Hydra.

PubMed

Tran, Cassidy M; Fu, Sharon; Rowe, Trevor; Collins, Eva-Maria S

2017-07-07

The interstitial cell lineage of Hydra includes multipotent stem cells, and their derivatives: gland cells, nematocytes, germ cells, and nerve cells. The interstitial cells can be eliminated through two consecutive treatments with colchicine, a plant-derived toxin that kills dividing cells, thus erasing the potential for renewal of the differentiated cells that are derived from the interstitial stem cells. This allows for the generation of Hydra that lack nerve cells. A nerve-free polyp cannot open its mouth to feed, egest, or regulate osmotic pressure. Such animals, however, can survive and be cultured indefinitely in the laboratory if regularly force-fed and burped. The lack of nerve cells allows for studies of the role of the nervous system in regulating animal behavior and regeneration. Previously published protocols for nerve-free Hydra maintenance involve outdated techniques such as mouth-pipetting with hand-pulled micropipette tips to feed and clean the Hydra. Here, an improved protocol for maintenance of nerve-free Hydra is introduced. Fine-tipped forceps are used to force open the mouth and insert freshly killed Artemia. Following force-feeding, the body cavity of the animal is flushed with fresh medium using a syringe and hypodermic needle to remove undigested material, referred to here as "burping". This new method of force-feeding and burping nerve-free Hydra through the use of forceps and syringes eliminates the need for mouth-pipetting using hand-pulled micropipette tips. It thus makes the process safer and significantly more time efficient. To ensure that the nerve cells in the hypostome have been eliminated, immunohistochemistry using anti-tyrosine-tubulin is conducted.

Valvular heart disease and heart failure: dental management considerations.

PubMed

Warburton, Gary; Caccamese, John F

2006-10-01

Approximately 5 million people are diagnosed with valvular heart disease in the United States each year. Many of these will present to the general dentist for routine dental care. The dentist must then understand the implications of this disease process to treat these patients safely and effectively. Of course patients with pathologic valve disease are managed in close consultation with their physicians. Even so, a dentist with knowledge of the disease process, as well as its diagnosis and treatment, has greater confidence when treating these patients. This article summarizes issues related to valvular heart disease and heart failure and provides guidance to dentists treating patients with such conditions.

Primary carcinoma of the distal male urethra: a case treated with lymphadenectomy and interstitial radiation therapy

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

Ticho, B.H.; Perez-Tamayo, C.; Konnak, J.W.

1988-06-01

We report a case of primary squamous cell carcinoma of the distal male urethra with a single inguinal node metastasis. Treatment consisted of unilateral pelvic and inguinal lymphadenectomy, and a combined course of external beam and interstitial radiation therapy to the distal urethra and penis by the Henschke modification of the Paris technique.

Characterization of the Chicken Ovarian Cancer Model

DTIC Science & Technology

2005-08-01

Typical staining of tumor in an area of stromal hyperplasia . Figure 5. Adenocarcinoma, Ovary, Chicken, Her2/neu. Intense staining of tumor cells in...variable amounts of interstitial fibrovascular tissue and/or smooth muscle bundles, which accounted for their scirrhous nature grossly. 22...Figure 25). Figure 25. Peritoneum, Adenocarcinoma. Interstitial fibrovascular tissue and/or smooth muscle bundles account for the scirrhous

Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

PubMed

Yamamoto, Yuzo; Okamoto, Isamu; Otsubo, Kohei; Iwama, Eiji; Hamada, Naoki; Harada, Taishi; Takayama, Koichi; Nakanishi, Yoichi

2015-10-01

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

Tricuspid and mitral regurgitation detected by color flow Doppler in the acute phase of Kawasaki disease

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

Suzuki, A.; Kamiya, T.; Tsuchiya, K.

Valvular lesions in the acute phase of Kawasaki disease were studied in 19 children. The patients were intensively observed by color flow Doppler every day from the day of hospitalization up to 12 days after the onset of the disease and 2 or more times a week thereafter, for up to 28 days. Mitral regurgitation (MR) was found in 9 patients (47%) and tricuspid regurgitation (TR) in 10 (53%). MRs were of transient type and confirmed from 7.5 +/- 1.6 (mean +/- standard deviation) to 13.1 +/- 6.5 days after the onset of the disease. Both types of valvular regurgitationmore » were mild. The direction of regurgitation was from the center of valvular coaptation toward the posterior wall of the atrium. Neither valvular prolapse nor valvular deformity was noted. In patients with MR, left ventricular ejection fraction on M-mode echocardiography was significantly lower in the acute phase than in the convalescent phase of the disease (p less than 0.05). Using gallium-67 scintigram, the positive uptake of the isotope was noted in 7 (88%) of 8 patients with MR, but not found at all in 8 patients free of MR. These results suggest that MR and TR are often transient in the acute phase of Kawasaki disease and could be attributed to myocarditis.« less

Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

PubMed Central

Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

2013-01-01

High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?

PubMed

Malik, Shabana T; Birch, Brian R; Voegeli, David; Fader, Mandy; Foria, Vipul; Cooper, Alan J; Walls, Andrew F; Lwaleed, Bashir A

2018-05-15

To identify the presence and geographical distribution of mast cell (MC) subtypes: MC T (tryptase positive-chymase negative) and MC TC (tryptase positive-chymase positive) in bladder tissue. Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MC T and MC TC ) and anti-MC chymase (for MC TC ). Stained sections were photographed, and positively stained MCs were quantified using ImageJ. Data were analysed using descriptive statistics and individual paired t-tests. There was a significant difference in the density of MCs between each layer of the disease bladder, with the greatest accumulation within the detrusor (p<0.001). There was a significant increase in MC TC subtype in the lamina (p=0.009) in painful bladder syndrome/interstitial cystitis. Our results suggest that mastocytosis is present within all layers of disease bladder, especially the muscle layer. The varying increase in MC subtypes in the lamina and mucosa may explain the variability in painful bladder syndrome/interstitial cystitis symptoms. A high influx of MC TC in the mucosa of individuals who also had ulceration noted within their diagnostic notes may be of the Hunner's ulcer subclassification. These findings suggest a relationship between the pathogenesis of MC subtypes and the clinical presentation of painful bladder syndrome/interstitial cystitis. A cohort study would further elucidate the diagnostic and/or therapeutic potential of MCs in patients with painful bladder syndrome/interstitial cystitis. © 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.

Using Na3PO4 to Enhance In vitro Animal Models of Aortic Valve Calcification.

PubMed

Lerman, Daniel Alejandro; Prasad, Sai; Alotti, Nasri

2016-01-07

The pathogenesis of calcific aortic valvular disease (CAVD) involves an active inflammatory process of valvular interstitial cells (VICs) characterized by the activation of specific osteogenic signaling pathways and apoptosis. This process can be studied by analyzing certain molecular markers and gene expression pathways of spontaneous calcification. The purpose of our study is to investigate the role of sodium phosphate (Na3PO4) as a calcification promoter, with the aim of improving in vitro animal models for testing potential calcification inhibitors. VICs were extracted from 6 healthy 6-month-old fresh porcine hearts by serial collagenase digestion. Quantitative polymerase chain reaction (qPCR) was used to quantify trans-differentiation of genes of interest during spontaneous calcification of VICs. Spontaneous calcification of VICs was increased by adding Na 3 PO 4 (3 mM, pH 7.4). The degree of calcification was estimated by Alizarin Red staining for calcium deposition, and Sirius Red staining for collagen. Colorimetric techniques were used to determine calcium and collagen deposition quantitatively. Additionally, the enzymatic activity of alkaline phosphatase (ALP) was measured by a kinetic assay. For statistical analysis we used SPSS and Microsoft Office Excel 2013. Porcine VICs calcify spontaneously with demonstrable calcium and collagen deposition. In this study we observed an increase of calcium and collagen deposition from day 0 to day 14 (calcium: 376%; P<0.001, collagen: 3553%; P<0.001). qPCR analysis of mRNA by day 14 showed the following results: α-actin, a marker of myoblast phenotype, was increased to 1.6-fold; P<0.001. Runx2, an osteoblast marker, rose to 1.3 fold; P<0.05, TGF-β, a promoter of osteogenesis, increased to 3.2-fold; P<0.001, and RhoA, a regulator of nodular formation in myoblasts, increased to 4.5-fold; P<0.001, compared to their levels at day 0. RANKL mRNA and calponin did not change significantly. Treatment of porcine VICs with Na3PO4 (3 mM, pH 7.4) led to a marked increase in calcium deposition by day 14 (522%; P<0.001), and a significant increase in ALP activity by day 7 (228%; P<0.05). There were no significant changes in ALP activity between the groups by day 14. This study has demonstrated the upregulation of some specific molecules during spontaneous calcification of aortic VICs with an active increase of calcium, collagen and ALP activity. In this in vitro model it was possible to increase spontaneous VICs calcification with Na 3 PO 4 (3 mM, pH 7.4) to a level in which inhibitors of calcification could be tested to identify a novel potential therapeutic strategy against calcific aortic stenosis.

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy.

PubMed

Fry, Christopher S; Kirby, Tyler J; Kosmac, Kate; McCarthy, John J; Peterson, Charlotte A

2017-01-05

Satellite cells, the predominant stem cell population in adult skeletal muscle, are activated in response to hypertrophic stimuli and give rise to myogenic progenitor cells (MPCs) within the extracellular matrix (ECM) that surrounds myofibers. This ECM is composed largely of collagens secreted by interstitial fibrogenic cells, which influence satellite cell activity and muscle repair during hypertrophy and aging. Here we show that MPCs interact with interstitial fibrogenic cells to ensure proper ECM deposition and optimal muscle remodeling in response to hypertrophic stimuli. MPC-dependent ECM remodeling during the first week of a growth stimulus is sufficient to ensure long-term myofiber hypertrophy. MPCs secrete exosomes containing miR-206, which represses Rrbp1, a master regulator of collagen biosynthesis, in fibrogenic cells to prevent excessive ECM deposition. These findings provide insights into how skeletal stem and progenitor cells interact with other cell types to actively regulate their extracellular environments for tissue maintenance and adaptation. Copyright © 2017 Elsevier Inc. All rights reserved.

Kidney pericytes: roles in regeneration and fibrosis.

PubMed

Kramann, Rafael; Humphreys, Benjamin D

2014-07-01

Renal pericytes have been neglected for many years, but recently they have become an intensively studied cell population in renal biology and pathophysiology. Pericytes are stromal cells that support vasculature, and a subset of pericytes are mesenchymal stem cells. In kidney, pericytes have been reported to play critical roles in angiogenesis, regulation of renal medullary and cortical blood flow, and serve as progenitors of interstitial myofibroblasts in renal fibrogenesis. They interact with endothelial cells through distinct signaling pathways and their activation and detachment from capillaries after acute or chronic kidney injury may be critical for driving chronic kidney disease progression. By contrast, during kidney homeostasis it is likely that pericytes serve as a local stem cell population that replenishes differentiated interstitial and vascular cells lost during aging. This review describes both the regenerative properties of pericytes as well as involvement in pathophysiologic conditions such as fibrogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Update of transcatheter valve treatment

PubMed Central

Liu, Xian-bao; Wang, Jian-an

2013-01-01

Transcatheter valve implantation or repair has been a very promising approach for the treatment of valvular heart diseases since transcatheter aortic valve implantation (TAVI) was successfully performed in 2002. Great achievements have been made in this field (especially TAVI and transcatheter mitral valve repair—MitraClip system) in recent years. Evidence from clinical trials or registry studies has proved that transcatheter valve treatment for valvular heart diseases is safe and effective in surgical high-risk or inoperable patients. As the evidence accumulates, transcatheter valve treatment might be an alterative surgery for younger patients with surgically low or intermediate risk valvular heart diseases in the near future. In this paper, the updates on transcatheter valve treatment are reviewed. PMID:23897785

Non-valvular main pulmonary artery vegetation associated with aortopulmonary window.

PubMed

Unal, M; Tuncer, C; Serçe, K; Bostan, M; Gökçe, M; Erem, C

1995-01-01

We present a 32-year-old female with aortopulmonary window and vegetation of non-valvular main pulmonary artery. The aortopulmonary window is a rare congenital disease in which the aorta and pulmonary arteries are communicated by a defect of variable diameter. The pulmonic valve is the least commonly involved valve in bacterial endocarditis, but there is no vegetation of non-valvular main pulmonary artery in the literature. Colour duplex sonography showed an aortopulmonary window with aortic regurgitation. Magnetic resonance (MR) imaging demonstrating the vegetation on the wall of main pulmonary artery, is an useful and complementary method, and can be used for demonstration of congenital and acquired cardiovascular pathologies including aortopulmonary window and subpulmonic or suprapulmonic vegetations.

Characterization of lymphocyte populations in nonspecific interstitial pneumonia*

PubMed Central

Keogh, Karina A; Limper, Andrew H

2005-01-01

Study objectives Nonspecific interstitial pneumonia (NSIP) has been identified as a distinct entity with a more favorable prognosis and better response to immunosuppressive therapies than usual interstitial pneumonia (UIP). However the inflammatory profile of NSIP has not been characterized. Design Using immunohistochemistry techniques on open lung biopsy specimens, the infiltrate in NSIP was characterized in terms of T and B cells, and macrophages, and the T cell population further identified as either CD4 (helper) or CD8 (suppressor-cytotoxic) T cells. The extent of Th1 and Th2 cytokine producing cells was determined and compared to specimens from patients with UIP. Results In ten NSIP tissue samples 41.4 ± 4% of mononuclear cells expressed CD3, 24.7 ± 1.8% CD4, 19.1 ± 2% CD8, 27.4 ± 3.9% CD20, and 14.3 ± 1.6% had CD68 expression. Mononuclear cells expressed INFγ 21.9 ± 1.9% of the time and IL-4 in 3.0 ± 1%. In contrast, biopsies from eight patients with UIP demonstrated substantially less cellular staining for either cytokine (INFγ; 4.6 ± 1.7% and IL-4; 0.6 ± 0.3%). Significant populations of CD20 positive B-cells were also identified. Conclusion The lymphocytic infiltrate in NSIP is characterized by an elevated CD4/CD8 T-cell ratio, and is predominantly of Th1 type, with additional populations rich in B-cells. Such features are consistent with the favorable clinical course observed in patients with NSIP compared to UIP. PMID:16287509

Ultrasound SIV measurement of helical valvular flow behind the great saphenous vein

NASA Astrophysics Data System (ADS)

Park, Jun Hong; Kim, Jeong Ju; Lee, Sang Joon; Yeom, Eunseop; Experimental Fluid Mechanics Laboratory Team; LaboratoryMicrothermal; Microfluidic Measurements Collaboration

2017-11-01

Dysfunction of venous valve and induced secondary abnormal flow are closely associated with venous diseases. Thus, detailed analysis of venous valvular flow is invaluable from biological and medical perspectives. However, most previous studies on venous perivalvular flows were based on qualitative analyses. On the contrary, quantitative analysis on the perivalvular flows has not been fully understood yet. In this study, 3D valvular flows under in vitro and in vivo conditions were experimentally investigated using ultrasound speckle image velocimetry (SIV) for analyzing their flow characteristics. The results for in vitro model obtained by the SIV technique were compared with those derived by numerical simulation and color Doppler method to validate its measurement accuracy. Then blood flow in the human great saphenous vein was measured using the SIV with respect to the dimensionless index, helical intensity. The results obtained by the SIV method are well matched well with those obtained by the numerical simulation and color Doppler method. The hemodynamic characteristics of 3D valvular flows measured by the validated SIV method would be helpful in diagnosis of valve-related venous diseases. None.

[Decompensated valvular disease and coarctation. One-stage repair using a median approach with an ascending aorta-abdominal aorta shunt].

PubMed

Baille, Y; Sigwalt, M; Vaillant, A; Sicard Desnuelle, M P; Varnet, B

1981-11-01

The tactical decision in patients with decompensated valvular disease associated with a severe stenosis of the aortic isthmus is always difficult. One stage surgical repair using two separate approaches is a long and high risk procedure. It would seem more logical and safer to treat the lesions in two stages a few weeks apart, the severest lesion being managed first. In the two cases reported. The isthmic stenoses and valvular lesions were of the same severity and made both classical techniques impracticable. Therefore the patients underwent a single stage procedure by a median approach associating valve replacement under cardiopulmonary bypass (mitral and tricuspid in one and aortic in the other case) and an ascending aorta-abdominal aorta dacron conduit. The present postoperative survival periods are 30 and 9 months. The functional result was good (Class 1 and 0) and postoperative angiography has shown the montage to be working satisfactorily. This technique is exceptional but may be useful in borderline cases with decompensated valvular disease and severe isthmic stenosis.

Detection of the valvular split within the second heart sound using the reassigned smoothed pseudo Wigner–Ville distribution

PubMed Central

2013-01-01

Background In this paper, we developed a novel algorithm to detect the valvular split between the aortic and pulmonary components in the second heart sound which is a valuable medical information. Methods The algorithm is based on the Reassigned smoothed pseudo Wigner–Ville distribution which is a modified time–frequency distribution of the Wigner–Ville distribution. A preprocessing amplitude recovery procedure is carried out on the analysed heart sound to improve the readability of the time–frequency representation. The simulated S2 heart sounds were generated by an overlapping frequency modulated chirp–based model at different valvular split durations. Results Simulated and real heart sounds are processed to highlight the performance of the proposed approach. The algorithm is also validated on real heart sounds of the LGB–IRCM (Laboratoire de Génie biomédical–Institut de recherches cliniques de Montréal) cardiac valve database. The A2–P2 valvular split is accurately detected by processing the obtained RSPWVD representations for both simulated and real data. PMID:23631738

Examination of mitral regurgitation with a goat heart model for the development of intelligent artificial papillary muscle.

PubMed

Shiraishi, Y; Yambe, T; Yoshizawa, M; Hashimoto, H; Yamada, A; Miura, H; Hashem, M; Kitano, T; Shiga, T; Homma, D

2012-01-01

Annuloplasty for functional mitral or tricuspid regurgitation has been made for surgical restoration of valvular diseases. However, these major techniques may sometimes be ineffective because of chamber dilation and valve tethering. We have been developing a sophisticated intelligent artificial papillary muscle (PM) by using an anisotropic shape memory alloy fiber for an alternative surgical reconstruction of the continuity of the mitral structural apparatus and the left ventricular myocardium. This study exhibited the mitral regurgitation with regard to the reduction in the PM tension quantitatively with an originally developed ventricular simulator using isolated goat hearts for the sophisticated artificial PM. Aortic and mitral valves with left ventricular free wall portions of isolated goat hearts (n=9) were secured on the elastic plastic membrane and statically pressurized, which led to valvular leaflet-papillary muscle positional change and central mitral regurgitation. PMs were connected to the load cell, and the relationship between the tension of regurgitation and PM tension were measured. Then we connected the left ventricular specimen model to our hydraulic ventricular simulator and achieved hemodynamic simulation with the controlled tension of PMs.

Interstitial Photodynamic Therapy in Treating Patients With Recurrent Head and Neck Cancer

ClinicalTrials.gov

2017-09-11

Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Tongue Carcinoma

Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.

PubMed

He, Wenjuan; Zhang, Min; Zhao, Min; Davis, Linda S; Blackwell, Timothy S; Yull, Fiona; Breyer, Matthew D; Hao, Chuan-Ming

2014-02-01

High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

Biological and mechanical evaluation of a Bio-Hybrid scaffold for autologous valve tissue engineering.

PubMed

Jahnavi, S; Saravanan, U; Arthi, N; Bhuvaneshwar, G S; Kumary, T V; Rajan, S; Verma, R S

2017-04-01

Major challenge in heart valve tissue engineering for paediatric patients is the development of an autologous valve with regenerative capacity. Hybrid tissue engineering approach is recently gaining popularity to design scaffolds with desired biological and mechanical properties that can remodel post implantation. In this study, we fabricated aligned nanofibrous Bio-Hybrid scaffold made of decellularized bovine pericardium: polycaprolactone-chitosan with optimized polymer thickness to yield the desired biological and mechanical properties. CD44 + , αSMA + , Vimentin + and CD105 - human valve interstitial cells were isolated and seeded on these Bio-Hybrid scaffolds. Subsequent biological evaluation revealed interstitial cell proliferation with dense extra cellular matrix deposition that indicated the viability for growth and proliferation of seeded cells on the scaffolds. Uniaxial mechanical tests along axial direction showed that the Bio-Hybrid scaffolds has at least 20 times the strength of the native valves and its stiffness is nearly 3 times more than that of native valves. Biaxial and uniaxial mechanical studies on valve interstitial cells cultured Bio-Hybrid scaffolds revealed that the response along the axial and circumferential direction was different, similar to native valves. Overall, our findings suggest that Bio-Hybrid scaffold is a promising material for future development of regenerative heart valve constructs in children. Copyright © 2016 Elsevier B.V. All rights reserved.

Expression of transforming growth factor-beta1, -beta2 and -beta3 in normal and diseased canine mitral valves.

PubMed

Aupperle, H; März, I; Thielebein, J; Schoon, H-A

2008-01-01

The pathogenesis of chronic valvular disease (CVD) in dogs remains unclear, but activation and proliferation of valvular stromal cells (VSC) and their transdifferentiation into myofibroblast-like cells has been described. These alterations may be influenced by transforming growth factor-beta (TGF-beta), a cytokine involved in extracellular matrix (ECM) regulation and mesenchymal cell differentiation. The present study investigates immunohistochemically the expression of TGF-beta1, -beta2, -beta3 and smooth muscle alpha actin (alpha-SMA) in normal canine mitral valves (MVs) (n=10) and in the valves of dogs with mild (n=7), moderate (n=14) and severe (n=9) CVD. In normal mitral valves there was no expression of alpha-SMA but VSC displayed variable expression of TGF-beta1 (10% of VSC labelled), TGF-beta2 (1-5% labelled) and TGF-beta3 (50% labelled). In mild CVD the affected atrialis contain activated and proliferating alpha-SMA-positive VSC, which strongly expressed TGF-beta1 and -beta3, but only 10% of these cells expressed TGF-beta2. In unaffected areas of the leaflet there was selective increase in expression of TGF-beta1 and -beta3. In advanced CVD the activated subendothelial VSC strongly expressed alpha-SMA, TGF-beta1 and -beta3. Inactive VSC within the centre of the nodules had much less labelling for TGF-beta1 and -beta3. TGF-beta1 labelling was strong within the ECM. These data suggest that TGF-beta plays a role in the pathogenesis of CVD by inducing myofibroblast-like differentiation of VSC and ECM secretion. Changed haemodynamic forces and expression of matrix metalloproteinases (MMPs) may in turn regulate TGF-beta expression.

IFPA Award in Placentology lecture: molecular regulation of human trophoblast invasion.

PubMed

Knöfler, M; Pollheimer, J

2012-02-01

Invasion of extravillous trophoblast cell types into maternal uterine tissues is essential for successful human placental development and progression of pregnancy. Whereas endovascular trophoblasts migrate into the maternal spiral arteries, interstitial trophoblasts invade the decidual stroma, colonize the vessels from outside and communicate with diverse uterine cell types such as decidual stromal cells, macrophages and uterine NK cells. For example, interstitial trophoblasts expressing polymorphic human leukocyte antigen-C interact with uterine NK cells through binding to their killer immunoglobulin-like receptors which likely plays a role in trophoblast invasion and reproductive success of pregnancy. Both extravillous trophoblast subtypes are critically involved in the vascular transformation of the spiral arteries into dilated conduits ensuring appropriate blood flow into the intervillous space. Failures in this remodeling process are thought to be associated with severe forms of fetal growth restriction, preeclampsia and other pregnancy complications warranting studies on the molecular regulation of extravillous trophoblast differentiation. Moreover, interstitial trophoblast-derived hormones may regulate diverse biological functions in the decidua. In particular, human chorionic gonadotrophin has been shown to promote angiogenesis and to suppress apoptosis of endometrial stromal cells. In return, decidual cells produce a plethora of soluble factors controlling trophoblast invasion in a time- and distance-dependent manner. However, the underlying mechanisms have not been fully elucidated. Here, we will summarize autocrine as well as paracrine factors regulating invasion of extravillous trophoblasts and discuss critical signaling cascades involved. In addition, we will focus on key regulatory transcription factors controlling cell column proliferation and differentiation of the human extravillous trophoblast. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mitral and tricuspid valve rupture after moderate blunt chest trauma.

PubMed

Bailey, P L; Peragallo, R; Karwande, S V; Lapunzina, P

2000-02-01

We present a patient with rupture of both atrioventricular valves in a previously healthy adult man who sustained a 5-foot fall. The mechanism of injury was such that it would not necessarily raise an adequate index of suspicion for valvular damage had valvular rupture not occurred. The usefulness of perioperative echocardiography is highlighted.

Black aorta in a patient with alkaptonuria (ochronosis).

PubMed

Concistrè, Giovanni; Fiorani, Brenno; Ranocchi, Federico; Casali, Giovanni; Loforte, Antonio; Musumeci, Francesco

2011-06-01

A rare cause of valvular heart disease is the deposition of foreign material in the valvular tissues, including material accumulating as a result of inborn errors of metabolism of the essential amino acids. Alkaptonuria can result in accumulation of homogentisic acid. We report the case of a patient with alkaptonuria undergoing surgery for aortic valve replacement.

The effect of interstitial pressure on tumor growth: coupling with the blood and lymphatic vascular systems

PubMed Central

Wu, Min; Frieboes, Hermann B.; McDougall, Steven R.; Chaplain, Mark A.J.; Cristini, Vittorio; Lowengrub, John

2013-01-01

The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. PMID:23220211

Ultrastructure of the genital organs in interstitial polychaetes. III. Penes and ejaculatory ducts in Hesionides arenaria (Hesionidae)

NASA Astrophysics Data System (ADS)

Westheide, W.

1982-12-01

The ejaculatory ducts of the two paired copulatory organs in the interstitial polychaete Hesionides arenaria are ciliated tubes, which open into simple, partly groove-like, non-stiffened penis papillae. The larger part of the ducts within the dorsal body wall is surrounded by circular muscle cells. Voluminous gland cell bodies lie between the pharynx-gut system and the body wall in the anterior part of the body; they extend anteriorly like long, thin necks, of which severl are always united in prominent strands. Their distal ends are expanded and penetrate the ducts. Six different types of glands can be distinguished according to the ultrastructure of their secretory granules. They produce the sheath of the double spermatophore or probably contain lytic enzymes that provide for the penetration of sperm into the body of the female. Differences in ultrastructure of the male organs in the interstitial genera Hesionides and Microphthalmus do not support the recent erection of the subfamily “Microphthalminae”.

Roles of interstitial fluid pH in diabetes mellitus: Glycolysis and mitochondrial function

PubMed Central

Marunaka, Yoshinori

2015-01-01

The pH of body fluids is one the most important key factors regulating various cell function such as enzyme activity and protein-protein interaction via modification of its binding affinity. Therefore, to keep cell function normal, the pH of body fluids is maintained constant by various systems. Insulin resistance is one of the most important, serious factors making the body condition worse in diabetes mellitus. I have recently found that the pH of body (interstitial) fluids is lower in diabetes mellitus than that in non-diabetic control, and that the lowered pH is one of the causes producing insulin resistance. In this review article, I introduce importance of body (interstitial) fluid pH in regulation of body function, evidence on abnormal regulation of body fluid pH in diabetes mellitus, and relationship between the body fluid pH and insulin resistance. Further, this review proposes perspective therapies on the basis of regulation of body fluid pH including propolis (honeybee product) diet. PMID:25685283

The interstitial stem cells in Hydractinia and their role in regeneration.

PubMed

Gahan, James M; Bradshaw, Brian; Flici, Hakima; Frank, Uri

2016-10-01

Hydractinia species have been animal models in developmental biology and comparative immunology for over a century, but are having a renaissance due to the establishment of modern genetic and genomic tools by the growing community of researchers utilizing them. Hydractinia has a predictable and accessible life cycle and its stem cell system, known as interstitial- or i-cells has been a paradigm for animal stem cells since the late 1800s. In adult Hydractinia, i-cells continuously provide progenitors to sustain clonal growth, tissue homeostasis, sexual reproduction and regeneration. We review recent developments in stem cell and regeneration research centered on this animal. Hydractinia joins an established team of cnidarian genetic models in times of rapid progress in these disciplines. While each animal is particularly suited to specific experimental settings, jointly they can provide an integrative insight into the diversity of animal stem cell systems, how they drive regeneration, and how they evolved. Copyright © 2016 Elsevier Ltd. All rights reserved.

Viruses and interstitial cystitis: adenovirus genomes cannot be demonstrated in urinary bladder biopsies.

PubMed

Hukkanen, V; Haarala, M; Nurmi, M; Klemi, P; Kiilholma, P

1996-01-01

Microbes may be involved in the pathogenesis of interstitial cystitis (IC). Adenoviruses and BK virus (BKV) can infect epithelial cells in urinary bladder and they are causative agents for hemorrhagic cystitis. We therefore studied the presence of adenovirus and BKV genomes in urinary bladder tissue specimens of patients with IC using polymerase chain reaction (PCR) and in situ hybridization (ISH). Controls were specimens from cases with transitional cell carcinoma of the bladder. Nucleic acids were extracted from paraffin sections of the bladder tissue for PCR. Primers detecting all adenovirus types were used. In situ hybridization was carried out for the paraffin sections using digoxigenin-labeled DNA probes for adenovirus and BKV. The adenovirus DNA PCR was able to detect one to two infected cells/specimen. All the seven IC cases studied and six controls were negative for adenovirus DNA by PCR and ISH. The ISH test for BKV genomes was also considered negative in IC cases and controls. The specimens which were negative in PCR tests yielded a signal with beta-globin primers, thus being amplifiable. We conclude that adenovirus and BKV do not play a major pathogenetic role in interstitial cystitis.

Valvular Dysfunction in Lymphoma Survivors Treated With Autologous Stem Cell Transplantation: A National Cross-Sectional Study.

PubMed

Murbraech, Klaus; Wethal, Torgeir; Smeland, Knut B; Holte, Harald; Loge, Jon Håvard; Holte, Espen; Rösner, Assami; Dalen, Håvard; Kiserud, Cecilie E; Aakhus, Svend

2016-03-01

This study assessed the prevalence and associated risk factors for valvular dysfunction (VD) observed in adult lymphoma survivors (LS) after autologous hematopoietic stem cell transplantation (auto-HCT), and to determine whether anthracycline-containing chemotherapy (ACCT) alone in these patients is associated with VD. The prevalence of and risk factors for VD in LS after auto-HCT is unknown. Anthracyclines may induce heart failure, but any association with VD is not well-defined. This national cross-sectional study included all adult LS receiving auto-HCT from 1987 to 2008 in Norway. VD was defined by echocardiography as either more than mild regurgitation or any stenosis. Observations in LS were compared with a healthy age- and gender-matched (1:1) control group. In total, 274 LS (69% of all eligible) participated. Mean age was 56 ± 12 years, mean follow-up time after lymphoma diagnosis was 13 ± 6 years, and 62% of participants were males. Mean cumulative anthracycline dosage was 316 ± 111 mg/m(2), and 35% had received radiation therapy involving the heart (cardiac-RT). VD was observed in 22.3% of the LS. Severe VD was rare (n = 9; 3.3% of all LS) and mainly aortic stenosis (n = 7). We observed VD in 16.7% of LS treated with ACCT alone (n = 177), corresponding with a 3-fold increased VD risk (odds ratio: 2.9; 95% confidence interval: 1.5 to 5.8; p = 0.002) compared with controls. Furthermore, the presence of aortic valve degeneration was increased in the LS after ACCT alone compared with controls (13.0% vs. 2.9%; p < 0.001). Female sex, age >50 years at lymphoma diagnosis, ≥3 lines of chemotherapy before auto-HCT, and cardiac-RT >30 Gy were identified as independent risk factors for VD in the LS. In LS, ACCT alone was significantly associated with VD and related to valvular degeneration. Overall, predominantly moderate VD was prevalent in LS, and longer observation time is needed to clarify the clinical significance of this finding. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Role of medullary progenitor cells in epithelial cell migration and proliferation

PubMed Central

Chen, Dong; Chen, Zhiyong; Zhang, Yuning; Park, Chanyoung; Al-Omari, Ahmed

2014-01-01

This study is aimed at characterizing medullary interstitial progenitor cells and to examine their capacity to induce tubular epithelial cell migration and proliferation. We have isolated a progenitor cell side population from a primary medullary interstitial cell line. We show that the medullary progenitor cells (MPCs) express CD24, CD44, CXCR7, CXCR4, nestin, and PAX7. MPCs are CD34 negative, which indicates that they are not bone marrow-derived stem cells. MPCs survive >50 passages, and when grown in epithelial differentiation medium develop phenotypic characteristics of epithelial cells. Inner medulla collecting duct (IMCD3) cells treated with conditioned medium from MPCs show significantly accelerated cell proliferation and migration. Conditioned medium from PGE2-treated MPCs induce tubule formation in IMCD3 cells grown in 3D Matrigel. Moreover, most of the MPCs express the pericyte marker PDGFR-b. Our study shows that the medullary interstitium harbors a side population of progenitor cells that can differentiate to epithelial cells and can stimulate tubular epithelial cell migration and proliferation. The findings of this study suggest that medullary pericyte/progenitor cells may play a critical role in collecting duct cell injury repair. PMID:24808539

Left atrial booster function in valvular heart disease.

PubMed

Heidenreich, F P; Shaver, J A; Thompson, M E; Leonard, J J

1970-09-01

This study was designed to assess atrial booster pump action in valvular heart disease and to dissect booster pump from reservoir-conduit functions. In five patients with aortic stenosis and six with mitral stenosis, sequential atrioventricular (A-V) pacing was instituted during the course of diagnostic cardiac catheterization. Continuous recording of valvular gradient allowed estimation of flow for each cardiac cycle by transposition of the Gorlin formula. Left ventricular ejection time and left ventricular stroke work in aortic stenosis or left ventricular mean systolic pressure in mitral stenosis were also determined. Control observations were recorded during sequential A-V pacing with well-timed atrial systole. Cardiac cycles were then produced with no atrial contraction but undisturbed atrial reservoir function by intermittently interrupting the atrial pacing stimulus during sequential A-V pacing. This intervention significantly reduced valvular gradient, flow, left ventricular ejection time, and left ventricular mean systolic pressure or stroke work. Cardiac cycles were then produced with atrial booster action eliminated by instituting synchronous A-V pacing. The resultant simultaneous contraction of the atrium and ventricle not only eliminated effective atrial systole but also placed atrial systole during the normal period of atrial reservoir function. This also significantly reduced all the hemodynamic measurements. However, comparison of the magnitude of change from these two different pacing interventions showed no greater impairment of hemodynamic state when both booster pump action and reservoir function were impaired than when booster pump action alone was impaired. The study confirms the potential benefit of well placed atrial booster pump action in valvular heart disease in man.

Clinical Benefit of Valvular Surgery in Patients with Chronic Kidney Disease.

PubMed

Chen, Yan; Au, Wing-Kuk; Chan, Daniel; Sit, Ko-Yung; Zhen, Zhe; Ho, Kar-Lai; Wong, Debbie; Ho, Lai-Ming; Yap, Desmond; Lam, Yui-Ming; Lau, Chu-Pak; Tse, Hung-Fat; Chan, Tak-Mao; Yiu, Kai-Hang

2018-06-20

Concomitant chronic kidney disease (CKD) is common in patients with significant valvular heart disease (VHD). This study sought to evaluate the clinical benefit of valvular surgery in patients with concomitant CKD.We evaluated 349 patients with significant VHD who were referred for surgery. Patients were divided into those with CKD stage ≥ 3 (CKD patients; n = 88) and those with CKD stage 1 or 2 (no CKD patients; n = 261). 63 patients did not receive surgery, of which 20 patients had CKD and 43 had no CKD. Mortality and change in eGFR were assessed after a median follow-up of 21 months.In the whole study population, 25% of the patients had CKD and these patients had higher mortality than those with no CKD. The annual mortality rates of patients with CKD who did and did not undergo surgery were 7.9% and 28.0%, respectively. In patients with no CKD, the annual mortality rates of those who did and did not undergo surgery were 1.8% and 2.3%, respectively. Importantly, surgery was associated with significant survival benefit in patients with CKD (log-rank test, P < 0.01), but was neutral in patients with no CKD. Multivariable analysis confirmed the survival benefit of valvular surgery in all patients, which was most significant in patients with CKD. Furthermore, eGFR was preserved in patients who underwent valvular surgery but declined significantly in those who did not.CKD is common in patients with significant VHD and, if left untreated surgically, these patients exhibit a high mortality.

[Major tricuspid insufficiency and absence of systolic valvular coaptation. Echocardiographic study. Apropos of 6 cases].

PubMed

Roudaut, R; Héraudeau, A; Gosse, P; Aouizerate, E; Dequecker, J L; Dallocchio, M

1986-09-01

In a retrospective series of 960 cases of tricuspid regurgitation studied by two-dimensional echocardiography 6 patients presented a systolic defect of valvular coaptation. The origin of this defect varied: one case was due to carcinoid, two to rheumatic cardiopathy, two to papyraceous right ventricle and one to sclerodermia associated with pulmonary arterial hypertension. The mechanism of the lacking coaptation varies according to the etiology: valvular retraction in carcinoid cardiopathy, right-ventricle dilatation, dilatation of the tricuspid ring and altered kinetics of the right ventricle in the other cases. Changed contractility of the right ventricle is the only element allowing to distinguish tricuspid regurgitation with and without a coaptation defect. Clinically this abnormality always points to an advanced stage of severe tricuspid regurgitation.

Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

PubMed

Lip, Gregory Y H; Collet, Jean Philippe; Caterina, Raffaele de; Fauchier, Laurent; Lane, Deirdre A; Larsen, Torben B; Marin, Francisco; Morais, Joao; Narasimhan, Calambur; Olshansky, Brian; Pierard, Luc; Potpara, Tatjana; Sarrafzadegan, Nizal; Sliwa, Karen; Varela, Gonzalo; Vilahur, Gemma; Weiss, Thomas; Boriani, Giuseppe; Rocca, Bianca

2017-11-01

Atrial fibrillation (AF) is a major worldwide public health problem, and AF in association with valvular heart disease (VHD) is also common. However, management strategies for this group of patients have been less informed by randomized trials, which have largely focused on 'non-valvular AF' patients. Thrombo-embolic risk also varies according to valve lesion and may also be associated with CHA2DS2VASc score risk factor components, rather than only the valve disease being causal. Given marked heterogeneity in the definition of valvular and non-valvular AF and variable management strategies, including non-vitamin K antagonist oral anticoagulants (NOACs) in patients with VHD other than prosthetic heart valves or haemodynamically significant mitral valve disease, there is a need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD. To address this topic, a Task Force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Thrombosis, with representation from the ESC Working Group on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to publish a joint consensus document on the management of patients with AF and associated VHD, with up-to-date consensus recommendations for clinical practice for different forms of VHD. This consensus document proposes that the term 'valvular AF' is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization in relation to the type of OAC use in patients with AF, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA); and (ii) EHRA Type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a Non-VKA oral anticoagulant (NOAC)', also taking into consideration CHA2DS2VASc score risk factor components. This consensus document also summarizes current developments in the field, and provides general recommendations for the management of these patients based on the principles of evidence-based medicine. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

The human uterotubal junction: a scanning electron microscope study during different phases of the menstrual cycle.

PubMed

Fadel, H E; Berns, D; Zaneveld, L J; Wilbanks, G D; Brueschke, E E

1976-10-01

Uterotubal junctions from surgically extirpated human uteri were examined. The specimens were obtained during different phases of the menstrual cycle. The interstitial portions of the tubes together with the cornual areas were dissected, excised, and their luminal surfaces exposed. The specimens were then processed for scanning electron microscopy. The surface epithelium of both the cornual endometrium and interstitial endosalpins. Ciliated cells were more numerous in the endosalpinx. Cyclic changes in ciliated cells were minimal, while cyclic secretory activity was demonstrated, especially in the endometrium. The transitional area between the endometrium and the endosalpinx was characterized by a marked increase in the number of ciliated cells, and a tendency of the secretory cells to assume a flattened, polygonal shape. These morphologic features suggest a possible role in the transport and/or maintenance of spermatozoa and/or ova.

Immunofluorescence reveals unusual patterns of labelling for connexin43 localized to calbindin-D28K-positive interstitial cells in the pineal gland.

PubMed

Tsao, D D; Wang, S G; Lynn, B D; Nagy, J I

2017-06-01

Gap junctions between cells in the pineal gland have been described ultrastructurally, but their connexin constituents have not been fully characterized. We used immunofluorescence in combination with markers of pineal cells to document the cellular localization of connexin43 (Cx43). Immunofluorescence labelling of Cx43 with several different antibodies was widely distributed throughout the pineal, whereas another connexin examined, connexin26, was not found in pineal but only in surrounding leptomeninges. Labelling apparently associated with plasma membranes was visualized either as fine Cx43-puncta (1-2 μm) or as unusually large pools of Cx43 ranging up to 4-7 μm in diameter or length. These puncta and pools were highly concentrated in perivascular spaces, where they were associated with numerous cells devoid of labelling for markers of pinealocytes (e.g. tryptophan hydroxylase and serotonin), and where they were minimally associated with blood vessels and lacked association with resident macrophages. Astrocytes labelled for glial fibrillary acidic protein were largely restricted to the anterior pole of the pineal gland, where they displayed only fine and sparse Cx43-puncta along their processes. Labelling for Cx43 was localized largely though not exclusively to the somata and long processes of a subpopulation of perivascular interstitial cells that were immunopositive for calbindin-D28K. These cells were often located among dense bundles or termination areas of sympathetic fibres labelled for tyrosine hydroxylase or serotonin. The results indicate that interstitial cells form abundant gap junctions composed of Cx43, and suggest that gap junction-mediated intracellular communication by these cells supports the activities of pinealocytes. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Inflammatory myofibroblastic tumors of the lung carrying a chimeric A2M-ALK gene: report of 2 infantile cases and review of the differential diagnosis of infantile pulmonary lesions.

PubMed

Tanaka, Mio; Kohashi, Kenichi; Kushitani, Kei; Yoshida, Misa; Kurihara, Sho; Kawashima, Masumi; Ueda, Yuka; Souzaki, Ryota; Kinoshita, Yoshiaki; Oda, Yoshinao; Takeshima, Yukio; Hiyama, Eiso; Taguchi, Tomoaki; Tanaka, Yukichi

2017-08-01

We report 2 infantile cases of pulmonary tumor carrying a chimeric A2M-ALK gene. A2M-ALK is a newly identified anaplastic lymphoma kinase (ALK)-related chimeric gene from a tumor diagnosed as fetal lung interstitial tumor (FLIT). FLIT is a recently recognized infantile pulmonary lesion defined as a mass-like lesion that morphologically resembles the fetal lung. Grossly, FLIT characteristically appears as a well-circumscribed spongy mass, whereas the tumors in these patients were solid and firm. Histologically, the tumors showed intrapulmonary lesions composed of densely proliferating polygonal or spindle-shaped mesenchymal cells with diffuse and dense infiltrations of inflammatory cells forming microcystic or micropapillary structures lined by thyroid transcription factor 1-positive pneumocytes, favoring inflammatory myofibroblastic tumor rather than FLIT. The proliferating cells were immunoreactive for ALK, and A2M-ALK was identified in both tumors with reverse-transcription polymerase chain reaction. The dense infiltration of inflammatory cells, immunoreactivity for ALK, and identification of an ALK-related chimeric gene suggested a diagnosis of inflammatory myofibroblastic tumor. Histologically, most reported FLITs show sparse inflammatory infiltrates and a relatively low density of interstitial cells in the septa, although prominent infiltration of inflammatory cells and high cellularity of interstitial cells are seen in some FLITs. The present cases suggest that ALK rearrangements, including the chimeric A2M-ALK gene, may be present in these infantile pulmonary lesions, especially those with inflammatory cell infiltration. We propose that these infantile pulmonary lesions containing a chimeric A2M-ALK gene be categorized as a specific type of inflammatory myofibroblastic tumor that develops exclusively in neonates and infants. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcatheter umbrella closure of valvular and paravalvular leaks.

PubMed

Hourihan, M; Perry, S B; Mandell, V S; Keane, J F; Rome, J J; Bittl, J A; Lock, J E

1992-11-15

Our aim was to adapt the technique of transcatheter umbrella closure of intracardiac defects for closure of valvular and paravalvular defects. The double-umbrella device developed by Rashkind and Cuaso has been safely and effectively delivered across a host of intracardiac defects, but transcatheter closure of valvular and paravalvular leaks has not been reported. Between February 1987 and September 1990, eight patients who were believed to be poor operative candidates were taken to the catheterization laboratory for transcatheter double-umbrella closure of a valvular or a paravalvular leak. Four patients had a paravalvular leak around a prosthetic aortic valve. The other four patients had a valvular leak: one patient with a regurgitant native aortic valve after a Stansel procedure and three patients with a regurgitant porcine valve in a left ventricular apex to descending aorta conduit. Placement of a double-umbrella device was attempted in seven of the eight patients and was successful in all seven. Device placement was not attempted in one patient because of the crescentic shape of his defect. Two patients required two devices for each closure; the other five required only one device each. Angiography, performed on six patients after device closure, demonstrated that three patients had a completely occluded defect, two had trivial residual flow and one patient had mild residual flow through the device. All significant complications occurred in one patient who had hemolysis and oliguria that resolved when the initial umbrella was replaced by a larger device. In addition, two devices migrated to the patient's pulmonary arteries but were retrieved in the catheterization laboratory without difficulty. No other early or late complications occurred in 21 to 50 months of follow-up. Of the four patients with a paravalvular leak, the one who did not receive a device died at operation, one patient died at operation for an associated defect (in the operating room the umbrella was found securely in place across the paraaortic defect) and two patients are clinically well at home after 21 and 32 months, respectively. Of the four patients with closure of a valvular leak, one patient remains well at home 50 months later, one patient died at operation for associated defects and two patients had additional successful surgical treatment and remain well 29 months after device placement. Transcatheter umbrella closure appears to be a reasonable alternative for closure of a valvular or paravalvular leak in patients who are poor operative candidates.

A Lifetime's Adventure in Extracellular K+ Regulation: The Scottish Connection.

PubMed

Brown, Angus M

2017-09-01

In a career that has spanned 45 years and shows no signs of slowing down, Dr Bruce Ransom has devoted considerable time and energy to studying regulation of interstitial K + . When Bruce commenced his studies in 1969 virtually nothing was known of the functions of glial cells, but Bruce's research contributed to the physiological assignation of function to mammalian astrocytes, namely interstitial K + buffering. The experiments that I describe in this review concern the response of the membrane potential (Em) of in vivo cat cortical astrocytes to changes in [K + ] o , an experimental manoeuvre that was achieved in two different ways. The first involved recording the Em of an astrocyte while the initial aCSF was switched to one with different K + , whereas in the second series of experiments the cortex was stimulated and the response of the astrocyte Em to the K + released from neighbouring neurons was recorded. The astrocytes responded in a qualitatively predictable manner, but quantitatively the changes were not as predicted by the Nernst equation. Elevations in interstitial K + are not sustained and K + returns to baseline rapidly due to the buffering capacity of astrocytes, a phenomenon studied by Bruce, and his son Chris, published 27 years after Bruce's initial publications. Thus, a lifetime spent investigating K + buffering has seen enormous advances in glial research, from the time cells were identified as 'presumed' glial cells or 'silent cells', to the present day, where glial cells are recognised as contributing to every important physiological brain function.

Expression of peroxisome proliferator-activated receptor alpha messenger ribonucleic acid and protein in human and rat testis.

PubMed

Schultz, R; Yan, W; Toppari, J; Völkl, A; Gustafsson, J A; Pelto-Huikko, M

1999-07-01

Peroxisome proliferator-activated receptor a (PPARalpha), a member of the steroid hormone receptor superfamily, has been linked to lipid homeostasis and tumorigenesis in tissues with high expression of receptor protein. On the other hand, the role of PPARalpha in tissues with a lower expression is not well known. Here we demonstrate the localization of PPARalpha messenger RNA (mRNA) and protein in developing and adult rat testis. Additionally, we demonstrate the expression of PPARalpha protein in adult human testis. Our experiments with Northern analysis, in situ hybridization and immunocytochemistry reveal a complex distribution of PPARalpha in tubular and interstitial cells of both adult and developing rat testis. The overall expression is rather low but may be modified by exogenous or endogenous stimuli. An up-regulation of PPARalpha mRNA could be observed after stimulation with FSH. In the developing rat testis, a clear expression of PPARalpha mRNA was present from the first days after birth. Additionally, PPARalpha mRNA and protein increased toward adulthood. In adult human testis PPARalpha immunoreactivity (IR) was present in interstitial Leydig cells and tubular cells. In the seminiferous epithelium of adult human testis the expression of PPARalpha-IR could be seen in meiotic spermatocytes, spermatids and myoid peritubular cells. The findings of our study suggest that PPARalpha may be involved in the regulation of growth and differentiation of tubular and interstitial cells in rat and human testis.

Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid

PubMed Central

Baronzio, Gianfranco; Parmar, Gurdev; Baronzio, Miriam

2015-01-01

Every drug used to treat cancer (chemotherapeutics, immunological, monoclonal antibodies, nanoparticles, radionuclides) must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells, they must overcome a number of impediments created by the tumor microenvironment (TME), beginning with tumor interstitial fluid pressure (TIFP), and a multifactorial increase in composition of the extracellular matrix (ECM). A primary modifier of TME is hypoxia, which increases the production of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor. These growth factors released by both tumor cells and bone marrow recruited myeloid cells form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass (tumor interstitial fluid), ultimately creating an increased pressure (TIFP). Fibroblasts are also up-regulated by the TME, and deposit fibers that further augment the density of the ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview, we will describe all the methods (drugs, nutraceuticals, and physical methods of treatment) able to lower TIFP and to modify ECM used for increasing drug concentration within the tumor tissue. PMID:26258072

Hymyc1 downregulation promotes stem cell proliferation in Hydra vulgaris.

PubMed

Ambrosone, Alfredo; Marchesano, Valentina; Tino, Angela; Hobmayer, Bert; Tortiglione, Claudia

2012-01-01

Hydra is a unique model for studying the mechanisms underlying stem cell biology. The activity of the three stem cell lineages structuring its body constantly replenishes mature cells lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. In vertebrates, one of many genes that participate in regulating stem cell homeostasis is the protooncogene c-myc, which has been recently identified also in Hydra, and found expressed in the interstitial stem cell lineage. In the present paper, by developing a novel strategy of RNA interference-mediated gene silencing (RNAi) based on an enhanced uptake of small interfering RNAi (siRNA), we provide molecular and biological evidence for an unexpected function of the Hydra myc gene (Hymyc1) in the homeostasis of the interstitial stem cell lineage. We found that Hymyc1 inhibition impairs the balance between stem cell self renewal/differentiation, as shown by the accumulation of stem cell intermediate and terminal differentiation products in genetically interfered animals. The identical phenotype induced by the 10058-F4 inhibitor, a disruptor of c-Myc/Max dimerization, demonstrates the specificity of the RNAi approach. We show the kinetic and the reversible feature of Hymyc1 RNAi, together with the effects displayed on regenerating animals. Our results show the involvement of Hymyc1 in the control of interstitial stem cell dynamics, provide new clues to decipher the molecular control of the cell and tissue plasticity in Hydra, and also provide further insights into the complex myc network in higher organisms. The ability of Hydra cells to uptake double stranded RNA and to trigger a RNAi response lays the foundations of a comprehensive analysis of the RNAi response in Hydra allowing us to track back in the evolution and the origin of this process.

Hymyc1 Downregulation Promotes Stem Cell Proliferation in Hydra vulgaris

PubMed Central

Ambrosone, Alfredo; Marchesano, Valentina; Tino, Angela; Hobmayer, Bert; Tortiglione, Claudia

2012-01-01

Hydra is a unique model for studying the mechanisms underlying stem cell biology. The activity of the three stem cell lineages structuring its body constantly replenishes mature cells lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. In vertebrates, one of many genes that participate in regulating stem cell homeostasis is the protooncogene c-myc, which has been recently identified also in Hydra, and found expressed in the interstitial stem cell lineage. In the present paper, by developing a novel strategy of RNA interference-mediated gene silencing (RNAi) based on an enhanced uptake of small interfering RNAi (siRNA), we provide molecular and biological evidence for an unexpected function of the Hydra myc gene (Hymyc1) in the homeostasis of the interstitial stem cell lineage. We found that Hymyc1 inhibition impairs the balance between stem cell self renewal/differentiation, as shown by the accumulation of stem cell intermediate and terminal differentiation products in genetically interfered animals. The identical phenotype induced by the 10058-F4 inhibitor, a disruptor of c-Myc/Max dimerization, demonstrates the specificity of the RNAi approach. We show the kinetic and the reversible feature of Hymyc1 RNAi, together with the effects displayed on regenerating animals. Our results show the involvement of Hymyc1 in the control of interstitial stem cell dynamics, provide new clues to decipher the molecular control of the cell and tissue plasticity in Hydra, and also provide further insights into the complex myc network in higher organisms. The ability of Hydra cells to uptake double stranded RNA and to trigger a RNAi response lays the foundations of a comprehensive analysis of the RNAi response in Hydra allowing us to track back in the evolution and the origin of this process. PMID:22292012

Unusual Giant Right Atrium in Rheumatic Mitral Stenosis and Tricuspid Insufficiency

PubMed Central

Anzouan-Kacou, Jean Baptiste; Konin, Christophe; Coulibaly, Iklo; N'guetta, Roland; Adoubi, Anicet; Soya, Esaïe; Boka, Bénédicte

2011-01-01

Dilation and hypertrophy of the atria occur in patients with valvular heart disease especially in mitral regurgitation, mitral stenosis or tricuspid abnormalities. In sub-saharan Africa, rheumatic fever is still the leading cause of valvular heart disease. We report a case of an unusual giant right atrium in context of rheumatic stenosis and severe tricuspid regurgitation in a 58-year-old woman. PMID:24826228

Cardiac surgery in Africa: a thirty-five year experience on open heart surgery in Cote d'Ivoire.

PubMed

Yangni-Angate, Koffi Herve; Meneas, Christophe; Diby, Florent; Diomande, Manga; Adoubi, Anicet; Tanauh, Yves

2016-10-01

Few centers for open heart surgery (OHS) are in Sub-Saharan Africa. Lack of OHS results is also noted. By reporting our African experience on OHS, the aim of this study was to fill the gap. It is a retrospective study on 2,612 patients who were subject to an OHS between 1978 and 2013. Data were collected from demographical, clinical, investigative studies, surgical and outcomes parameters. There were 1,475 cases of rheumatic heart diseases (RHD), 126 endomyocardial fibrosis (EMF), 741 congenital heart diseases (CHDs) and 270 various affections. Related to rheumatic valvular surgery we enumerated 1,175 monovalvular (mitral n=778, aortic n=336, tricuspid n=61); 280 bivalvular (mitral + aortic n=150, mitral + tricuspid n=130) and 20 trivalvular. For RHD, average age was 26±10.1 years (4-69 years) and 60% of our patients presented a functional class III or IV according to New York Heart Association (NYHA) classification. A total of 1,481 valvular replacements (bioprostheses n=489, mechanical prostheses n=992) and 445 valvular repair were carried out with a global and late mortality surgery respectively at 7% and 8%. One hundred and twenty-six [126] cases of EMF with right sided form 39, left sided form 40, and bilateral form 47 were colligated. Average age was 12±0.6 years (2-15 years). All patients with EMF underwent surgery; an endocardectomy in all patients combined with valvular reconstruction (n=36) or valvular replacement (n=90) was carried out with a hospital mortality at 16% (n=20). Concerning CHD, the most frequent were ventricular septal defect (VSD) (n=240), atrial septal defect (ASD) (n=200), partial atrio-ventricular sepal defect (n=30) and tetralogy of Fallot (T4F) (n=220), a total correction was performed for those CHD with an early mortality at 6.4% (n=44). OHS in Cote d'Ivoire was successfully performed in most of our patients, the spectrum of acquired valvular heart diseases and CHDs in our country is similar to others in Sub-Saharan Africa.

Echocardiographic evidence for valvular toxicity of benfluorex: a double-blind randomised trial in patients with type 2 diabetes mellitus.

PubMed

Derumeaux, Geneviève; Ernande, Laura; Serusclat, André; Servan, Evelyne; Bruckert, Eric; Rousset, Hugues; Senn, Stephen; Van Gaal, Luc; Picandet, Brigitte; Gavini, François; Moulin, Philippe

2012-01-01

REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. At baseline, patients were 59.1 ± 10.5 years old with HbA1c 8.3 ± 0.8%, and DM duration 7.1 ± 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 ± 0.80 to 7.77 ± 1.31 versus pioglitazone: from 8.30 ± 0.80 to 7.45 ± 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug.

Cardiac surgery in Africa: a thirty-five year experience on open heart surgery in Cote d’Ivoire

PubMed Central

Meneas, Christophe; Diby, Florent; Diomande, Manga; Adoubi, Anicet; Tanauh, Yves

2016-01-01

Background Few centers for open heart surgery (OHS) are in Sub-Saharan Africa. Lack of OHS results is also noted. By reporting our African experience on OHS, the aim of this study was to fill the gap. Methods It is a retrospective study on 2,612 patients who were subject to an OHS between 1978 and 2013. Data were collected from demographical, clinical, investigative studies, surgical and outcomes parameters. Results There were 1,475 cases of rheumatic heart diseases (RHD), 126 endomyocardial fibrosis (EMF), 741 congenital heart diseases (CHDs) and 270 various affections. Related to rheumatic valvular surgery we enumerated 1,175 monovalvular (mitral n=778, aortic n=336, tricuspid n=61); 280 bivalvular (mitral + aortic n=150, mitral + tricuspid n=130) and 20 trivalvular. For RHD, average age was 26±10.1 years (4–69 years) and 60% of our patients presented a functional class III or IV according to New York Heart Association (NYHA) classification. A total of 1,481 valvular replacements (bioprostheses n=489, mechanical prostheses n=992) and 445 valvular repair were carried out with a global and late mortality surgery respectively at 7% and 8%. One hundred and twenty-six [126] cases of EMF with right sided form 39, left sided form 40, and bilateral form 47 were colligated. Average age was 12±0.6 years (2–15 years). All patients with EMF underwent surgery; an endocardectomy in all patients combined with valvular reconstruction (n=36) or valvular replacement (n=90) was carried out with a hospital mortality at 16% (n=20). Concerning CHD, the most frequent were ventricular septal defect (VSD) (n=240), atrial septal defect (ASD) (n=200), partial atrio-ventricular sepal defect (n=30) and tetralogy of Fallot (T4F) (n=220), a total correction was performed for those CHD with an early mortality at 6.4% (n=44). Conclusions OHS in Cote d’Ivoire was successfully performed in most of our patients, the spectrum of acquired valvular heart diseases and CHDs in our country is similar to others in Sub-Saharan Africa. PMID:27904843

Populations of subplate and interstitial neurons in fetal and adult human telencephalon.

PubMed

Judaš, Miloš; Sedmak, Goran; Pletikos, Mihovil; Jovanov-Milošević, Nataša

2010-10-01

In the adult human telencephalon, subcortical (gyral) white matter contains a special population of interstitial neurons considered to be surviving descendants of fetal subplate neurons [Kostovic & Rakic (1980) Cytology and the time of origin of interstitial neurons in the white matter in infant and adult human and monkey telencephalon. J Neurocytol9, 219]. We designate this population of cells as superficial (gyral) interstitial neurons and describe their morphology and distribution in the postnatal and adult human cerebrum. Human fetal subplate neurons cannot be regarded as interstitial, because the subplate zone is an essential part of the fetal cortex, the major site of synaptogenesis and the 'waiting' compartment for growing cortical afferents, and contains both projection neurons and interneurons with distinct input-output connectivity. However, although the subplate zone is a transient fetal structure, many subplate neurons survive postnatally as superficial (gyral) interstitial neurons. The fetal white matter is represented by the intermediate zone and well-defined deep periventricular tracts of growing axons, such as the corpus callosum, anterior commissure, internal and external capsule, and the fountainhead of the corona radiata. These tracts gradually occupy the territory of transient fetal subventricular and ventricular zones.The human fetal white matter also contains distinct populations of deep fetal interstitial neurons, which, by virtue of their location, morphology, molecular phenotypes and advanced level of dendritic maturation, remain distinct from subplate neurons and neurons in adjacent structures (e.g. basal ganglia, basal forebrain). We describe the morphological, histochemical (nicotinamide-adenine dinucleotide phosphate-diaphorase) and immunocytochemical (neuron-specific nuclear protein, microtubule-associated protein-2, calbindin, calretinin, neuropeptide Y) features of both deep fetal interstitial neurons and deep (periventricular) interstitial neurons in the postnatal and adult deep cerebral white matter (i.e. corpus callosum, anterior commissure, internal and external capsule and the corona radiata/centrum semiovale). Although these deep interstitial neurons are poorly developed or absent in the brains of rodents, they represent a prominent feature of the significantly enlarged white matter of human and non-human primate brains. © 2010 The Authors. Journal of Anatomy © 2010 Anatomical Society of Great Britain and Ireland.

Early history of subplate and interstitial neurons: from Theodor Meynert (1867) to the discovery of the subplate zone (1974)

PubMed Central

Judaš, Miloš; Sedmak, Goran; Pletikos, Mihovil

2010-01-01

In this historical review, we trace the early history of research on the fetal subplate zone, subplate neurons and interstitial neurons in the white matter of the adult nervous system. We arrive at several general conclusions. First, a century of research clearly testifies that interstitial neurons, subplate neurons and the subplate zone were first observed and variously described in the human brain – or, in more general terms, in large brains of gyrencephalic mammals, characterized by an abundant white matter and slow and protracted prenatal and postnatal development. Secondly, the subplate zone cannot be meaningfully defined using a single criterion – be it a specific population of cells, fibres or a specific molecular or genetic marker. The subplate zone is a highly dynamic architectonic compartment and its size and cellular composition do not remain constant during development. Thirdly, it is important to make a clear distinction between the subplate zone and the subplate (and interstitial) neurons. The transient existence of the subplate zone (as a specific architectonic compartment of the fetal telencephalic wall) should not be equated with the putative transient existence of subplate neurons. It is clear that in rodents, and to an even greater extent in humans and monkeys, a significant number of subplate cells survive and remain functional throughout life. PMID:20979585

Retinoid agonist isotretinoin ameliorates obstructive renal injury.

PubMed

Schaier, Matthias; Jocks, Thomas; Grone, Hermann-Josef; Ritz, Eberhard; Wagner, Juergen

2003-10-01

Interstitial fibrosis is a major cause of end stage renal failure. Retinoids, which are involved in tissue repair and fibrosis, inhibit inflammatory and proliferative pathways. Therefore, we studied the dose dependent effects of the retinoid receptor agonist isotretinoin 13-cis retinoic acid in the unilateral ureteral obstruction model (UUO). Sham operated control rats were compared with UUO rats treated with vehicle (UUO-Veh), or low (5 mg/kg body weight (UUO-LD) or high (25 mg/kg) (UUO-HD) dose isotretinoin. Kidneys were evaluated using reverse transcriptase-polymerase chain reaction and immunohistology 7 days after UUO. Renal injury and fibrosis were quantified by immunostaining and expression measurements of the genes involved in renal fibrosis. In UUO-Veh kidneys the interstitial area was expanded 5-fold but only 3-fold in UUO-HD and 3.5-fold in UUO-LD rats. Interstitial cell counts were 3-fold higher in UUO-Veh rats but significantly less in UUO-HD or UUO-LD animals. Tubular and interstitial cell proliferation was significantly higher in UUO-Veh rats compared with sham operated control plus vehicle animals but less so in UUO-LD and UUO-HD rats. In UUO-Veh rats interstitial infiltration by monocytes/macrophages was higher compared with unobstructed controls. It was significantly less after isotretinoin treatment. In UUO-Veh rats mRNA for procollagen I, and transforming growth factor-beta1 and II receptor was significantly increased. It was significantly less after treatment with isotretinoin. Fibronectin and collagen I immunostaining was also decreased by isotretinoin. Since isotretinoin limits proliferation, inflammation and fibrosis after UUO, retinoids should be further investigated as potentially promising therapeutic agents for renal disease.

Telocytes and putative stem cells in ageing human heart

PubMed Central

Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

2015-01-01

Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit http://www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days–1 year), children (6–17 years) and adults (34–60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52–62%; vascular smooth muscle cells and pericytes 22–28%, Schwann cells with nerve endings 6–7%, fibroblasts 3–10%, macrophages 1–8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID:25545142

Mid-Term Results of Surgical Treatment of Atrial Fibrillation in Valvular Heart Disease Assesed by Speckle Tracking Echocardiography

PubMed Central

Lorenzo, Natalia; Mendez, Irene; Taibo, Mikel; Martinis, Gianfranco; Badia, Sara; Reyes, Guillermo; Aguilar, Rio

2018-01-01

Background Atrial fibrillation frequently affects patients with valvular heart disease. Ablation of atrial fibrillation during valvular surgery is an alternative for restoring sinus rhythm. Objectives This study aimed to evaluate mid-term results of successful atrial fibrillation surgical ablation during valvular heart disease surgery, to explore left atrium post-ablation mechanics and to identify predictors of recurrence. Methods Fifty-three consecutive candidates were included. Eligibility criteria for ablation included persistent atrial fibrillation <10 years and left atrium diameter < 6.0 cm. Three months after surgery, echocardiogram, 24-hour Holter monitoring and electrocardiograms were performed in all candidates who maintained sinus rhythm (44 patients). Echo-study included left atrial deformation parameters (strain and strain rate), using 2-dimensional speckle-tracking echocardiography. Simultaneously, 30 healthy individuals (controls) were analyzed with the same protocol for left atrial performance. Significance was considered with a P value of < 0.05. Results After a mean follow up of 17 ± 2 months, 13 new post-operative cases of recurrent atrial fibrillation were identified. A total of 1,245 left atrial segments were analysed. Left atrium was severely dilated in the post-surgery group and, mechanical properties of left atrium did not recover after surgery when compared with normal values. Left atrial volume (≥ 64 mL/m2) was the only independent predictor of atrial fibrillation recurrence (p = 0.03). Conclusions Left atrial volume was larger in patients with atrial fibrillation recurrence and emerges as the main predictor of recurrences, thereby improving the selection of candidates for this therapy; however, no differences were found regarding myocardial deformation parameters. Despite electrical maintenance of sinus rhythm, left atrium mechanics did not recover after atrial fibrillation ablation performed during valvular heart disease surgery. PMID:29561964

Resting heart rate and the incidence and progression of valvular calcium: The Multi-Ethnic Study of Atherosclerosis (MESA).

PubMed

Amoakwa, Kojo; Fashanu, Oluwaseun E; Tibuakuu, Martin; Zhao, Di; Guallar, Eliseo; Whelton, Seamus P; O'Neal, Wesley T; Post, Wendy S; Budoff, Matthew J; Michos, Erin D

2018-06-01

Left-sided valvular calcification is associated with cardiovascular disease (CVD) morbidity and mortality. Resting heart rate (RHR) may influence valvular calcium progression through shear stress. Whether RHR, an established CVD risk factor, is associated with valvular calcium progression is unknown. We assessed whether RHR predicts incidence and progression of mitral annular calcium (MAC) and aortic valve calcium (AVC) in a community-based cohort free of CVD at baseline. RHR was obtained from baseline electrocardiograms of 5498 MESA participants. MAC and AVC were quantified using Agatston scoring from cardiac computed tomography scans obtained at baseline and at a second examination during follow-up. We examined associations of RHR with incident MAC/AVC and annual change in MAC/AVC scores, after adjusting for demographics, CVD risk factors, physical activity, and atrioventricular nodal blocker use. At baseline, participants had mean age of 62 ± 10 years and mean RHR of 63 ± 10 bpm; 12.3% and 8.9% had prevalent AVC and MAC, respectively. Over a median of 2.3 years, 4.1% and 4.5% developed incident AVC and MAC, respectively. Each 10 bpm higher RHR was significantly associated with incident MAC [Risk Ratio 1.17 (95% CI 1.03-1.34)], but not incident AVC. However, RHR was associated with AVC progression [β = 1.62 (0.45-2.80) Agatston units/year for every 10 bpm increment], but not MAC progression. Higher RHR was associated with MAC incidence and AVC progression, independent of traditional CVD risk factors. Future studies are needed to determine whether modification of RHR through lifestyle or pharmacologic interventions can reduce valvular calcium incidence or progression. Copyright © 2018 Elsevier B.V. All rights reserved.

Aspirin Compared to Low Intensity Anticoagulation in Patients with Non-Valvular Atrial Fibrillation. A Systematic Review and Meta-Analysis

PubMed Central

Vazquez, Fernando J.; Gonzalez, Joaquín P.; Gándara, Esteban

2015-01-01

Background Despite its lack of efficacy, aspirin is commonly used for stroke prevention in atrial fibrillation. Since prior studies have suggested a benefit of low-intensity anticoagulation over aspirin in the prevention of vascular events, the aim of this systematic review was to compare the outcomes of patients with non-valvular atrial fibrillation treated with low-intensity anticoagulation with Vitamin K antagonists or aspirin. Methods We conducted a systematic review searching Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, from 1946 to October 14th, 2015. Randomized controlled trials were included if they reported the outcomes of patients with non-valvular atrial fibrillation treated with a low-intensity anticoagulation compared to patients treated with aspirin. The primary outcome was a combination of ischemic stroke or systemic embolism. The random-effects model odds ratio was used as the outcome measure. Results Our initial search identified 6309relevant articles of which three satisfied our inclusion criteria and were included. Compared to low-intensity anticoagulation, aspirin alone did not reduce the incidence of ischemic stroke or systemic embolism OR 0.94 (95% CI 0.57–1.56), major bleeding OR 1.06 (95% CI 0.42–2.62) or vascular death OR 1.04 (95% CI 0.61–1.75). The use of aspirin was associated with a significant increase in all-cause mortality OR 1.66 (95% CI 1.12–2.48). Conclusion In patients with non-valvular atrial fibrillation, aspirin provides no benefits over low-intensity anticoagulation. Furthermore, the use of aspirin appears to be associated with an increased risk in all-cause mortality. Our study provides more evidence against the use aspirin in patients with non-valvular atrial fibrillation. PMID:26561858

Association Between Echocardiography Laboratory Accreditation and the Quality of Imaging and Reporting for Valvular Heart Disease.

PubMed

Thaden, Jeremy J; Tsang, Michael Y; Ayoub, Chadi; Padang, Ratnasari; Nkomo, Vuyisile T; Tucker, Stephen F; Cassidy, Cynthia S; Bremer, Merri; Kane, Garvan C; Pellikka, Patricia A

2017-08-01

It is presumed that echocardiographic laboratory accreditation leads to improved quality, but there are few data. We sought to compare the quality of echocardiographic examinations performed at accredited versus nonaccredited laboratories for the evaluation of valvular heart disease. We enrolled 335 consecutive valvular heart disease subjects who underwent echocardiography at our institution and an external accredited or nonaccredited institution within 6 months. Completeness and quality of echocardiographic reports and images were assessed by investigators blinded to the external laboratory accreditation status and echocardiographic results. Compared with nonaccredited laboratories, accredited sites more frequently reported patient sex (94% versus 78%; P <0.001), height and weight (96% versus 63%; P <0.001), blood pressure (86% versus 39%; P <0.001), left ventricular size (96% versus 83%; P <0.001), right ventricular size (94% versus 80%; P =0.001), and right ventricular function (87% versus 73%; P =0.006). Accredited laboratories had higher rates of complete and diagnostic color (58% versus 35%; P =0.002) and spectral Doppler imaging (45% versus 21%; P <0.0001). Concordance between external and internal grading of external studies was improved when diagnostic quantification was performed (85% versus 69%; P =0.003), and in patients with mitral regurgitation, reproducibility was improved with higher quality color Doppler imaging. Accredited echocardiographic laboratories had more complete reporting and better image quality, while echocardiographic quantification and color Doppler image quality were associated with improved concordance in grading valvular heart disease. Future quality improvement initiatives should highlight the importance of high-quality color Doppler imaging and echocardiographic quantification to improve the accuracy, reproducibility, and quality of echocardiographic studies for valvular heart disease. © 2017 American Heart Association, Inc.

Automated flow quantification in valvular heart disease based on backscattered Doppler power analysis: implementation on matrix-array ultrasound imaging systems.

PubMed

Buck, Thomas; Hwang, Shawn M; Plicht, Björn; Mucci, Ronald A; Hunold, Peter; Erbel, Raimund; Levine, Robert A

2008-06-01

Cardiac ultrasound imaging systems are limited in the noninvasive quantification of valvular regurgitation due to indirect measurements and inaccurate hemodynamic assumptions. We recently demonstrated that the principle of integration of backscattered acoustic Doppler power times velocity can be used for flow quantification in valvular regurgitation directly at the vena contracta of a regurgitant flow jet. We now aimed to accomplish implementation of automated Doppler power flow analysis software on a standard cardiac ultrasound system utilizing novel matrix-array transducer technology with detailed description of system requirements, components and software contributing to the system. This system based on a 3.5 MHz, matrix-array cardiac ultrasound scanner (Sonos 5500, Philips Medical Systems) was validated by means of comprehensive experimental signal generator trials, in vitro flow phantom trials and in vivo testing in 48 patients with mitral regurgitation of different severity and etiology using magnetic resonance imaging (MRI) for reference. All measurements displayed good correlation to the reference values, indicating successful implementation of automated Doppler power flow analysis on a matrix-array ultrasound imaging system. Systematic underestimation of effective regurgitant orifice areas >0.65 cm(2) and volumes >40 ml was found due to currently limited Doppler beam width that could be readily overcome by the use of new generation 2D matrix-array technology. Automated flow quantification in valvular heart disease based on backscattered Doppler power can be fully implemented on board a routinely used matrix-array ultrasound imaging systems. Such automated Doppler power flow analysis of valvular regurgitant flow directly, noninvasively, and user independent overcomes the practical limitations of current techniques.

Primary Prevention of Sudden Death in Patients With Valvular Cardiomyopathy.

PubMed

Rodríguez-Mañero, Moisés; Barrio-López, María Teresa; Assi, Emad Abu; Expósito-García, Víctor; Bertomeu-González, Vicente; Sánchez-Gómez, Juan Miguel; González-Torres, Luis; García-Bolao, Ignacio; Gaztañaga, Larraitz; Cabanas-Grandío, Pilar; Iglesias-Bravo, José Antonio; Arce-León, Álvaro; la Huerta, Ana Andrés; Fernández-Armenta, Juan; Peinado, Rafael; Arias, Miguel Angel; Díaz-Infante, Ernesto

2016-03-01

Few data exist on the outcomes of valvular cardiomyopathy patients referred for defibrillator implantation for primary prevention. The aim of the present study was to describe the outcomes of this cardiomyopathy subgroup. This multicenter retrospective study included consecutive patients referred for defibrillator implantation to 15 Spanish centers in 2010 and 2011, and to 3 centers after 1 January 2008. Of 1174 patients, 73 (6.2%) had valvular cardiomyopathy. These patients had worse functional class, wider QRS, and a history of atrial fibrillation vs patients with ischemic (n=659; 56.1%) or dilated (n=442; 37.6%) cardiomyopathy. During a follow-up of 38.1 ± 21.3 months, 197 patients (16.7%) died, without significant differences among the groups (19.2% in the valvular cardiomyopathy group, 15.8% in the ischemic cardiomyopathy group, and 17.9% in the dilated cardiomyopathy group; P=.2); 136 died of cardiovascular causes (11.6%), without significant differences among the groups (12.3%, 10.5%, and 13.1%, respectively; P=.1). Although there were no differences in the proportion of appropriate defibrillator interventions (13.7%, 17.9%, and 18.8%; P=.4), there was a difference in inappropriate interventions (8.2%, 7.1%, and 12.0%, respectively; P=.03). All-cause and cardiovascular mortality in patients with valvular cardiomyopathy were similar to those in other patients referred for defibrillator implantation. They also had similar rates of appropriate interventions. These data suggest that defibrillator implantation in this patient group confers a similar benefit to that obtained by patients with ischemic or dilated cardiomyopathy. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Heart Transplant in Patients with Predominantly Rheumatic Valvular Heart Disease.

PubMed

Rosa, Vitor E E; Lopes, Antonio S S A; Accorsi, Tarso A D; Fernandes, Joao Ricardo C; Spina, Guilherme S; Sampaio, Roney O; Bacal, Fernando; Tarasoutchi, Flavio

2015-09-01

International records indicate that only 2.6% of patients with heart transplants have valvular heart disease. The study aim was to evaluate the epidemiological and clinical profile of patients with valvular heart disease undergoing heart transplantation. Between 1985 and 2013, a total of 569 heart transplants was performed at the authors' institution. Twenty patients (13 men, seven women; mean age 39.5 +/- 15.2 years) underwent heart transplant due to structural (primary) valvular disease. Analyses were made of the patients' clinical profile, laboratory data, echocardiographic and histopathological data, and mortality and rejection. Of the patients, 18 (90%) had a rheumatic etiology, with 85% having undergone previous valve surgery (45% had one or more operations), and 95% with a normal functioning valve prosthesis at the time of transplantation. Atrial fibrillation was present in seven patients (35%), while nine (45%) were in NYHA functional class IV and eight (40%) in class III. The indication for cardiac transplantation was refractory heart failure in seven patients (35%) and persistent NYHA class III/IV in ten (50%). The mean left ventricular ejection fraction (LVEF) was 26.6 +/- 7.9%. The one-year mortality was 20%. Histological examination of the recipients' hearts showed five (27.7%) to have reactivated rheumatic myocarditis without prior diagnosis at the time of transplantation. Univariate analysis showed that age, gender, LVEF, rheumatic activity and rejection were not associated with mortality at one year. Among the present patient cohort, rheumatic heart disease was the leading cause of heart transplantation, and a significant proportion of these patients had reactivated myocarditis diagnosed in the histological analyses. Thus, it appears valid to investigate the existence of rheumatic activity, especially in valvular cardiomyopathy with severe systolic dysfunction before transplantation.

Are gadolinium-based contrast media nephrotoxic? A renal biopsy study.

PubMed

Akgun, Hulya; Gonlusen, Gulfiliz; Cartwright, Joiner; Suki, Wadi N; Truong, Luan D

2006-09-01

Gadolinium-based contrast media were originally introduced as alternatives to iodinated media for magnetic resonance imaging. Although originally thought to be nonnephrotoxic, gadolinium-based contrast media have recently been reported to be associated with acute renal failure; the mechanism and the underlying renal injury are not completely understood. We report what is, to our knowledge, the first renal biopsy in this context. A 56-year-old patient underwent 2 consecutive vascular imaging procedures in conjunction with gadolinium-based contrast medium administration. A few days later, the patient developed acute renal failure. A renal biopsy showed acute tubular cell injury including patchy tubular cell necrosis, tubular cell degeneration, and marked proliferation of tubular cells, together with mild interstitial edema and interstitial inflammation, but without significant glomerular or vascular changes. During supportive therapy, renal function was partially regained. This case emphasizes the potential nephrotoxicity of gadolinium-based contrast media and suggests that the nephrotoxicity is related to potentially reversible acute tubular cell injury.

The evolution of a valved hepatoduodenal intestinal conduit.

PubMed

Kaufman, B H; Luck, S R; Raffensperger, J G

1981-06-01

Ascending cholangitis remains among the most serious complications following operations for biliary disorders. The bacterial count of refluxing intestinal contents can be reduced by using an enteric conduit from the biliary tract to the relatively sterile duodenum. A valvular conduit prohibits reflux of intestinal contents and permits unobstructed antegrade flow of bile. This can be created by intussuscepting approximately 1 cm of intestine in the midportion of the conduit. During the last 3 yr, valvular conduits were created in 11 patients. Seven of these children were treated for biliary atresia, and 4 had operations for choledochal duct cysts. There have been no deaths or morbidity resulting from the use of the valvular conduits. The postoperative courses in these patients indicate that the use of an intussusception valve may be beneficial in the prevention of ascending cholangitis.

Accumulation of BDCA1⁺ dendritic cells in interstitial fibrotic lung diseases and Th2-high asthma.

PubMed

Greer, Alexandra M; Matthay, Michael A; Kukreja, Jasleen; Bhakta, Nirav R; Nguyen, Christine P; Wolters, Paul J; Woodruff, Prescott G; Fahy, John V; Shin, Jeoung-Sook

2014-01-01

Dendritic cells (DCs) significantly contribute to the pathology of several mouse lung disease models. However, little is known of the contribution of DCs to human lung diseases. In this study, we examined infiltration with BDCA1⁺ DCs of human lungs in patients with interstitial lung diseases or asthma. Using flow cytometry, we found that these DCs increased by 5∼6 fold in the lungs of patients with idiopathic pulmonary fibrosis or hypersensitivity pneumonitis, which are both characterized by extensive fibrosis in parenchyma. The same DC subset also significantly increased in the lung parenchyma of patients with chronic obstructive pulmonary disease, although the degree of increase was relatively modest. By employing immunofluorescence microscopy using FcεRI and MHCII as the specific markers for BDCA1⁺ DCs, we found that the numbers of BDCA1⁺ DCs also significantly increased in the airway epithelium of Th2 inflammation-associated asthma. These findings suggest a potential contribution of BDCA1⁺ DCs in human lung diseases associated with interstitial fibrosis or Th2 airway inflammation.

Release of enzymes from cells: transport and distribution within the extracellular space.

PubMed

Mattenheimer, H; Friedel, R

1977-01-01

The distribution in the extracellular space of enzymes released from organ cells was investigated using three models: (1) comparison of enzyme activities in blood plasma and lymph of the ductus thoracicus (dog) and plasma and intestinal lymph (rat); (2) i.v. injection of heterologous, homologous and autologous enzymes in order to increase acutely the activities and to measure the rate constants for the distribution and elimination of the enzymes (rat); or (3) plasmapheresis in order to create an enzyme activity gradient from the interstitial space and to determine the rate constants for the reestablishment of the equilibrium between the extra and intravascular compartments (rat). The results suggest that the enzymes are mainly released into the interstitial fluid and transported via the lymph into the intravascular compartment. From there the enzymes diffuse back into the interstitial compartment and are eliminated by a yet unknown mechanism. Transport of enzymes across the capillary membranes in both directions depends on (1) the permeability of the capillary membranes, which varies from region to region and (2) the molecular seizes of the enzymes.

Cellular complexity in subcortical white matter: a distributed control circuit?

PubMed

Colombo, Jorge A

2018-03-01

The subcortical white matter (SWM) has been traditionally considered as a site for passive-neutral-information transfer through cerebral cortex association and projection fibers. Yet, the presence of subcortical neuronal and glial "interstitial" cells expressing immunolabelled neurotransmitters/neuromodulators and synaptic vesicular proteins, and recent immunohistochemical and electrophysiological observations on the rat visual cortex as well as interactive regulation of myelinating processes support the possibility that SWM nests subcortical, regionally variable, distributed neuronal-glial circuits, that could influence information transfer. Their hypothetical involvement in regulating the timing and signal transfer probability at the SWM axonal components ought to be considered and experimentally analysed. Thus, the "interstitial" neuronal cells-associated with local glial cells-traditionally considered to be vestigial and functionally inert under normal conditions, they may well turn to be critical in regulating information transfer at the SWM.

Effects of Arg-Gly-Asp sequence peptide and hyperosmolarity on the permeability of interstitial matrix and fenestrated endothelium in joints.

PubMed

Poli, A; Mason, R M; Levick, J R

2004-09-01

The aims were to assess the contribution of arg-gly-asp (RGD) mediated cell integrin-matrix bonds to interstitial hydraulic resistance and to fenestrated endothelial permeability in joints. Joint fluid is generated by filtration from fenestrated capillaries and drains through a fibronectin-rich synovial intercellular matrix. The role of parenchymal cell-matrix bonding in determining tissue hydraulic resistance is unknown. The knee cavity of anesthetized rabbits was infused with saline or the competitive hexapeptide blocker GRGDTP, with or without added osmotic stress (600 mosm saline). Intra-articular pressure Pj, net trans-synovial drainage rate s, and the permeation of Evans blue-labeled albumin (EVA) from plasma into the joint cavity were measured. GRGDTP increased the hydraulic conductance of the synovial drainage pathway, ds/dPj, by 71% (p =.02, paired t test, n = 6 animals). Synovial plasma EVA clearance (control 7.1 +/- 0.8 microL h-1, mean +/- SEM, n = 15) was unaffected by GRGDTP (7.0 +/- 2.3 microL h(-1), n = 6) or hyperosmolarity (4.9 +/- 1.5 microL h(-1), n = 8) but was increased by GRGDTP and hyperosmolarity together (15.9 +/- 4.8 microL h(-1), n = 5) (p =.01, ANOVA). Changes in dPj/dt evoked by GRGDTP plus hyperosmolarity, but neither alone, demonstrated increased microvascular filtration into the joint cavity (p <.001, ANOVA), as did changes in fluid absorption from the infusion system at fixed Pj. RGD-mediated bonds between the parenchymal cells and interstitial polymers reduce the interstitial hydraulic conductance by 42%. This helps to retain the lubricating fluid inside a joint cavity. RGD-mediated bonds also support the macromolecular barrier function of fenestrated endothelium, but in vivo this is evident only in stressed endothelium (cf. in vitro).

A case of pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma.

PubMed

Saito, Yoshinobu; Nagayama, Mikie; Miura, Yukiko; Ogushi, Satoko; Suzuki, Yasutomo; Noro, Rintaro; Minegishi, Yuji; Kimura, Go; Kondo, Yukihiro; Gemma, Akihiko

2013-05-01

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprim-sulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of β-d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

Nomograms for two-dimensional echocardiography derived valvular and arterial dimensions in Caucasian children.

PubMed

Cantinotti, Massimiliano; Giordano, Raffaele; Scalese, Marco; Murzi, Bruno; Assanta, Nadia; Spadoni, Isabella; Maura, Crocetti; Marco, Marotta; Molinaro, Sabrina; Kutty, Shelby; Iervasi, Giorgio

2017-01-01

Despite recent advances, current pediatric echocardiographic nomograms for valvular and arterial dimensions remain limited. We prospectively studied healthy Caucasian Italian children by two-dimensional (2D) echocardiography. Echocardiographic measurements for 18 valvular and arterial dimensions were performed and models were generated testing for linear, logarithmic, exponential, and square root relationships. Heteroscedasticity was accounted for by White or Breusch-Pagan test. Age, weight, height, heart rate, and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Structured Z-scores were then computed. In all, 1151 subjects (age 0 days to 17 years; 45% females; BSA 0.12-2.12m 2 ) were studied. The Haycock formula was used when presenting data as predicted values (mean±2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. The predicted values and Z-score boundaries for all measurements are presented. We report echocardiographic nomograms for valvular and arterial dimensions derived from a large population of children. Integration of these data with those of previous reports would allow for a comprehensive coverage of pediatric 2D echocardiographic nomograms for measurement of 2D cardiac structures. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Results of Contemporary Valve Surgery in Patients with Carcinoid Heart Disease.

PubMed

Kuntze, Thomas; Owais, Tamer; Secknus, Maria-Anna; Kaemmerer, Daniel; Baum, Richard; Girdauskas, Evaldas

2016-05-01

Carcinoid tumor is a slow-growing type of neuroendocrine tumor, originating from enterochromaffin cells and secreting mainly serotonin. The diagnosis is based on clinical symptoms, hormone blood levels, radiological and nuclear imaging, and histological confirmation. However, most patients have metastases at the time of diagnosis because the clinical signs often remain unnoticed or are attributed to other abdominal conditions. In up to 50% of patients the endocardium is affected due to a hormonally active tumor profile. The study aim was to report the outcome of surgical treatment in patients with carcinoid heart disease, including the data of radiological and nuclear imaging, histological diagnosis, and follow up information. Between 2008 and 2014, a total of 39 consecutive patients (28 males, 11 females; mean age 66 years; range: 28-84 years) with carcinoid heart syndrome were operated on at the authors' institution. Valvular heart disease was diagnosed with two-dimensional echocardiography. The study population included 26 patients (67%) with severe metastatic disease, who underwent radiotherapy preoperatively, and 13 patients (33%) who were metastasis-free and did not receive preoperative systemic therapy. Follow up was available for all hospital survivors, all of whom underwent serial echocardiographic follow up postoperatively. Adverse cardiac events were defined as cardiac-related death, a need for valvular reintervention, the occurrence of valve prosthesis-related complications, or echocardiographic evidence of new, high-degree valvular dysfunction during follow up. The majority of patients (n = 34; 87%) underwent isolated tricuspid valve replacement, while simultaneous pulmonary valve replacement was performed in five patients (13%). Postoperative complications included reoperation for bleeding in five patients (13%) and new heart block requiring pacemaker implantation in 10 (25%). The in-hospital mortality was 5% (n = 2). The overall survival was 43% at six years postoperatively. At the latest follow up, 12 of the 17 survivors were in NYHA class I, and five in NYHA class II. The adverse cardiac event rate was 71%. Echocardiographically, 46% of patients (6/13) showed at least stationary or mild improvement in the right ventricular ejection fraction at follow up, with no evidence of paravalvular leak, infective endocarditis, or progressive other native valvular carcinoid affection. Postoperatively, the right atrial dimensions were preserved as normal in 23 patients (59%), mildly dilated in six (15%), moderately dilated in three (8%), and severely dilated in seven (18%). Valve-in-valve transcatheter aortic valve implantation was performed in two patients (12%) due to structural degeneration of the valve bioprosthesis and native valve disease progression. Despite advanced systemic disease, the surgical treatment of patients with carcinoid heart syndrome is associated with an acceptable perioperative risk and satisfactory mid-term survival. Those patients who survived valve surgery benefited from a significant improvement in their functional capacity. Percutaneous procedures may represent a useful tool to reduce the risk of late valvular reinterventions.

The clinical significance of the atrial subendocardial smooth muscle layer and cardiac myofibroblasts in human atrial tissue with valvular atrial fibrillation.

PubMed

Park, Jae Hyung; Pak, Hui-Nam; Lee, Sak; Park, Han Ki; Seo, Jeong-Wook; Chang, Byung-Chul

2013-01-01

The existence of myofibroblasts (MFBs) and the role of subendocardial smooth muscle (SSM) layer of human atrial tissue in atrial fibrillation (AF) have not yet been elucidated. We hypothesized that the SSM layer and MFB play some roles in atrial structural remodeling and maintenance of valvular AF in patients who undergo cardiac surgery. We analyzed immunohistochemical staining of left atrial (LA) appendage tissues taken from 17 patients with AF and 15 patients remaining in sinus rhythm (SR) who underwent cardiac surgery (male 50.0%, 54.1 ± 14.2 years old, valve surgery 87.5%). SSM was quantified by α-smooth muscle actin (α-SMA) stain excluding vascular structure. MFB was defined as α-SMA+ cells with disorganized Connexin 43-positive gap junctions in Sirius red-positive fibrotic area. The SSM layer of atrium was significantly thicker in patients with AF than in those with SR (P=.0091). Patients with SSM layer ≥ 14 μm had a larger LA size (P=.0006) and greater fibrotic area (P=.0094) than those patients whose SSM layer <14 μm. MFBs were found in 7 of 17 (41.2%) patients with AF and 2 of 15 (13.3%) in SR group (P=.0456) in SSM area, colocalized with Periodic Acid-Schiff (PAS) stain-positive glycogen storage cells (95.5%). SSM layer was closely related to the existence of AF, degrees of atrial remodeling, and fibrosis in patients who underwent open heart surgery. We found that MFB does exist in SSM layer of human atrial tissue co-localized with PAS-positive cells. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Role of GTP-protein and endothelium in contraction induced by ethanol in pig coronary artery.

PubMed Central

Kuroiwa, M; Aoki, H; Kobayashi, S; Nishimura, J; Kanaide, H

1993-01-01

1. We examined the effects of ethanol on the contractility of strips of porcine coronary artery, with and without endothelium, and following permeabilization with alpha-toxin, and of aortic valvular endothelial cells, in situ. Changes in cytosolic Ca2+ concentration ([Ca2+]i) of the coronary artery smooth muscle cells and of the valvular endothelial cells were monitored using front-surface fluorometry of the calcium indicator dye, fura-2. In permeabilized preparations, [Ca2+]i was clamped using 10 mM ethyleneglycol-bis-(beta-aminoethylether)-N,N,N',N'-tetra ace tic acid (EGTA) and 10 microM A23187 (a calcium ionophore). 2. The strips without endothelium were placed in normal physiological salt solution (normal PSS) in the presence of ethanol (100-1000 mM). There were dose-dependent increases in [Ca2+]i and a rapid sustained rise in tension. In Ca(2+)-free PSS, ethanol increased [Ca2+]i and tension, similar to, but much smaller than, findings with normal PSS. 3. For a given change in [Ca2+]i induced by ethanol, the developed tension was greater than that observed during contractions induced by high [K+]o. Thus, the [Ca2+]-tension curve for ethanol was shifted to the left of that for high [K+]o. The [Ca2+]-tension curve for the contraction induced by ethanol in the absence of extracellular Ca2+ was shifted further to the left from that obtained in the presence of [Ca2+]o. 4. The mechanisms involved in this Ca(2+)-sensitizing effect of ethanol were investigated using alpha-toxin-permeabilized coronary medial strips. Ethanol increased the tension development, in a concentration-dependent manner, at a fixed concentration of Ca2+ (pCa = 6.3) in the presence of guanosine-5'-triphosphate (GTP), an effect antagonized by guanosine-5'-O-(beta-thiodiphosphate) (GDP beta S), a non-hydrolysable GDP analogue. 5. With intact endothelium, the ethanol-induced tension development was markedly reduced, although inhibition in the increase in [Ca2+]i was slight. The [Ca2+]-tension relationship of this contraction overlapped with that obtained with high [K+]o-induced contraction and was shifted to the right from that obtained in the absence of the endothelium. This endothelium-dependent reduction of [Ca2+]i and tension induced by ethanol was inhibited when the strips were exposed to NG-monomethyl-L-arginine (L-NMMA). 6. Ethanol induced a gradual and sustained increase in [Ca2+]i in normal PSS, and a transient, concentration-dependent increase in [Ca2+]i in Ca(2+)-free PSS in porcine aortic valvular endothelial cells in situ.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8308741

Integrated external and interstitial radiation therapy for primary carcinoma of the vagina

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

Puthawala, A.; Syed, A.M.; Nalick, R.

1983-09-01

Twenty-seven patients with the diagnosis of primary carcinoma of the vagina were treated by definitive radiotherapy. Twenty-three patients received a combination of external and interstitial iridium-192 implant irradiation and four patients received only interstitial irradiation. Twenty-one patients had squamous cell carcinoma and six had adenocarcinoma. All patients were staged according to the FIGO classification. More than 70% of patients had relatively advanced local disease and conventional intracavitary irradiation was unsuitable. Local tumor control was observed in 85% (23 of 27 patients), and 56% of the patients remain alive and free of disease for a median follow-up period of 50 monthsmore » to a maximum follow-up period of 84 months. Fifteen percent of the patients suffered from treatment-related complications.« less

Abnormal myocardial fluid retention as an early manifestation of ischemic injury.

PubMed Central

Willerson, J. T.; Scales, F.; Mukherjee, A.; Platt, M.; Templeton, G. H.; Fink, G. S.; Buja, L. M.

1977-01-01

Fifty-seven isolated, blood perfused, continuously weighed canine hearts have been utilized to study the development of abnormal myocardial fluid retention during early myocardial ischemic injury. Inflatable balloon catheters were positioned around the left anterior descending coronary arteries (LAD) of 54 hearts or the proximal left circumflex coronary arteries of three hearts for study of the following intervals of coronary occlusion: a) 10 minutes followed by 20 minutes of reflow, b) 40 minutes followed by either no reflow or by 20 minutes of reflow, and c) 60 minutes without reflow. After 60 minutes of fixed coronary occlusion, histologic and ultrastructural examination revealed mild swelling of many ischemic cardiac muscle cells in the absence of interstitial edema, cardiac weight gain, and obvious structural defects in cell membrane integrity. After 40 minutes of coronary occlusion and 20 minutes of reflow, significant cardiac weight gain occurred in association with characteristic alterations in the ischemic region, including widespread interstitial edema and focal vascular congestion and hemorrhage and swelling of cardiac muscle cells. Focal structural defects in cell membrane integrity were also noted. The development of abnormal myocardial fluid retention after 40 minutes of LAD occlusion occurred in association with a significant reduction in sodium-potassium-ATPase activity in the ischemic area, but with no significant alteration in either creatine phosphokinase or citrate synthase activity in the same region. Despite the abnormal myocardial fluid retention in these hearts, it was possible pharmacologically to vasodilate coronary vessels with adenosine and nitroglycerin infusion to maintain a consistently high coronary flow following release of the coronary occlusion after 40 minutes and to even exceed initial hyperemic flow values following release of the occlusion when adenosine and nitroglycerin infusion was delayed until 15 minutes after reflow. Thus, the data indicate that impaired cell volume regulation and interstitial fluid accumulation and focal structural defects in cell membrane integrity are early manifestations of ischemic injury followed by reflow, but fail to establish a major role for the abnormal fluid retention in altering coronary blood flow prior to the development of extensive myocardial necrosis. In contrast, fixed coronary occlusion for 60 minutes results in mild intracellular swelling but no significant interstitial edema and no obvious structural defects in cell membrane integrity. Images Figure 1 Figure 5 Figure 6 Figure 2 Figure 3 Figure 4 PMID:139829

Interstitial Photoacoustic Sensor for the Measurement of Tissue Temperature during Interstitial Laser Phototherapy

PubMed Central

Li, Zhifang; Chen, Haiyu; Zhou, Feifan; Li, Hui; Chen, Wei R.

2015-01-01

Photothermal therapy is an effective means to induce tumor cell death, since tumor tissue is more sensitive to temperature increases than normal tissue. Biological responses depend on tissue temperature; target tissue temperature needs to be precisely measured and controlled to achieve desired thermal effects. In this work, a unique photoacoustic (PA) sensor is proposed for temperature measurement during interstitial laser phototherapy. A continuous-wave laser light and a pulsed laser light, for photothermal irradiation and photoacoustic temperature measurement, respectively, were delivered to the target tissue through a fiber coupler. During laser irradiation, the PA amplitude was measured. The Grüneisen parameter and the bioheat equation were used to determine the temperature in strategic positions in the target tissue. Our results demonstrate that the interstitial PA amplitude is a linear function of temperature in the range of 22 to 55 °C, as confirmed by thermocouple measurement. Furthermore, by choosing appropriate laser parameters, the maximum temperature surrounding the active diffuse fiber tip in tissue can be controlled in the range of 41 to 55 °C. Thus, this sensor could potentially be used for fast, accurate, and convenient three-dimensional temperature measurement, and for real-time feedback and control of interstitial laser phototherapy in cancer treatment. PMID:25756865

Transcellular Pathways in Lymphatic Endothelial Cells Regulate Changes in Solute Transport by Fluid Stress.

PubMed

Triacca, Valentina; Güç, Esra; Kilarski, Witold W; Pisano, Marco; Swartz, Melody A

2017-04-28

The transport of interstitial fluid and solutes into lymphatic vessels is important for maintaining interstitial homeostasis and delivering antigens and soluble factors to the lymph node for immune surveillance. Transendothelial transport across lymphatic endothelial cells (LECs) is commonly considered to occur paracellularly, or between cell-cell junctions, and driven by local pressure and concentration gradients. However, emerging evidence suggests that LECs also play active roles in regulating interstitial solute balance and can scavenge and store antigens, raising the possibility that vesicular or transcellular pathways may be important in lymphatic solute transport. The aim of this study was to determine the relative importance of transcellular (vesicular) versus paracellular transport pathways by LECs and how mechanical stress (ie, fluid flow conditioning) alters either pathway. We demonstrate that transcellular transport mechanisms substantially contribute to lymphatic solute transport and that solute uptake occurs in both caveolae- and clathrin-coated vesicles. In vivo, intracelluar uptake of fluorescently labeled albumin after intradermal injection by LECs was similar to that of dermal dendritic cells. In vitro, we developed a method to differentially quantify intracellular solute uptake versus transendothelial transport by LECs. LECs preconditioned to 1 µm/s transmural flow demonstrated increased uptake and basal-to-apical solute transport, which could be substantially reversed by blocking dynamin-dependent vesicle formation. These findings reveal the importance of intracellular transport in steady-state lymph formation and suggest that LECs use transcellular mechanisms in parallel to the well-described paracellular route to modulate solute transport from the interstitium according to biomechanical cues. © 2017 American Heart Association, Inc.

Flow through internal elastic lamina affects shear stress on smooth muscle cells (3D simulations).

PubMed

Tada, Shigeru; Tarbell, John M

2002-02-01

We describe a three-dimensional numerical simulation of interstitial flow through the medial layer of an artery accounting for the complex entrance condition associated with fenestral pores in the internal elastic lamina (IEL) to investigate the fluid mechanical environment around the smooth muscle cells (SMCs) right beneath the IEL. The IEL was modeled as an impermeable barrier to water flow except for the fenestral pores, which were assumed to be uniformly distributed over the IEL. The medial layer was modeled as a heterogeneous medium composed of a periodic array of cylindrical SMCs embedded in a continuous porous medium representing the interstitial proteoglycan and collagen matrix. Depending on the distance between the IEL bottom surface and the upstream end of the proximal layer of SMCs, the local shear stress on SMCs right beneath the fenestral pore could be more than 10 times higher than that on the cells far removed from the IEL under the conditions that the fenestral pore diameter and area fraction of pores were kept constant at 1.4 microm and 0.05, respectively. Thus these proximal SMCs may experience shear stress levels that are even higher than endothelial cells exposed to normal blood flow (order of 10 dyn/cm(2)). Furthermore, entrance flow through fenestral pores alters considerably the interstitial flow field in the medial layer over a spatial length scale of the order of the fenestral pore diameter. Thus the spatial gradient of shear stress on the most superficial SMC is noticeably higher than computed for endothelial cell surfaces.

Renal denervation prevents long-term sequelae of ischemic renal injury

PubMed Central

Kim, Jinu; Padanilam, Babu J.

2014-01-01

Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation is manifest even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury.. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post-injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-β1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury. PMID:25207878

Selective propensity of bovine jugular vein material to bacterial adhesions: An in-vitro study.

PubMed

Jalal, Zakaria; Galmiche, Louise; Lebeaux, David; Villemain, Olivier; Brugada, Georgia; Patel, Mehul; Ghigo, Jean-Marc; Beloin, Christophe; Boudjemline, Younes

2015-11-01

Percutaneous pulmonary valve implantation (PPVI) using Melody valve made of bovine jugular vein is safe and effective. However, infective endocarditis has been reported for unclear reasons. We sought to assess the impact of valvular substrates on selective bacterial adhesion. Three valved stents (Melody valve, homemade stents with bovine and porcine pericardium) were tested in-vitro for bacterial adhesion using Staphylococcus aureus and Streptococcus sanguinis strains. Bacterial adhesion was higher on bovine jugular venous wall for S. aureus and on Melody valvular leaflets for S. sanguinis in control groups and significantly increased in traumatized Melody valvular leaflets with both bacteria (traumatized vs non traumatized: p=0.05). Bacterial adhesion was lower on bovine pericardial leaflets. Selective adhesion of S. aureus and S. sanguinis pathogenic strains to Melody valve tissue was noted on healthy tissue and increased after implantation procedural steps. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pathogenesis of Idiopathic Pulmonary Fibrosis

PubMed Central

Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

Interstitial lung disease associated with Equine Infectious Anemia Virus infection in horses

PubMed Central

2013-01-01

EIA (Equine Infectious Anemia) is a blood-borne disease primarily transmitted by haematophagous insects or needle punctures. Other routes of transmission have been poorly explored. We evaluated the potential of EIAV (Equine Infectious Anemia Virus) to induce pulmonary lesions in naturally infected equids. Lungs from 77 EIAV seropositive horses have been collected in Romania and France. Three types of lesions have been scored on paraffin-embedded lungs: lymphocyte infiltration, bronchiolar inflammation, and thickness of the alveolar septa. Expression of the p26 EIAV capsid (CA) protein has been evaluated by immunostaining. Compared to EIAV-negative horses, 52% of the EIAV-positive horses displayed a mild inflammation around the bronchioles, 22% had a moderate inflammation with inflammatory cells inside the wall and epithelial bronchiolar hyperplasia and 6.5% had a moderate to severe inflammation, with destruction of the bronchiolar epithelium and accumulation of smooth muscle cells within the pulmonary parenchyma. Changes in the thickness of the alveolar septa were also present. Expression of EIAV capsid has been evidenced in macrophages, endothelial as well as in alveolar and bronchiolar epithelial cells, as determined by their morphology and localization. To summarize, we found lesions of interstitial lung disease similar to that observed during other lentiviral infections such as FIV in cats, SRLV in sheep and goats or HIV in children. The presence of EIAV capsid in lung epithelial cells suggests that EIAV might be responsible for the broncho-interstitial damages observed. PMID:24289102

Interstitial lung disease associated with Equine Infectious Anemia Virus infection in horses.

PubMed

Bolfa, Pompei; Nolf, Marie; Cadoré, Jean-Luc; Catoi, Cornel; Archer, Fabienne; Dolmazon, Christine; Mornex, Jean-François; Leroux, Caroline

2013-12-01

EIA (Equine Infectious Anemia) is a blood-borne disease primarily transmitted by haematophagous insects or needle punctures. Other routes of transmission have been poorly explored. We evaluated the potential of EIAV (Equine Infectious Anemia Virus) to induce pulmonary lesions in naturally infected equids. Lungs from 77 EIAV seropositive horses have been collected in Romania and France. Three types of lesions have been scored on paraffin-embedded lungs: lymphocyte infiltration, bronchiolar inflammation, and thickness of the alveolar septa. Expression of the p26 EIAV capsid (CA) protein has been evaluated by immunostaining. Compared to EIAV-negative horses, 52% of the EIAV-positive horses displayed a mild inflammation around the bronchioles, 22% had a moderate inflammation with inflammatory cells inside the wall and epithelial bronchiolar hyperplasia and 6.5% had a moderate to severe inflammation, with destruction of the bronchiolar epithelium and accumulation of smooth muscle cells within the pulmonary parenchyma. Changes in the thickness of the alveolar septa were also present. Expression of EIAV capsid has been evidenced in macrophages, endothelial as well as in alveolar and bronchiolar epithelial cells, as determined by their morphology and localization. To summarize, we found lesions of interstitial lung disease similar to that observed during other lentiviral infections such as FIV in cats, SRLV in sheep and goats or HIV in children. The presence of EIAV capsid in lung epithelial cells suggests that EIAV might be responsible for the broncho-interstitial damages observed.

Renalase Protects against Renal Fibrosis by Inhibiting the Activation of the ERK Signaling Pathways

PubMed Central

Wu, Yiru; Wang, Liyan; Deng, Dai; Zhang, Qidong; Liu, Wenhu

2017-01-01

Renal interstitial fibrosis is a common pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease. Renalase, acting as a signaling molecule, has been reported to have cardiovascular and renal protective effects. However, its role in renal fibrosis remains unknown. In this study, we evaluated the therapeutic efficacy of renalase in rats with complete unilateral ureteral obstruction (UUO) and examined the inhibitory effects of renalase on transforming growth factor-β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human proximal renal tubular epithelial (HK-2) cells. We found that in the UUO model, the expression of renalase was markedly downregulated and adenoviral-mediated expression of renalase significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin expression and suppressed expression of α-smooth muscle actin (α-SMA), fibronectin and collagen-I. In vitro, renalase inhibited TGF-β1-mediated upregulation of α-SMA and downregulation of E-cadherin. Increased levels of Phospho-extracellular regulated protein kinases (p-ERK1/2) in TGF-β1-stimulated cells were reversed by renalase cotreatment. When ERK1 was overexpressed, the inhibition of TGF-β1-induced EMT and fibrosis mediated by renalase was attenuated. Our study provides the first evidence that renalase can ameliorate renal interstitial fibrosis by suppression of tubular EMT through inhibition of the ERK pathway. These results suggest that renalase has potential renoprotective effects in renal interstitial fibrosis and may be an effective agent for slowing CKD progression. PMID:28448446

Non-invasive imaging of barriers to drug delivery in tumors.

PubMed

Hassid, Yaron; Eyal, Erez; Margalit, Raanan; Furman-Haran, Edna; Degani, Hadassa

2008-08-01

Solid tumors often develop high interstitial fluid pressure (IFP) as a result of increased water leakage and impaired lymphatic drainage, as well as changes in the extracellular matrix composition and elasticity. This high fluid pressure forms a barrier to drug delivery and hence, resistance to therapy. We have developed techniques based on contrast enhanced magnetic resonance imaging for mapping in tumors the vascular and transport parameters determining the delivery efficiency of blood borne substances. Sequential images are recorded during continuous infusion of a Gd-based contrast agent and analyzed according to a new physiological model, yielding maps of microvascular transfer constants, as well as outward convective interstitial transfer constants and steady state interstitial contrast agent concentrations both reflecting IFP distribution. We further demonstrated in non small cell human lung cancer xenografts the capability of our techniques to monitor in vivo collagenase induced increase in contrast agent delivery as a result of decreased IFP. These techniques can be applied to test drugs that affect angiogenesis and modulate interstitial fluid pressure and has the potential to be extended to cancer patients for assessing resistance to drug delivery.

Non-Invasive Imaging of Barriers to Drug Delivery in Tumors

PubMed Central

Hassid, Yaron; Eyal, Erez; Margalit, Raanan; Furman-Haran, Edna; Degani, Hadassa

2011-01-01

Solid tumors often develop high interstitial fluid pressure (IFP) as a result of increased water leakage and impaired lymphatic drainage, as well as changes in the extracellular matrix composition and elasticity. This high fluid pressure forms a barrier to drug delivery and hence, resistance to therapy. We have developed techniques based on contrast enhanced magnetic resonance imaging for mapping in tumors the vascular and transport parameters determining the delivery efficiency of blood borne substances. Sequential images are recorded during continuous infusion of a Gd-based contrast agent and analyzed according to a new physiological model, yielding maps of microvascular transfer constants, as well as outward convective interstitial transfer constants and steady state interstitial contrast agent concentrations both reflecting IFP distribution. We further demonstrated in non small cell human lung cancer xenografts the capability of our techniques to monitor in vivo collagenase induced increase in contrast agent delivery as a result of decreased IFP. These techniques can be applied to test drugs that affect angiogenesis and modulate interstitial fluid pressure and has the potential to be extended to cancer patients for assessing resistance to drug delivery. PMID:18638494

/sup 125/I interstitial implants in the RIF-1 murine flank tumor: an animal model for brachytherapy

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

Bernstein, M.; Gutin, P.H.; Weaver, D.A.

1982-09-01

The development of a model for interstitial brachytherapy that uses high-activity, removable /sup 125/I sources in the RIF-1 murine flank tumor is reported. Experimental end points are clonogenic cell and tumor regrowth delay assays. For the clonogenic cell assay, interestitial radiation is delivered at total doses of 500-10,000 rad at dose rates of 0.9-2.7 rad/min to cells in annuli of tissue in the tumor. Dose-survival curves are characterized by an initial shoulder followed by a straight (exponential) portion, with D/sub 0/ similar to that of the curve obtained by external irradiation of the RIF-1 tumor in a self-contained cesium irradiatormore » at similar dose rates. Tumor regrowth curves have been obtained for minimum tumor doses of 500-5000 rad; marked tumor regression has been observed with minimum tumor doses as low as 2000 rad, but results are not as reproducible as the results obtained with the clonogenic cell assay.« less

THE LOCALIZATION OF HOMOLGOUS PLASMA PROTEINS IN THE TISSUES OF YOUNG HUMAN BEINGS AS DEMONSTRATED WITH FLUORESCENT ANTIBODIES

PubMed Central

Gitlin, David; Landing, Benjamin H.; Whipple, Ann

1953-01-01

Employing fluorescent antibodies for the detection of homologous plasma proteins in tissue sections, the distribution of plasma albumin, γ-globulin, β-lipoprotein, β1-metal-combining globulin, and fibrinogen has been studied in the tissues of infants and children. Plasma albumin, γ-globulin, and β1-metal-combining globulin were found in many cells and particularly cell nuclei, connective tissues and interstitial spaces, lymphatics, and blood vessels. β-Lipoprotein was found mostly in the nuclei of all cell types while fibrinogen was restricted largely to the lymphatic and vascular channels, connective tissues and the interstitial spaces. The widespread distribution of these plasma proteins in cells and connective tissues indicates the magnitude of the extravascular plasma protein pool which is in equilibrium with circulating plasma. Unfortunately, these results do not permit accurate localization of the sites of production of these plasma proteins, but do give some idea of their intimate relationship to the tissues. PMID:13022871

Mechanisms of leading edge protrusion in interstitial migration

PubMed Central

Wilson, Kerry; Lewalle, Alexandre; Fritzsche, Marco; Thorogate, Richard; Duke, Tom; Charras, Guillaume

2013-01-01

While the molecular and biophysical mechanisms underlying cell protrusion on two-dimensional substrates are well understood, our knowledge of the actin structures driving protrusion in three-dimensional environments is poor, despite relevance to inflammation, development and cancer. Here we report that, during chemotactic migration through microchannels with 5 μm × 5 μm cross-sections, HL60 neutrophil-like cells assemble an actin-rich slab filling the whole channel cross-section at their front. This leading edge comprises two distinct F-actin networks: an adherent network that polymerizes perpendicular to cell-wall interfaces and a ‘free’ network that grows from the free membrane at the cell front. Each network is polymerized by a distinct nucleator and, due to their geometrical arrangement, the networks interact mechanically. On the basis of our experimental data, we propose that, during interstitial migration, medial growth of the adherent network compresses the free network preventing its retrograde movement and enabling new polymerization to be converted into forward protrusion. PMID:24305616

Antithrombotic Therapy in Atrial Fibrillation Associated with Valvular Heart Disease: Executive Summary of a Joint Consensus Document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, Endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

PubMed

Lip, Gregory Y H; Collet, Jean Philippe; de Caterina, Raffaele; Fauchier, Laurent; Lane, Deirdre A; Larsen, Torben B; Marin, Francisco; Morais, Joao; Narasimhan, Calambur; Olshansky, Brian; Pierard, Luc; Potpara, Tatjana; Sarrafzadegan, Nizal; Sliwa, Karen; Varela, Gonzalo; Vilahur, Gemma; Weiss, Thomas; Boriani, Giuseppe; Rocca, Bianca

2017-12-01

Management strategies for patients with atrial fibrillation (AF) in association with valvular heart disease (VHD) have been less informed by randomized trials, which have largely focused on ‘non-valvular AF’ patients. Thromboembolic risk also varies according to valve lesion and may also be associated with CHA2DS2-VASc score risk factor components, rather than only the valve disease being causal. Given the need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD, a task force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group (WG) on Thrombosis, with representation from the ESC WG on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to produce a consensus document on the management of patients with AF and associated VHD, with up-to-date consensus statements for clinical practice for different forms of VHD, based on the principles of evidence-based medicine. This is an executive summary of a consensus document which proposes that the term ‘valvular AF’ is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) categorization in relation to the type of OAC use in patients with AF, as follows: (1) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 1 VHD, which refers to AF patients with ‘VHD needing therapy with a vitamin K antagonist (VKA)’ and (2) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 2 VHD, which refers to AF patients with ‘VHD needing therapy with a VKA or a non-VKA oral anticoagulant also taking into consideration CHA2DS2-VASc score risk factor components.

Association Between Valvular Surgery and Mortality Among Patients With Infective Endocarditis Complicated by Heart Failure

PubMed Central

Kiefer, Todd; Park, Lawrence; Tribouilloy, Christophe; Cortes, Claudia; Casillo, Roberta; Chu, Vivian; Delahaye, Francois; Durante-Mangoni, Emanuele; Edathodu, Jameela; Falces, Carlos; Logar, Mateja; Miró, José M.; Naber, Christophe; Tripodi, Marie Françoise; Murdoch, David R.; Moreillon, Philippe; Utili, Riccardo; Wang, Andrew

2016-01-01

Context Heart failure (HF) is the most common complication of infective endocarditis. However, clinical characteristics of HF in patients with infective endocarditis, use of surgical therapy, and their associations with patient outcome are not well described. Objectives To determine the clinical, echocardiographic, and microbiological variables associated with HF in patients with definite infective endocarditis and to examine variables independently associated with in-hospital and 1-year mortality for patients with infective endocarditis and HF, including the use and association of surgery with outcome. Design, Setting, and Patients The International Collaboration on Endocarditis–Prospective Cohort Study, a prospective, multicenter study enrolling 4166 patients with definite native- or prosthetic-valve infective endocarditis from 61 centers in 28 countries between June 2000 and December 2006. Main Outcome Measures In-hospital and 1-year mortality. Results Of 4075 patients with infective endocarditis and known HF status enrolled, 1359 (33.4% [95% CI, 31.9%–34.8%]) had HF, and 906 (66.7% [95% CI, 64.2%–69.2%]) were classified as having New York Heart Association class III or IV symptom status. Within the subset with HF, 839 (61.7% [95% CI, 59.2%–64.3%]) underwent valvular surgery during the index hospitalization. In-hospital mortality was 29.7% (95% CI, 27.2%–32.1%) for the entire HF cohort, with lower mortality observed in patients undergoing valvular surgery compared with medical therapy alone (20.6% [95% CI, 17.9%–23.4%] vs 44.8% [95% CI, 40.4%–49.0%], respectively; P<.001). One-year mortality was 29.1% (95% CI, 26.0%–32.2%) in patients undergoing valvular surgery vs 58.4% (95% CI, 54.1%–62.6%) in those not undergoing surgery (P<.001). Cox proportional hazards modeling with propensity score adjustment for surgery showed that advanced age, diabetes mellitus, health care–associated infection, causative microorganism (Staphylococcus aureus or fungi), severe HF (New York Heart Association class III or IV), stroke, and paravalvular complications were independently associated with 1-year mortality, whereas valvular surgery during the initial hospitalization was associated with lower mortality. Conclusion In this cohort of patients with infective endocarditis complicated by HF, severity of HF was strongly associated with surgical therapy and subsequent mortality, whereas valvular surgery was associated with lower in-hospital and 1-year mortality. PMID:22110106

Echocardiographic Evidence for Valvular Toxicity of Benfluorex: A Double-Blind Randomised Trial in Patients with Type 2 Diabetes Mellitus

PubMed Central

Derumeaux, Geneviève; Ernande, Laura; Serusclat, André; Servan, Evelyne; Bruckert, Eric; Rousset, Hugues; Senn, Stephen; Van Gaal, Luc; Picandet, Brigitte; Gavini, François; Moulin, Philippe

2012-01-01

Objectives REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. Methods Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA1c. Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. Results At baseline, patients were 59.1±10.5 years old with HbA1c 8.3±0.8%, and DM duration 7.1±6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30±0.80 to 7.77±1.31 versus pioglitazone: from 8.30±0.80 to 7.45±1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. Conclusion After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug. Trial registration www.controlled-trials.com ISRCTN 27354239. isrctn27354239 PMID:22723853

Endothelial necrosis at 1h post-burn predicts progression of tissue injury

PubMed Central

Hirth, Douglas; McClain, Steve A.; Singer, Adam J.; Clark, Richard A.F.

2013-01-01

Burn injury progression has not been well characterized at the cellular level. To define burn injury progression in terms of cell death, histopathologic spatiotemporal relationships of cellular necrosis and apoptosis were investigated in a validated porcine model of vertical burn injury progression. Cell necrosis was identified by High Mobility Group Box 1 protein and apoptosis by Caspase 3a staining of tissue samples taken 1h, 24h and 7 days post-burn. Level of endothelial cell necrosis at 1h was predictive of level of apoptosis at 24h (Pearson's r=0.87) and of level of tissue necrosis at 7 days (Pearson's r=0.87). Furthermore, endothelial cell necrosis was deeper than interstitial cell necrosis at 1h (p<0.001). Endothelial cell necrosis at 1h divided the zone of injury progression (Jackson's zone of stasis) into an upper subzone with necrotic endothelial cells and initially viable adnexal and interstitial cells at 1h that progressed to necrosis by 24h, and a lower zone with initially viable endothelial cells at 1h, but necrosis and apoptosis of all cell types by 24h. Importantly, this spatiotemporal series of events and rapid progression resembles myocardial infarction and stroke, and implicates mechanisms of these injuries, ischemia, ischemia reperfusion, and programmed cell death, in burn progression. PMID:23627744

Lipid Interventions in Aortic Valvular Disease.

PubMed

Choi, Kwang Jin; Tsomidou, Christiana; Lerakis, Stamatios; Madanieh, Raef; Vittorio, Timothy J; Kosmas, Constantine E

2015-10-01

Aortic valve stenosis is the most common valvular disease in the elderly population. Presently, there is increasing evidence that aortic stenosis (AS) is an active process of lipid deposition, inflammation, fibrosis and calcium deposition. The pathogenesis of AS shares many similarities to that of atherosclerosis; therefore, it was hypothesized that certain lipid interventions could prevent or slow the progression of aortic valve stenosis. Despite the early enthusiasm that statins may slow the progression of AS, recent large clinical trials did not consistently demonstrate a decrease in the progression of AS. However, some researchers believe that statins may have a benefit early on in the disease process, where inflammation (and not calcification) is the predominant process, in contrast to severe or advanced AS, where calcification (and not inflammation) predominates. Positron emission tomography using 18F-fluorodeoxyglucose and 18F-sodium fluoride can demonstrate the relative contributions of valvular calcification and inflammation in AS, and thus this method might potentially be useful in providing the answer as to whether lipid interventions at the earlier stages of AS would be more effective in slowing the progression of the disease. Currently, there is a strong interest in recombinant apolipoprotein A-1 Milano and in the development of new pharmacological agents, targeting reduction of lipoprotein (a) levels and possibly reduction of the expression of lipoprotein-associated phospholipase A2, as potential means to slow the progression of aortic valvular stenosis.

Anti-fibrin antibody binding in valvular vegetations and kidney lesions during experimental endocarditis.

PubMed

Yokota, M; Basi, D L; Herzberg, M C; Meyer, M W

2001-01-01

In Streptococcus sanguinis (sanguis) induced experimental endocarditis, we sought evidence that the development of aortic valvular vegetation depends on the availability of fibrin. Endocarditis was induced in New Zealand white rabbits by catheter placement into the left ventricle and inoculation of the bacteria. Fibrin was localized in the developing vegetation with 99mTechnetium (Tc)-labeled anti-fibrin antibody one or three days later. When rabbit anti-fibrin antibody was given intravenously on day 1, the mass of aortic valvular vegetation was significantly reduced at day 3; infusion of non-specific rabbit IgG showed no effect. The 99mTc-labeled anti-fibrin antibody also labeled kidneys that showed macroscopic subcapsular hemorrhage. To learn if the deposition of fibrin in the kidneys was a consequence of endocarditis required a comparison of farm-bred and specific pathogen-free rabbits before and after the induction of endocarditis. Before induction, the kidneys of farm-bred rabbits were labeled, but specific pathogen-free rabbits were free of labeling and signs of macroscopic hemorrhage. After 3 days of endocarditis, kidneys of 10 of 14 specific pathogen-free rabbits labeled with 99mTc-labeled anti-fibrin antibody and showed hemorrhage. Kidney lesions were suggested to be a frequent sequellae of S. sanguinis infective endocarditis. For the first time, fibrin was shown to be required for the continued development of aortic valvular vegetations.

Prediction of aortic valvular area and gradient by noninvasive techniques.

PubMed

Cousins, A L; Eddleman, E E; Reeves, T J

1978-03-01

Sixty-two patients with isolated aortic valvular stenosis were analyzed by a series of common noninvasive procedures and by cardiac catheterization. The data from 50 of these were evaluated in a retrospective fashion by multiple regression methods to determine significant objectively obtained predictors of aortic-left ventricular gradient and valvular area. Formulae were derived from these analyses and an additional 12 patients were then studied prospectively to evaluate the validity of the predictive formulae. Forty-three of 50 patients (86 per cent) were correctly identified as to a gradient of greater or less than 50 mm. Hg in the initial group, and all those in the prospectively studied sample were correctly classified. Thiry-five of 43 patients (82 per cent) of those with valve area data in the first application were correctly classified as to valve area or greater or less than 0.8 cm.2, and all patients in the prospectively studied group were appropriately identified as to the same area. The combined application of the observations of calcification of the aortic valve, shudder waves on the anacrotic limb, prolonged time to peak of the percussion wave and alteration of the dicrotic notch of the carotid pulse tracing, left ventricular hypertrophy by electrocardiogram, and the altered duration of ventricular ejection time were reliable predictors of elevated aortic-left ventricular gradient and decreased aortic valvular size.

Image-guided Interstitial Photodynamic Therapy for Squamous Cell Carcinomas: Preclinical investigation

PubMed Central

Sajisevi, Mirabelle; Rigual, Nestor R; Bellnier, David A.; Seshadri, Mukund

2014-01-01

Objective Photodynamic therapy (PDT) is a clinically approved minimally invasive treatment for cancer. In this preclinical study, using an imaging-guided approach, we examined the potential utility of PDT in the management of bulky squamous cell carcinomas (SCCs). Methods To mimic bulky oropharyngeal cancers seen in the clinical setting, intramuscular SCCs were established in six-to-eight week old female C3H mice. Animals were injected with the photosensitizer, 2-[hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH; 0.4 μmol/kg, i.v.) and tumors were illuminated 24 hours post injection with 665 nm light. PDT as a single treatment modality was administered by surface illumination or by interstitial placement of fibers (iPDT). Magnetic resonance imaging was used to guide treatment and assess tumor response to PDT along with correlative histopathologic assessment. Results Interstitial HPPH-PDT resulted in a marked change on T2 maps 24 hours post treatment compared to untreated controls or transcutaneous illumination. Corresponding apparent diffusion coefficient maps also showed hyperintense areas in tumors following iPDT suggestive of effective photodynamic cell kill. Histologic sections (H&E) confirmed presence of extensive tumor necrosis following iPDT. Conclusions These results highlight the potential utility of PDT in the treatment of bulky oropharyngeal cancers. The findings of our study also demonstrate the utility of MRI as a non-invasive tool for mapping of early tissue response to PDT. PMID:25750858

Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts

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

Chao, Louis Kuoping; Chang, W.-T.; Shih, Y.-W.

2010-04-15

Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulatedmore » kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.« less

Physiological water model development

NASA Technical Reports Server (NTRS)

Doty, Susan

1993-01-01

The water of the human body can be categorized as existing in two main compartments: intracellular water and extracellular water. The intracellular water consists of all the water within the cells and constitutes over half of the total body water. Since red blood cells are surrounded by plasma, and all other cells are surrounded by interstitial fluid, the intracellular compartment has been subdivided to represent these two cell types. The extracellular water, which includes all of the fluid outside of the cells, can be further subdivided into compartments which represent the interstitial fluid, circulating blood plasma, lymph, and transcellular water. The interstitial fluid surrounds cells outside of the vascular system whereas plasma is contained within the blood vessels. Avascular tissues such as dense connective tissue and cartilage contain interstitial water which slowly equilibrates with tracers used to determine extracellular fluid volume. For this reason, additional compartments are sometimes used to represent these avascular tissues. The average size of each compartment, in terms of percent body weight, has been determined for adult males and females. These compartments and the forces which cause flow between them are presented. The kidneys, a main compartment, receive about 25 percent of the cardiac output and filters out a fluid similar to plasma. The composition of this filtered fluid changes as it flows through the kidney tubules since compounds are continually being secreted and reabsorbed. Through this mechanism, the kidneys eliminate wastes while conserving body water, electrolytes, and metabolites. Since sodium accounts for over 90 percent of the cations in the extracellular fluid, and the number of cations is balanced by the number of anions, considering the renal handling sodium and water only should sufficiently describe the relationship between the plasma compartment and kidneys. A kidney function model is presented which has been adapted from a previous model of normal renal function in man. To test the validity of the proposed kidney model, results predicted by the model will be compared to actual data involving injected or ingested fluids and subsequent urine flow rates. Comparison of the model simulation to actual data following the ingestion of 1 liter of water is shown. The model simulation is also shown with actual data following the intravenous infusion of hypertonic saline.

Preventing light-induced degradation in multicrystalline silicon

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

Lindroos, J., E-mail: jeanette.lindroos@aalto.fi; Boulfrad, Y.; Yli-Koski, M.

2014-04-21

Multicrystalline silicon (mc-Si) is currently dominating the silicon solar cell market due to low ingot costs, but its efficiency is limited by transition metals, extended defects, and light-induced degradation (LID). LID is traditionally associated with a boron-oxygen complex, but the origin of the degradation in the top of the commercial mc-Si brick is revealed to be interstitial copper. We demonstrate that both a large negative corona charge and an aluminum oxide thin film with a built-in negative charge decrease the interstitial copper concentration in the bulk, preventing LID in mc-Si.

Preventing light-induced degradation in multicrystalline silicon

NASA Astrophysics Data System (ADS)

Lindroos, J.; Boulfrad, Y.; Yli-Koski, M.; Savin, H.

2014-04-01

Multicrystalline silicon (mc-Si) is currently dominating the silicon solar cell market due to low ingot costs, but its efficiency is limited by transition metals, extended defects, and light-induced degradation (LID). LID is traditionally associated with a boron-oxygen complex, but the origin of the degradation in the top of the commercial mc-Si brick is revealed to be interstitial copper. We demonstrate that both a large negative corona charge and an aluminum oxide thin film with a built-in negative charge decrease the interstitial copper concentration in the bulk, preventing LID in mc-Si.

[Effect of CsA bleomycin-induced interstitial pulmonary disease in mice].

PubMed

Ren, Ying; Yang, Hui; Zhu, Ping; Fan, Chun-mei; Wang, Yan-hong; Li, Jia; Liu, Hui

2012-03-01

To observe the therapeutic effect of cyclosporine A (CsA) on bleomycin (BLM) induced pulmonary fibrosis and to investigate its mechanism. One hundred and twenty C57BL/6 female mice were divided randomly into five groups: BLM model group, control saline group, CsA30 mg treatment group, CsA50 mg treatment group and control treatment group. Treatment groups and model groups were administrated BLM intratracheally to induce interstitial pulmonary disease model, with control saline group administrated with equal volume of normal saline instead. Mice in treatment groups were intraperitoneal injected with CsA, while control treatment group were injected with equal volume of normal saline instead. On the 4th, 7th and 14th day after administration, 8 mice of each group were sacrificed, and the peripheral blood was obtained to count total leucocytes with counting chamber and quantify CD4(+); T cells, CD14(+); monocytes and CD19(+); B cells by flow cytometry (FCM). Bronchoalveolar levage fluid was harvested for cell counting and Giemsa staining. Lung tissues were harvested for immunohistochemical staining and pathological examination. The quantity of total leucocyte was higher in BLM model group than those in control saline group.The proportion of CD14(+); T cells and CD19(+);B cells in BLM model group were increased markedly than those in control saline group on the 4th, 7th and 14th day post BLM. With CsA treatment, The proportion of CD14(+); T cells was lower than BLM model group at the same time point, especially on the 4th day. The proportion of CD19(+); B cells were significantly lower than those of BLM model group at the same time point(7 d, 14 d). The total and classification of cells of BLM model group were increased markedly than those in control saline group, and decreased obviously in the treatment groups at the same time point. Examination of lung tissues: With the prolonged time of BLM administration, it showed wider alveolar septum, more collagen deposition, as well as more infiltrating inflammatory cells which consisted of generous lymphocyte and few mononuclear macrophages than those in saline control group. With the prolonged time of CsA injection, the interstitial pulmonary inflammation was remissive, and there was less fibroblast infiltration and collagen deposition in pulmonary interstitium and periphery of bronchiole. Alveolar epithelial cells, bronchiolar epithelial cells, mononuclear macrophages, neutrophils and lymphocytes were demonstrated to express CD147, there was higher CD147 expression in BLM model group than those in CsA treatment groups. CsA may heal BLM induced interstitial pulmonary disease by blocking CD147-CypA interaction, then decreasing chemotaxis for the immunocyte, and reducing migration of immunocytes to the lung and collagen deposition in the lung.

Luteinizing hormone (LH) blood test

MedlinePlus

ICSH - blood test; Luteinizing hormone - blood test; Interstitial cell stimulating hormone - blood test ... to temporarily stop medicines that may affect the test results. Be sure to tell your provider about ...

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

PubMed Central

Wittmann, Thomas; Frixel, Sabrina; Höppner, Stefanie; Schindlbeck, Ulrike; Schams, Andrea; Kappler, Matthias; Hegermann, Jan; Wrede, Christoph; Liebisch, Gerhard; Vierzig, Anne; Zacharasiewicz, Angela; Kopp, Matthias Volkmar; Poets, Christian F; Baden, Winfried; Hartl, Dominik; van Kaam, Anton H; Lohse, Peter; Aslanidis, Charalampos; Zarbock, Ralf; Griese, Matthias

2016-01-01

The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children’s interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume. PMID:26928390

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease.

PubMed

Naito, Yoshiro; Fujii, Aya; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Masuyama, Tohru

2015-07-01

Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

Prion protein- and cardiac troponin T-marked interstitial cells from the adult myocardium spontaneously develop into beating cardiomyocytes

PubMed Central

Omatsu-Kanbe, Mariko; Nishino, Yuka; Nozuchi, Nozomi; Sugihara, Hiroyuki; Matsuura, Hiroshi

2014-01-01

Atypically-shaped cardiomyocytes (ACMs) constitute a novel subpopulation of beating heart cells found in the cultures of cardiac myocyte-removed crude fraction cells obtained from adult mouse cardiac ventricles. Although ~500 beating ACMs are observed under microscope in the cell cultures obtained from the hearts of either male or female mice, the origin of these cells in cardiac tissue has yet to be elucidated due to the lack of exclusive markers. In the present study, we demonstrate the efficacy of cellular prion protein (PrP) as a surface marker of ACMs. Cells expressing PrP at the plasma membrane in the culture of the crude fraction cells were found to develop into beating ACMs by themselves or fuse with each other to become larger multinuclear beating ACMs. Combining PrP with a cardiac-specific contractile protein cardiac troponin T (cTnT) allowed us to identify native ACMs in the mouse cardiac ventricles as either clustered or solitary cells. PrP- and cTnT-marked cells were also found in the adult, even aged, human cardiac ventricles. These findings suggest that interstitial cells marked by PrP and cTnT, native ACMs, exhibit life-long survival in the cardiac ventricles of both mice and humans. PMID:25466571

Interstitial radiation therapy for carcinoma of the penis using iridium 192 wires: the Henri Mondor experience (1970-1979)

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

Mazeron, J.J.; Langlois, D.; Lobo, P.A.

1984-10-01

From 1970 to 1979, a group of 50 patients was treated for squamous cell carcinoma of the penis by interstitial irradiation using an afterloading technique and iridium 192 wires. The group included 9 patients with T1 tumors, 27 with T2 tumors, and 14 with T3 tumors. Forty-five patients presented with no metastatic inguinal nodes (NO), 3 patients with N1 nodes, and 2 patients had N3 nodes. After treatment, 11 patients (1 T1, 6 T2 and 4 T3) developed local recurrences. Three patients developed post-therapeutic necrosis which necessitated partial amputation in 2 cases. Eight patients developed post-therapeutic urethral stenosis, which requiredmore » surgical treatment in three of the cases. Twenty-one percent of the patients died of their disease. The authors advocate interstitial irradiation using iridium 192 wires for the treatment of non-infiltrating or moderately infiltrating squamous cell carcinoma of the penis in which the largest dimension does no exceed 4 cm. When regular follow-up can be assurred, it is reasonable to forgo prophylactic treatment of the inguinal nodes in patients presenting without groin metastasis.« less

Comparison of P-wave dispersion in healthy dogs, dogs with chronic valvular disease and dogs with disturbances of supraventricular conduction

PubMed Central

2011-01-01

Background P-wave dispersion (Pd) is a new ECG index used in human cardiology and veterinary medicine. It is defined as the difference between the maximum and the minimum P-wave duration recorded from multiple different ECG leads. So far no studies were performed assessing the importance of P-wave dispersion in dogs. Methods The current study was aimed at determining proper value of Pd in healthy dogs (group I), dogs with chronic valvular disease (group II) and dogs with disturbances of supraventricular conduction (group III). The tests were carried out in 53 healthy dogs, 23 dogs with chronic valvular disease and 12 dogs with disturbances of supraventricular conduction of various breeds, sexes and body weight from 1,5 to 80 kg, aged between 0,5 and 17 years, submitted to the ECG examination. ECG was acquired in dogs in a standing position with BTL SD-8 electrocardiographic device and analyzed once the recording was enlarged. P-wave duration was calculated in 9 ECG leads (I, II, III, aVR, aVL, aVF, V1, V2, V4) from 5 cardiac cycles. Results The proper P-wave dispersion in healthy dogs was determined at up to 24 ms. P-wave dispersion was statistically significant increased (p < 0.01) in dogs with chronic valvular disease and dogs with disturbances of supraventricular conduction. In dogs with the atrial enlargement the P-wave dispersion is also higher than in healthy dogs, although no significant correlation between the size of left atria and Pd was noticed (p = 0.1, r = 0,17). Conclusions The P-wave dispersion is a constant index in healthy dogs, that is why it can be used for evaluating P wave change in dogs with chronic valvular disease and in dogs with disturbances of supraventricular conduction. PMID:21396110

[Optimization of postoperative medical therapy of infective endocarditis in patients with congenital valvular heart disease].

PubMed

Chistyakov, I S; Medvedev, A P; Pichugin, V V

2016-01-01

The purpose of this study was to evaluate the effectiveness of combined surgical and medical treatment of infective endocarditis in patients with congenital valvular heart disease when included in a regimen of the drug Reamberin. In this regard, the analysis of the effectiveness of a combination regimen of 74 patients with valvular congenital heart diseases complicated with infective endocarditis. Given the indications for surgical correction operative technique features and possible technical difficulties in carrying out such operations, due to the inflammatory changes and tissue destruction, and ways to overcome them. For the correction of metabolic disorders in the postoperative period, 47 patients (main group) was appointed Reamberin: once, intravenous drip 400 ml/day during the first 5 days after surgery. 27 patients (control group) was conducted infusion therapy depending on the severity of the condition according to the classical scheme. In addition to standard clinical and laboratory examination, to assess the effectiveness of Reamberin was investigated catalase activity of CPK in blood serum in the dynamics of observation (1, 3 and 5 days after surgery). It is revealed that surgical approach, used in complex treatment of patients with valvular congenital heart diseases, including reorganization of the cavities of the heart, increasing the frequency of joints and the use of reinforcing strips of synthetic material that prevents the cutting of sutures through the inflamed tissue has achieved good short-and long-term results. Infective endocarditis and destruction of the valvular annulus fibrosus the use of a frame of strips of polytetrafluoroethylene allows you to restore its integrity and to implant a mechanical prosthesis. The inclusion in the regimen of patients with infective endocarditis complicated by cardiac insufficiency in the early postoperative period the drug Reamberin improves the efficiency of treatment by a more rapid restoration of the normal metabolism of cardiomyocytes and accelerates elimination of signs of heart failure.

Out-of-range INR values and outcomes among new warfarin patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, Chandrasekharrao V; Schein, Jeffrey R

2015-02-01

Although efficacious in stroke prevention in non-valvular atrial fibrillation, many warfarin patients are sub-optimally managed. To evaluate the association of international normalized ratio control and clinical outcomes among new warfarin patients with non-valvular atrial fibrillation. Adult non-valvular atrial fibrillation patients (≥18 years) initiating warfarin treatment were selected from the US Veterans Health Administration dataset between 10/2007 and 9/2012. Valid international normalized ratio values were examined from the warfarin initiation date through the earlier of the first clinical outcome, end of warfarin exposure or death. Each patient contributed multiple in-range and out-of-range time periods. The relative risk ratios of clinical outcomes associated with international normalized ratio control were estimated. 34,346 patients were included for analysis. During the warfarin exposure period, the incidence of events per 100 person-years was highest when patients had international normalized ratio <2:13.66 for acute coronary syndrome; 10.30 for ischemic stroke; 2.93 for transient ischemic attack; 1.81 for systemic embolism; and 4.55 for major bleeding. Poisson regression confirmed that during periods with international normalized ratio <2, patients were at increased risk of developing acute coronary syndrome (relative risk ratio: 7.9; 95 % confidence interval 6.9-9.1), ischemic stroke (relative risk ratio: 7.6; 95 % confidence interval 6.5-8.9), transient ischemic attack (relative risk ratio: 8.2; 95 % confidence interval 6.1-11.2), systemic embolism (relative risk ratio: 6.3; 95 % confidence interval 4.4-8.9) and major bleeding (relative risk ratio: 2.6; 95 % confidence interval 2.2-3.0). During time periods with international normalized ratio >3, patients had significantly increased risk of major bleeding (relative risk ratio: 1.5; 95 % confidence interval 1.2-2.0). In a Veterans Health Administration non-valvular atrial fibrillation population, exposure to out-of-range international normalized ratio values was associated with significantly increased risk of adverse clinical outcomes.

Comparison of P-wave dispersion in healthy dogs, dogs with chronic valvular disease and dogs with disturbances of supraventricular conduction.

PubMed

Noszczyk-Nowak, Agnieszka; Szałas, Anna; Pasławska, Urszula; Nicpoń, Józef

2011-03-11

P-wave dispersion (Pd) is a new ECG index used in human cardiology and veterinary medicine. It is defined as the difference between the maximum and the minimum P-wave duration recorded from multiple different ECG leads. So far no studies were performed assessing the importance of P-wave dispersion in dogs. The current study was aimed at determining proper value of Pd in healthy dogs (group I), dogs with chronic valvular disease (group II) and dogs with disturbances of supraventricular conduction (group III). The tests were carried out in 53 healthy dogs, 23 dogs with chronic valvular disease and 12 dogs with disturbances of supraventricular conduction of various breeds, sexes and body weight from 1,5 to 80 kg, aged between 0,5 and 17 years, submitted to the ECG examination. ECG was acquired in dogs in a standing position with BTL SD-8 electrocardiographic device and analyzed once the recording was enlarged. P-wave duration was calculated in 9 ECG leads (I, II, III, aVR, aVL, aVF, V1, V2, V4) from 5 cardiac cycles. The proper P-wave dispersion in healthy dogs was determined at up to 24 ms. P-wave dispersion was statistically significant increased (p<0.01) in dogs with chronic valvular disease and dogs with disturbances of supraventricular conduction. In dogs with the atrial enlargement the P-wave dispersion is also higher than in healthy dogs, although no significant correlation between the size of left atria and Pd was noticed (p=0.1, r=0,17). The P-wave dispersion is a constant index in healthy dogs, that is why it can be used for evaluating P wave change in dogs with chronic valvular disease and in dogs with disturbances of supraventricular conduction.

[The best of valvular heart disease in 2002].

PubMed

Hanania, G; Acar, C; Michel, P L; Maroni, J P

2003-01-01

For AS, besides a very thorough update by Carabello on their management, new experimental work confirms that the pathophysiology of the condition is closer to atherosclerotic and inflammatory processes than pure degeneration. Moreover this year brings a batch of long term post-operative results, one of which is an important series relating to 2194 bioprostheses followed up for 15 years. The choice of valvular substitute between 60 and 70 years old is the subject for several studies. A series of 259 re-operations for bioprosthesis deterioration allows quantification of the operative risk to which those with this substitute are subjected in case of degeneration. Finally, the strategy to adopt in a patient with an indication for aortocoronary bypass but also with a not-tight AS is discussed (abstention, decalcification, or "preventive" valvular replacement?). For aortic insufficiency (AI) some new results for the Ross operation have been published and the first publications reporting on the attempts of experimental positioning of bioprostheses via the percutaneous route in animals are appearing. As for mitral valvulopathies, MI has carved a privileged place. Much work this year relates amongst other things to functional MI in dilated cardiomyopathies with dilatation of the ring, to the natural history of mitral valvular prolapse detailed in an important series of 833 patients, and to the evolutive risk of atrial fibrillation (AF) with MI and its treatment during plasty or mitral valvular replacement procedures. Anticoagulant treatment for mechanical prostheses is the subject of much work drawn from a large German prospective study (GELIA) confirming the general tendency for alleviation of intensity in aortic especially but also mitral valvulopathies, stressing the advantages of autocontrol. Finally, the Valvulopathy Working Group of the European Society of Cardiology publishes its recommendations for asymptomatic valvulopathies, recalling the echographic criteria of dilatation and left ventricular function to be retained for operative indications, emphasising furthermore the significance of the stress test in the follow up of asymptomatic AS.

[Clinical evaluation of regurgitant blood flow by rapid cine magnetic resonance imaging in patients with valvular heart disease].

PubMed

Onishi, S; Fukui, S; Atsumi, C; Morita, R; Fujii, K; Kusuoka, H; Kitabatake, A; Kamada, T; Takizawa, O

1989-06-01

The clinical usefulness of magnetic resonance imaging (MRI) for evaluating regurgitant blood flow in patients with valvular heart disease was studied. The study subjects comprised three healthy volunteers and nine patients with valvular heart disease (aortic regurgitation 3, mitral regurgitation 2, tricuspid regurgitation 2, and pulmonary regurgitation 2). Five were men and seven were women, ranging in age from 31 to 85 years. Valvular heart disease was diagnosed by two-dimensional Doppler echocardiography. MRI was performed using a 1.5 tesla super-conductive magnet system (MAGNETOM, Siemens AG). A rapid MRI technique (fast low-angle shot [FLASH], flip angle = 30 degrees, TR = 65-90 msec, TE = 10-38 msec) was used to generate 11 frames throughout one cardiac cycle in the transaxial, coronal and oblique planes. These sequential frames were displayed in cine mode on a CRT. 1. Intracavitary blood was imaged as a high signal intensity on gradient echo images, while surrounding cardiac structures had somewhat lower signal intensities. 2. In healthy volunteers, systolic ejection blood flow from the left ventricle was observed on coronal images in the cine mode display. The influx of atrial blood into the left and right ventricles was also clearly observed on transaxial cine images. 3. Aortic regurgitant flow was observed as areas of no signal intensity within the left ventricular cavity during diastole on coronal images. 4. Mitral and tricuspid regurgitations were observed within the left and right atria, respectively, as areas of no signal intensity on transaxial images. The extent of regurgitant flow was determined in the vertical long-axis plane, equivalent to the right anterior oblique projection. 5. The vertical oblique scan was suitable for detecting pulmonary regurgitant flow. These results indicate that the rapid cine MRI technique is a useful tool for noninvasively determining regurgitant blood flow in patients with various valvular heart diseases.

Intermediate-grade mammary gland adenocarcinoma in an 18-year-old female black leopard (Panthera pardus) with acute pancreatic necrosis and chronic interstitial nephropathy.

PubMed

Nakamura, Misato; Yoshida, Toshinori; Eguchi, Ayumi; Inohana, Mari; Nagahara, Rei; Shiraki, Ayako; Ito, Nanao; Shibutani, Makoto

2018-03-02

An 18-year-old female black leopard (Panthera pardus) showed renal failure, leukocytosis and presence of subcutaneous masses in the lower abdominal region and right shoulder; she eventually died. Histopathological observations included a mammary gland carcinoma with comedo, solid and tubulopapillary patterns in subcutaneous tissue, and highly proliferated tumor cells in systemic organs. The tumor cells were positive for cytokeratin AE1/AE3. The mammary gland tumor was diagnosed as intermediate-grade adenocarcinoma, based on a previously reported histological grading system of feline mammary carcinomas. Chronic interstitial nephritis was estimated to have been ongoing for 5 years, whilst acute necrotic pancreatitis in relation to tumor metastasis could have been the cause of death.

Disorders of interstitial cells of Cajal in a neonate with segmental dilatation of the intestine.

PubMed

Okada, Tadao; Sasaki, Fumiaki; Honda, Shohei; Cho, Kazutosi; Matsuno, Yoshihiro; Itoh, Tomoo; Kubota, Kanako C; Todo, Satoru

2010-06-01

Localized myopathy of the muscular layers may be an important factor contributing to segmental dilatation of the intestine (SDI). Only one report has described SDI of the jejunum in a neonate showing no abnormality of the interstitial cells of Cajal (ICC). The present report describes the very rare case of a neonatal girl with segmental dilatation of the distal duodenum and proximal jejunum with irregular arrangements of Auerbach's plexus and ICC and the successful surgical treatment of SDI. We review the literature on this type of relationship between abnormality of ICC and SDI and discuss the clinical features of this complication. Furthermore, the possible neuropathic cause of SDI complicated with disorders of ICC was explored in this report. Copyright 2010 Elsevier Inc. All rights reserved.

Mitral valve-sparing procedures and prosthetic heart valve failure: A case report

PubMed Central

Khan, Nasir A; Butany, Jagdish; Leong, Shaun W; Rao, Vivek; Cusimano, Robert J; Ross, Heather J

2009-01-01

Prosthetic heart valve dysfunction due to thrombus or pannus formation can be a life-threatening complication. The present report describes a 47-year-old woman who developed valvular cardiomyopathy after chorda-sparing mitral valve replacement, and subsequently underwent heart transplantation for progressive heart failure. The explanted mitral valve prosthesis showed significant thrombus and pannus leading to reduced leaflet mobility and valvular stenosis. The present report illustrates the role of the subvalvular apparatus and pannus in prosthesis dysfunction. PMID:19279993

Compositional changes in lipid microdomains of air-blood barrier plasma membranes in pulmonary interstitial edema.

PubMed

Palestini, Paola; Calvi, Chiara; Conforti, Elena; Daffara, Rossella; Botto, Laura; Miserocchi, Giuseppe

2003-10-01

We evaluated in anesthetized rabbits the compositional changes of plasmalemmal lipid microdomains from lung tissue samples after inducing pulmonary interstitial edema (0.5 ml/kg for 3 h, leading to approximately 5% increase in extravascular water). Lipid microdomains (lipid rafts and caveolae) were present in the detergent-resistant fraction (DRF) obtained after discontinuous sucrose density gradient. DRF was enriched in caveolin-1, flotillin, aquaporin-1, GM1, cholesterol, sphingomyelin, and phosphatidylserine, and their contents significantly increased in interstitial edema. The higher DRF content in caveolin, flotillin, and aquaporin-1 and of the ganglioside GM1 suggests an increase both in caveolar domains and in lipid rafts, respectively. Compositional changes could be ascribed to endothelial and epithelial cells that provide most of plasma membrane surface area in the air-blood barrier. Alterations in lipid components in the plasma membrane may reflect rearrangement of floating lipid platforms within the membrane and/or lipid translocation from intracellular stores. Lipid traffic could be stimulated by the marked increase in hydraulic interstitial pressure after initial water accumulation, from approximately -10 to 5 cmH2O, due to the low compliance of the pulmonary tissue, in particular in the basement membranes and in the interfibrillar substance. Compositional changes in lipid microdomains represent a sign of cellular activation and suggest the potential role of mechanotransduction in response to developing interstitial edema.

Cellular origin of fibronectin in interspecies hybrid kidneys

PubMed Central

1984-01-01

The cellular origin of fibronectin in the kidney was studied in three experimental models. Immunohistochemical techniques that use cross- reacting or species-specific antibodies against mouse or chicken fibronectin were employed. In the first model studied, initially avascular mouse kidneys cultured on avian chorioallantoic membranes differentiate into epithelial kidney tubules and become vascularized by chorioallantoic vessels. Subsequently, hybrid glomeruli composed of mouse podocytes and avian endothelial-mesangial cells form. In immunohistochemical studies, cross-reacting antibodies to fibronectin stained vascular walls, tubular basement membranes, interstitium, and glomeruli of mouse kidney grafts. The species-specific antibodies reacting only with mouse fibronectin stained interstitial areas and tubular basement membranes, but showed no reaction with hybrid glomeruli and avian vascular walls. In contrast, species-specific antibodies against chicken fibronectin stained both the interstitial areas and the vascular walls as well as the endothelial-mesangial areas of the hybrid glomeruli, but did not stain the mouse-derived epithelial structures of the kidneys. In the second model, embryonic kidneys cultured under avascular conditions in vitro develop glomerular tufts, which are devoid of endothelial cells. These explants showed fluorescence staining for fibronectin only in tubular basement membranes and in interstitium. The avascular, purely epithelial glomerular bodies remained unstained. Finally, in outgrowths of separated embryonic glomeruli, the cross-reacting fibronectin antibodies revealed two populations of cells: one devoid of fibronectin and another expressing fibronectin in strong fibrillar and granular patterns. These results favor the idea that the main endogenous cellular sources for fibronectin in the embryonic kidney are the interstitial and vascular cells. All experiments presented here suggest that fibronectin is not synthesized by glomerular epithelial cells in vivo. PMID:6389571

Identification and characterization of VEGF and FGF from Hydra.

PubMed

Krishnapati, Lakshmi-Surekha; Ghaskadbi, Surendra

2013-01-01

Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play important roles in the formation of the blood vascular system and in axon guidance, nervous system development and function. Here, we report isolation and characterization of VEGF and FGF homologues from Hydra vulgaris Ind-Pune, a Cnidarian which exhibits an organized nervous system and primitive epithelio-muscular cells. VEGF expression was prominent in the endoderm of the peduncle region and tentacles, as evident from in situ hybridization of whole polyps and its transverse sections. High levels of FGF were detected in the ectoderm of the budding region. The expression of VEGF in endodermal and FGF in interstitial cells was confirmed using sf-1 hydra, a temperature-sensitive mutant strain of Hydra magnipapillata. Tissue-specific expression of VEGF and FGF was confirmed by semi quantitative RT-PCR for ectodermal and endodermal tissues in H. vulgaris Ind-Pune. Treatment with SU5416, a specific inhibitor of the VEGF receptor, did not affect the whole polyp, but did delay both budding and head regeneration, suggesting a possible role of VEGF in nerve cell development, tube formation and/or in branching. FGF expression in the ectoderm of budding region, where the majority of interstitial stem cells reside suggests its role in interstitial stem cell maintenance. Further, activation of canonical Wnt signalling with the glycogen synthase kinase-3β (GSK-3β) inhibitor alsterpaullone caused down-regulation of VEGF and FGF, suggesting an antagonistic relationship between the Wnt and VEGF/FGF pathways. Our results indicate that VEGF and FGF evolved early in evolution, before the development of the blood vascular system, and open up the possibility of elucidating the evolutionarily ancient functions of VEGF and FGF.

[Aortic stenosis and mitral regurgitation complicated by hemolytic anemia and positive Direct Coombs test: a case report].

PubMed

Tamura, Shinjiro; Kitaoka, Hiroaki; Yamasaki, Naohito; Okawa, Makoto; Kubo, Toru; Matsumura, Yoshihisa; Furuno, Takashi; Takata, Jun; Nishinaga, Masanori; Sasaguri, Shiro; Doi, Yoshinori

2005-09-01

A 83-year-old man was admitted because of heart failure due to severe aortic stenosis and mitral regurgitation secondary to chordal rupture of the anterior leaflet. Mild anemia and elevated serum lactate dehydrogenase were present with reticulocytosis and haptoglobinemia. Direct Coombs test was positive. Coexistence of autoimmune hemolytic anemia was identified, but the main cause of his hemolysis was thought to be mechanical hemolysis due to stenotic valve and/or ruptured chordae because of the presence of red cell fragmentation. The patient successfully underwent double valve replacement. Improvement of anemia was coupled with reduction of the serum lactate dehydrogenase level. Valvular shear stress on the red cells and reduction of red cell deformability secondary to autoimmune hemolytic anemia were thought to be responsible for his hemolysis.

Electron Microscopic Observations of the Carotid Body of the Cat

PubMed Central

Ross, Leonard L.

1959-01-01

Carotid bodies were removed from cats, fixed in buffered 1 per cent osmic acid, embedded in deaerated, nitrogenated methacrylate, and cut into thin sections for electron microscopic study. The carotid body is seen to be composed of islands of chemoreceptor and sustentacular cells surrounded by wide irregular sinusoids. These cells are separated from the sinusoids by relatively broad interstitial spaces which are filled with collagen, fibroblasts, and many unmyelinated nerve fibers with their Schwann cell sheaths. The chemoreceptor cells are surrounded by the flattened, multiprocessed sustentacular cells which serve to convey the axons from an interstitial to a pericellular location. These sustentacular cells are assumed to be lemmoblastic in origin. Relatively few axons are seen to abut on the chemoreceptor cells. The cytoplasm of the chemoreceptor cell is characterized by numerous small mitochondria, units of granular endoplasmic reticulum, a small Golgi complex, and a variety of vesicles. There are many small vesicles diffusely scattered throughout the cytoplasm. In addition, there is a small number of dark-cored vesicles of the type which has been previously described in the adrenal medulla. These are usually associated with the Golgi complex. These findings are discussed in relation to the concepts of the origin of the chemoreceptor cell and the nature of the synapse. PMID:14439171

Feasibility of pig and human-derived aortic valve interstitial cells seeding on fixative-free decellularized animal pericardium.

PubMed

Santoro, Rosaria; Consolo, Filippo; Spiccia, Marco; Piola, Marco; Kassem, Samer; Prandi, Francesca; Vinci, Maria Cristina; Forti, Elisa; Polvani, Gianluca; Fiore, Gianfranco Beniamino; Soncini, Monica; Pesce, Maurizio

2016-02-01

Glutaraldehyde-fixed pericardium of animal origin is the elective material for the fabrication of bio-prosthetic valves for surgical replacement of insufficient/stenotic cardiac valves. However, the pericardial tissue employed to this aim undergoes severe calcification due to chronic inflammation resulting from a non-complete immunological compatibility of the animal-derived pericardial tissue resulting from failure to remove animal-derived xeno-antigens. In the mid/long-term, this leads to structural deterioration, mechanical failure, and prosthesis leaflets rupture, with consequent need for re-intervention. In the search for novel procedures to maximize biological compatibility of the pericardial tissue into immunocompetent background, we have recently devised a procedure to decellularize the human pericardium as an alternative to fixation with aldehydes. In the present contribution, we used this procedure to derive sheets of decellularized pig pericardium. The decellularized tissue was first tested for the presence of 1,3 α-galactose (αGal), one of the main xenoantigens involved in prosthetic valve rejection, as well as for mechanical tensile behavior and distensibility, and finally seeded with pig- and human-derived aortic valve interstitial cells. We demonstrate that the decellularization procedure removed the αGAL antigen, maintained the mechanical characteristics of the native pig pericardium, and ensured an efficient surface colonization of the tissue by animal- and human-derived aortic valve interstitial cells. This establishes, for the first time, the feasibility of fixative-free pericardial tissue seeding with valve competent cells for derivation of tissue engineered heart valve leaflets. © 2015 Wiley Periodicals, Inc.

Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis upon Unilateral Ureteral Obstruction

PubMed Central

Allam, Ramanjaneyulu; Ryu, Mi; Clauss, Sebastian; Susanti, Heni Eka; Römmele, Christoph; Garlanda, Cecilia; Mantovani, Alberto; Anders, Hans-Joachim

2011-01-01

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis. PMID:21544241

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

PubMed Central

La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J.; Mecucci, Cristina

2016-01-01

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. PMID:27151989

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.

PubMed

La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J; Mecucci, Cristina

2016-08-01

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. Copyright© Ferrata Storti Foundation.

Assessment of Parylene C Thin Films for Heart Valve Tissue Engineering

PubMed Central

Marei, Isra; Chester, Adrian; Carubelli, Ivan; Prodromakis, Themistoklis; Trantidou, Tatiana

2015-01-01

Background: Scaffolds are a key component of tissue-engineered heart valves (TEHVs). Several approaches had been adopted in the design of scaffolds using both natural and synthetic resources. We have investigated the suitability of parylene C (PC), a vapor deposited polymeric material, for the use as a scaffold in TEHV. Aims: To evaluate the adsorption of extracellular matrix components onto plasma-activated PC and study the biocompatibility of PC by measuring cellular adhesion, viability, apoptosis, and phenotypic expression of valve endothelial and interstitial cells. Finally, the mechanical properties of PC were compared with those of native aortic valve cusp tissue. Methods: PC slides were plasma activated and then coated with gelatin, type I collagen, or fibronectin. Porcine pulmonary valve endothelial and interstitial cells were then grown on plasma oxidized PC with different types of coatings and their adhesion was observed after 20 h of incubation. Cell viability was tested using the MTS assay, and apoptosis was estimated using TUNEL staining. The mechanical properties of PC and valve tissue were measured using a Bose Mechanical Tester. Finally, cell-seeded PC films were exposed to pulsatile pressure and aortic shear stress, respectively, to test their durability in a dynamic environment. Results: Our findings show that collagen and fibronectin could bind to plasma oxidized PC. Both valve endothelial and interstitial cells adhered to protein-coated ECM. PC had a profile of mechanical stiffness and ultimate tensile strength that were comparable with or in excess of those seen in porcine aortic valve cusps. Cells were still attached to PC films after 3 days of exposure to up to 50 mmHg pulsatile pressure or aortic levels of shear stress. Conclusion: PC is a promising candidate for use as a scaffold in tissue engineering heart valves. Additional studies are required to determine both the durability and long-term performance of cell-seeded PC when in a similar hemodynamic environment to that of the aortic valve. PMID:26101808

Radiation-Induce Immune Modulation in Prostate Cancer

DTIC Science & Technology

2005-01-01

Prostate-specific antigen Prostate carcinoma Mammoglobin-A Breast carcinoma Overexpressed Alpha - fetoprotein Hepatocellular carcinoma and yolk-sac tumors...Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor...additional subsets, e.g. Langerhans cells of the epidermis, and dermal or interstitial DC. PDC are the major interferon- alpha (IFNca) producing cells

* A Rat Model for the In Vivo Assessment of Biological and Tissue-Engineered Valvular and Vascular Grafts.

PubMed

Sugimura, Yukiharu; Schmidt, Anna Kathrin; Lichtenberg, Artur; Assmann, Alexander; Akhyari, Payam

2017-12-01

The demand for an improvement of the biocompatibility and durability of vascular and valvular implants requires translational animal models to study the in vivo fate of cardiovascular grafts. In the present article, a review on the development and application of a microsurgical rat model of infrarenal implantation of aortic grafts and aortic valved conduits is provided. By refinement of surgical techniques and inclusion of hemodynamic considerations, a functional model has been created, which provides a modular platform for the in vivo assessment of biological and tissue-engineered grafts. Through optional addition of procalcific diets, disease-inducing agents, and genetic modifications, complex multimorbidity scenarios mimicking the clinical reality in cardiovascular patients can be simulated. Applying this model, crucial aspects of the biocompatibility, biofunctionality and degeneration of vascular and valvular implants in dependency on graft preparation, and modification as well as systemic antidegenerative treatment of the recipient have been and will be addressed.

Inhibition of WISE preserves renal allograft function.

PubMed

Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xupeng; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, Vincent D; Williams, Alexia; Valente, Eliane G; Pretorius, Jim; Stevens, Jennitte L; Tipton, Barbara; Winters, Aaron G; Graham, Kevin; Harriss, Lindsey; Baker, Daniel M; Damore, Michael; Salimi-Moosavi, Hossein; Gao, Yongming; Elkhal, Abdallah; Paszty, Chris; Simonet, W Scott; Richards, William G; Tullius, Stefan G

2013-01-01

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

Role of lipids in the progression of renal disease in systemic lupus erythematosus patients.

PubMed

Luzar, B; Ferluga, D

2000-08-25

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease marked by immune-complex mediated lesions in small blood vessels of various organs, especially the kidneys, although other factors may also be implicated in the pathogenesis of the disease. This article focuses on the role of lipids in the progression of glomerular, vascular and tubulo-interstitial lesions in two patients with lupus nephritis associated with pronounced hyper- and dyslipidemia. The pathogenesis of progressive glomerulosclerosis in both patients appears to be multifactorial. In addition to immune complex mediated lupus glomerulonephritis, progressively active in the first patient, severe nephrotic-range persistent proteinuria, arterial hypertension associated with hyperfiltration and hyperperfusion injuries and, to a minor extent, hyper- and dyslipidemia were observed. Immunological and non-immunological factors were shown to contribute to the development of tubulo-interstitial lesions. In both patients, in addition to local immune deposits, prominent tubulo-interstitial lipid deposits were probably causally related to both hyperlipidemia and the increased permeability of the glomerular filtration barrier. Tubular lesions were highlighted by intracytoplasmic lipid droplets as well as small cleft-like spaces found to be impacted in the tubular lumina. They were seen to penetrate tubular epithelial cells and eventually lodge in the interstitium, surrounded by mononuclear cell infiltrates and foam cells. In both patients, hypertensive angiopathy and extraglomerular vascular immune deposits were demonstrated. In addition, in the second patient, arteriolar and small arterial hyaline was found at the age of 28 years to be full of lipids and calcium precipitates, suggesting a peripheral atherosclerosis-like process which never occurs as a natural age-related condition. In conclusion, all parts of the nephron may be involved in the pathogenetic process causally related or influenced by hyper- or dyslipidemia. Associated either with endothelial cell injury and consequent insudation of lipids in the vascular walls, glomerular filtration barrier injury with hyperfiltration, or tubulo-interstitial lipid deposition, the mechanism of tissue damage by lipids in all parts of the nephron shares similarities with the pathogenesis of systemic atherosclerosis.

Coronary risk stratification of patients undergoing surgery for valvular heart disease.

PubMed

Hasselbalch, Rasmus Bo; Engstrøm, Thomas; Pries-Heje, Mia; Heitmann, Merete; Pedersen, Frants; Schou, Morten; Mickley, Hans; Elming, Hanne; Steffensen, Rolf; Køber, Lars; Iversen, Kasper

2017-01-15

Multislice computed tomography (MSCT) is a non-invasive, less expensive, low-radiation alternative to coronary angiography (CAG) prior to valvular heart surgery. MSCT has a high negative predictive value for coronary artery disease (CAD) but previous studies of patients with valvular disease have shown that MSCT, as the primary evaluation technique, lead to re-evaluation with CAG in about a third of cases and it is therefore not recommended. If a subgroup of patients with low- to intermediate risk of CAD could be identified and examined with MSCT, it could be cost-effective, reduce radiation and the risk of complications associated with CAG. The study cohort was derived from a national registry of patients undergoing CAG prior to valvular heart surgery. Using logistic regression, we identified significant risk factors for CAD and developed a risk score (CT-valve score). The score was validated on a similar cohort of patients from another registry. The study cohort consisted of 2221 patients, 521 (23.5%) had CAD. The validation cohort consisted of 2575 patients, 771 (29.9%) had CAD. The identified risk factors were male sex, age, smoking, hyperlipidemia, hypertension, aortic valve disease, extracardiac arteriopathy, ejection fraction <30% and diabetes mellitus. CT-valve score could identify a third of the population with a risk about 10%. A score based on risk factors of CAD can identify patients that might benefit from using MSCT as a gatekeeper to CAG prior to heart valve surgery. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Whipple's disease endocarditis: report of 5 cases and review of the literature].

PubMed

Aïouaz, H; Célard, M; Puget, M; Vandenesch, F; Mercusot, A; Fenollar, F; Delahaye, F; Obadia, J F; Tebib, J; Rousset, H

2005-10-01

Endocarditic lesions (infectious endocarditis) associated with Whipple's disease are exceptional. We report five cases from the cardiovascular and pneumologic hospital Louis Pradel in Lyon. We have collected all cases of Tropheryma whipplei endocarditis diagnosed between 1995 and 2004. Five men with a mean age of 53 years at time of diagnosis. The symptoms were essentially cardiovascular: murmur, embolism in 3 cases, and heart failure secondary to valvular insufficiency in 2 cases. The valvular involvement, double in 3 cases, was more often aortic. Vegetations were present in all patients and valvular destruction sometimes very important. A low grade fever was present in 4 cases, associated with weight loss in 2 cases. The only extra-cardiac symptoms were arthralgias or arthritis in all cases, considered in 3 patients as seronegative rheumatoid arthritis, B27+ spondylarthritis, and psoriasic arthritis. Their was no other clinical manifestations of Whipple's disease, particularly digestive, ocular, neurologic or adenopathy, and duodenal biopsies secondarily performed in 4 cases were non contributive. This differs from literature as an extra-cardiac location was identified in 11 out of 17 cases. The diagnosis was obtained by histology and PCR on the cardiac valves, as all the patients underwent surgery. The evolution was favourable with a prolonged antibiotic therapy. These report confirms the existence of endocarditic forms of the Whipple's disease, in which the single extra-cardiac manifestation is rheumatologic, and reminds us the usefulness of histology and PCR on the cardiac valves at the time of valvular surgery.

Wavelet packet-based insufficiency murmurs analysis method

NASA Astrophysics Data System (ADS)

Choi, Samjin; Jiang, Zhongwei

2007-12-01

In this paper, the aortic and mitral insufficiency murmurs analysis method using the wavelet packet technique is proposed for classifying the valvular heart defects. Considering the different frequency distributions between the normal sound and insufficiency murmurs in frequency domain, we used two properties such as the relative wavelet energy and the Shannon wavelet entropy which described the energy information and the entropy information at the selected frequency band, respectively. Then, the signal to murmur ratio (SMR) measures which could mean the ratio between the frequency bands for normal heart sounds and for aortic and mitral insufficiency murmurs allocated to 15.62-187.50 Hz and 187.50-703.12 Hz respectively, were employed as a classification manner to identify insufficiency murmurs. The proposed measures were validated by some case studies. The 194 heart sound signals with 48 normal and 146 abnormal sound cases acquired from 6 healthy volunteers and 30 patients were tested. The normal sound signals recorded by applying a self-produced wireless electric stethoscope system to subjects with no history of other heart complications were used. Insufficiency murmurs were grouped into two valvular heart defects such as aortic insufficiency and mitral insufficiency. These murmur subjects included no other coexistent valvular defects. As a result, the proposed insufficiency murmurs detection method showed relatively very high classification efficiency. Therefore, the proposed heart sound classification method based on the wavelet packet was validated for the classification of valvular heart defects, especially insufficiency murmurs.

Expression of the Intermediate Filament Nestin in Gastrointestinal Stromal Tumors and Interstitial Cells of Cajal

PubMed Central

Tsujimura, Tohru; Makiishi-Shimobayashi, Chiaki; Lundkvist, Johan; Lendahl, Urban; Nakasho, Keiji; Sugihara, Ayako; Iwasaki, Teruo; Mano, Masayuki; Yamada, Naoko; Yamashita, Kunihiro; Toyosaka, Akihiro; Terada, Nobuyuki

2001-01-01

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype. PMID:11238030

The role of lead and excess oxygen in uranite

USGS Publications Warehouse

Berman, Robert Morris

1957-01-01

Analysed samples of uraninite were x-rayed, annealed by heating to 550° and 900° for various times in a nitrogen atmosphere, and x-rayed again. A decrease in unit cell size was generally observed. Calculations on the basis of Vegard's Law showed that the ordering of the interstitial oxygen ions could account for the decrease in cell size on annealing. The interstitial oxygens are not necessarily completely disordered before annealing. The degree of original disorder is dependent on the Rare Earth/ThO2 ratio; for high ThO2 and low rare earths, the interstitial oxygens are completely random. The degree of disorder apparently depends solely on the composition, and not on the past history of the sample; this implies that the oxygens are being continuously disordered, perhaps by alpha particles, to the equilibrium point determined by the R.E./ThO2 ratio. The degree of ordering of the interstitial oxygens also accounts for the difference in cell size between vein pitchblendes and those from the sediments of the Colorado Plateau. A study was also made of the degree of oxidation of uraninites. Although the uranium in many pegmatitic uraninites is more oxidized than can be obtained with the cubic UO2 phase in the laboratory, if the atoms proxying for uranium are calculated into the structural formula, and the lead is assumed to be radiogenic and calculated as original uranium, almost all pegmatitic uraninites fall into the range of interstitial oxygen content obtainable in the laboratory. This fact supports the auto-oxidation hypothesis. Many of the vein and sedimentary pitchblendes have compositions close to U3O8, although they are cubic. They may gave crystallized as U3O8, the decomposed to the cubic phase and a amorphous phase. This suggests that the stability range of U3O8 includes only very exceptional natural conditions. Vegard's Law calculations, studies of zoning in crystals, differential leaching, polished section textures, and other lines of evidence indicate that lead, including radiogenic lead, is exsolved from uraninite. A study of x-ray line intensities indicates that it exsolves as oriented monomolecular layers of orthohombic PbO (massicot) along cube planes in the uraninite, separating the uraninite crystallites so that the x-ray reflections interfere destructively to different degrees for different reflections.

Radiation damage to the microvasculature in the rabbit ear chamber. An electron microscope study. [X radiation

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

Yang, V.V.; Stearner, S.P.; Dimitrievich, G.S.

1977-04-01

Cell aggregates in increased numbers appear along blood vessel walls within a few days after local x irradiation of the tissue within rabbit ear chambers. At 7 days after irradiation with 400 or 700 rad of 250 kVp of x rays, electron microscopic studies of the microvasculature were carried out to determine the morphological characteristics of the cell types involved in the aggregates and the relation of these cells to vascular repair. The cell aggregates usually occur in the interstitial region subjacent to the endothelium. The cells that make up the aggregates show morphological characteristics of relatively undifferentiated mesenchymal cells;more » they have an irregularly rounded shape and contain large amounts of rough endoplasmic reticulum, Golgi vesicles, and mitochondria. In a few instances, cells of similar morphology also occur as part of the lining of the blood vessels. The perivascular cell aggregates may originate from the pericyte population or from undifferentiated mesenchymal cells that occur in the interstitial region surrounding blood vessels; it is improbable that they are dedifferentiated smooth muscle cells. It is suggested that the cells that make up these aggregates contribute to the repair of the microvasculation after radiation injury. The radiosensitivity of vascular endothelium reported by previous investigators seems to preclude endothelial proliferation as the principal repair mechanism at higher radiation doses.« less

Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction.

PubMed

Xiao, Xia; Du, Chunyang; Yan, Zhe; Shi, Yonghong; Duan, Huijun; Ren, Yunzhuo

2017-01-01

Inflammation plays a crucial role in renal interstitial fibrosis, the pathway of chronic kidney diseases. Necroptosis is a novel form of regulated cell death, which plays a potential role in inflammation and renal diseases. The small molecule necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. This study was aimed at determining the role of necroptosis, RIP1/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway, in renal inflammation and interstitial fibrosis related to primitive tubulointerstitial injury. It was also aimed at evaluating the effect of Nec-1 in renal fibrosis induced by unilateral ureteral obstruction (UUO). Renal histology, immunohistochemistry, western blot, and real-time polymerase chain reaction were performed using UUO C57BL/6J mice model. Moreover, we tested whether Nec-1 was renal-protective in the interstitial fibrosis kidney. Mice were exposed to UUO and injected intraperitoneal with Nec-1 or vehicle. The levels of RIP1/RIP3/MLKL protein and mRNA were increased in the obstructed kidneys 7 days after UUO; this was accompanied by changes in renal pathological lesions. Renal histological examination showed lesser renal damage in Nec-1-treated UUO mice. Renal inflammation, assessed by tumor necrosis factor-α, interleukin-1β, and monocyte chemotactic protein-1 was markedly attenuated by Nec-1. Furthermore, Nec-1 treatment also significantly reduced TGF-β and α-smooth muscle actin, indicating lesser renal interstitial fibrosis. These findings suggest that the participation of necroptosis in UUO is partly demonstrated. And necroptosis inhibition may have a potential role in the treatment of diseases with increased inflammatory response and interstitial fibrosis in renal. © 2017 S. Karger AG, Basel.

Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators.

PubMed

Wei, Ruihan; Parsons, Sean P; Huizinga, Jan D

2017-03-01

What is the central question of this study? What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns? What is the main finding and its importance? Two-dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns. Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two-dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow-wave-driven contraction patterns in the mouse intestine and pacemaker slow-wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non-propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow-wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Testicular leiomyosarcoma and marked alopecia in a cryptorchid ferret (Mustela putorius furo).

PubMed

Kammeyer, P; Ziege, S; Wellhöner, S; Cichowski, S; Baumgärtner, W

2014-01-01

A 3.5-year-old male ferret, bought as male castrated, was presented to the veterinarian with marked alopecia of back, neck, abdomen and tail, a pronounced sexual behaviour and weight loss. An inguinal mass of about 2.5 cm in diameter was diagnosed as potentially tumorous inguinal testicle by ultrasound and fine-needle aspiration. Adrenal glands and prostate were ultrasonographically unremarkable. The surgically removed cryptorchid testicle contained a greyish tumour that was histologically composed of spindle-shaped cells with elongated nuclei, embedded in a fibro-vascular stroma. Up to two mitotic figures per high power field were noted. Additionally, an interstitial cell hyperplasia and marked reactive proliferation of a collagen-rich fibrous tissue were observed. Tumour cells were positive for α-smooth muscle actin, desmin, and occasionally vimentin and S-100, leading to the diagnosis of an intratesticular leiomyosarcoma. As an adrenal-associated endocrinopathy was excluded and a complete fur recovery was observed after removal of the cryptorchid testicle the alopecia was eventually due to hormones produced by the hyperplastic interstitial (Leydig) cells.

Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.

PubMed

Noguchi, Satoru; Ogawa, Megumu; Malicdan, May Christine; Nonaka, Ikuya; Nishino, Ichizo

2017-02-01

Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1 GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1 GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Involvement of mitochondrial Na+–Ca2+ exchange in intestinal pacemaking activity

PubMed Central

Kim, Byung Joo; Jun, Jae Yeoul; So, Insuk; Kim, Ki Whan

2006-01-01

AIM: Interstitial cells of Cajal (ICCs) are the pacemaker cells that generate slow waves in the gastrointestinal (GI) tract. We have aimed to investigate the involvement of mitochondrial Na+-Ca2+ exchange in intestinal pacemaking activity in cultured interstitial cells of Cajal. METHODS: Enzymatic digestions were used to dissociate ICCs from the small intestine of a mouse. The whole-cell patch-clamp configuration was used to record membrane currents (voltage clamp) and potentials (current clamp) from cultured ICCs. RESULTS: Clonazepam and CGP37157 inhibited the pacemaking activity of ICCs in a dose-dependent manner. Clonazepam from 20 to 60 µmol/L and CGP37157 from 10 to 30 µmol/L effectively inhibited Ca2+ efflux from mitochondria in pacemaking activity of ICCs. The IC50s of clonazepam and CGP37157 were 37.1 and 18.2 µmol/L, respectively. The addition of 20 µmol/L NiCl2 to the internal solution caused a “wax and wane” phenomenon of pacemaking activity of ICCs. CONCLUSION: These results suggest that mitochondrial Na+-Ca2+ exchange has an important role in intestinal pacemaking activity. PMID:16521198

38 CFR 4.115b - Ratings of the genitourinary system-diagnoses.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... 7537Interstitial nephritis: Rate as renal dysfunction. 7538Papillary necrosis: Rate as renal dysfunction. 7539Renal... necrosis: Rate as renal dysfunction. 7541Renal involvement in diabetes mellitus, sickle cell anemia...

38 CFR 4.115b - Ratings of the genitourinary system-diagnoses.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... 7537Interstitial nephritis: Rate as renal dysfunction. 7538Papillary necrosis: Rate as renal dysfunction. 7539Renal... necrosis: Rate as renal dysfunction. 7541Renal involvement in diabetes mellitus, sickle cell anemia...

38 CFR 4.115b - Ratings of the genitourinary system-diagnoses.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... 7537Interstitial nephritis: Rate as renal dysfunction. 7538Papillary necrosis: Rate as renal dysfunction. 7539Renal... necrosis: Rate as renal dysfunction. 7541Renal involvement in diabetes mellitus, sickle cell anemia...

Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient.

PubMed

Azar, Ibrahim; Esfandiarifard, Saghi; Sinai, Pedram; Wazir, Ali; Foulke, Llewellyn; Mehdi, Syed

2017-01-01

Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.

Sudden death of an Indian peafowl (Pavo cristatus) at a zoo due to non-pigmented Serratia marcescens infection

PubMed Central

LEE, Seung-Hun; PARK, Sang-Joon; KWAK, Dongmi; KIM, Kyoo-Tae

2017-01-01

A 16-year-old female Indian peafowl (Pavo cristatus) died two days after recognition of conjunctivitis in the right eye, anorexia and depression. Gross necropsy revealed a thick pseudomembrane under the eyelid and hydropericardium. Histopathological examination revealed hepatocellular necrosis, sinusoidal and vascular congestion and infiltrated inflammatory cells. Infiltration by inflammatory cells was noted in the epicardium. The lungs had mild interstitial pneumonia with the extensive congestion within the capillaries of the air sacs. Tubular interstitial congestion and necrosis was noted in the kidneys. Bacterial culture and nucleotide sequencing of the inflammatory specimens identified the causative agent as Serratia marcescens, an uncommon bacterium in birds. In summary, this study describes the sudden death of an Indian peafowl due to S. marcescens infection, which is rarely seen in animals. PMID:29081475

Mefunidone Attenuates Tubulointerstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

PubMed Central

Liu, Chunyan; Mei, Wenjuan; Tang, Juan; Yuan, Qiongjing; Huang, Ling; Lu, Miaomiao; Wu, Lin; Peng, Zhangzhe; Meng, Jie; Yang, Huixiang; Shen, Hong; Lv, Ben; Hu, Gaoyun; Tao, Lijian

2015-01-01

Background Inflammation has a crucial role in renal interstitial fibrosis, which is the common pathway of chronic kidney diseases. Mefunidone (MFD) is a new compound which could effectively inhibit the proliferation of renal fibroblasts in vitro. However, the overall effect of Mefunidone in renal fibrosis remains unknown. Methods Sprague-Dawley rats were randomly divided intro 6 groups: sham operation, unilateral ureteral obstruction (UUO), UUO/Mefunidone (25, 50, 100mg/kg/day) and UUO/PFD (500mg/kg/day). The rats were sacrificed respectively on days 3, 7, and 14 after the operation. Tubulointerstitial injury index, interstitial collagen deposition, expression of fibronectin (FN), α-smooth muscle actin (α-SMA), type I and III collagen and the number of CD3+ and CD68+ cells were determined. The expressions of proinflammatory cytokines, p-ERK, p-IκB, and p-STAT3 were measured in human renal proximal tubular epithelial cells of HK-2 or macrophages. Results Mefunidone treatment significantly attenuated tubulointerstitial injury, interstitial collagen deposition, expression of FN, α-SMA, type I and III collagen in the obstructive kidneys, which correlated with significantly reduced the number of T cells and macrophages in the obstructive kidneys. Mechanistically, Mefunidone significantly inhibited tumor necrosis factor-α (TNF-α-) or lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. This effect is possibly due to the inhibition of phosphorylation of ERK, IκB, and STAT3. Conclusion Mefunidone treatment attenuated tubulointerstitial fibrosis in a rat model of UUO, at least in part, through inhibition of inflammation. PMID:26042668

Roles of interleukin-9 in the growth and cholecystokinin-induced intracellular calcium signaling of cultured interstitial cells of Cajal.

PubMed

Gong, Yaoyao; Huang, Lei; Cheng, Wenfang; Li, Xueliang; Lu, Jia; Lin, Lin; Si, Xinmin

2014-01-01

Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract and loss of ICC is associated with many GI motility disorders. Previous studies have shown that ICC have the capacity to regenerate or restore, and several growth factors are critical to their growth, maintenance or regeneration. The present study aimed to investigate the roles of interleukin-9 (IL-9) in the growth, maintenance and pacemaker functions of cultured ICC. Here, we report that IL-9 promotes proliferation of ICC, and culturing ICC with IL-9 enhances cholecystokinin-8-induced Ca²⁺ transients, which is probably caused by facilitating maintenance of ICC functions under culture condition. We also show co-localizations of cholecystokinin-1 receptor and IL-9 receptor with c-kit by double-immunohistochemical labeling. In conclusion, IL-9 can promote ICC growth and help maintain ICC functions; IL-9 probably performs its functions via IL-9 receptors on ICC.

Double valvular insufficiency in a Burmese python (Python molurus bivittatus, Linnaeus, 1758) suffering from concomitant bacterial pneumonia.

PubMed

Schilliger, Lionel; Tréhiou-Sechi, Emilie; Petit, Amandine M P; Misbach, Charlotte; Chetboul, Valérie

2010-12-01

Ultrasonography, and, to a lesser extent, echocardiography are now well-established, noninvasive, and painless diagnostic tools in herpetologic medicine. Various cardiac lesions have been previously described in reptiles, but valvulopathy is rarely documented in these animals and, consequently, is poorly understood. In this report, sinoatrial and atrioventricular insufficiencies were diagnosed in a 5-yr-old captive dyspneic Burmese python (Python molurus bivittatus) on the basis of echocardiographic and Doppler examination. This case report is the first to document Doppler assessment of valvular regurgitations in a reptile.

Valvular dysplasia and congestive heart failure in a juvenile African penguin (Spheniscus demersus).

PubMed

McNaughton, Allyson; Frasca, Salvatore; Mishra, Neha; Tuttle, Allison D

2014-12-01

Abstract: An aquarium-housed, 6-mo-old African penguin (Spheniscus demersus) presented with acute respiratory distress. Auscultation revealed a grade II-III systolic murmur in the absence of adventitial sounds, and an enlarged heart without pulmonary edema was seen radiographically. Echocardiographic evaluation revealed atrioventricular (AV) valvular dysplasia and ventricular enlargement. The penguin was treated with enalapril, furosemide, and pimobendan but died within 3 wk of detection of the murmur. Congenital dysplasia of the right AV valve with right atrial and ventricular dilation and ventricular hypertrophy were diagnosed on postmortem examination.

Elevated anticardiolipin antibodies in a patient with vibration-white-finger, valvular heart disease and psoriatic arthritis.

PubMed

McHugh, N J; Elvins, D M; Ring, E F

1993-03-01

We describe a case of irreversible severe vibration-white-finger (VWF) occurring in a male who used a compression-hammer daily at work for a 20-year period. Infra-red thermography following either a cold provocation or a vibratory stress was a sensitive objective method of documenting the condition. Persistent elevation of IgG anticardiolipin antibodies (aCL) was found in his serum and may be a marker of endothelial damage associated with either VWF or the patient's coincidental valvular heart disease.

The role of Cajal cells in chronic prostatitis.

PubMed

Haki Yuksel, Ozgur; Urkmez, Ahmet; Verit, Ayhan

2016-07-04

Types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. Etiopathogenesis of chronic prostatitis is not well defined. Moreover, its treatment outcomes are not satisfactory. Presence of c-kit positive interstitial cells in human prostate is already known. It has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. In the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. Impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. Both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. We think that in this neuromuscular mechanism interstitial Cajal cells have an important role in chronic prostatitis. Our hypothesis is that curability of prostatitis is correlated with the number of Cajal cells not subjected to apoptosis.

Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

PubMed

Schmiedt, C W; Brainard, B M; Hinson, W; Brown, S A; Brown, C A

2016-01-01

The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease. © The Author(s) 2015.

Fluorescein angiography of the bladder: technique and relevance to bladder cancer and interstitial cystitis patients.

PubMed

Zimmern, P E; Laub, D; Leach, G E

1995-07-01

Fluorescein angiography has been used in the study of bleeding vessels, neovascularity, tumors and ischemic tissues in a variety of disorders. This pilot study was designed to evaluate the feasibility, safety and relevance of this interesting technology for the evaluation of bladder wall vessels in patients with interstitial cystitis and bladder cancer. Five patients with National Institutes of Health defined interstitial cystitis symptoms and 10 with bladder cancer were studied during cytoscopy while they were under general anesthesia. A yellow-green barrier filter (520 nm.) was placed over the cystoscope eyepiece and a blue exciter filter (465 nm.) was attached to the light source. Patients received a 5 ml. bolus of 10% fluorescein intravenously. After hydrodistension, glomerulations in interstitial cystitis patients were more prominent with fluorescein angiography and occurred in the venule phase. Areas of papillary transitional cell tumor and carcinoma in situ developed a brilliant yellow-green fluorescence. Adjacent normal urothelium was nonfluorescent and provided a contrasting dark background facilitating the detection of all lesions. No allergic reaction or other adverse effect related to the fluorescein injection was observed. These unique observations in a limited number of patients suggest that fluorescein angiography of the bladder is a safe and simple procedure. This preliminary report underscores the relevance of fluorescein angiography in the detection of bladder tumor and offers a new approach to the evaluation of bladder wall vessels in interstitial cystitis patients.

Characterization of Breast Cancer Interstitial Fluids by TmT Labeling, LTQ-Orbitrap Velos Mass Spectrometry and Pathway Analysis

PubMed Central

Cinzia, Raso; Carlo, Cosentino; Marco, Gaspari; Natalia, Malara; Xuemei, Han; Daniel, McClatchy; Kyu, Park Sung; Maria, Renne; Nuria, Vadalà; Ubaldo, Prati; Giovanni, Cuda; Vincenzo, Mollace; Francesco, Amato; Yates, John R.

2012-01-01

Cancer is currently considered as the end point of numerous genomic and epigenomic mutations and as the result of the interaction of transformed cells within the stromal microenvironment. The present work focuses on breast cancer, one of the most common malignancies affecting the female population in industrialized countries. In this study we perform a proteomic analysis of bioptic samples from human breast cancer, namely interstitial fluids and primary cells, normal vs disease tissues, using Tandem mass Tags (TmT) quantitative mass spectrometry combined with the MudPIT technique. To the best of our knowledge this work, with over 1700 proteins identified, represents the most comprehensive characterization of the breast cancer interstitial fluid proteome to date. Network analysis was used to identify functionally active networks in the breast cancer associated samples. From the list of differentially expressed genes we have retrieved the associated functional interaction networks. Many different signaling pathways were found activated, strongly linked to invasion, metastasis development, proliferation and with a significant cross-talking rate. This pilot study presents evidence that the proposed quantitative proteomic approach can be applied to discriminate between normal and tumoral samples and for the discovery of yet unknown carcinogenesis mechanisms and therapeutic strategies. PMID:22563702

Sphere based fluid systems

NASA Technical Reports Server (NTRS)

Elleman, Daniel D. (Inventor); Wang, Taylor G. (Inventor)

1989-01-01

Systems are described for using multiple closely-packed spheres. In one system for passing fluid, a multiplicity of spheres lie within a container, with all of the spheres having the same outside diameter and with the spheres being closely nested in one another to create multiple interstitial passages of a known size and configuration and smooth walls. The container has an inlet and outlet for passing fluid through the interstitial passages formed between the nested spheres. The small interstitial passages can be used to filter out material, especially biological material such as cells in a fluid, where the cells can be easily destroyed if passed across sharp edges. The outer surface of the spheres can contain a material that absorbs a constitutent in the flowing fluid, such as a particular contamination gas, or can contain a catalyst to chemically react the fluid passing therethrough, the use of multiple small spheres assuring a large area of contact of these surfaces of the spheres with the fluid. In a system for storing and releasing a fluid such as hydrogen as a fuel, the spheres can include a hollow shell containing the fluid to be stored, and located within a compressable container that can be compressed to break the shells and release the stored fluid.

A role for MCP-1/CCR2 in interstitial lung disease in children

PubMed Central

Hartl, Dominik; Griese, Matthias; Nicolai, Thomas; Zissel, Gernot; Prell, Christine; Reinhardt, Dietrich; Schendel, Dolores J; Krauss-Etschmann, Susanne

2005-01-01

Background Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+ T cells accumulate in pediatric ILD and are related to disease severity. Methods Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+ and CXCR3+ T cells were quantified by flow-cytometry. Results CCR2+ T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+ T cells in bronchoalveolar lavage fluid compared to non-fibrotic children. Conclusion The results indicate that pulmonary CCR2+ T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies. PMID:16095529

Maturation State and Matrix Microstructure Regulate Interstitial Cell Migration in Dense Connective Tissues.

PubMed

Qu, Feini; Li, Qing; Wang, Xiao; Cao, Xuan; Zgonis, Miltiadis H; Esterhai, John L; Shenoy, Vivek B; Han, Lin; Mauck, Robert L

2018-02-19

Few regenerative approaches exist for the treatment of injuries to adult dense connective tissues. Compared to fetal tissues, adult connective tissues are hypocellular and show limited healing after injury. We hypothesized that robust repair can occur in fetal tissues with an immature extracellular matrix (ECM) that is conducive to cell migration, and that this process fails in adults due to the biophysical barriers imposed by the mature ECM. Using the knee meniscus as a platform, we evaluated the evolving micromechanics and microstructure of fetal and adult tissues, and interrogated the interstitial migratory capacity of adult meniscal cells through fetal and adult tissue microenvironments with or without partial enzymatic digestion. To integrate our findings, a computational model was implemented to determine how changing biophysical parameters impact cell migration through these dense networks. Our results show that the micromechanics and microstructure of the adult meniscus ECM sterically hinder cell mobility, and that modulation of these ECM attributes via an exogenous matrix-degrading enzyme permits migration through this otherwise impenetrable network. By addressing the inherent limitations to repair imposed by the mature ECM, these studies may define new clinical strategies to promote repair of damaged dense connective tissues in adults.

Spleen and Lymphatic System (For Parents)

MedlinePlus

... they have many tiny openings that allow gases, water, and nutrients to pass through to the surrounding cells, nourishing them and taking away waste products. When lymph fluid leaks through in this way it is called interstitial ...

Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment.

PubMed

Hockemeyer, K; Janetopoulos, C; Terekhov, A; Hofmeister, W; Vilgelm, A; Costa, Lino; Wikswo, J P; Richmond, A

2014-07-01

Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-μm channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the "single file" pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12.

Post-embryonic larval development and metamorphosis of the hydroid Eudendrium racemosum (Cavolini) (Hydrozoa, Cnidaria)

NASA Astrophysics Data System (ADS)

Sommer, C.

1990-09-01

The morphology and histology of the planula larva of Eudendrium racemosum (Cavolini) and its metamorphosis into the primary polyp are described from light microscopic observations. The planula hatches as a differentiated gastrula. During the lecithotrophic larval period, large ectodermal mucous cells, embedded between epitheliomuscular cells, secrete a sticky slime. Two granulated cell types occur in the ectoderm that are interpreted as secretory and sensorynervous cells, but might also be representatives of only one cell type with a multiple function. The entoderm consists of yolk-storing gastrodermal cells, digestive gland cells, interstitial cells, cnidoblasts, and premature cnidocytes. The larva starts metamorphosis by affixing its blunt aboral pole to a substratum. While the planula flattens down, the mucous cells penetrate the mesolamella and migrate through the entoderm into the gastral cavity where they are lysed. Subsequently, interstitial cells, cnidoblasts, and premature cnidocytes migrate in the opposite direction, i.e. from entoderm to ectoderm. Then, the polypoid body organization, comprising head (hydranth), stem and foot, all covered by peridermal secretion, becomes recognisable. An oral constriction divides the hypostomal portion of the gastral cavity from the stomachic portion. Within the hypostomal entoderm, cells containing secretory granules differentiate. Following growth and the multiplication of tentacles, the head periderm disappears. A ring of gland cells differentiates at the hydranth's base. The positioning of cnidae in the tentacle ectoderm, penetration of the mouth opening and the multiplication of digestive gland cells enable the polyp to change from lecithotrophic to planktotrophic nutrition.

Role of Semaphorin 7a signaling in TGF-β1 induced lung fibrosis and scleroderma-related interstitial lung disease

PubMed Central

Gan, Ye; Reilkoff, Ronald; Peng, Xueyan; Russell, Thomas; Chen, Qingsheng; Mathai, Susan K.; Homer, Robert; Gulati, Mridu; Siner, Jonathan; Elias, Jack; Bucala, Richard; Herzog, Erica

2012-01-01

Objective Semaphorin (Sema) 7a regulates TGF- β1 induced fibrosis. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGF- β1 gene is overexpressed in the lung, we tested the hypothesis that Sema-7a exerts its pro-fibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes. Methods Fibrosis and fibrocytes were evaluated in TGF- β1 transgenic mice in which the Sema-7a locus had been disrupted. The effect of replacement or deletion of Sema-7a on bone marrow derived cells was ascertained using bone marrow transplantation. The role of the Sema-7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGF-β1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease. Results The appearance of fibrocytes in the lungs in TGF- β1 transgenic mice requires Sema-7a. Replacement of Sema-7a in bone marrow derived cells restores lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduces pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells from patients with scleroderma-related interstitial lung disease show increased mRNA for Sema-7a and the β1 integrin, with Sema-7a located on collagen producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth is enhanced in these patients. Stimulation of normal human peripheral blood mononuclear cells with recombinant Sema-7a enhances fibrocyte differentiation; these effects are attenuated by β1 integrin neutralization. Conclusion Interventions that reduce Sema-7a expression or prevent the Sema-7a - β1 integrin interaction may be ameliorative in TGF- β1-driven or fibrocyte-associated autoimmune fibroses. PMID:21484765

Cytokine expression in patients with bladder pain syndrome/interstitial cystitis ESSIC type 3C.

PubMed

Logadottir, Yr; Delbro, Dick; Fall, Magnus; Gjertsson, Inger; Jirholt, Pernilla; Lindholm, Catharina; Peeker, Ralph

2014-11-01

Bladder wall nitric oxide production in patients with bladder pain syndrome type 3C is increased compared to undetectable nitric oxide in patients with nonHunner bladder pain syndrome and healthy controls. However, the underlying mechanism/s of the increased nitric oxide production is largely unknown. We compared mRNA expression of a select group of cytokines in patients with bladder pain syndrome/interstitial cystitis type 3C and in pain-free controls. Cold cup biopsies from 7 patients with bladder pain syndrome type 3C and 6 healthy subjects were analyzed. mRNA expression of IL-4, 6, 10 and 17A, iNOS, TNF-α, TGF-β and IFN-γ was estimated by real-time polymerase chain reaction. IL-17 protein expression was determined by immunohistochemistry. Mast cells were labeled with tryptase to evaluate cell appearance and count. IL-6, 10 and 17A, and iNOS mRNA levels as well as the number of mast cells infiltrating the bladder mucosa were significantly increased in patients with bladder pain syndrome type 3C compared to healthy controls. TNF-α, TGF-β and IFN-γ mRNA levels were similar in patients and controls. IL-17A expression at the protein level was up-regulated and localized to inflammatory cells and urothelium in patients with bladder pain syndrome type 3C. Patients with bladder pain syndrome/interstitial cystitis had increased mRNA levels of IL-17A, 10 and 6, and iNOS. IL-17A might be important in the inflammatory process. To our knowledge the increase in IL-17A is a novel finding that may have new treatment implications. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis

PubMed Central

Kullmann, F. Aura; McDonnell, Bronagh M.; Wolf-Johnston, Amanda S.; Lynn, Andrew M.; Getchell, Samuel E.; Ruiz, Wily G.; Zabbarova, Irina V.; Ikeda, Youko; Kanai, Anthony J.; Roppolo, James R.; Bastacky, Sheldon I.; Apodaca, Gerard; Buffington, C. A. Tony; Birder, Lori A.

2018-01-01

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC) reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP) of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX)-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunn’s nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons), in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a “sensory network” and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans with this syndrome. PMID:29706873

Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

PubMed

Welter, Michael; Rieger, Heiko

2013-01-01

Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells.

CARDIAC SURGERY FOR VALVULAR HEART DISEASE AT A REFERRAL HOSPITAL IN ETHIOPIA: A REVIEW OF CASES OPERATED IN THE LAST 30 YEARS.

PubMed

Guteta, Senbeta; Yadeta, Dejuma; Azazh, Aklilu; Mekonnen, Dufera

2016-04-01

Valvular heart disease has been a significant cause of heart disease worldwide. In Ethiopia, it particularly affects young individuals and constitutes the major cause of cardiovascular disease. Factors associated with choice of treatment for advanced valvular heart disease are variable. The objective of this study is to review surgery done for Ethiopian patients with valvular heart disease. We analyzed data on patients who had valve surgery and follow-up at the Tikur Anbessa Specialized Hospital cardiology unit. We collected data on sociodemographic characteristics, the pre-operative status of effected valves and co-morbidities, and assessed their associations with patient management options. A total of 157 valve surgeries were done from 1983 to 2013. Mean age at time of surgery was 26.7 years and females constituted 66% of the cases. Patients with rheumatic heart disease were younger, more likely to be female and have atrial fibrillation, but less likely to have impaired left ventricular systolic function when compared to patients with non-rheumatic heart disease. More than 75% of the surgical procedures done were mechanical valve replacement. Mechanical valves, compared with bioprosthetic valves, were more likely to be used in patients with rheumatic heart disease. The median age of those receiving mechanical valves, 24 (IQR 22-28) years, was lower than those receiving bioprosthetic valves, 31.5 (IQR 29.9-37.9) years. Mechanical valve replacement was significantly higher in those under the age of 20 years (Adjusted Odds Ratio 41.0, 95% CI: 3.0-557.2) and in those between 20 and 29 years of age (Adjusted Odds Ratio 14.3, 95% CI: 2.3-88.6). Valve surgery for valvular heart diseases has been more common performed for young and female patients. A great majority of the replacements done have been with mechanical valves. As many of the patients have been younger and female, the choice of valve surgery and the need for anticoagulation impacts subsequent management of rheumatic heart disease and associated morbidities, lifestyle plans and pregnancy.

Dynamic heart phantom with functional mitral and aortic valves

NASA Astrophysics Data System (ADS)

Vannelli, Claire; Moore, John; McLeod, Jonathan; Ceh, Dennis; Peters, Terry

2015-03-01

Cardiac valvular stenosis, prolapse and regurgitation are increasingly common conditions, particularly in an elderly population with limited potential for on-pump cardiac surgery. NeoChord©, MitraClipand numerous stent-based transcatheter aortic valve implantation (TAVI) devices provide an alternative to intrusive cardiac operations; performed while the heart is beating, these procedures require surgeons and cardiologists to learn new image-guidance based techniques. Developing these visual aids and protocols is a challenging task that benefits from sophisticated simulators. Existing models lack features needed to simulate off-pump valvular procedures: functional, dynamic valves, apical and vascular access, and user flexibility for different activation patterns such as variable heart rates and rapid pacing. We present a left ventricle phantom with these characteristics. The phantom can be used to simulate valvular repair and replacement procedures with magnetic tracking, augmented reality, fluoroscopy and ultrasound guidance. This tool serves as a platform to develop image-guidance and image processing techniques required for a range of minimally invasive cardiac interventions. The phantom mimics in vivo mitral and aortic valve motion, permitting realistic ultrasound images of these components to be acquired. It also has a physiological realistic left ventricular ejection fraction of 50%. Given its realistic imaging properties and non-biodegradable composition—silicone for tissue, water for blood—the system promises to reduce the number of animal trials required to develop image guidance applications for valvular repair and replacement. The phantom has been used in validation studies for both TAVI image-guidance techniques1, and image-based mitral valve tracking algorithms2.

Computational prediction of the effects of the intra-aortic balloon pump on heart failure with valvular regurgitation using a 3D cardiac electromechanical model.

PubMed

Kim, Chang-Hyun; Song, Kwang-Soup; Trayanova, Natalia A; Lim, Ki Moo

2018-05-01

Intra-aortic balloon pump (IABP) is normally contraindicated in significant aortic regurgitation (AR). It causes and aggravates pre-existing AR while performing well in the event of mitral regurgitation (MR). Indirect parameters, such as the mean systolic pressure, product of heart rate and peak systolic pressure, and pressure-volume are used to quantify the effect of IABP on ventricular workload. However, to date, no studies have directly quantified the reduction in workload with IABP. The goal of this study is to examine the effect of IABP therapy on ventricular mechanics under valvular insufficiency by using a computational model of the heart. For this purpose, the 3D electromechanical model of the failing ventricles used in previous studies was coupled with a lumped parameter model of valvular regurgitation and the IABP-treated vascular system. The IABP therapy was disturbed in terms of reducing the myocardial tension generation and contractile ATP consumption by valvular regurgitation, particularly in the AR condition. The IABP worsened the problem of ventricular expansion induced as a result of the regurgitated blood volume during the diastole under the AR condition. The IABP reduced the LV stroke work in the AR, MR, and no regurgitation conditions. Therefore, the IABP helped the ventricle to pump blood and reduced the ventricular workload. In conclusion, the IABP partially performed its role in the MR condition. However, it was disturbed by the AR and worsened the cardiovascular responses that followed the AR. Therefore, this study computationally proved the reason for the clinical contraindication of IABP in AR patients.

[Valvular heart disease associated with coronary artery disease].

PubMed

Yildirir, Aylin

2009-07-01

Nowadays, age-related degenerative etiologies have largely replaced the rheumatic ones and as a natural result of this etiologic change, coronary artery disease has become associated with valvular heart disease to a greater extent. Degenerative aortic valve disease has an important pathophysiological similarity to atherosclerosis and is the leader in this association. There is a general consensus that severely stenotic aortic valve should be replaced during bypass surgery for severe coronary artery disease. For moderate degree aortic stenosis, aortic valve replacement is usually performed during coronary bypass surgery. Ischemic mitral regurgitation has recently received great attention from both diagnostic and therapeutic points of view. Ischemic mitral regurgitation significantly alters the prognosis of the patient with coronary artery disease. Severe ischemic mitral regurgitation should be corrected during coronary bypass surgery and mitral valve repair should be preferred to valve replacement. For moderate degree ischemic mitral regurgitation, many authors prefer valve surgery with coronary bypass surgery. In this review, the main characteristics of patients with coronary artery disease accompanying valvular heart disease and the therapeutic options based on individual valve pathology are discussed.

Novel anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Jalota, A; Scarabelli, T M; Saravolatz, L; Bakhsh, M U; Agrawal, P; Jalota, R; Chen-Scarabelli, C; Fuster, V; Halperin, J

2014-06-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

Mast cells in airway diseases and interstitial lung disease.

PubMed

Cruse, Glenn; Bradding, Peter

2016-05-05

Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease. Published by Elsevier B.V.

Serosurvey for the Prevalence of Brucella Canis Antibodies in Dogs in Central Ohio

DTIC Science & Technology

1983-01-01

negative urease production ...................... positive indol production ....................... negative1 0 ,58 ,6 2 citrate utilization...retained its spermatogenic ability. The epididymides had ac- cumulations of lymphocytes in the interstitial cell layers ranging from a few cells to large...There was diffuse in- filtration of plasma cells between the inner plexiform layer and the nerve fiber layer of the retina. Some serous exudate and a few

[Cellular mechanism of the generation of spontaneous activity in gastric muscle].

PubMed

Nakamura, Eri; Kito, Yoshihiko; Fukuta, Hiroyasu; Yanai, Yoshimasa; Hashitani, Hikaru; Yamamoto, Yoshimichi; Suzuki, Hikaru

2004-03-01

In gastric smooth muscles, interstitial cells of Cajal (ICC) might be the pacemaker cells of spontaneous activities since ICC are rich in mitochondria and are connected with smooth muscle cells via gap junctions. Several types of ICC are distributed widely in the stomach wall. A group of ICC distributed in the myenteric layer (ICC-MY) were the pacemaker cells of gastrointestinal smooth muscles. Pacemaker potentials were generated in ICC-MY, and the potentials were conducted to circular smooth muscles to trigger slow waves and also conducted to longitudinal muscles to form follower potentials. In circular muscle preparations, interstitial cells distributed within muscle bundles (ICC-IM) produced unitary potentials, which were conducted to circular muscles to form slow potentials by summation. In mutant mice lacking inositol trisphosphate (IP(3)) receptor, slow waves were absent in gastric smooth muscles. The generation of spontaneous activity was impaired by the inhibition of Ca(2+)-release from internal stores through IP(3) receptors, inhibition of mitochondrial Ca(2+)-handling with proton pump inhibitors, and inhibition of ATP-sensitive K(+)-channels at the mitochondrial inner membrane. These results suggested that mitochondrial Ca(2+)-handling causes the generation of spontaneous activity in pacemaker cells. Possible involvement of protein kinase C (PKC) in the Ca(2+) signaling system was also suggested.

FoxO and Stress Responses in the Cnidarian Hydra vulgaris

PubMed Central

Bridge, Diane; Theofiles, Alexander G.; Holler, Rebecca L.; Marcinkevicius, Emily; Steele, Robert E.; Martínez, Daniel E.

2010-01-01

Background In the face of changing environmental conditions, the mechanisms underlying stress responses in diverse organisms are of increasing interest. In vertebrates, Drosophila, and Caenorhabditis elegans, FoxO transcription factors mediate cellular responses to stress, including oxidative stress and dietary restriction. Although FoxO genes have been identified in early-arising animal lineages including sponges and cnidarians, little is known about their roles in these organisms. Methods/Principal Findings We have examined the regulation of FoxO activity in members of the well-studied cnidarian genus Hydra. We find that Hydra FoxO is expressed at high levels in cells of the interstitial lineage, a cell lineage that includes multipotent stem cells that give rise to neurons, stinging cells, secretory cells and gametes. Using transgenic Hydra that express a FoxO-GFP fusion protein in cells of the interstitial lineage, we have determined that heat shock causes localization of the fusion protein to the nucleus. Our results also provide evidence that, as in bilaterian animals, Hydra FoxO activity is regulated by both Akt and JNK kinases. Conclusions These findings imply that basic mechanisms of FoxO regulation arose before the evolution of bilaterians and raise the possibility that FoxO is involved in stress responses of other cnidarian species, including corals. PMID:20657733

FoxO and stress responses in the cnidarian Hydra vulgaris.

PubMed

Bridge, Diane; Theofiles, Alexander G; Holler, Rebecca L; Marcinkevicius, Emily; Steele, Robert E; Martínez, Daniel E

2010-07-21

In the face of changing environmental conditions, the mechanisms underlying stress responses in diverse organisms are of increasing interest. In vertebrates, Drosophila, and Caenorhabditis elegans, FoxO transcription factors mediate cellular responses to stress, including oxidative stress and dietary restriction. Although FoxO genes have been identified in early-arising animal lineages including sponges and cnidarians, little is known about their roles in these organisms. We have examined the regulation of FoxO activity in members of the well-studied cnidarian genus Hydra. We find that Hydra FoxO is expressed at high levels in cells of the interstitial lineage, a cell lineage that includes multipotent stem cells that give rise to neurons, stinging cells, secretory cells and gametes. Using transgenic Hydra that express a FoxO-GFP fusion protein in cells of the interstitial lineage, we have determined that heat shock causes localization of the fusion protein to the nucleus. Our results also provide evidence that, as in bilaterian animals, Hydra FoxO activity is regulated by both Akt and JNK kinases. These findings imply that basic mechanisms of FoxO regulation arose before the evolution of bilaterians and raise the possibility that FoxO is involved in stress responses of other cnidarian species, including corals.

Fluid Mechanics, Arterial Disease, and Gene Expression.

PubMed

Tarbell, John M; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong

2014-01-01

This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow-induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial) cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid me chanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs.

Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition.

PubMed

Butcher, Jonathan T; McQuinn, Tim C; Sedmera, David; Turner, Debi; Markwald, Roger R

2007-05-25

Endocardial cushions are critical to maintain unidirectional blood flow under constantly increasing hemodynamic forces, but the interrelationship between endocardial cushion structure and the mechanics of atrioventricular junction function is poorly understood. Atrioventricular (AV) canal motions and blood velocities of embryonic chicks at Hamburger and Hamilton (HH) stages 17, 21, and 25 were quantified using ultrasonography. Similar to the embryonic zebrafish heart, the HH17 AV segment functions like a suction pump, with the cushions expanding in a wave during peak myocardial contraction and becoming undetectable during the relaxation phase. By HH25, the AV canal contributes almost nothing to the piston-like propulsion of blood, but the cushions function as stoppers apposing blood flow with near constant thickness. Using a custom built mesomechanical testing system, we quantified the nonlinear pseudoelastic biomechanics of developing AV cushions, and found that both AV cushions increased in effective modulus between HH17 and HH25. Enzymatic digestion of major structural constituent collagens or glycosaminoglycans resulted in distinctly different stress-strain curves suggestive of their individual contributions. Mixture theory using histologically determined volume fractions of cells, collagen, and glycosaminoglycans showed good prediction of cushion material properties regardless of stage and cushion position. These results have important implications in valvular development, as biomechanics may play a larger role in stimulating valvulogenic events than previously thought.

Anesthetic Considerations for Transcatheter Pulmonary Valve Replacement.

PubMed

Gregory, Stephen H; Zoller, Jonathan K; Shahanavaz, Shabana; Chilson, Kelly L; Ridley, Clare H

2018-02-01

The introduction of transcatheter therapy for valvular heart disease has revolutionized the care of patients with valvular disorders. Pathologic regurgitation or stenosis of the pulmonary valve, right ventricular outflow tract, or a right ventricle-to-pulmonary artery conduit represent emerging indications for transcatheter therapy. To date, minimal literature exists detailing the anesthetic management of patients undergoing transcatheter pulmonary valve replacement. In this review, the pathophysiology and indications for transcatheter pulmonary valve replacement and possible complications unique to this procedure are reviewed. Anesthetic management, including preoperative assessment, intraoperative considerations, and early postoperative monitoring, are discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Successful treatment of a congenital pulmonic valvular stenosis in a snow leopard (Uncia uncia) by percutaneous balloon valvuloplasty.

PubMed

Chai, Norin; Behr, Luc; Chetboul, Valérie; Pouchelon, Jean Louis; Wedlarski, Rudy; Tréhiou-Sechi, Emilie; Gouni, Vassiliki; Misbach, Charlotte; Petit, Amandine M P; Bourgeois, Aude; Hazan, Thierry; Borenstein, Nicolas

2010-12-01

A 3-yr-old intact female snow leopard (Uncia uncia) was evaluated for progressive apathy, lethargy, and decreased appetite. Cardiac auscultation revealed a left basal grade IV/VI systolic ejection murmur, and an echocardiogram confirmed a severe pulmonic valvular stenosis (pressure gradient of 98 mm Hg). The lesion was managed by balloon valvuloplasty, resulting in a marked pressure gradient reduction (30 mm Hg). The cat recovered well, and clinical signs resolved. This is the first description of a pulmonary valve stenosis and management with balloon valvuloplasty in a wild felid.

[Assessment of Tricuspid Insufficiency and the Function of Right Ventricle Using Cardiac Magnetic Resonance Imaging Combined with Echocardiography].

PubMed

Chen, Hui; Zhao, Yanling; Yu, Jianqun

2015-08-01

Right-sided cardiac valvular diseases have traditionally been considered less important than disease of mitral or aortic valve. However, severe tricuspid regurgitation could lead to right ventricle dysfunction and reduce patients' survival rate. In clinic setting, tricuspid valve disease should be paid more attention for patients with secondary tricuspid regurgitation caused by left-sided valvular surgery combined with irreversible annular dilatation increasing the risk of reoperation. In this review, we summarize the epidemiology, anatomy, pathology, diagnosis, ultrasound and cardiac magnetic resonance imaging findings in patients with tricuspid regurgitation.

[Familial occurrence of acquired heart valve defect].

PubMed

Schieche, M

1975-09-15

A report is given on a family examination, issuing from 213 persons with an acquired valvular defect for the establishment of further cases on altogether 783 relations of the direct line. In 19 families other 21 patients with an acquired valvular defect were found; this corresponds to a share of 2.7 % of the relations examined and 8.1% of the families affected, respectively. The result repays the expenditure and, apart from this, leads to an essential furthering of the confidence between physician, patient and family as the smallest social unity for prophylaxis, diagnostics, therapy and metaphylaxis of chronic diseases.

Framework 'interstitial' oxygen in La(10)(GeO(4))(5-)(GeO(5))O(2) apatite electrolyte.

PubMed

Pramana, Stevin S; Klooster, Wim T; White, T J

2007-08-01

Oxygen conduction at low temperatures in apatites make these materials potentially useful as electrolytes in solid-oxide fuel cells, but our understanding of the defect structures enabling ion migration is incomplete. While conduction along [001] channels is dominant, considerable inter-tunnel mobility has been recognized. Using neutron powder diffraction of stoichiometric 'La(10)(GeO(4))(6)O(3)', it has been shown that this compound is more correctly described as an La(10)(GeO(4))(5-)(GeO(5))O(2) apatite, in which high concentrations of interstitial oxygen reside within the channel walls. It is suggested that these framework interstitial O atoms provide a reservoir of ions that can migrate into the conducting channels of apatite, via a mechanism of inter-tunnel oxygen diffusion that transiently converts GeO(4) tetrahedra to GeO(5) distorted trigonal bipyramids. This structural modification is consistent with known crystal chemistry and may occur generally in oxide apatites.

Advances in the treatment of rheumatic interstitial lung disease.

PubMed

Vassallo, Robert; Thomas, Charles F

2004-05-01

Interstitial lung disease frequently complicates the rheumatic diseases. The purpose of this review is to outline recent advances and current concepts regarding the management of these interstitial lung diseases. Several histologic lesions cause interstitial lung disease in rheumatic diseases, including nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Although the relative frequency of occurrence of these histopathologic lesions is not definitively established, it seems that nonspecific interstitial pneumonia accounts for a large proportion of rheumatic disease-associated interstitial lung diseases. Although usual interstitial pneumonia generally responds poorly to corticosteroid therapy, other forms of interstitial pneumonia are often steroid responsive and have a more favorable long-term prognosis. Pulmonary hypertension is increasingly recognized as a complication of these interstitial lung diseases. Treatment of pulmonary hypertension in these patients provides clinical benefit and may suppress pulmonary inflammation and fibrosis. Lung transplantation is a treatment option for selected patients with severe pulmonary involvement and limited life expectancy. Interstitial lung disease is common in the rheumatic diseases, may be caused by a variety of lesions that respond differently to treatment, and may lead to the development of pulmonary hypertension. Whether the prognosis of interstitial lung disease associated with rheumatic disease is similar to that associated with the idiopathic interstitial pneumonias is not known. Treatment of these interstitial lung diseases should take into account the specific histologic lesion, the activity of the underlying rheumatic disease, and associated pulmonary hypertension, if present. The diagnosis of a rheumatic disease is no longer an absolute contraindication to lung transplantation.

Bardoxolone Methyl Evaluation in Patients With Pulmonary Hypertension (PH) - LARIAT

ClinicalTrials.gov

2018-06-08

Pulmonary Arterial Hypertension; Pulmonary Hypertension; Interstitial Lung Disease; Idiopathic Interstitial Pneumonia; Idiopathic Pulmonary Fibrosis; Sarcoidosis; Respiratory Bronchiolitis Associated Interstitial Lung Disease; Desquamative Interstitial Pneumonia; Cryptogenic Organizing Pneumonia; Acute Interstitial Pneumonitis; Idiopathic Lymphoid Interstitial Pneumonia; Idiopathic Pleuroparenchymal Fibroelastosis

The multiple faces of leukocyte interstitial migration

PubMed Central

Lämmermann, Tim; Germain, Ronald N.

2014-01-01

Spatiotemporal control of leukocyte dynamics within tissues is critical for successful innate and adaptive immune responses. Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell–cell interaction. In contrast to mesenchymal cells, leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic. The interplay of actin network expansion, contraction, and adhesion shapes the exact mode of amoeboid migration, and in this review, we explore how leukocyte subsets potentially harness the same basic biomechanical mechanisms in a cell-type-specific manner. Most of our detailed understanding of these processes derives from in vitro migration studies in three-dimensional gels and confined spaces that mimic geometrical aspects of physiological tissues. We summarize these in vitro results and then critically compare them to data from intravital imaging of leukocyte interstitial migration in mouse tissues. We outline the technical challenges of obtaining conclusive mechanistic results from intravital studies, discuss leukocyte migration strategies in vivo, and present examples of mode switching during physiological interstitial migration. These findings are also placed in the context of leukocyte migration defects in primary immunodeficiencies. This overview of both in vitro and in vivo studies highlights recent progress in understanding the molecular and biophysical mechanisms that shape robust leukocyte migration responses in physiologically complex and heterogeneous environments. PMID:24573488

Do we understand any more about bladder interstitial cells?-ICI-RS 2013.

PubMed

Kanai, Anthony; Fry, Christopher; Hanna-Mitchell, Ann; Birder, Lori; Zabbarova, Irina; Bijos, Dominika; Ikeda, Youko

2014-06-01

To present a brief review on discussions from "Do we understand any more about lower urinary tract interstitial cells?" session at the 2013 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. Discussion focused on bladder interstitial cell (IC) subtypes, their localization and characterization, and communication between themselves, the urothelium, and detrusor smooth muscle. The role of ICs in bladder pathologies and new methods for studying ICs were also addressed. ICs have been studied extensively in the lower urinary tract and have been characterized based on comparisons with ICs of Cajal in the gastro-intestinal tract. In fetal bladders it is believed that ICs drive intrinsic contractions to expel urine through the urachus. These contractions diminish postpartum as bladder innervation develops. Voiding in human neonates occurs when filling triggers a spinal cord reflex that contracts the detrusor; in rodents, maternal stimulation of the perineum triggers voiding. Following spinal cord injury, intrinsic contractions, and spinal micturition reflexes develop, similar to those seen during neonatal development. These enhanced contractions may stimulate nociceptive and mechanosensitive afferents contributing to neurogenic detrusor overactivity and incontinence. The IC-mediated activity is believed to be initiated in the lamina propria by responding to urothelial factors. These IC may act syncytially through gap junction coupling and modulate detrusor activity through unknown mechanisms. There has been a great deal of information discovered regarding bladder ICs, however, many of their (patho)physiological functions and mechanisms are still unclear and necessitates further research. Neurourol. Urodynam. 33:573-576, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

A Contractile Network of Interstitial Cells of Cajal in the Supratarsal Mueller's Smooth Muscle Fibers With Sparse Sympathetic Innervation

PubMed Central

Yuzuriha, Shunsuke; Matsuo, Kiyoshi; Ban, Ryokuya; Yano, Shiharu; Moriizumi, Tetsuji

2012-01-01

Background: We previously reported that the supratarsal Mueller's muscle is innervated by both sympathetic efferent fibers and trigeminal proprioceptive afferent fibers, which function as mechanoreceptors-inducing reflexive contractions of both the levator and frontalis muscles. Controversy still persists regarding the role of the mechanoreceptors in Mueller's muscle; therefore, we clinically and histologically investigated Mueller's muscle. Methods: We evaluated the role of phenylephrine administration into the upper fornix in contraction of Mueller's smooth muscle fibers and how intraoperative stretching of Mueller's muscle alters the degree of eyelid retraction in 20 patients with aponeurotic blepharoptosis. In addition, we stained Mueller's muscle in 7 cadavers with antibodies against α-smooth muscle actin, S100, tyrosine hydroxylase, c-kit, and connexin 43. Results: Maximal eyelid retraction occurred approximately 3.8 minutes after administration of phenylephrine and prolonged eyelid retraction for at least 20 minutes after administration. Intraoperative stretching of Mueller's muscle increased eyelid retraction due to its reflexive contraction. The tyrosine hydroxylase antibody sparsely stained postganglionic sympathetic nerve fibers, whereas the S100 and c-kit antibodies densely stained the interstitial cells of Cajal (ICCs) among Mueller's smooth muscle fibers. A connexin 43 antibody failed to stain Mueller's muscle. Conclusions: A contractile network of ICCs may mediate neurotransmission within Mueller's multiunit smooth muscle fibers that are sparsely innervated by postganglionic sympathetic fibers. Interstitial cells of Cajal may also serve as mechanoreceptors that reflexively contract Mueller's smooth muscle fibers, forming intimate associations with intramuscular trigeminal proprioceptive fibers to induce reflexive contraction of the levator and frontalis muscles. PMID:22359687

Mapping bone interstitial fluid movement: Displacement of ferritin tracer during histological processing

PubMed Central

Ciani, Cesare; Doty, Stephen B.; Fritton, Susannah P.

2014-01-01

Bone interstitial fluid flow is thought to play a fundamental role in the mechanical stimulation of bone cells, either via shear stresses or cytoskeletal deformations. Recent evidence indicates that osteocytes are surrounded by a fiber matrix that may be involved in the mechanotransduction of external stimuli as well as in nutrient exchange. In our previous tracer studies designed to map how different-sized molecules travel through the bone porosities, we found that injected ferritin was confined to blood vessels and did not pass into the mineralized matrix. However, other investigators have shown that ferritin forms halo-shaped labeling that enters the mineralized matrix around blood vessels. This labeling is widely used to explain normal interstitial fluid movement in bone; in particular, it is said to demonstrate bulk centrifugal interstitial fluid movement away from a highly pressurized vascular porosity. In addition, appositional ferritin fronts are said to demonstrate centrifugal interstitial fluid movement from the medullary canal to the periosteal surface. The purpose of this study was to investigate the conflicting ferritin labeling results by evaluating the role of different histological processes in the formation of ferritin “halos.” Ferritin was injected into the rat vasculature and allowed to circulate for 5 min. Samples obtained from tibiae were reacted for different times with Perl's reagent and then were either paraffin-embedded or sectioned with a cryostat. Halo-like labeling surrounding vascular pores was found in all groups, ranging from 1.2–3.9% for the samples treated with the shortest histological processes (unembedded, frozen sections) to 5.6–15% for the samples treated with the longest histological processes (paraffin-embedded sections). These results indicate that different histological processing methods are able to create ferritin “halos,” with some processing methods allowing more redistribution of the ferritin tracer than others. Based on these results and the fact that “halo” labeling has not been found with any other tracer, as we seek to further delineate the movement of interstitial fluid and the role it plays in bone mechanotransduction, we believe that ferritin “halo” labeling should not be used to demonstrate physiological bone interstitial fluid flow. PMID:15964255

Mapping bone interstitial fluid movement: displacement of ferritin tracer during histological processing.

PubMed

Ciani, Cesare; Doty, Stephen B; Fritton, Susannah P

2005-09-01

Bone interstitial fluid flow is thought to play a fundamental role in the mechanical stimulation of bone cells, either via shear stresses or cytoskeletal deformations. Recent evidence indicates that osteocytes are surrounded by a fiber matrix that may be involved in the mechanotransduction of external stimuli as well as in nutrient exchange. In our previous tracer studies designed to map how different-sized molecules travel through the bone porosities, we found that injected ferritin was confined to blood vessels and did not pass into the mineralized matrix. However, other investigators have shown that ferritin forms halo-shaped labeling that enters the mineralized matrix around blood vessels. This labeling is widely used to explain normal interstitial fluid movement in bone; in particular, it is said to demonstrate bulk centrifugal interstitial fluid movement away from a highly pressurized vascular porosity. In addition, appositional ferritin fronts are said to demonstrate centrifugal interstitial fluid movement from the medullary canal to the periosteal surface. The purpose of this study was to investigate the conflicting ferritin labeling results by evaluating the role of different histological processes in the formation of ferritin "halos." Ferritin was injected into the rat vasculature and allowed to circulate for 5 min. Samples obtained from tibiae were reacted for different times with Perl's reagent and then were either paraffin-embedded or sectioned with a cryostat. Halo-like labeling surrounding vascular pores was found in all groups, ranging from 1.2-3.9% for the samples treated with the shortest histological processes (unembedded, frozen sections) to 5.6-15% for the samples treated with the longest histological processes (paraffin-embedded sections). These results indicate that different histological processing methods are able to create ferritin "halos," with some processing methods allowing more redistribution of the ferritin tracer than others. Based on these results and the fact that "halo" labeling has not been found with any other tracer, as we seek to further delineate the movement of interstitial fluid and the role it plays in bone mechanotransduction, we believe that ferritin "halo" labeling should not be used to demonstrate physiological bone interstitial fluid flow.

Infrared spectroscopic analysis of human interstitial fluid in vitro and in vivo using FT-IR spectroscopy and pulsed quantum cascade lasers (QCL): Establishing a new approach to non invasive glucose measurement.

PubMed

Pleitez, Miguel; von Lilienfeld-Toal, Hermann; Mäntele, Werner

2012-01-01

Interstitial fluid, i.e. the liquid present in the outermost layer of living cells of the skin between the Stratum corneum and the Stratum spinosum, was analyzed by Fourier transform infrared spectroscopy and by infrared spectroscopy using pulsed quantum cascade infrared lasers with photoacoustic detection. IR spectra of simulated interstitial fluid samples and of real samples from volunteers in the 850-1800cm(-1) range revealed that the major components of interstitial fluid are albumin and glucose within the physiological range, with only traces of sodium lactate if at all. The IR absorbance of glucose in interstitial fluid in vivo was probed in healthy volunteers using a setup with quantum cascade lasers and photoacoustic detection previously described. A variation of blood glucose between approx. 80mg/dl and 250mg/dl in the volunteers was obtained using the standard oral glucose tolerance test (OGT). At two IR wavelengths, 1054cm(-1) and 1084cm(-1), a reasonable correlation between the photoacoustic signal from the skin and the blood glucose value as determined by conventional glucose test sticks using blood from the finger tip was obtained. The infrared photoacoustic glucose signal (PAGS) may serve as the key for a non-invasive glucose measurement, since the glucose content in interstitial fluid closely follows blood glucose in the time course and in the level (a delay of some minutes and a level of approx. 80-90% of the glucose level in blood). Interstitial fluid is present in skin layers at a depth of only 15-50μm and is thus within the reach of mid-IR energy in an absorbance measurement. A non-invasive glucose measurement for diabetes patients based on mid-infrared quantum cascade lasers and photoacoustic detection could replace the conventional measurement using enzymatic test stripes and a drop of blood from the finger tip, thus reducing pain and being a cost-efficient alternative for millions of diabetes patients. Copyright © 2011 Elsevier B.V. All rights reserved.

Infrared spectroscopic analysis of human interstitial fluid in vitro and in vivo using FT-IR spectroscopy and pulsed quantum cascade lasers (QCL): Establishing a new approach to non invasive glucose measurement

NASA Astrophysics Data System (ADS)

Pleitez, Miguel; von Lilienfeld-Toal, Hermann; Mäntele, Werner

2012-01-01

Interstitial fluid, i.e. the liquid present in the outermost layer of living cells of the skin between the Stratum corneum and the Stratum spinosum, was analyzed by Fourier transform infrared spectroscopy and by infrared spectroscopy using pulsed quantum cascade infrared lasers with photoacoustic detection. IR spectra of simulated interstitial fluid samples and of real samples from volunteers in the 850-1800 cm -1 range revealed that the major components of interstitial fluid are albumin and glucose within the physiological range, with only traces of sodium lactate if at all. The IR absorbance of glucose in interstitial fluid in vivo was probed in healthy volunteers using a setup with quantum cascade lasers and photoacoustic detection previously described [11]. A variation of blood glucose between approx. 80 mg/dl and 250 mg/dl in the volunteers was obtained using the standard oral glucose tolerance test (OGT). At two IR wavelengths, 1054 cm -1 and 1084 cm -1, a reasonable correlation between the photoacoustic signal from the skin and the blood glucose value as determined by conventional glucose test sticks using blood from the finger tip was obtained. The infrared photoacoustic glucose signal (PAGS) may serve as the key for a non-invasive glucose measurement, since the glucose content in interstitial fluid closely follows blood glucose in the time course and in the level (a delay of some minutes and a level of approx. 80-90% of the glucose level in blood). Interstitial fluid is present in skin layers at a depth of only 15-50 μm and is thus within the reach of mid-IR energy in an absorbance measurement. A non-invasive glucose measurement for diabetes patients based on mid-infrared quantum cascade lasers and photoacoustic detection could replace the conventional measurement using enzymatic test stripes and a drop of blood from the finger tip, thus reducing pain and being a cost-efficient alternative for millions of diabetes patients.

Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal

PubMed Central

Collins, Clinton; Klausner, Adam P; Herrick, Benjamin; Koo, Harry P; Miner, Amy S; Henderson, Scott C; Ratz, Paul H

2009-01-01

Interstitial cells of Cajal (ICCs) have been identified as pacemaker cells in the upper urinary tract and urethra, but the role of ICCs in the bladder remains to be determined. We tested the hypotheses that ICCs express cyclooxygenase (COX), and that COX products (prostaglandins), are the cause of spontaneous rhythmic contraction (SRC) of isolated strips of rabbit bladder free of urothelium. SRC was abolished by 10 μM indomethacin and ibuprofen (non-selective COX inhibitors). SRC was concentration-dependently inhibited by selective COX-1 (SC-560 and FR-122047) and COX-2 inhibitors (NS-398 and LM-1685), and by SC-51089, a selective antagonist for the PGE-2 receptor (EP) and ICI-192,605 and SQ-29,548, selective antagonists for thromboxane receptors (TP). The partial agonist/antagonist of the PGF-2α receptor (FP), AL-8810, inhibited SRC by ∼50%. Maximum inhibition was ∼90% by SC-51089, ∼80–85% by the COX inhibitors and ∼70% by TP receptor antagonists. In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2α and U-46619 (thromboxane mimetic) caused rhythmic contractions that mimicked SRC. Fluorescence immunohistochemistry coupled with confocal laser scanning microscopy revealed that c-Kit and vimentin co-localized to interstitial cells surrounding detrusor smooth muscle bundles, indicating the presence of extensive ICCs in rabbit bladder. Co-localization of COX-1 and vimentin, and COX-2 and vimentin by ICCs supports the hypothesis that ICCs were the predominant cell type in rabbit bladder expressing both COX isoforms. These data together suggest that ICCs appear to be an important source of prostaglandins that likely play a role in regulation of SRC. Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder. PMID:19243470

Skeletal muscle-derived interstitial progenitor cells (PICs) display stem cell properties, being clonogenic, self-renewing, and multi-potent in vitro and in vivo.

PubMed

Cottle, Beverley J; Lewis, Fiona C; Shone, Victoria; Ellison-Hughes, Georgina M

2017-07-04

The development of cellular therapies to treat muscle wastage with disease or age is paramount. Resident muscle satellite cells are not currently regarded as a viable cell source due to their limited migration and growth capability ex vivo. This study investigated the potential of muscle-derived PW1 + /Pax7 - interstitial progenitor cells (PICs) as a source of tissue-specific stem/progenitor cells with stem cell properties and multipotency. Sca-1 + /PW1 + PICs were identified on tissue sections from hind limb muscle of 21-day-old mice, isolated by magnetic-activated cell sorting (MACS) technology and their phenotype and characteristics assessed over time in culture. Green fluorescent protein (GFP)-labelled PICs were used to determine multipotency in vivo in a tumour formation assay. Isolated PICs expressed markers of pluripotency (Oct3/4, Sox2, and Nanog), were clonogenic, and self-renewing with >60 population doublings, and a population doubling time of 15.8 ± 2.9 h. PICs demonstrated an ability to generate both striated and smooth muscle, whilst also displaying the potential to differentiate into cell types of the three germ layers both in vitro and in vivo. Moreover, PICs did not form tumours in vivo. These findings open new avenues for a variety of solid tissue engineering and regeneration approaches, utilising a single multipotent stem cell type isolated from an easily accessible source such as skeletal muscle.

Influence of dislocation strain fields on the diffusion of interstitial iron impurities in silicon

NASA Astrophysics Data System (ADS)

Ziebarth, Benedikt; Mrovec, Matous; Elsässer, Christian; Gumbsch, Peter

2015-09-01

The efficiency of silicon (Si)-based solar cells is strongly affected by crystal defects and impurities. Metallic impurities, in particular interstitial iron (Fe) atoms, cause large electric losses because they act as recombination centers for photogenerated charge carriers. Here, we present a systematic first-principles density functional theory (DFT) study focusing on the influence of hydrostatic, uniaxial, and shear strains on the thermodynamic stability and the diffusivity of Fe impurities in crystalline Si. Our calculations show that the formation energy of neutral Fe interstitials in tetrahedral interstitial sites is almost unaffected by uniform deformations of the Si crystal up to strains of 5%. In contrast, the migration barrier varies significantly with strain, especially for hydrostatic deformation. In order to determine effective diffusion coefficients for different strain states, a kinetic Monte Carlo (kMC) model was set up based on the activation energy barriers and frequency factors obtained from the DFT simulations. By using the strain dependence of the migration barrier, we examined the migration of Fe interstitials in the vicinity of perfect 1 /2 <110 > screw and 60∘ mixed dislocations, and 1 /6 <112 > 90∘ and 30∘ partial dislocations. While the strain field of the perfect screw dislocation always enhances the local Fe diffusion, the existence of tensile and compressive regions around the 60∘ mixed dislocation results in a strong anisotropic diffusion profile with significantly faster and slower diffusivities on its tensile and compressive sides. The influences of the partial dislocations are qualitatively similar to that of the 60∘ mixed dislocation.

Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve.

PubMed

Odelin, Gaëlle; Faure, Emilie; Coulpier, Fanny; Di Bonito, Maria; Bajolle, Fanny; Studer, Michèle; Avierinos, Jean-François; Charnay, Patrick; Topilko, Piotr; Zaffran, Stéphane

2018-01-03

Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20 -deficient embryos. Genetic lineage tracing in Krox20 -/- mutant mice shows that endothelial-derived cells are normal, whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20 -expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for Krox20 in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve. © 2018. Published by The Company of Biologists Ltd.

Microfluidic device to control interstitial flow-mediated homotypic and heterotypic cellular communication.

PubMed

Alonzo, Luis F; Moya, Monica L; Shirure, Venktesh S; George, Steven C

2015-09-07

Tissue engineering can potentially recreate in vivo cellular microenvironments in vitro for an array of applications such as biological inquiry and drug discovery. However, the majority of current in vitro systems still neglect many biological, chemical, and mechanical cues that are known to impact cellular functions such as proliferation, migration, and differentiation. To address this gap, we have developed a novel microfluidic device that precisely controls the spatial and temporal interactions between adjacent three-dimensional cellular environments. The device consists of four interconnected microtissue compartments (~0.1 mm(3)) arranged in a square. The top and bottom pairs of compartments can be sequentially loaded with discrete cellularized hydrogels creating the opportunity to investigate homotypic (left to right or x-direction) and heterotypic (top to bottom or y-direction) cell-cell communication. A controlled hydrostatic pressure difference across the tissue compartments in both x and y direction induces interstitial flow and modulates communication via soluble factors. To validate the biological significance of this novel platform, we examined the role of stromal cells in the process of vasculogenesis. Our device confirms previous observations that soluble mediators derived from normal human lung fibroblasts (NHLFs) are necessary to form a vascular network derived from endothelial colony forming cell-derived endothelial cells (ECFC-ECs). We conclude that this platform could be used to study important physiological and pathological processes that rely on homotypic and heterotypic cell-cell communication.

Redox signaling is an early event in the pathogenesis of renovascular hypertension.

PubMed

Hartono, Stella P; Knudsen, Bruce E; Zubair, Adeel S; Nath, Karl A; Textor, Stephen J; Lerman, Lilach O; Grande, Joseph P

2013-09-10

Activation of the renin-angiotensin-aldosterone system plays a critical role in the development of chronic renal damage in patients with renovascular hypertension. Although angiotensin II (Ang II) promotes oxidative stress, inflammation, and fibrosis, it is not known how these pathways intersect to produce chronic renal damage. We tested the hypothesis that renal parenchymal cells are subjected to oxidant stress early in the development of RVH and produce signals that promote influx of inflammatory cells, which may then propagate chronic renal injury. We established a reproducible murine model of RVH by placing a tetrafluoroethylene cuff on the right renal artery. Three days after cuff placement, renal tissue demonstrates no histologic abnormalities despite up regulation of both pro- and anti-oxidant genes. Mild renal atrophy was observed after seven days and was associated with induction of Tnfα and influx of CD3⁺ T cells and F4/80⁺ macrophages. By 28 days, kidneys developed severe renal atrophy with interstitial inflammation and fibrosis, despite normalization of plasma renin activity. Based on these considerations, we propose that renal parenchymal cells initiate a progressive cascade of events leading to oxidative stress, interstitial inflammation, renal fibrosis, and atrophy.

Inhibitory effect of tributyltin on expression of steroidogenic enzymes in mouse testis.

PubMed

Kim, Suel-Kee; Kim, Jong-Hoon; Han, Jung Ho; Yoon, Yong-Dal

2008-01-01

Tributyltin (TBT) is known to disrupt the development of reproductive organs, thereby reducing fertility. The aim of this study was to evaluate the acute toxicity of TBT on the testicular development and steroid hormone production. Immature (3-week-old) male mice were given a single administration of 25, 50, or 100 mg/kg of TBT by oral gavage. Lumen formation in seminiferous tubule was remarkably delayed, and the number of apoptotic germ cells found inside the tubules was increased in the TBT-exposed animals, whereas no apoptotic signal was observed in interstitial Leydig cells. Reduced serum testosterone concentration and down-regulated expressions of the mRNAs for cholesterol side-chain cleavage enzyme (P450scc), 17alpha -hydroxylase/C(17-20) lyase (P450(17alpha)), 3beta -hydroxysteroid-dehydrogenase (3beta -HSD), and 17beta -hydroxysteroid-dehydrogenase (17beta -HSD) were also observed after TBT exposure. Altogether, these findings demonstrate that exposure to TBT is associated with induced apoptosis of testicular germ cells and inhibition of steroidogenesis by reduction in the expression of steroidogenic enzymes in interstitial Leydig cells. These adverse effects of TBT would cause serious defects in testicular development and function.

On Demand Internal Short Circuit Device Enables Verification of Safer, Higher Performing Battery Designs

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

Darcy, Eric; Keyser, Matthew

The Internal Short Circuit (ISC) device enables critical battery safety verification. With the aluminum interstitial heat sink between the cells, normal trigger cells cannot be driven into thermal runaway without excessive temperature bias of adjacent cells. With an implantable, on-demand ISC device, thermal runaway tests show that the conductive heat sinks protected adjacent cells from propagation. High heat dissipation and structural support of Al heat sinks show high promise for safer, higher performing batteries.

Do pulmonary artery catheters cause or increase tricuspid or pulmonic valvular regurgitation?

PubMed

Sherman, S V; Wall, M H; Kennedy, D J; Brooker, R F; Butterworth, J

2001-05-01

There are few quantitative data on the extent or mechanism of pulmonary artery catheter (PAC)-induced valvular dysfunction. We hypothesized that PACs cause or worsen tricuspid and pulmonic valvular regurgitation, and tested this hypothesis by using transesophageal echocardiography. In 54 anesthetized adult patients, we measured color Doppler jet areas of tricuspid regurgitation (TR) in two planes (midesophageal [ME] 4-chamber and right ventricular inflow-outflow views) and pulmonic insufficiency (PI) in one plane (ME aortic valve long-axis view), both before and after we advanced a PAC into the pulmonary artery. Regurgitant jet areas and hemodynamic measurements were compared by using paired t-test. There were no significant changes in blood pressure or heart rate after passage of the PAC. After PAC placement, the mean PI jet area was not significantly increased. The mean TR jet area increased significantly in the right ventricular inflow-outflow view (+0.37 +/- 0.11 cm(2)) (P = 0.0014), but did not increase at the ME 4-chamber view. Seventeen percent of patients had an increase in TR jet area > or =1 cm(2); 8% of patients had an increase in PI jet area >/=1 cm(2). In patients without pulmonic or tricuspid valvular pathology, placement of a pulmonary artery catheter (PAC) worsened tricuspid regurgitation, which is consistently visualized in the right ventricular inflow-outflow view, and often not seen in the midesophageal 4-chamber view. This is consistent with malcoaptation of the anterior and posterior leaflets. PAC-induced pulmonic insufficiency was rarely detected in the midesophageal aortic valve long-axis view. We conclude that a PAC is very unlikely to be the sole cause of severe tricuspid regurgitation or pulmonic insufficiency.

Therapeutic Decision-Making for Elderly Patients With Symptomatic Severe Valvular Heart Diseases.

PubMed

Hu, Kui; Wan, Yun; Hong, Tao; Lu, Shu Yang; Guo, Chang Fa; Li, Jun; Wang, Chun Sheng

2016-07-27

The aim of this study was to determine how older age and co-morbidities affect the treatment decision-making and long-term survival in elderly patients with symptomatic severe valvular heart diseases.A total of 181 elderly patients (mean age, 78.4 ± 3.4 years) hospitalized between January 2003 and June 2012 with symptomatic severe valvular heart diseases were enrolled. Cardiac and geriatric factors associated with treatment decision-making were analyzed. Survival outcomes were investigated.Surgical treatment was performed in 116 (64%) patients (surgical group) and 65 patients (36%) were treated conservatively (conservative group). The most common [62% (40/65)] reason for refusing surgical treatment was high operative risk as assessed by the physicians who initially cared for the patients. Multivariate logistic regression analysis identified female gender, chronic renal insufficiency, older age, pneumonia, and emergent status as independent predictors of the conservative treatment. Patients with isolated aortic valve disease tended to undergo an operation. Overall 5-year survival in the surgical group was 76.8% versus 42.9% in the conservative group (P < 0.0001). After matching using the propensity score, the surgical group still had a better long-term survival than the conservative group (P = 0.001). Cox regression analysis revealed conservative treatment as the single risk factor associated with poor long-term survival in all series.Approximately 40% of the elderly patients with symptomatic severe heart valve disease were treated conservatively despite a definite indication for surgical intervention. Cardiac and geriatric co-morbidities profoundly affect the treatment decision-making. Interdisciplinary discussion should be encouraged to optimize therapeutic options for elderly patients with valvular heart disease.

[Comprehensive outpatient treatment of varicose disease of the lower limbs].

PubMed

Gavrilov, V A; Chabbarov, R G; Piatnitskiĭ, A G; Khvorostukhin, V S

2008-01-01

The article deals with the findings obtained in examining a total of 8,000 people presenting with varicose disease of the lower extremities. The examination included a clinical (physical) examination and coloured duplex scanning of the lower-limb veins. The examination was carried out in outpatient conditions, whereas surgical treatment was performed either out-patiently, or at a hospital. Revealing complete valvular insufficiency of the great saphenous vein was followed by surgical treatment - intraoperative stem catheter scleroobliteration (SSO) or short-term screening and postoperative puncture sclerotherapy. Detecting partial valvular insufficiency of the greater saphenous vein (pathological sapheno-femoral reflux only in the vertical position) was managed by applying the principle of the so-called : i. e. the patients were subjected to the procedure of puncture sclerotherapy of varicose veins on the crus in ambulatory conditions to be followed by secondary ultrasonographic scanning with permanent dynamic follow-up. The cases of preserved reflux along the greater saphenous vein were subjected to sclerosurgical management. Valvular insufficiency of perforating veins was coped with by minimally invasive surgical interventions: subtotal endoscopic dissection of incompetent perforating veins, suprafascial ligation from a miniaccess and echosclerotherapy of the perforating veins. Also performed were histological and histochemical studies of the portions the greater saphenous vein and surrounding tissues procured during cross-ectomy of the sapheno-femoral anastomosis in 43 patients, who had endured preliminary puncture sclerotherapy on the crus. Good functional and cosmetically pleasing outcomes were achieved in the majority of cases. In 75% of the patients with partial valvular insufficiency of the greater saphenous vein, we managed to avoid operations since repeat ultrasonographic study revealed no pathological veno-venous shunts.

[Phonomechanocardiography in the evaluation of the functional status of valvular prosthesis].

PubMed

Esquivel Avila, J; Molina Zapata, B; Martínez Ríos, M A; Flamand, E

1975-01-01

The FMCG in 22 patients with valvular prosthesis is analyzed and its clinical, hemodynamic and surgical correlation are established (11 from the I.N.C. and 11 from the Hospital Infantil I.M.A.N.). The average age of the patients was 15 years old, 18 had a mitral and six aortic valvulopathy, and they all required a valvular replacement. Of the mitral prosthesis, 14 were Starr-Edwards (13 of ball valve and one of disc), three Lillehei-Kaster and one Börck-Shiley. In 5 patients, the FMCG suspected disfunction that was later corroborated by catheterism in three patients and by surgery in all of them. The important differences of the FMCG between the group with good and the one with bad function were: the aparition of a rumble, a decrease in the amplitud of the closing snap, index of closing snap opering snap of less than one, lenghtening of fases PFVP and IVCP, and shortening of IVDRP. In the patients with auricular fibrilation, after long dyastoles; that would represent an adequate atrial emptying; the closing snap was more intense, the PFVP was lennthened the IVDRP was shortened when the prosthesis was not properly functioning. All the aortic prosthesis were ball valve Starr-Edwards type; in one the FMCG suspected disfunction and the patient had a sudden death outside of the Hospital. The significant differences of the FMCG were the decrease in the intensity of the opening snap, with a Hylen index of less than one, lengthening of the PFVP, IVCP and of the expulsive period (EP). The authors conclude that the FMCG is a good method for an early detection of the disfunctions of valvular prosthesis.

Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.

PubMed

Ritelli, Marco; Morlino, Silvia; Giacopuzzi, Edoardo; Carini, Giulia; Cinquina, Valeria; Chiarelli, Nicola; Majore, Silvia; Colombi, Marina; Castori, Marco

2017-01-01

Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Clinical outcomes of redo valvular operations: a 20-year experience.

PubMed

Fukunaga, Naoto; Okada, Yukikatsu; Konishi, Yasunobu; Murashita, Takashi; Yuzaki, Mitsuru; Shomura, Yu; Fujiwara, Hiroshi; Koyama, Tadaaki

2012-12-01

A higher operative mortality rate has been reported after redo valvular procedures than after the primary operation. Outcomes of 330 consecutive patients undergoing 433 redo valvular operations at our institute during a 20-year period (January 1990 to December 2010) were reviewed retrospectively. The mean follow-up was 6.4 years (range, 0.05 to 1.3 years). Logistic regression analysis was used to identify factors associated with hospital death. The overall hospital mortality rate was 6.7% (29 of 433 procedures). Logistic regression analysis identified only advanced New York Heart Association (NYHA) class as an independent predictor of hospital death. Overall survival at 5, 10, and 15 years was 83.6%±2.2%, 70.7%±3.4%, and 61.5%±4.5%, respectively. The 5-, 10-, and 15-year survivals for the first redo vs more than second redo groups were 86.5%±2.4% vs 74.7%±5.5%, 71.8%±3.9% vs 66.8%±6.6%, and 60.2%±5.7% vs 63.1%±7.2%, respectively (log-rank P=0.505). The 5- and 10-year survivals for NYHA class I/II vs III/IV patients were 91.5%±2.1% vs 70.4%±4.5% and 77.8%±4.1% vs 58.5%±5.6%, respectively (log-rank p<0.005). Redo valvular operation in NYHA class III/IV patients is associated with high hospital death and poor long-term survival. To achieve low hospital death and good long-term survival, redo operations, including more than third redo operations, should be performed in patients with lower NYHA class. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Antiphospholipid Antibody Syndrome With Valvular Vegetations in Acute Q Fever.

PubMed

Million, Matthieu; Thuny, Franck; Bardin, Nathalie; Angelakis, Emmanouil; Edouard, Sophie; Bessis, Simon; Guimard, Thomas; Weitten, Thierry; Martin-Barbaz, François; Texereau, Michèle; Ayouz, Khelifa; Protopopescu, Camelia; Carrieri, Patrizia; Habib, Gilbert; Raoult, Didier

2016-03-01

Coxiella burnetii endocarditis is considered to be a late complication of Q fever in patients with preexisting valvular heart disease (VHD). We observed a large transient aortic vegetation in a patient with acute Q fever and high levels of IgG anticardiolipin antibodies (IgG aCL). Therefore, we sought to determine how commonly acute Q fever could cause valvular vegetations associated with antiphospholipid antibody syndrome, which would be a new clinical entity. We performed a consecutive case series between January 2007 and April 2014 at the French National Referral Center for Q fever. Age, sex, history of VHD, immunosuppression, and IgG aCL assessed by enzyme-linked immunosorbent assay were tested as potential predictors. Of the 759 patients with acute Q fever and available echocardiographic results, 9 (1.2%) were considered to have acute Q fever endocarditis, none of whom had a previously known VHD. After multiple adjustment, very high IgG aCL levels (>100 immunoglobulin G-type phospholipid units; relative risk [RR], 24.9 [95% confidence interval {CI}, 4.5-140.2]; P = .002) and immunosuppression (RR, 10.1 [95% CI, 3.0-32.4]; P = .002) were independently associated with acute Q fever endocarditis. Antiphospholipid antibody syndrome with valvular vegetations in acute Q fever is a new clinical entity. This would suggest the value of systematically testing for C. burnetii in antiphospholipid-associated cardiac valve disease, and performing early echocardiography and antiphospholipid dosages in patients with acute Q fever. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Passivation of interstitial and vacancy mediated trap-states for efficient and stable triple-cation perovskite solar cells

NASA Astrophysics Data System (ADS)

Mahmud, Md Arafat; Elumalai, Naveen Kumar; Upama, Mushfika Baishakhi; Wang, Dian; Gonçales, Vinicius R.; Wright, Matthew; Xu, Cheng; Haque, Faiazul; Uddin, Ashraf

2018-04-01

The current work reports the concurrent passivation of interstitial and oxygen vacancy mediated defect states in low temperature processed ZnO electron transport layer (ETL) via Ultraviolet-Ozone (UVO) treatment for fabricating highly efficient (maximum efficiency: 16.70%), triple cation based MA0.57FA0.38Rb0.05PbI3 (MA: methyl ammonium, FA: formamidinium, Rb: rubidium) perovskite solar cell (PSC). Under UV exposure, ozone decomposes to free atomic oxygen and intercalates into the interstitial and oxygen vacancy induced defect sites in the ZnO lattice matrix, which contributes to suppressed trap-assisted recombination phenomena in perovskite device. UVO treatment also reduces the content of functional hydroxyl group on ZnO surface, that increases the inter-particle connectivity and grain size of perovskite film on UVO treated ZnO ETL. Owing to this, the perovskite film atop UVO treated ZnO film exhibits reduced micro-strain and dislocation density values, which contribute to the enhanced photovoltaic performance of PSC with modified ZnO ETL. The modified PSCs exhibit higher recombination resistance (RRec) ∼40% compared to pristine ZnO ETL based control devices. Adding to the merit, the UVO treated ZnO PSC also demonstrates superior device stability, retaining about 88% of its initial PCE in the course of a month-long, systematic degradation study.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

PubMed

Kojima, Yoko; Okudela, Koji; Matsumura, Mai; Omori, Takahiro; Baba, Tomohisa; Sekine, Akimasa; Woo, Tetsukan; Umeda, Shigeaki; Takemura, Tamiko; Mitsui, Hideaki; Suzuki, Takehisa; Tateishi, Yoko; Iwasawa, Tae; Arai, Hiromasa; Tajiri, Michihiko; Ogura, Takashi; Kameda, Yoichi; Masuda, Munetaka; Ohashi, Kenich

2017-03-01

To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features. © 2016 John Wiley & Sons Ltd.

Rare variants in RTEL1 are associated with familial interstitial pneumonia.

PubMed

Cogan, Joy D; Kropski, Jonathan A; Zhao, Min; Mitchell, Daphne B; Rives, Lynette; Markin, Cheryl; Garnett, Errine T; Montgomery, Keri H; Mason, Wendi R; McKean, David F; Powers, Julia; Murphy, Elissa; Olson, Lana M; Choi, Leena; Cheng, Dong-Sheng; Blue, Elizabeth Marchani; Young, Lisa R; Lancaster, Lisa H; Steele, Mark P; Brown, Kevin K; Schwarz, Marvin I; Fingerlin, Tasha E; Schwartz, David A; Lawson, William E; Loyd, James E; Zhao, Zhongming; Phillips, John A; Blackwell, Timothy S

2015-03-15

Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families. To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function. Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

Increased matrix metalloproteinases as possible cause of osseoarticular tissue destruction in long-term haemodialysis and beta 2-microglobulin amyloidosis.

PubMed

Ohashi, K; Kawai, R; Hara, M; Okada, Y; Tachibana, S; Ogura, Y

1996-04-01

Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in periarticular tissues of beta 2-microglobulin amyloidosis patients was investigated. MMP-1 (interstitial collagenase) the most strongly expressed of the MMPs, was localized in the synovial lining cells, mesenchymal cells in granulation tissue and nodular amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression of MMP-1 was correlated with the degree of macrophage infiltration and synovial cell hyperplasia, but it was not correlated with the degree of amyloid deposition or haemodialysis period. Expression of MMP-1 appeared more intense than that of TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the interstitial fibroblasts and MMP-3 was faintly stained in the extracellular matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly positive in the osteoclasts which increased in the progressing osteolytic lesion from the destructive arthropathy. These results suggest involvement of MMPs in inflammation with an imbalance between expression of MMPs and TIMPs being closely related to pathogenesis of the destructive arthropathy.

Dysregulated Functions of Lung Macrophage Populations in COPD.

PubMed

Kapellos, Theodore S; Bassler, Kevin; Aschenbrenner, Anna C; Fujii, Wataru; Schultze, Joachim L

2018-01-01

Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD.

The alveolar macrophage.

PubMed

Bowden, D H

1984-04-01

The pulmonary macrophagic system is critical to the defense of the lung, keeping the alveoli clean and sterile and responding on demand with an adaptive outpouring of new cells into the air sacs. Under basal conditions alveolar macrophages, in common with other mononuclear phagocytes, are derived from the bone marrow. A population of macrophage precursors within the pulmonary interstitium provides a reserve pool capable of proliferation and delivery of phagocytes in response to unusually heavy loads of inhaled particles. This reserve system also produces macrophages when monocytic precursors in the bone marrow are depleted by diseases such as leukemia. The alveolar macrophage is destined to ingest particulate matter and to be eliminated along the mucociliary pathway; clearance by lymphatics is of minor importance and macrophages probably do not recross the alveolar epithelium to reach the pulmonary interstitial compartment. Although the protective role of the macrophage is dominant, this cell may participate, directly or indirectly, in the genesis of two major groups of chronic pulmonary disease, interstitial fibrosis and emphysema. Such inappropriate responses involve interactions with fibroblastic cells and tissue injury initiated by proteases secreted by the macrophage.

Dysregulated Functions of Lung Macrophage Populations in COPD

PubMed Central

Bassler, Kevin; Aschenbrenner, Anna C.

2018-01-01

Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD. PMID:29670919

Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis

PubMed Central

Bonventre, Joseph V

2014-01-01

Tubular injury has a major etiological role in fibrosis. For many years, this relationship has been dominated by the perception that epithelial cells are transformed into myofibroblasts that proliferate and generate fibrotic matrix—the so-called epithelial-to-mesenchymal transition. Here we focus on mechanisms by which injury to the tubule results in fibrosis because of paracrine mechanisms. Specific injury to the proximal tubule results in inflammation, reversible injury, and adaptive repair if the insult is mild, self-limited in time, and occurs in a background of a normal kidney. Repeated injury, in contrast, leads to maladaptive repair with sustained tubule injury, chronic inflammation, proliferation of interstitial myofibroblasts, vascular rarefaction, interstitial fibrosis, and glomerular sclerosis. During the maladaptive repair process after the renal insult, many tubular cells become arrested in the G2/M phase of the cell cycle. This results in activation of the DNA repair response with the resultant synthesis and secretion of pro-fibrotic factors. Pharmacologic interventions that enhance the movement through G2/M or facilitate apoptosis of cells that otherwise would be blocked in G2/M may reduce the development of fibrosis after kidney injury and reduce the progression of chronic kidney disease. PMID:26310195

Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca2+ and H+

PubMed Central

Wei, Wei-Chun; Jacobs, Benjamin; Becker, Esther B. E.; Glitsch, Maike D.

2015-01-01

G protein-coupled receptors (GPCRs) are cell surface receptors that detect a wide range of extracellular messengers and convey this information to the inside of cells. Extracellular calcium-sensing receptor (CaSR) and ovarian cancer gene receptor 1 (OGR1) are two GPCRs that sense extracellular Ca2+ and H+, respectively. These two ions are key components of the interstitial fluid, and their concentrations change in an activity-dependent manner. Importantly, the interstitial fluid forms part of the microenvironment that influences cell function in health and disease; however, the exact mechanisms through which changes in the microenvironment influence cell function remain largely unknown. We show that CaSR and OGR1 reciprocally inhibit signaling through each other in central neurons, and that this is lost in their transformed counterparts. Furthermore, strong intracellular acidification impairs CaSR function, but potentiates OGR1 function. Thus, CaSR and OGR1 activities can be regulated in a seesaw manner, whereby conditions promoting signaling through one receptor simultaneously inhibit signaling through the other receptor, potentiating the difference in their relative signaling activity. Our results provide insight into how small but consistent changes in the ionic microenvironment of cells can significantly alter the balance between two signaling pathways, which may contribute to disease progression. PMID:26261299

Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma.

PubMed

Gritsenko, Pavlo; Leenders, William; Friedl, Peter

2017-10-01

Diffuse invasion of glioma cells into the brain parenchyma leads to nonresectable brain tumors and poor prognosis of glioma disease. In vivo, glioma cells can adopt a range of invasion strategies and routes, by moving as single cells, collective strands and multicellular networks along perivascular, perineuronal and interstitial guidance cues. Current in vitro assays to probe glioma cell invasion, however, are limited in recapitulating the modes and adaptability of glioma invasion observed in brain parenchyma, including collective behaviours. To mimic in vivo-like glioma cell invasion in vitro, we here applied three tissue-inspired 3D environments combining multicellular glioma spheroids and reconstituted microanatomic features of vascular and interstitial brain structures. Radial migration from multicellular glioma spheroids of human cell lines and patient-derived xenograft cells was monitored using (1) reconstituted basement membrane/hyaluronan interfaces representing the space along brain vessels; (2) 3D scaffolds generated by multi-layered mouse astrocytes to reflect brain interstitium; and (3) freshly isolated mouse brain slice culture ex vivo. The invasion patterns in vitro were validated using histological analysis of brain sections from glioblastoma patients and glioma xenografts infiltrating the mouse brain. Each 3D assay recapitulated distinct aspects of major glioma invasion patterns identified in mouse xenografts and patient brain samples, including individually migrating cells, collective strands extending along blood vessels, and multicellular networks of interconnected glioma cells infiltrating the neuropil. In conjunction, these organotypic assays enable a range of invasion modes used by glioma cells and will be applicable for mechanistic analysis and targeting of glioma cell dissemination.

Characterization of Epicardial-Derived Cardiac Interstitial Cells: Differentiation and Mobilization of Heart Fibroblast Progenitors

PubMed Central

Ehrbar, Martin; Pérez-Pomares, José M.

2013-01-01

The non-muscular cells that populate the space found between cardiomyocyte fibers are known as ‘cardiac interstitial cells’ (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease. PMID:23349729

Cell cycle arrest and the evolution of chronic kidney disease from acute kidney injury.

PubMed

Canaud, Guillaume; Bonventre, Joseph V

2015-04-01

For several decades, acute kidney injury (AKI) was generally considered a reversible process leading to complete kidney recovery if the individual survived the acute illness. Recent evidence from epidemiologic studies and animal models, however, have highlighted that AKI can lead to the development of fibrosis and facilitate the progression of chronic renal failure. When kidney injury is mild and baseline function is normal, the repair process can be adaptive with few long-term consequences. When the injury is more severe, repeated, or to a kidney with underlying disease, the repair can be maladaptive and epithelial cell cycle arrest may play an important role in the development of fibrosis. Indeed, during the maladaptive repair after a renal insult, many tubular cells that are undergoing cell division spend a prolonged period in the G2/M phase of the cell cycle. These tubular cells recruit intracellular pathways leading to the synthesis and the secretion of profibrotic factors, which then act in a paracrine fashion on interstitial pericytes/fibroblasts to accelerate proliferation of these cells and production of interstitial matrix. Thus, the tubule cells assume a senescent secretory phenotype. Characteristic features of these cells may represent new biomarkers of fibrosis progression and the G2/M-arrested cells may represent a new therapeutic target to prevent, delay or arrest progression of chronic kidney disease. Here, we summarize recent advances in our understanding of the biology of the cell cycle and how cell cycle arrest links AKI to chronic kidney disease. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: Shared Mechanistic and Phenotypic Traits Suggest Overlapping Disease Mechanisms.

PubMed

Paulin, Francisco; Doyle, Tracy J; Fletcher, Elaine A; Ascherman, Dana P; Rosas, Ivan O

2015-01-01

The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

Microfluidic engineered high cell density three-dimensional neural cultures

NASA Astrophysics Data System (ADS)

Cullen, D. Kacy; Vukasinovic, Jelena; Glezer, Ari; La Placa, Michelle C.

2007-06-01

Three-dimensional (3D) neural cultures with cells distributed throughout a thick, bioactive protein scaffold may better represent neurobiological phenomena than planar correlates lacking matrix support. Neural cells in vivo interact within a complex, multicellular environment with tightly coupled 3D cell-cell/cell-matrix interactions; however, thick 3D neural cultures at cell densities approaching that of brain rapidly decay, presumably due to diffusion limited interstitial mass transport. To address this issue, we have developed a novel perfusion platform that utilizes forced intercellular convection to enhance mass transport. First, we demonstrated that in thick (>500 µm) 3D neural cultures supported by passive diffusion, cell densities <=5.0 × 103 cells mm-3 were required for survival. In 3D neuronal and neuronal-astrocytic co-cultures with increased cell density (>=104 cells mm-3), continuous medium perfusion at 2.0-11.0 µL min-1 improved viability compared to non-perfused cultures (p < 0.01), which exhibited widespread cell death and matrix degradation. In perfused cultures, survival was dependent on proximity to the perfusion source at 2.00-6.25 µL min-1 (p < 0.05); however, at perfusion rates of 10.0-11.0 µL min-1 survival did not depend on the distance from the perfusion source, and resulted in a preservation of cell density with >90% viability in both neuronal cultures and neuronal-astrocytic co-cultures. This work demonstrates the utility of forced interstitial convection in improving the survival of high cell density 3D engineered neural constructs and may aid in the development of novel tissue-engineered systems reconstituting 3D cell-cell/cell-matrix interactions.

Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator.

PubMed

Ibañez Rodriguez, María P; Noctor, Stephen C; Muñoz, Estela M

2016-01-01

The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. We applied systematic double, triple and quadruple labeling of cell-specific markers on prenatal, postnatal and mature rat pineal gland tissue combined with confocal microscopy to provide a comprehensive view of the cellular dynamics and cell lineages that contribute to pineal gland development. The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers.

Cell adhesion molecules expression pattern indicates that somatic cells arbitrate gonadal sex of differentiating bipotential fetal mouse gonad.

PubMed

Piprek, Rafal P; Kolasa, Michal; Podkowa, Dagmara; Kloc, Malgorzata; Kubiak, Jacek Z

2017-10-01

Unlike other organ anlagens, the primordial gonad is sexually bipotential in all animals. In mouse, the bipotential gonad differentiates into testis or ovary depending on the genetic sex (XY or XX) of the fetus. During gonad development cells segregate, depending on genetic sex, into distinct compartments: testis cords and interstitium form in XY gonad, and germ cell cysts and stroma in XX gonad. However, our knowledge of mechanisms governing gonadal sex differentiation remains very vague. Because it is known that adhesion molecules (CAMs) play a key role in organogenesis, we suspected that diversified expression of CAMs should also play a crucial role in gonad development. Using microarray analysis we identified 129 CAMs and factors regulating cell adhesion during sexual differentiation of mouse gonad. To identify genes expressed differentially in three cell lines in XY and XX gonads: i) supporting (Sertoli or follicular cells), ii) interstitial or stromal cells, and iii) germ cells, we used transgenic mice expressing EGFP reporter gene and FACS cell sorting. Although a large number of CAMs expressed ubiquitously, expression of certain genes was cell line- and genetic sex-specific. The sets of CAMs differentially expressed in supporting versus interstitial/stromal cells may be responsible for segregation of these two cell lines during gonadal development. There was also a significant difference in CAMs expression pattern between XY supporting (Sertoli) and XX supporting (follicular) cells but not between XY and XX germ cells. This indicates that differential CAMs expression pattern in the somatic cells but not in the germ line arbitrates structural organization of gonadal anlagen into testis or ovary. Copyright © 2017 Elsevier B.V. All rights reserved.

Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator

PubMed Central

Ibañez Rodriguez, María P.

2016-01-01

The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. We applied systematic double, triple and quadruple labeling of cell-specific markers on prenatal, postnatal and mature rat pineal gland tissue combined with confocal microscopy to provide a comprehensive view of the cellular dynamics and cell lineages that contribute to pineal gland development. The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers. PMID:27861587

A unique case of "double-orifice aortic valve"-comprehensive assessment by 2-, 3-dimensional, and color Doppler echocardiography.

PubMed

Stirrup, James E; Cowburn, Peter J; Pousios, Dimitrios; Ohri, Sunil K; Shah, Benoy N

2016-09-01

Transesophageal echocardiography (TEE) is a powerful imaging tool for the comprehensive assessment of valvular structure and function. TEE may be of added benefit when anatomy is difficult to delineate accurately by transthoracic echocardiography. In this article, we present 2-, 3-dimensional, and color Doppler TEE images from a male patient with aortic stenosis. A highly unusual and complex pattern of valvular calcification created a functionally "double-orifice" valve. Such an abnormality may have implications for the accuracy of continuous-wave Doppler echocardiography, which assumes a single orifice valve in native aortic valves. © 2016, Wiley Periodicals, Inc.

Septic pulmonary arteriovenous fistula. An unusual conduit for systemic embolization in right-sided valvular endocarditis.

PubMed

Stagaman, D J; Presti, C; Rees, C; Miller, D D

1990-06-01

Right-sided valvular (tricuspid, pulmonic) endocarditis is frequently complicated by septic pulmonary embolization. Systemic embolization may also rarely occur due to associated left-sided endocarditis or right-to-left shunting in patients with septal defects. This report documents the occurrence of systemic embolization causing a cerebrovascular accident in an intravenous drug abuser with recurrent tricuspid valve endocarditis due to an isolated peripheral septic pulmonary arteriovenous fistula. Noninvasive diagnosis of the fistula by cardiac auscultation, contrast echocardiography, and nuclear magnetic resonance imaging was confirmed by selective pulmonary angiography. Subselective balloon embolization of the pulmonary arteries feeding this fistula was accomplished.

Lyme Endocarditis.

PubMed

Paim, Ana C; Baddour, Larry M; Pritt, Bobbi S; Schuetz, Audrey N; Wilson, John W

2018-03-29

We describe a case of Lyme endocarditis which, to our knowledge, is the first reported case confirmed by molecular diagnostics in the United States. Valvular involvement as a manifestation of Lyme carditis is rare 4 . The first case describing a possible association between Lyme disease and cardiac valvular disease in the United States was published in 1993 5 . Since that time, there have been 2 cases of Lyme endocarditis confirmed by Borrelia positive 16S rRNA polymerase chain reaction (PCR) and sequencing from valvular tissue 8,10 and reported from Europe. We present the case of a 68-year-old male with progressive dyspnea had mitral valve perforation with severe mitral valve insufficiency and perforation seen on transesophageal echocardiogram. Subsequently resected valve tissue had sings of acute inflammation without organisms seen. Although blood and valve tissue cultures were negative, 16S rRNA PCR and sequencing demonstrated Borrelia burgdorferi. Lyme endocarditis can be a challenging diagnosis to confirm, given the rarity of cases and the need for molecular tools of resected valve tissue. It should be included among diagnostic possibilities in patients with culture-negative endocarditis who have exposure to ticks in endemic and emerging areas of Lyme disease. Copyright © 2018. Published by Elsevier Inc.

Current indications for left thoracotomy in coronary revascularization and valvular procedures.

PubMed

Pratt, J W; Williams, T E; Michler, R E; Brown, D A

2000-10-01

Left thoracotomy is infrequently used for cardiac procedures, but its application in reoperative and minimally invasive coronary revascularization and in valvular procedures has been reported recently. Three case reports and a review of the current literature illustrate the unique benefits of this approach for myocardial revascularization and valve replacement. Reoperative coronary revascularization of the left anterior descending and circumflex coronary arteries was performed off-pump via a left posterolateral thoracotomy. For the second case, this approach was used for coronary artery bypass grafting of the right coronary and left anterior descending arteries with femoral-femoral cardiopulmonary bypass in a patient with congestive heart failure and coronary artery disease who also required closure of a patent ductus arteriosus. In the third case, mitral valve replacement using femoral venous and aortic cannulation for cardiopulmonary bypass was performed via a left thoracotomy to avoid a retrosternal gastric conduit in a patient with severe mitral stenosis and congestive heart failure. All patients returned to normal activity and are asymptomatic. These case reports and a comprehensive review of the literature demonstrate the utility of left thoracotomy as an alternative approach to standard median sternotomy in selected cases of revascularization and valvular procedures.

Surgical Treatment of Valvular Heart Disease: Overview of Mechanical and Tissue Prostheses, Advantages, Disadvantages, and Implications for Clinical Use.

PubMed

Fiedler, Amy G; Tolis, George

2018-02-05

Valvular heart disease (VHD) affects a large number of patients annually. From a surgical standpoint, there are two primary options for valve replacement: mechanical or bioprosthetic. While there are clear advantages and disadvantages to either option, and recent literature does challenge some of the prior dictums of valve choice, a handful of absolutes remain true. Mechanical valves provide superior durability and freedom from re-operation when compared to their bioprosthetic counterparts, at the expense of bleeding or thrombotic complications associated with the need for lifelong oral anticoagulation. Unless a clear contraindication to oral anticoagulation exists, we recommend implanting mechanical valves for patients less than 60 years old and those who are older than 65 but maintained on anticoagulation for reasons other than their valvular disease. Bioprosthetic valves should be placed in patients who are greater than 65 years old or those patients who have a postoperative life expectancy of less than 10 years. Valve choice in patients between the ages of 60 to 70 is not dictated by guidelines and is less clear, with patient preference playing a larger role than their age range.

Platelet dysfunction detected at high shear in patients with heart valve disease.

PubMed

Francis, J L

2000-05-01

Whether patients with valvular heart disease have a defect of platelet function has been unclear. Despite evidence that these individuals have an abnormality detectable only under conditions of high shear stress, no methods have been widely available to adequately assess platelet function under such conditions. The Platelet Function Analyzer (PFA)-100 measures platelet function in a high shear environment and is well suited to the detection of platelet dysfunction in the clinical laboratory. The instrument records the time for platelets to occlude a membrane coated with collagen and either epinephrine (CEPI) or ADP (CADP). We studied the PFA-100 in 398 patients before open heart surgery; 308 for coronary artery bypass grafting (CABG) and 90 for aortic or mitral valve replacement (VR). Patients were classified as normal (CEPI < or = 153 s); 'aspirin effect' (CEPI > 153 s but CADP < or = 109 s) or abnormal (CEPI > 153 s and CADP > 109 s). In the CABG group, 41.2% were classified as normal, 43.2% as 'aspirin effect' and 15.6% as abnormal. In contrast, in patients undergoing VR, these values were 6.7, 11.1 and 82.4%, respectively. Patients with valvular disease had significantly longer closure times for both CEPI and CADP tests (P < 0.001). In addition, the valvular disease group had a significantly higher proportion of patients with markedly prolonged (> 150 s) closure times in the CADP cartridge (43.3 vs. 3.6%, respectively). Only one (0.3%) patient in the CABG group had non-closure (> 300 s) in the CADP test compared to seven (7.8%) in the valvular disease group. Three of six patients in the latter group bled excessively during surgery. We conclude that abnormal CADP closure is much more frequent among patients with aortic or mitral valve disease compared to those with coronary artery disease. This may reflect pre-existing high-shear damage to platelets that renders them refractory to subsequent shear activation and aggregation in the PFA-100 system. Further studies are needed to more precisely define the platelet defect in these patients. Markedly prolonged CADP closure in patients with valvular disease may indicate an increased likelihood of intra-operative bleeding, although an appropriately designed prospective study is needed to adequately address this hypothesis.

Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways

PubMed Central

Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, DL; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

2015-01-01

Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm2) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID:25435370

Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.

PubMed

Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, D L; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

2015-08-27

Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm(2)) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified.

Interstitial cells of Cajal in chagasic megaesophagus.

PubMed

de Lima, Marcus Aurelho; Cabrine-Santos, Marlene; Tavares, Marcelo Garcia; Gerolin, Gustavo Pacheco; Lages-Silva, Eliane; Ramirez, Luis Eduardo

2008-08-01

Chagasic visceromegalies are the most important digestive manifestations of Chagas disease and are characterized by motor disorders and dilation of organs such as esophagus and colon. One of the theories raised to explain the physiopathogenesis of chagasic megas is the plexus theory. Recent studies have shown a reduction of interstitial cells of Cajal (ICCs) in the colon of chagasic patients. These cells are present throughout the gastrointestinal tract and are considered to be pacemaker cells, that is, they are responsible for coordinating peristalsis and for mediating nerve impulses. In view of the lack of studies on these cells in megaesophagus and the previous observation of a reduction of ICCs in chagasic megacolons, we compared the distribution of ICCs in the esophagus of chagasic and nonchagasic patients to contribute to a better understanding of the physiopathogenesis of this esophageal disease. Esophageal biopsy samples from 10 chagasic and 5 nonchagasic patients were used. Cells were identified with the anti-CD117 antibody. The number of ICCs was quantified in longitudinal and circular muscle layers and myenteric plexus. The results were analyzed statistically by comparison of means. An intense reduction in the number of ICCs was observed in muscle layers and in the myenteric plexus of patients with megaesophagus. We conclude that there is an intense reduction of ICCs in the esophagus of chagasic patients when compared to nonchagasic patients, a finding supporting the important role of these cells in gastrointestinal tract motility. A deficiency in these cells might be implied in the genesis of megaesophagus.

Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features.

PubMed

Karvonen, Henna M; Lehtonen, Siri T; Sormunen, Raija T; Harju, Terttu H; Lappi-Blanco, Elisa; Bloigu, Risto S; Kaarteenaho, Riitta L

2012-09-01

The characteristic features of myofibroblasts in various lung disorders are poorly understood. We have evaluated the ultrastructure and invasive capacities of myofibroblasts cultured from small volumes of diagnostic bronchoalveolar lavage (BAL) fluid samples from patients with different types of lung diseases. Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and immunoelectron microscopy to achieve ultrastructural localization of alpha-smooth muscle actin (α-SMA) and fibronectin. The levels of α-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured cells were either fibroblasts or myofibroblasts. The structure of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions of myofibroblasts varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and α-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of myofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases.

Submicrostructure and typing of female genital condylomata.

PubMed

He, Y C; Shen, L S; Xie, Z J; Yang, C L; Li, H; Zheng, Y; Zhu, G C; Zhao, S Z; Wang, C X; Zhang, J H

1993-04-01

Thirty biopsies from female genital condylomata were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study structural characteristics and typing of condylomata. It was found that cytoplasmic clearing was marked in acuminate condylomata, diffuse interstitial and epithelial proliferation in nodular condylomata (flat condylomata), and invagination of the lesions into the interstitial tissue or glandular ducts in endophytic condylomata. In nodular condylomata, SEM also showed some structural features similar to those of intra-epithelial neoplasia. Microridges on the surface of squamous cells had villiform of granular changes. On the surface of a percentage of squamous or columnar cells, there were holes with a diameter of about 3 to 5 microns. A number of giant cells were seen among other cells. The cervical squamatization zone contained groups of special cells covered with dense microvilli. TEM of nodular condylomata revealed some pictures resembling active proliferation of tumor cells, such as enlarged or irregular nuclei (large N/C ratio), evaginated or invaginated nuclear membranes, condensed chromatin attached to the inner part of the nuclear membrane, transparent nucleoplasm, and frequent nucleosomes and karyokinesis. Virus particles with the morphological characteristics of HPV (naked hexagon-like particles with an average diameter of 45-50 nm) were seen in some nuclei with markedly condensed chromatin. It is suggested that HPV-induced genital condylomata, especially nodular one (flat condylomata), entail a potential progression to malignancy.

Interstitial telomeric repeats are not preferentially involved in radiation-induced chromosome aberrations in human cells.

PubMed

Desmaze, C; Pirzio, L M; Blaise, R; Mondello, C; Giulotto, E; Murnane, J P; Sabatier, L

2004-01-01

Telomeric repeat sequences, located at the end of eukaryotic chromosomes, have been detected at intrachromosomal locations in many species. Large blocks of telomeric sequences are located near the centromeres in hamster cells, and have been reported to break spontaneously or after exposure to ionizing radiation, leading to chromosome aberrations. In human cells, interstitial telomeric sequences (ITS) can be composed of short tracts of telomeric repeats (less than twenty), or of longer stretches of exact and degenerated hexanucleotides, mainly localized at subtelomeres. In this paper, we analyzed the radiation sensitivity of a naturally occurring short ITS localized in 2q31 and we found that this region is not a hot spot of radiation-induced chromosome breaks. We then selected a human cell line in which approximately 800 bp of telomeric DNA had been introduced by transfection into an internal euchromatic chromosomal region in chromosome 4q. In parallel, a cell line containing the plasmid without telomeric sequences was also analyzed. Both regions containing the transfected plasmids showed a higher frequency of radiation-induced breaks than expected, indicating that the instability of the regions containing the transfected sequences is not due to the presence of telomeric sequences. Taken together, our data show that ITS themselves do not enhance the formation of radiation-induced chromosome rearrangements in these human cell lines. Copyright 2003 S. Karger AG, Basel

Diffusion and interactions of interstitials in hard-sphere interstitial solid solutions

NASA Astrophysics Data System (ADS)

van der Meer, Berend; Lathouwers, Emma; Smallenburg, Frank; Filion, Laura

2017-12-01

Using computer simulations, we study the dynamics and interactions of interstitial particles in hard-sphere interstitial solid solutions. We calculate the free-energy barriers associated with their diffusion for a range of size ratios and densities. By applying classical transition state theory to these free-energy barriers, we predict the diffusion coefficients, which we find to be in good agreement with diffusion coefficients as measured using event-driven molecular dynamics simulations. These results highlight that transition state theory can capture the interstitial dynamics in the hard-sphere model system. Additionally, we quantify the interactions between the interstitials. We find that, apart from excluded volume interactions, the interstitial-interstitial interactions are almost ideal in our system. Lastly, we show that the interstitial diffusivity can be inferred from the large-particle fluctuations alone, thus providing an empirical relationship between the large-particle fluctuations and the interstitial diffusivity.

Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.

PubMed

Fischer, Rebecca S B; Vangala, Chandan; Truong, Luan; Mandayam, Sreedhar; Chavarria, Denis; Granera Llanes, Orlando M; Fonseca Laguna, Marcos U; Guerra Baez, Alvaro; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O

2018-03-01

Mesoamerican nephropathy is a devastating disease of unknown etiology that affects mostly young agricultural workers in Central America. An understanding of the mechanism of injury and the early disease process is urgently needed and will aid in identification of the underlying cause and direct treatment and prevention efforts. We sought to describe the renal pathology in Mesoamerican nephropathy at its earliest clinical appearance in prospectively identified acute case patients in Nicaragua. We considered those with elevated (or increased at least 0.3 mg/dL or 1.5-fold from baseline) serum creatinine, leukocyturia, and either leukocytosis or neutrophilia for inclusion in this biopsy study. Renal tissue was obtained by ultrasound-guided biopsy for examination by light, immunofluorescence, and electron microscopy. All 11 individuals who underwent renal biopsy showed tubulointerstitial nephritis, with varying degrees of inflammation and chronicity. Interstitial cellular infiltrates (predominantly T lymphocytes and monocytes), mostly in the corticomedullary junction; neutrophilic accumulation in the tubular lumens; largely preserved glomeruli; few mild ischemic changes; and no immune deposits were noted. The acute components of tubulointerstitial nephritis were acute tubular cell injury, interstitial edema, and early fibrosis. Chronic tubulointerstitial nephritis included severe tubular atrophy, thickened tubular basement membrane, and interstitial fibrosis. Thus, renal histopathology in Mesoamerican nephropathy reveals primary interstitial disease with intact glomeruli. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Production of Fibronectin by the Human Alveolar Macrophage: Mechanism for the Recruitment of Fibroblasts to Sites of Tissue Injury in Interstitial Lung Diseases

NASA Astrophysics Data System (ADS)

Rennard, Stephen I.; Hunninghake, Gary W.; Bitterman, Peter B.; Crystal, Ronald G.

1981-11-01

Because cells of the mononuclear phagocyte system are known to produce fibronectin and because alveolar macrophages are activated in many interstitial lung diseases, the present study was designed to evaluate a role for the alveolar macrophage as a source of the increased levels of fibronectin found in the lower respiratory tract in interstitial lung diseases and to determine if such fibronectin might contribute to the development of the fibrosis found in these disorders by being a chemoattractant for human lung fibroblasts. Production of fibronectin by human alveolar macrophages obtained by bronchoalveolar lavage and maintained in short-term culture in serum-free conditions was demonstrated; de novo synthesis was confirmed by the incorporation of [14C]proline. This fibronectin had a monomer molecular weight of 220,000 and was antigenically similar to plasma fibronectin. Macrophages from patients with idiopathic pulmonary fibrosis produced fibronectin at a rate 20 times higher than did normal macrophages; macrophages from patients with pulmonary sarcoidosis produced fibronectin at 10 times the normal rate. Macrophages from 6 of 10 patients with various other interstitial disorders produced fibronectin at rates greater than the rate of highest normal control. Human alveolar macrophage fibronectin was chemotactic for human lung fibroblasts, suggesting a functional role for this fibronectin in the derangement of the alveolar structures that is characteristic of these disorders.

Pulmonary hypertension in patients with interstitial lung disease.

PubMed

Karampitsakos, Theodoros; Tzouvelekis, Argyrios; Chrysikos, Serafeim; Bouros, Demosthenes; Tsangaris, Iraklis; Fares, Wassim H

2018-06-01

Interstitial lung diseases (ILDs) comprise a broad and heterogeneous group of more than two hundred diseases with common functional characteristics. Their diagnosis and management require a multidisciplinary approach. This multidisciplinary approach involves the assessment of comorbid conditions including pulmonary hypertension (PH) that exerts a dramatic impact on survival. The current World Health Organization (WHO) classification of PH encompasses many of the interstitial lung diseases into WHO Group 3, while sarcoidosis, Pulmonary Langerhans Cell Histiocytosis and lymphangioleiomyomatosis are placed into WHO Group 5 as diseases with unclear or multifactorial mechanisms. Connective tissue diseases could span any of the 5 WHO groups based on the primary phenotype into which they manifest. Interestingly, several challenging phenotypes present with features that overlap between two or more WHO PH groups. Currently, PH-specific treatment is recommended only for patients classified into WHO Group 1 PH. The lack of specific treatment for other groups, including PH in the setting of ILD, reflects the poor outcomes of these patients. Thus, identification of the optimal strategy for ILD patients with PH remains an amenable need. This review article provides a brief overview of biomarkers indicative of vascular remodeling in interstitial lung disease, summarizes the current state of knowledge regarding patients with PH and ILD and highlights future perspectives that remain to be addressed. Copyright © 2018 Elsevier Ltd. All rights reserved.

La interstitial defect-induced insulator-metal transition in the oxide heterostructures LaAl O3 /SrTi O3

NASA Astrophysics Data System (ADS)

Zhou, Jun; Yang, Ming; Feng, Yuan Ping; Rusydi, Andrivo

2017-11-01

Perovskite oxide interfaces have attracted tremendous research interest for their fundamental physics and promising all-oxide electronic applications. Here, based on first-principles calculations, we propose a surface La interstitial promoted interface insulator-metal transition in LaAl O3 /SrTi O3 (110). Compared with surface oxygen vacancies, which play a determining role on the insulator-metal transition of LaAl O3 /SrTi O3 (001) interfaces, we find that surface La interstitials can be more experimentally realistic and accessible for manipulation and more stable in an ambient atmospheric environment. Interestingly, these surface La interstitials also induce significant spin-splitting states with a Ti dy z/dx z character at a conducting LaAl O3 /SrTi O3 (110) interface. On the other hand, for insulating LaAl O3 /SrTi O3 (110) (<4 unit cells LaAl O3 thickness), a distortion between La (Al) and O atoms is found at the LaAl O3 side, partially compensating the polarization divergence. Our results reveal the origin of the metal-insulator transition in LaAl O3 /SrTi O3 (110) heterostructures, and also shed light on the manipulation of the superior properties of LaAl O3 /SrTi O3 (110) for different possibilities in electronic and magnetic applications.

Fibroblasts and the extracellular matrix in right ventricular disease.

PubMed

Frangogiannis, Nikolaos G

2017-10-01

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin-angiotensin-aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-β. Endothelin-1, TGF-βs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Elemental analysis of occupational and environmental lung diseases by electron probe microanalyzer with wavelength dispersive spectrometer.

PubMed

Takada, Toshinori; Moriyama, Hiroshi; Suzuki, Eiichi

2014-01-01

Occupational and environmental lung diseases are a group of pulmonary disorders caused by inhalation of harmful particles, mists, vapors or gases. Mineralogical analysis is not generally required in the diagnosis of most cases of these diseases. Apart from minerals that are encountered rarely or only in specific occupations, small quantities of mineral dusts are present in the healthy lung. As such when mineralogical analysis is required, quantitative or semi-quantitative methods must be employed. An electron probe microanalyzer with wavelength dispersive spectrometer (EPMA-WDS) enables analysis of human lung tissue for deposits of elements by both qualitative and semi-quantitative methods. Since 1993, we have analyzed 162 cases of suspected occupational and environmental lung diseases using an EPMA-WDS. Our institute has been accepting online requests for elemental analysis of lung tissue samples by EPMA-WDS since January 2011. Hard metal lung disease is an occupational interstitial lung disease that primarily affects workers exposed to the dust of tungsten carbide. The characteristic pathological findings of the disease are giant cell interstitial pneumonia (GIP) with centrilobular fibrosis, surrounded by mild alveolitis with giant cells within the alveolar space. EPMA-WDS analysis of biopsied lung tissue from patients with GIP has demonstrated that tungsten and/or cobalt is distributed in the giant cells and centrilobular fibrosing lesion in GIP. Pneumoconiosis, caused by amorphous silica, and acute interstitial pneumonia, associated with the giant tsunami, were also elementally analyzed by EPMA-WDS. The results suggest that commonly found elements, such as silicon, aluminum, and iron, may cause occupational and environmental lung diseases. Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: Analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy

PubMed Central

Winslow, Timothy B.; Eranki, Annu; Ullas, Soumya; Singh, Anurag K.; Repasky, Elizabeth A.; Sen, Arindam

2015-01-01

Purpose The tumour microenvironment is frequently hypoxic, poorly perfused, and exhibits abnormally high interstitial fluid pressure. These factors can significantly reduce efficacy of chemo and radiation therapies. The present study aims to determine whether mild systemic heating alters these parameters and improves response to radiation in human head and neck tumour xenografts in SCID mice. Materials and methods SCID mice were injected with FaDu cells (a human head and neck carcinoma cell line), or implanted with a resected patient head and neck squamous cell carcinoma grown as a xenograft, followed by mild systemic heating. Body temperature during heating was maintained at 39.5 ± 0.5 °C for 4 h. Interstitial fluid pressure (IFP), hypoxia and relative tumour perfusion in the tumours were measured at 2 and 24 h post-heating. Tumour vessel perfusion was measured 24 h post-heating, coinciding with the first dose of fractionated radiotherapy. Results Heating tumour-bearing mice resulted in significant decrease in intratumoural IFP, increased the number of perfused tumour blood vessels as well as relative tumour perfusion in both tumour models. Intratumoural hypoxia was also reduced in tumours of mice that received heat treatment. Mice bearing FaDu tumours heated 24 h prior to five daily radiation treatments exhibited significantly enhanced tumour response compared to tumours in control mice. Conclusions Mild systemic heating can significantly alter the tumour microenvironment of human head and neck tumour xenograft models, decreasing IFP and hypoxia while increasing microvascular perfusion. Collectively, these effects could be responsible for the improved response to radiotherapy. PMID:25986432

A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: Analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy.

PubMed

Winslow, Timothy B; Eranki, Annu; Ullas, Soumya; Singh, Anurag K; Repasky, Elizabeth A; Sen, Arindam

2015-01-01

The tumour microenvironment is frequently hypoxic, poorly perfused, and exhibits abnormally high interstitial fluid pressure. These factors can significantly reduce efficacy of chemo and radiation therapies. The present study aims to determine whether mild systemic heating alters these parameters and improves response to radiation in human head and neck tumour xenografts in SCID mice. SCID mice were injected with FaDu cells (a human head and neck carcinoma cell line), or implanted with a resected patient head and neck squamous cell carcinoma grown as a xenograft, followed by mild systemic heating. Body temperature during heating was maintained at 39.5 ± 0.5 °C for 4 h. Interstitial fluid pressure (IFP), hypoxia and relative tumour perfusion in the tumours were measured at 2 and 24 h post-heating. Tumour vessel perfusion was measured 24 h post-heating, coinciding with the first dose of fractionated radiotherapy. Heating tumour-bearing mice resulted in significant decrease in intratumoural IFP, increased the number of perfused tumour blood vessels as well as relative tumour perfusion in both tumour models. Intratumoural hypoxia was also reduced in tumours of mice that received heat treatment. Mice bearing FaDu tumours heated 24 h prior to five daily radiation treatments exhibited significantly enhanced tumour response compared to tumours in control mice. Mild systemic heating can significantly alter the tumour microenvironment of human head and neck tumour xenograft models, decreasing IFP and hypoxia while increasing microvascular perfusion. Collectively, these effects could be responsible for the improved response to radiotherapy.

Expression of the estrogen receptor GPER by testicular peritubular cells is linked to sexual maturation and male fertility

PubMed Central

Sandner, F; Welter, H; Schwarzer, JU; Köhn, FM; Urbanski, HF; Mayerhofer, A

2014-01-01

Besides the two nuclear estrogen receptors (ESR1/ESR2), the G protein-coupled estrogen receptor (GPER) was described in the human testis but little is known about testicular GPER during development or male infertility. We performed an immunohistochemical analysis using human and rhesus monkey testicular samples. The results obtained in adult primate testes showed GPER in interstitial and vascular cells as well as in the smooth muscle-like peritubular cells, which build the wall of seminiferous tubules. Expression of GPER was also found in cultured human testicular peritubular cells (HPTCs) by Western blotting and RT-PCR/sequencing. Furthermore, as seen in time-lapse videos of cultured cells, addition of a specific GPER agonist (G1) significantly reduced the numbers of HTPCs within 24 h. A GPER antagonist (G15) prevented this action, implying a role for GPER related to the control of cell proliferation or cell death of peritubular cells. Peritubular cell functions and their phenotype change, for example, during postnatal development and in cases of male infertility. The study of non-human primate samples revealed that GPER in peritubular cells was detectable only from the time of puberty onwards, while in samples from infantile and prepubertal monkeys only interstitial cells showed immunopositive staining. In testicular biopsies of men with mixed atrophy a reduction or loss of immunoreactive GPER was found in peritubular cells surrounding those tubules, in which spermatogenesis was impaired. In other cases of impaired spermatogenesis, namely when the tubular wall was fibrotically remodeled, a complete loss of GPER was seen. Thus, the observed inverse relation between the state of fertility and GPER expression by peritubular cells implies that the regulation of primate testicular peritubular cells by estrogens is mediated by GPER in both, health and disease. PMID:25052196

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion.

PubMed

Du, Yan; Cao, Manlin; Liu, Yiwen; He, Yiqing; Yang, Cuixia; Wu, Man; Zhang, Guoliang; Gao, Feng

2016-01-01

Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo . Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-β-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.

Elsholtzia ciliata (Thunb.) Hylander attenuates renal inflammation and interstitial fibrosis via regulation of TGF-ß and Smad3 expression on unilateral ureteral obstruction rat model.

PubMed

Kim, Tae-Won; Kim, Young-Jung; Seo, Chang-Seob; Kim, Hyun-Tae; Park, Se-Ra; Lee, Mee-Young; Jung, Ju-Young

2016-04-15

Renal interstitial fibrosis is characterized by excessive accumulation of extracellular matrix, which leads to end-stage renal failure. The aim of this study was to explore the effect of Elsholtzia ciliata (Thunb.) Hylander ethanol extract (ECE) on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). After quantitative analysis of ECE using the high performance liquid chromatography-photodiode array (HPLC-PDA) method, an in vitro study was performed to assess the anti-inflammatory and anti-fibrotic effects of ECE, using lipopolysaccharide (LPS) and transforming growth factor-ß (TGF-ß), respectively. For in vivo study, all male Sprague Dawley (SD) rats (n=10/group), except for those in the control group, underwent UUO. The rats were orally treated with water (control), captopril (positive control, 200 mg/kg), and ECE (300 and 500 mg/kg) for 14 days. In ECE, luteolin and rosmarinic acid were relatively abundant among the other flavonoids and phenolic acids. ECE treatment ameliorated LPS-induced overexpression of nuclear factor-κB, tumor necrosis factor (TNF-α), and interleukin-6 and improved oxidative stress in RAW 264.7 cells. Furthermore, ECE treatment suppressed TGF-ß-induced α-smooth muscle actin and matrix metalloproteinase 9 expression in human renal mesangial cells. In the UUO model, 14 consecutive days of ECE treatment improved UUO-induced renal damage and attenuated histopathological alterations and interstitial fibrosis. Moreover, the renal expression of TNF-α, TGF-ß, and Smad 3 were inhibited by ECE treatment. Taken together, the effects of ECE may be mediated by blocking the activation of TGF-ß and inflammatory cytokines, leading subsequently to degradation of the ECM accumulation pathway. Based on these findings, ECE might serve as an improved treatment strategy for renal fibrotic disease. Copyright © 2016 Elsevier GmbH. All rights reserved.

Novel actions of tissue-type plasminogen activator in chronic kidney disease: a paradigm shift

PubMed Central

Hu, Kebin; Mars, Wendy M.; Liu, Youhua

2009-01-01

Tissue-type plasminogen activator (tPA) is traditionally viewed as a simple serine protease whose main function is to convert plasminogen into biologically active plasmin. As a protease, tPA plays a crucial role in regulating blood fibrinolysis, in maintaining the homeostasis of extracellular matrix (ECM) and in modulating the post-translational activation of growth factors. However, emerging evidence indicates that tPA may also function as a cytokine that transmits its signal across the cell membrane, initiates a diverse array of intracellular signaling, and dictates gene expression in the nuclei. Structurally, tPA is a kringle-containing protein that shares significant similarity to other classic cytokines such as hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP). Although there is no dedicated receptor, tPA binds to the cell membrane low density lipoprotein (LDL) receptor-related protein-1 (LRP-1), triggers LRP-1 tyrosine phosphorylation, and activates various intracellular signaling. As a cytokine, tPA plays a pivotal role in the pathogenesis of renal interstitial fibrosis through diverse mechanisms. It induces matrix matelloproteinase-9 (MMP-9) gene expression in renal interstitial fibroblasts, which causes the destruction of the tubular basement membrane (TBM), thereby facilitating tubular epithelial to mesenchymal transition (EMT). tPA also potentiates myofibroblast activation from quiescent interstitial fibroblasts through LRP-1-mediated recruitment of β1 integrin signaling. Furthermore, tPA acts as a survival factor that protects renal interstitial fibroblasts/myofibroblasts from apoptosis, thereby resulting in an expansion of myofibroblast populations in diseased kidney. Together, a growing body of evidence has implicated tPA as a fibrogenic cytokine that promotes the progression of kidney diseases. These new findings have radically changed our conception of tPA in renal fibrogenesis and represent a paradigm shift towards uncovering its cytokine function. A better understanding of renal tPA biology will ultimately translate into more rational therapeutic remedies for patients with chronic kidney fibrosis. PMID:18508579

Interstitial Fluid Flow and Drug Delivery in Vascularized Tumors: A Computational Model

PubMed Central

Welter, Michael; Rieger, Heiko

2013-01-01

Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider–with the help of a theoretical model–the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells. PMID:23940570

An integrated approach in the diagnosis of smoking-related interstitial lung diseases.

PubMed

Caminati, Antonella; Cavazza, Alberto; Sverzellati, Nicola; Harari, Sergio

2012-09-01

Cigarette smoke consists of several chemical compounds with a variety of effects in many organs. In the lung, apart being the main cause of chronic obstructive pulmonary disease, carcinoma and idiopathic spontaneous pneumothorax, tobacco smoke is associated with interstitial lung diseases (ILDs), including respiratory bronchiolitis-associated ILD (RB-ILD), desquamative interstitial pneumonia (DIP), pulmonary Langerhans' cell histiocytosis (PLCH), idiopathic pulmonary fibrosis, acute eosinophilic pneumonia, ILD in rheumatoid arthritis and pulmonary haemorrhage in Goodpasture syndrome. This review will focus on the diseases with a stronger epidemiological association with tobacco smoke, namely RB-ILD, DIP and PLCH. Although the exact pathogenetic evidence linking smoking with these disorders is still not completely understood, there is growing evidence that tobacco smoke targets the terminal or respiratory bronchioles in these diseases, and the differences are reflective of the degree of severity of small airway and parenchymal reaction to the smoke exposure. Despite considerable clinical, radiological and histological overlap between RB-ILD, DIP and PLCH, it is useful to retain the separate classifications for prognostic and therapeutic implications.

Interstitial lung disease induced by alectinib (CH5424802/RO5424802).

PubMed

Ikeda, Satoshi; Yoshioka, Hiroshige; Arita, Machiko; Sakai, Takahiro; Sone, Naoyuki; Nishiyama, Akihiro; Niwa, Takashi; Hotta, Machiko; Tanaka, Tomohiro; Ishida, Tadashi

2015-02-01

A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy.

PubMed

Jungmann, Sven; Ludwig, Wolf-Dieter; Schönfeld, Nicolas; Blum, Torsten-Gerriet; Großwendt, Claudia; Boch, Christian; Rehbock, Beate; Griff, Sergej; Schmittel, Alexander; Bauer, Torsten T

2017-01-01

We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib.

Telocyte dynamics in psoriasis

PubMed Central

Manole, CG; Gherghiceanu, Mihaela; Simionescu, Olga

2015-01-01

The presence of telocytes (TCs) as distinct interstitial cells was previously documented in human dermis. TCs are interstitial cells completely different than dermal fibroblasts. TCs are interconnected in normal dermis in a 3D network and may be involved in skin homeostasis, remodelling, regeneration and repair. The number, distribution and ultrastructure of TCs were recently shown to be affected in systemic scleroderma. Psoriasis is a common inflammatory skin condition (estimated to affect about 0.1–11.8% of population), a keratinization disorder on a genetic background. In psoriasis, the dermis contribution to pathogenesis is frequently eclipsed by remarkable epidermal phenomena. Because of the particular distribution of TCs around blood vessels, we have investigated TCs in the dermis of patients with psoriasis vulgaris using immunohistochemistry (IHC), immunofluorescence (IF), and transmission electron microscopy (TEM). IHC and IF revealed that CD34/PDGFRα-positive TCs are present in human papillary dermis. More TCs were present in the dermis of uninvolved skin and treated skin than in psoriatic dermis. In uninvolved skin, TEM revealed TCs with typical ultrastructural features being involved in a 3D interstitial network in close vicinity to blood vessels in contact with immunoreactive cells in normal and treated skin. In contrast, the number of TCs was significantly decreased in psoriatic plaque. The remaining TCs demonstrated multiple degenerative features: apoptosis, membrane disintegration, cytoplasm fragmentation and nuclear extrusion. We also found changes in the phenotype of vascular smooth muscle cells in small blood vessels that lost the protective envelope formed by TCs. Therefore, impaired TCs could be a ‘missed’ trigger for the characteristic vascular pathology in psoriasis. Our data explain the mechanism of Auspitz’s sign, the most pathognomonic clinical sign of psoriasis vulgaris. This study offers new insights on the cellularity of psoriatic lesions and we suggest that TCs should be considered new cellular targets in forthcoming therapies. PMID:25991475

Mathematical modeling of atherosclerotic plaque destabilization: Role of neovascularization and intraplaque hemorrhage.

PubMed

Guo, Muyi; Cai, Yan; Yao, Xinke; Li, Zhiyong

2018-08-07

Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neovascularization and hemodynamic calculation with plaque destabilization for the quantitative evaluation of the role of neoangiogenesis and IPH in the vulnerable atherosclerotic plaque formation. An angiogenic microvasculature is generated by two-dimensional nine-point discretization of endothelial cell proliferation and migration from the vasa vasorum. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the plaque progression model, and described by the reaction-diffusion partial differential equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the vulnerable progression of an atherosclerotic plaque, including the expanding necrotic core, the exacerbated inflammation, the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the IPH. The important role of IPH in the plaque destabilization is evidenced by simulations with varied model parameters. It is found that the IPH can significantly speed up the plaque vulnerability by increasing necrotic core and thinning fibrous cap. In addition, the decreased MVD and vessel permeability may slow down the process of plaque destabilization by reducing the IPH dramatically. We envision that the present model and its future advances can serve as a valuable theoretical platform for studying the dynamic changes in the microenvironment during the plaque destabilization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Textural versus electrostatic exclusion-enrichment effects in the effective chemical transport within the cortical bone: a numerical investigation.

PubMed

Lemaire, T; Kaiser, J; Naili, S; Sansalone, V

2013-11-01

Interstitial fluid within bone tissue is known to govern the remodelling signals' expression. Bone fluid flow is generated by skeleton deformation during the daily activities. Due to the presence of charged surfaces in the bone porous matrix, the electrochemical phenomena occurring in the vicinity of mechanosensitive bone cells, the osteocytes, are key elements in the cellular communication. In this study, a multiscale model of interstitial fluid transport within bone tissues is proposed. Based on an asymptotic homogenization method, our modelling takes into account the physicochemical properties of bone tissue. Thanks to this multiphysical approach, the transport of nutrients and waste between the blood vessels and the bone cells can be quantified to better understand the mechanotransduction of bone remodelling. In particular, it is shown that the electrochemical tortuosity may have stronger implications in the mass transport within the bone than the purely morphological one. Copyright © 2013 John Wiley & Sons, Ltd.

Asbestos bodies in bronchoalveolar lavage fluid. A study of 20 asbestos-exposed individuals and comparison to patients with other chronic interstitial lung diseases

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

Roggli, V.L.; Piantadosi, C.A.; Bell, D.Y.

1986-09-01

We studied the asbestos body (AB) content of bronchoalveolar lavage fluid from 20 patients with a history of occupational asbestos exposure, 31 patients with sarcoidosis and 5 patients with idiopathic pulmonary fibrosis. The cellular lavage pellet was digested in sodium hypochlorite and filtered onto Nuclepore filters for AB quantification by light microscopy. ABs were found in 15 of 20 asbestos-exposed individuals, 9 of 31 sarcoidosis cases and 2 of 5 patients with idiopathic pulmonary fibrosis. There was a statistically significant difference in the number of ABs per million cells recovered or per milliliter of recovered lavage fluid in the asbestos-exposedmore » group as compared to the other categories of chronic interstitial lung disease. The highest levels occurred in patients with asbestosis. Large numbers of asbestos bodies in the lavage fluid (greater than 1 AB/10(6) cells) were indicative of considerable occupational asbestos exposure, whereas occasional bodies were a nonspecific finding.« less

Squamous cell carcinoma of the bladder mimicking interstitial cystitis and voiding dysfunction.

PubMed

Prudnick, Colton; Morley, Chad; Shapiro, Robert; Zaslau, Stanley

2013-01-01

Squamous cell carcinoma (SCC) of the bladder is a relatively uncommon cause of bladder cancer accounting for <5% of bladder tumors in the western countries. SCC has a slight male predominance and tends to occur in the seventh decade of life. The main presenting symptom of SCC is hematuria, and development of this tumor in the western world is associated most closely with chronic indwelling catheters and spinal cord injuries. A 39-year-old Caucasian female presented with bladder and lower abdominal pain, urinary frequency, and nocturia which was originally believed to be interstitial cystitis (IC) but was later diagnosed as SCC of the bladder. Presentation of SCC without hematuria is an uncommon presentation, but the absence of this symptom should not lead a practitioner to exclude the diagnosis of SCC. This case is being reported in an attempt to explain the delay and difficulty of diagnosis. Background on the risk factors for SCC of the bladder and the typical presenting symptoms of bladder SCC and IC are also reviewed.

Annihilating vacancies via dynamic reflection and emission of interstitials in nano-crystal tungsten

NASA Astrophysics Data System (ADS)

Li, Xiangyan; Duan, Guohua; Xu, Yichun; Zhang, Yange; Liu, Wei; Liu, C. S.; Liang, Yunfeng; Chen, Jun-Ling; Luo, G.-N.

2017-11-01

Radiation damage not only seriously degrades the mechanical properties of tungsten (W) but also enhances hydrogen retention in the material. Introducing a large amount of defect sinks, e.g. grain boundaries (GBs) is an effective method for improving radiation-resistance of W. However, the mechanism by which the vacancies are dynamically annihilated at long timescale in nano-crystal W is still not clear. The dynamic picture for eliminating vacancies with single interstitials and small interstitial-clusters has been investigated by combining molecular dynamics, molecular statics and object Kinetic Monte Carlo methods. On one hand, the annihilation of bulk vacancies was enhanced due to the reflection of an interstitial-cluster of parallel ≤ft< 1 1 1 \\right> crowdions by the GB. The interstitial-cluster was observed to be reflected back into the grain interior when approaching a locally dense GB region. Near this region, the energy landscape for the interstitial was featured by a shoulder, different to the decreasing energy landscape of the interstitial near a locally loose region as indicative of the sink role of the GB. The bulk vacancy on the reflection path was annihilated. On the other hand, the dynamic interstitial emission efficiently anneals bulk vacancies. The single interstitial trapped at the GB firstly moved along the GB quickly and clustered to be the di-interstitial therein, reducing its mobility to a value comparable to that that for bulk vacancy diffusion. Then, the bulk vacancy was recombined via the coupled motion of the di-interstitial along the GB, the diffusion of the vacancy towards the GB and the accompanying interstitial emission. These results suggest that GBs play an efficient role in improving radiation-tolerance of nano-crystal W via reflecting highly-mobile interstitials and interstitial-clusters into the bulk and annihilating bulk vacancies, and via complex coupling of in-boundary interstitial diffusion, clustering of the interstitial and vacancy diffusion in the bulk.

Effects of a simulated microgravity model on cell structure and function in rat testis and epididymis

NASA Technical Reports Server (NTRS)

Hadley, Jill A.; Hall, Joseph C.; O'Brien, Ami; Ball, Richard

1992-01-01

The effect of simulated microgravity on the structure and function of the testis and epididymis cells was investigated in rats subjected to 7 days of tail suspension. Results of a histological examination revealed presence of disorganized seminiferous tubules and accumulation of large multinucleated cells and spermatids in the lumen of the epididymis. In addition, decreases in the content of testis protein and in testosterone levels in the testis, the interstitial fluid, and the epididymis were observed.

Expression of inducible nitric oxide synthase in spontaneous bovine bronchopneumonia.

PubMed

Fligger, J M; Waldvogel, A S; Pfister, H; Jungi, T W

1999-09-01

The expression of inducible nitric oxide synthase (iNOS), major histocompatibility class II molecules (MHC-II), CD68, and the calcium-binding proteins S100A8 and S100A9 (also called MRP8 and MRP14, respectively) was assessed in lung tissues from cattle that succumbed to pneumonia. Expression patterns of these markers were related to the types of lung lesion. iNOS expression was only observed in lungs infected with Arcanobacterium pyogenes or Pasteurella haemolytica but not in lungs from cattle with subacute chronic interstitial pneumonia and acute interstitial pneumonia due to Escherichia coli infection. High levels of iNOS were expressed by cells (probably leukocytes) surrounding necrotic foci. Occasionally, iNOS was expressed by intraalveolar macrophages in viable parenchyma, by leukocytes within the airways, and by some chondrocytes in the supporting cartilage of bronchi. Cells expressing MHC-II were distributed relatively evenly throughout areas of inflammation and did not display any clear association with necrotic foci. Cell types expressing MHC-II included type II alveolar epithelial cells, spindle-shaped cells of the interstitium, cells in bronchus-associated lymphoid tissue, and leukocytes in lymph and blood vessels but largely excluded iNOS-positive cells. Likewise, CD68-positive cells were rarely positive for iNOS and were not confined to the areas surrounding necrotic tissue. As with MHC-II and CD68, there was little if any coexpression of iNOS and either of the S100 proteins tested. Thus, in cattle with necrotizing bronchopneumonia, iNOS-expressing cells were largely restricted to the cellular zone surrounding necrotic areas.

Lack of spontaneous and radiation-induced chromosome breakage at interstitial telomeric sites in murine scid cells.

PubMed

Wong, H-P; Mozdarani, H; Finnegan, C; McIlrath, J; Bryant, P E; Slijepcevic, P

2004-01-01

Interstitial telomeric sites (ITSs) in chromosomes from DNA repair-proficient mammalian cells are sensitive to both spontaneous and radiation-induced chromosome breakage. Exact mechanisms of this chromosome breakage sensitivity are not known. To investigate factors that predispose ITSs to chromosome breakage we used murine scid cells. These cells lack functional DNA-PKcs, an enzyme involved in the repair of DNA double-strand breaks. Interestingly, our results revealed lack of both spontaneous and radiation-induced chromosome breakage at ITSs found in scid chromosomes. Therefore, it is possible that increased sensitivity of ITSs to chromosome breakage is associated with the functional DNA double-strand break repair machinery. To investigate if this is the case we used scid cells in which DNA-PKcs deficiency was corrected. Our results revealed complete disappearance of ITSs in scid cells with functional DNA-PKcs, presumably through chromosome breakage at ITSs, but their unchanged frequency in positive and negative control cells. Therefore, our results indicate that the functional DNA double-strand break machinery is required for elevated sensitivity of ITSs to chromosome breakage. Interestingly, we observed significant differences in mitotic chromosome condensation between scid cells and their counterparts with restored DNA-PKcs activity suggesting that lack of functional DNA-PKcs may cause a defect in chromatin organization. Increased condensation of mitotic chromosomes in the scid background was also confirmed in vivo. Therefore, our results indicate a previously unanticipated role of DNA-PKcs in chromatin organisation, which could contribute to the lack of ITS sensitivity to chromosome breakage in murine scid cells. Copyright 2003 S. Karger AG, Basel

Acute resolution of pulmonary alveolar infiltrates in 10 dogs with pulmonary hypertension treated with sildenafil citrate: 2005-2014.

PubMed

Kellihan, Heidi B; Waller, Kenneth R; Pinkos, Alyssa; Steinberg, Howard; Bates, Melissa L

2015-09-01

To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. Ten client-owned dogs. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002). A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil. Copyright © 2015 Elsevier B.V. All rights reserved.

Inflammation and Fibrosis in Polycystic Kidney Disease.

PubMed

Song, Cheng Jack; Zimmerman, Kurt A; Henke, Scott J; Yoder, Bradley K

Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443-448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518-526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477-1485, 2008; Zeier et al., Kidney Int 42:1259-1265, 1992; Ibrahim, Sci World J 7:1757-1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317-330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129-144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980-989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522-534, 1993, Kidney Int 60:2087-2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809-1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863-868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis (Ta et al., Nephrology 18:317-330, 2013). These cytokines are produced by interstitial fibroblasts, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309-1318, 2012; Park et al., Am J Nephrol 32:169-178, 2010; Bhunia et al., Cell 109:157-168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic growth factors observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32-36, 2000; Wilson et al., J Cell Physiol 150:360-369, 1992; Song et al., Hum Mol Genet 18:2328-2343, 2009; Schieren et al., Nephrol Dial Transplant 21:1816-1824, 2006). These growth factors trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.

Radiation damage in cubic ZrO 2 and yttria-stabilized zirconia from molecular dynamics simulations

DOE PAGES

Aidhy, Dilpuneet S.; Zhang, Yanwen; Weber, William J.

2014-11-20

Here, we perform molecular dynamics simulation on cubic ZrO 2 and yttria-stabilized zirconia (YSZ) to elucidate defect cluster formation resulting from radiation damage, and evaluate the impact of Y-dopants. Interstitial clusters composed of split-interstitial building blocks, i.e., Zr-Zr or Y-Zr are formed. Moreover, oxygen vacancies control cation defect migration; in their presence, Zr interstitials aggregate to form split-interstitials whereas in their absence Zr interstitials remain immobile, as isolated single-interstitials. Y-doping prevents interstitial cluster formation due to sequestration of oxygen vacancies.

Effects of Electroacupuncture on Interstitial Cells of Cajal (ICC) Ultrastructure and Connexin 43 Protein Expression in the Gastrointestinal Tract of Functional Dyspepsia (FD) Rats.

PubMed

Zhang, Guoshan; Xie, Shen; Hu, Wei; Liu, Yuer; Liu, Mailan; Liu, Mi; Chang, Xiaorong

2016-06-14

BACKGROUND Gastrointestinal motility disorder is the main clinical manifestation in functional dyspepsia (FD) patients. Electroacupuncture is effective in improving gastrointestinal motility disorder in FD; however, the underlying mechanism remains unclear. It has been demonstrated that interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract, and the pacemaker potential is transmitted to nearby cells through gap junctions between ICC or ICC and the smooth muscle. Therefore, this study aimed to assess the effects of electroacupuncture on ICC ultrastructure and expression of the gap junction protein connexin 43 (Cx43) in FD rats. MATERIAL AND METHODS The animals were randomized into 3 groups: control, model, and electroacupuncture. Electroacupuncture was applied at Zusanli (ST36) in the electroacupuncture group daily for 10 days, while no electroacupuncture was applied to model group animals. RESULTS Ultrastructure of ICC recovered normally in gastric antrum and small intestine specimens was improved, with Cx43 expression levels in these tissues significantly increased in the electroacupuncture group compared with the model group. CONCLUSIONS These findings indicated that electroacupuncture is effective in alleviating ICC damage and reduces Cx43 levels in FD rats, and suggest that ICC and Cx43 are involved in electroacupuncture treatment in rats with FD to improve gastrointestinal motility disorders.

Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system

PubMed Central

Poole, Daniel P.; Lee, Mike; Tso, Patrick; Bunnett, Nigel W.; Yo, Sek Jin; Lieu, TinaMarie; Shiu, Amy; Wang, Jen-Chywan; Nomura, Daniel K.

2014-01-01

Lymphatic fluid is a plasma filtrate that can be viewed as having biological activity through the passive accumulation of molecules from the interstitial fluid. The possibility that lymphatic fluid is part of an active self-contained signaling process that parallels the endocrine system, through the activation of G-protein coupled receptors (GPCR), has remained unexplored. We show that the GPCR lysophosphatidic acid 5 (LPA5) is found in sensory nerve fibers expressing calcitonin gene-related peptide (CGRP) that innervate the lumen of lymphatic lacteals and enteric nerves. Using LPA5 as a model for nutrient-responsive GPCRs present on sensory nerves, we demonstrate that dietary protein hydrolysate (peptone) can induce c-Fos expression in enterocytes and nerves that express LPA5. Mesenteric lymphatic fluid (MLF) mobilizes intracellular calcium in cell models expressing LPA5 upon feeding in a time- and dose-dependent manner. Primary cultured neurons of the dorsal root ganglia expressing CGRP are activated by MLF, which is enhanced upon LPA5 overexpression. Activation is independent of the known LPA5 agonists, lysophosphatidic acid and farnesyl pyrophosphate. These data bring forth a pathway for the direct stimulation of sensory nerves by luminal contents and interstitial fluid. Thus, by activating LPA5 on sensory nerves, MLF provides a means for known and yet to be identified constituents of the interstitial fluid to act as signals to comprise a “neurolymphocrine” system. PMID:24578341

High levels of the extracellular matrix proteoglycan decorin are associated with inhibition of testicular function

PubMed Central

Adam, Marion; Urbanski, Henryk F.; Garyfallou, Vasilios T.; Welsch, Ulrich; Köhn, Frank M.; Schwarzer, J. Ullrich; Strauss, Leena; Poutanen, Matti; Mayerhofer, Artur

2011-01-01

Decorin (DCN), a component of the extracellular matrix of the peritubular wall and the interstitial areas of the human testis, can interact with growth factor (GF) signaling, thereby blocking downstream actions of GFs. In the present study the expression and regulation of DCN using both human testes and two experimental animal models, namely the rhesus monkey and mouse, were examined. DCN protein was present in peritubular and interstitial areas of adult human and monkey testes, while it was almost undetectable in adult wild-type mice. Interestingly, the levels and sites of testicular DCN expression in the monkeys were inversely correlated with testicular maturation markers. A strong DCN expression associated with the abundant connective tissue of the interstitial areas in the postnatal through prepubertal phases was observed. In adult and old monkeys the DCN pattern was similar to the one in normal human testes, presenting strong expression at the peritubular region. In the testes of both infertile men and in a mouse model of inflammation associated infertility (aromatase-overexpressing transgenic mice), the fibrotic changes and increased numbers of Tumor necrosis factor (TNF)-α-producing immune cells were shown to be associated with increased production of DCN. Furthermore, studies with human testicular peritubular cells isolated from fibrotic testis indicated that TNF-α significantly increased DCN production. The data, thus, show that an increased DCN level is associated with impaired testicular function, supporting our hypothesis that DCN interferes with paracrine signaling of the testis in health and disease. PMID:22413766

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

PubMed Central

Cogan, Joy D.; Zhao, Min; Mitchell, Daphne B.; Rives, Lynette; Markin, Cheryl; Garnett, Errine T.; Montgomery, Keri H.; Mason, Wendi R.; McKean, David F.; Powers, Julia; Murphy, Elissa; Olson, Lana M.; Choi, Leena; Cheng, Dong-Sheng; Blue, Elizabeth Marchani; Young, Lisa R.; Lancaster, Lisa H.; Steele, Mark P.; Brown, Kevin K.; Schwarz, Marvin I.; Fingerlin, Tasha E.; Schwartz, David A.; Lawson, William E.; Loyd, James E.; Zhao, Zhongming; Phillips, John A.; Blackwell, Timothy S.

2015-01-01

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families. Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. Measurements and Main Results: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function. Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis. PMID:25607374

Interstitial cystitis - resources

MedlinePlus

Resources - interstitial cystitis ... The following organizations are good resources for information on interstitial cystitis : Interstitial Cystitis Association -- www.ichelp.org National Institute of Diabetes and Digestive and Kidney Diseases -- www. ...

Increased radiation resistance in lithium-counterdoped silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Swartz, C. K.; Mehta, S.

1984-01-01

Lithium-counterdoped n(+)p silicon solar cells are found to exhibit significantly increased radiation resistance to 1-MeV electron irradiation when compared to boron-doped n(+)p silicon solar cells. In addition to improved radiation resistance, considerable damage recovery by annealing is observed in the counterdoped cells at T less than or equal to 100 C. Deep level transient spectroscopy measurements are used to identify the defect whose removal results in the low-temperature aneal. It is suggested that the increased radiation resistance of the counterdoped cells is primarily due to interaction of the lithium with interstitial oxygen.

TNF-α inhibits SCF, ghrelin, and substance P expressions through the NF-κB pathway activation in interstitial cells of Cajal.

PubMed

Ren, Keyu; Yong, Chunming; Yuan, Hao; Cao, Bin; Zhao, Kun; Wang, Jin

2018-01-01

Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1β, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1β and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.

Bcl-2 protects tubular epithelial cells from ischemia reperfusion injury by inhibiting apoptosis.

PubMed

Suzuki, Chigure; Isaka, Yoshitaka; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Takabatake, Yoshitsugu; Ito, Takahito; Takahara, Shiro; Imai, Enyu

2008-01-01

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of graft dysfunction in kidney transplantation subjected to ischemia. The mechanism that triggers inflammation and renal injury after ischemia remains to be elucidated; however, cellular stress may induce apoptosis during the first hours and days after transplantation, which might play a crucial role in early graft dysfunction. Bcl-2 is known to inhibit apoptosis induced by the etiological factors promoting ischemia and reperfusion injury. Accordingly, we hypothesized that an augmentation of the antiapoptotic factor Bcl-2 may thus protect tubular epithelial cells by inhibiting apoptosis, thereby ameliorating the subsequent tubulointerstitial injury. We examined the effects of Bcl-2 overexpression on ischemia-reperfusion (I/R) injury using Bcl-2 transgenic mice (Bcl-2 TG) and their wild-type littermates (WT). To investigate the effects of I/R injury, the left renal artery and vein were clamped for 45 min, followed by reperfusion for 0-96 h. Bcl-2 TG exhibited decreased active caspase protein in the tubular cells, which led to a reduction in TUNEL-positive apoptotic cells. Consequently, interstitial fibrosis and phenotypic changes were ameliorated in Bcl-2 TG. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R, and subsequent interstitial injury by inhibiting tubular apoptosis.

Conservation of the Nucleotide Excision Repair Pathway: Characterization of Hydra Xeroderma Pigmentosum Group F Homolog

PubMed Central

Barve, Apurva; Ghaskadbi, Saroj; Ghaskadbi, Surendra

2013-01-01

Hydra, one of the earliest metazoans with tissue grade organization and nervous system, is an animal with a remarkable regeneration capacity and shows no signs of organismal aging. We have for the first time identified genes of the nucleotide excision repair (NER) pathway from hydra. Here we report cloning and characterization of hydra homolog of xeroderma pigmentosum group F (XPF) gene that encodes a structure-specific 5′ endonuclease which is a crucial component of NER. In silico analysis shows that hydra XPF amino acid sequence is very similar to its counterparts from other animals, especially vertebrates, and shows all features essential for its function. By in situ hybridization, we show that hydra XPF is expressed prominently in the multipotent stem cell niche in the central region of the body column. Ectoderm of the diploblastic hydra was shown to express higher levels of XPF as compared to the endoderm by semi-quantitative RT-PCR. Semi-quantitative RT-PCR analysis also demonstrated that interstitial cells, a multipotent and rapidly cycling stem cell lineage of hydra, express higher levels of XPF mRNA than other cell types. Our data show that XPF and by extension, the NER pathway is highly conserved during evolution. The prominent expression of an NER gene in interstitial cells may have implications for the lack of senescence in hydra. PMID:23577191

Conservation of the nucleotide excision repair pathway: characterization of hydra Xeroderma Pigmentosum group F homolog.

PubMed

Barve, Apurva; Ghaskadbi, Saroj; Ghaskadbi, Surendra

2013-01-01

Hydra, one of the earliest metazoans with tissue grade organization and nervous system, is an animal with a remarkable regeneration capacity and shows no signs of organismal aging. We have for the first time identified genes of the nucleotide excision repair (NER) pathway from hydra. Here we report cloning and characterization of hydra homolog of xeroderma pigmentosum group F (XPF) gene that encodes a structure-specific 5' endonuclease which is a crucial component of NER. In silico analysis shows that hydra XPF amino acid sequence is very similar to its counterparts from other animals, especially vertebrates, and shows all features essential for its function. By in situ hybridization, we show that hydra XPF is expressed prominently in the multipotent stem cell niche in the central region of the body column. Ectoderm of the diploblastic hydra was shown to express higher levels of XPF as compared to the endoderm by semi-quantitative RT-PCR. Semi-quantitative RT-PCR analysis also demonstrated that interstitial cells, a multipotent and rapidly cycling stem cell lineage of hydra, express higher levels of XPF mRNA than other cell types. Our data show that XPF and by extension, the NER pathway is highly conserved during evolution. The prominent expression of an NER gene in interstitial cells may have implications for the lack of senescence in hydra.

EFFECTS OF CAGING DENSITY ON PITUITARY AND TESTICLE RELATED RESPONSES

EPA Science Inventory

Effects of caging density on pituitary and testicle related responses

A significant negative correlation between the incidence of testicular interstitial cell tumors (ICT) and of pituitary tumors (PT) in control male F344 rats is reported associated with the number of ani...

Fatal toxoplasmosis in a vinaceous Amazon parrot (Amazona vinacea).

PubMed

Ferreira, Francisco Carlos; Donatti, Rogerio Venâncio; Marques, Marcus Vinícius Romero; Ecco, Roselene; Preis, Ingred Sales; Shivaprasad, H L; Vilela, Daniel Ambrózio da Rocha; Martins, Nelson Rodrigo da Silva

2012-12-01

Toxoplasmosis was diagnosed in a vinaceous Amazon parrot based on histopathology and immunohistochemistry. The bird was prostrate on the bottom of the cage and died. Necropsy revealed edema and congestion of the lungs, cloudy air sacs, and mild hepatomegaly. Histopathology revealed severe pulmonary congestion and edema and interstitial mononuclear cell inflammation associated with many cysts containing bradyzoites of Toxoplasma gondii scattered throughout. The heart had mild multifocal lymphocytic myocarditis and free tachyzoites in the muscle fibers, and the kidneys had mild interstitial nephritis and a few cysts containing bradyzoites of T. gondii. Immunohistochemistry was negative for Sarcocystis falcatula and Neospora caninum and confirmed the protozoa as T. gondii. This is the first description of T. gondii in an endangered species ofa Brazilian psittacine.

External and interstitial radiation therapy of carcinoma of the oral tongue. A review of 32 years' experience.

PubMed

Fu, K K; Ray, J W; Chan, E K; Phillips, T L

1976-01-01

In 204 patients with squamous cell carcinoma of the oral tongue treated with radiation therapy, the most significant prognostic factors appeared to be the presence of neck lymph node metastasis on presentation and the status of the disease three months after treatment. The most common site of failure was the primary lesion, either alone or with neck disease. External irradiation alone was seldom successful. Use of peroral cone irradiation or interstitial implants, either alone or in combination with external irradiation, achieved good local control in early lesions. When the primary tumor was uncontrolled by radiation therapy, salvage with surgery was rare. When failure occurred in the neck alone, radical neck dissection was successful in the majority of cases.

Velo-cardio-facial and partial DiGeorge phenotype in a child with interstitial deletion at 10p13 - implications for cytogenetics and molecular biology

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

Lipson, A.; Sholler, G.; Issacs, D.

We report on a female with a interstitial deletion of 10p13 and a phenotype similar to that seen with the 22q deletion syndromes (DiGeorge/velo-cardio-facial). She had a posterior cleft palate, perimembranous ventricular septal defect, dyscoordinate swallowing, T-cell subset abnormalities, small ears, maxillary and mandibular hypoplasia, broad nasal bridge, deficient alae nasi, contractures of fingers and developmental delay. This could indicate homology of some developmental genes at 22q and 10p so that patients with the velocardiofacial phenotype who do not prove to be deleted on 22q are candidates for a 10p deletion. 58 refs., 3 figs.

Polycystic kidney disease in a European roe deer (Capreolus capreolus).

PubMed

Blutke, Andreas; März, Kristian; Matenaers, Cyrill; Oswald, Karl; Hermanns, Walter; Wanke, Rüdiger

2013-06-01

A severe case of polycystic nephropathy was seen in an adult European roe deer (Capreolus capreolus), culled in a German hunting district. The doe had bilaterally drastically enlarged kidneys, completely riddled with variably sized, fluid-filled cysts of up to 4 cm in diameter. Histopathologic and ultrastructural examination revealed disseminated formation of cysts with flattened epithelial cell linings in the entire renal parenchyma, as well as severe dilations of renal tubules, marked interstitial fibrosis, nephron atrophy, and chronic interstitial lymphoplasmacytic infiltrations in the intercystic kidney tissue. These morphologic findings most likely resemble the hallmarks of autosomal dominant polycystic disease in humans, and present the first detailed description of a case of polycystic kidney disease in a roe deer.

Inflammation induced by mast cell deficiency rather than the loss of interstitial cells of Cajal causes smooth muscle dysfunction in W/Wv mice

PubMed Central

Winston, John H.; Chen, Jinghong; Shi, Xuan-Zheng; Sarna, Sushil K.

2014-01-01

The initial hypothesis suggested that the interstitial cells of Cajal (ICC) played an essential role in mediating enteric neuronal input to smooth muscle cells. Much information for this hypothesis came from studies in W/Wv mice lacking ICC. However, mast cells, which play critical roles in regulating inflammation in their microenvironment, are also absent in W/Wv mice. We tested the hypothesis that the depletion of mast cells in W/Wv mice generates inflammation in fundus muscularis externa (ME) that impairs smooth muscle reactivity to Ach, independent of the depletion of ICC. We performed experiments on the fundus ME from wild type (WT) and W/Wv mice before and after reconstitution of mast cells by bone marrow transplant. We found that mast cell deficiency in W/Wv mice significantly increased COX-2 and iNOS expression and decreased smooth muscle reactivity to Ach. Mast cell reconstitution or concurrent blockade of COX-2 and iNOS restored smooth muscle contractility without affecting the suppression of c-kit in W/Wv mice. The expression of nNOS and ChAT were suppressed in W/Wv mice; mast cell reconstitution did not restore them. We conclude that innate inflammation induced by mast cell deficiency in W/Wv mice impairs smooth muscle contractility independent of ICC deficiency. The impairment of smooth muscle contractility and the suppression of the enzymes regulating the synthesis of Ach and NO in W/Wv mice need to be considered in evaluating the role of ICC in regulating smooth muscle and enteric neuronal function in W/Wv mice. PMID:24550836

Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion.

PubMed

Dave, Maneesh; Hayashi, Yujiro; Gajdos, Gabriella B; Smyrk, Thomas C; Svingen, Phyllis A; Kvasha, Sergiy M; Lorincz, Andrea; Dong, Haidong; Faubion, William A; Ordog, Tamas

2015-05-01

After allogeneic transplantation, murine stem cells (SCs) for interstitial cells of Cajal (ICCs), electrical pacemaker, and neuromodulator cells of the gut, were incorporated into gastric ICC networks, indicating in vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSCs), which are emerging as potential therapeutic agents against autoimmune diseases, including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SCs could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways. Isolated ICC-SCs were studied by transcriptome profiling, cytokine assays, flow cytometry, mixed lymphocyte reaction, and T-cell proliferation assay. Mice with acute and chronic colitis induced by dextran sulfate sodium and T-cell transfer, respectively, were administered ICC-SCs intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging. Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SCs preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SCs profoundly suppressed T-cell proliferation in vitro. Similar to MSCs, ICC-SCs strongly expressed cyclooxygenase 1/2 and basally secreted prostaglandin E2. Indomethacin, a cyclooxygenase inhibitor, countered the ICC-SC-mediated suppression of T-cell proliferation. In contrast, we found no role for regulatory T-cell-, programmed death receptor-, and transforming growth factor-β-mediated mechanisms reported in MSCs; and transcriptome profiling did not support a relationship between ICC-SCs and MSCs. Murine ICC-SCs belong to a class different from MSCs and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Regulation of prohibitin expression during follicular development and atresia in the mammalian ovary.

PubMed

Thompson, Winston E; Asselin, Eric; Branch, Alicia; Stiles, Jonathan K; Sutovsky, Peter; Lai, Liangxue; Im, Gi-Sun; Prather, Randall S; Isom, S Clay; Rucker, Edmund; Tsang, Benjamin K

2004-07-01

Prohibitin is a ubiquitous and highly conserved protein implicated as an important regulator in cell survival. Prohibitin content is inversely associated with cell proliferation, but it increases during granulosa cell differentiation as well as in earlier events of apoptosis in a temperature-sensitive granulosa cell line. In the present study, we have characterized the spatial expression patterns for prohibitin using established in vivo models for the induction of follicular development and atresia in the mammalian ovary. Comparative Western blot analyses of granulosa cell lysates from control ovaries and from ovaries primed with eCG or treated with eCG plus anti-eCG (gonadotropin withdrawal) were conducted. Prohibitin was immunolocalized in rat ovarian sections probed with antibodies against either proliferating cell nuclear antigen (PCNA) or cholesterol side-chain cleavage cytochrome P450 (P450(scc)) or in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeled sections. Additionally, porcine oocytes, zygotes, and blastocyts were also immunolocalized with prohibitin antibody. Immunolocalization revealed the presence of prohibitin in granulosa cells, theca-interstitial cells, and the oocyte. The results indicate that prohibitin protein expression in the gonadotropin-treated cells was upregulated. Immunoreactivity of prohibitin was inversely related to PCNA expression during follicular maturation and colocalized with P450(scc). Prohibitin appeared to be translocated from the cytoplasm to the nucleus in atretic follicles, germinal vesicle-stage oocytes, zygotes, and blastocysts. These results suggest that prohibitin has several functional regulatory roles in granulosa and theca-interstitial cells and in the ovum during follicular maturation and atresia. It is likely that prohibitin may play an important role in determining the fate of these cells and eventual follicular destiny.

Analysis of Dissolved Organic Nutrients in the Interstitial Water of Natural Biofilms.

PubMed

Tsuchiya, Yuki; Eda, Shima; Kiriyama, Chiho; Asada, Tomoya; Morisaki, Hisao

2016-07-01

In biofilms, the matrix of extracellular polymeric substances (EPSs) retains water in the interstitial region of the EPS. This interstitial water is the ambient environment for microorganisms in the biofilms. The nutrient condition in the interstitial water may affect microbial activity in the biofilms. In the present study, we measured the concentrations of dissolved organic nutrients, i.e., saccharides and proteins, contained in the interstitial water of biofilms formed on the stones. We also analyzed the molecular weight distribution, chemical species, and availability to bacteria of some saccharides in the interstitial water. Colorimetric assays showed that the concentrations of saccharides and proteins in the biofilm interstitial water were significantly higher (ca. 750 times) than those in the surrounding lake waters (p < 0.05). Chromatographic analyses demonstrated that the saccharides in the interstitial waters were mainly of low molecular-weight saccharides such as glucose and maltose, while proteins in the interstitial water were high molecular-weight proteins (over 7000 Da). Bacterial growth and production of EPS occurred simultaneously with the decrease in the low molecular-weight saccharide concentrations when a small portion of biofilm suspension was inoculated to the collected interstitial water, suggesting that the dissolved saccharides in the interstitial water support bacterial growth and formation of biofilms.

A novel approach: trans-ascending aorta balloon aortic valvuloplasty via sternotomy for treating severe valvular aortic stenosis in a low-weight infant.

PubMed

Gao, Lei; Wu, Qin; Xu, Xinhua; Zhao, Tianli; Jin, Wancun; Yang, Yifeng

2014-02-01

Severe congenital aortic stenosis in infants is a life-threatening congenital heart anomaly that is typically treated using percutaneous balloon aortic valvuloplasty. The usual route is the femoral artery under radiographic guidance. However, this procedure may be limited by the small size of the femoral artery in low-weight infants. An infant weighing only 7 kg with severe aortic stenosis (peak gradient was 103 mmHg) was successfully treated with a novel approach, that is trans-ascending aorta balloon aortic valvuloplasty guided by transesophageal echocardiography. The patient tolerated the procedure well, and no major complications developed. After the intervention, transesophageal echocardiography indicated a significant reduction of the aortic valvular peak gradient from 103 mmHg to 22 mmHg, no aortic regurgitation was found. Eighteen months after the intervention, echocardiography revealed that the aortic valvular peak gradient had increased to 38 mmHg and that still no aortic regurgitation had occurred. In our limited experience, trans-ascending aorta balloon aortic valvuloplasty for severe aortic stenosis under transesophageal echocardiography guidance effectively reduces the aortic peak gradient. As this is a new procedure, long-term follow up and management will need to be established. It may be an alternative technique to treat congenital aortic stenosis in low-weight patients.

Evaluation of atrial electromechanical conduction delay in case of hemodynamically insignificant rheumatic heart disease: A tissue Doppler study.

PubMed

Cagdas, Metin; Velibey, Yalcin; Guvenc, Tolga Sinan; Gungor, Baris; Guzelburc, Ozge; Calik, Nazmi; Ugur, Murat; Tekkesin, Ahmet Ilker; Gurkan, Kadir; Eren, Mehmet

2015-01-01

Atrial electromechanical delay (AEMD) that reflects delayed conduction may show us the clinical reflection of pathological changes in the atria. The main objective of the present study is to investigate AEMD in patients who had previous rheumatic carditis but without hemodynamically significant valvular disease. A total of 40 patients, previously diagnosed as rheumatic carditis but without significant valvular stenosis/regurgitation and atrial enlargement; and 39 age- and-sex matched controls were enrolled for the present study. Parameters of AEMD (lateral mitral annulus electromechanical delay, septal mitral annulus electromechanical delay and lateral tricuspid annulus electromechanical delay) were measured with tissue Doppler echocardiography and left intra-atrial and inter-atrial conduction times were calculated accordingly. A 24h ambulatory Holter monitoring was used in both groups to detect atrial fibrillation episodes and quantify atrial extrasystoles. Parameters of AEMD, including left intra-atrial and inter-atrial conduction times of subjects in the study group were longer compared to the control group (23.7 ± 7.0 vs. 18.3 ± 6.2). Increased AEMD is observed in patients with previous rheumatic carditis and no significant valvular stenosis/regurgitation and atrial enlargement, which may partly explain the increased incidence of atrial fibrillation observed in these patients.

Role of modern 3D echocardiography in valvular heart disease

PubMed Central

2014-01-01

Three-dimensional (3D) echocardiography has been conceived as one of the most promising methods for the diagnosis of valvular heart disease, and recently has become an integral clinical tool thanks to the development of high quality real-time transesophageal echocardiography (TEE). In particular, for mitral valve diseases, this new approach has proven to be the most unique, powerful, and convincing method for understanding the complicated anatomy of the mitral valve and its dynamism. The method has been useful for surgical management, including robotic mitral valve repair. Moreover, this method has become indispensable for nonsurgical mitral procedures such as edge to edge mitral repair and transcatheter closure of paravaluvular leaks. In addition, color Doppler 3D echo has been valuable to identify the location of the regurgitant orifice and the severity of the mitral regurgitation. For aortic and tricuspid valve diseases, this method may not be quite as valuable as for the mitral valve. However, the necessity of 3D echo is recognized for certain situations even for these valves, such as for evaluating the aortic annulus for transcatheter aortic valve implantation. It is now clear that this method, especially with the continued development of real-time 3D TEE technology, will enhance the diagnosis and management of patients with these valvular heart diseases. PMID:25378966

The emerging role of exercise testing and stress echocardiography in valvular heart disease.

PubMed

Picano, Eugenio; Pibarot, Philippe; Lancellotti, Patrizio; Monin, Jean Luc; Bonow, Robert O

2009-12-08

Exercise testing has an established role in the evaluation of patients with valvular heart disease and can aid clinical decision making. Because symptoms may develop slowly and indolently in chronic valve diseases and are often not recognized by patients and their physicians, the symptomatic, blood pressure, and electrocardiographic responses to exercise can help identify patients who would benefit from early valve repair or replacement. In addition, stress echocardiography has emerged as an important component of stress testing in patients with valvular heart disease, with relevant established and potential applications. Stress echocardiography has the advantages of its wide availability, low cost, and versatility for the assessment of disease severity. The versatile applications of stress echocardiography can be tailored to the individual patient with aortic or mitral valve disease, both before and after valve replacement or repair. Hence, exercise-induced changes in valve hemodynamics, ventricular function, and pulmonary artery pressure, together with exercise capacity and symptomatic responses to exercise, provide the clinician with diagnostic and prognostic information that can contribute to subsequent clinical decisions. Nevertheless, there is a lack of convincing evidence that the results of stress echocardiography lead to clinical decisions that result in better outcomes, and therefore large-scale prospective randomized studies focusing on patient outcomes are needed in the future.

Experience with single photon emission computerized tomography (SPECT) in follow-up of sternotomy healing.

PubMed

Harjula, A; Järvinen, A; Mattila, S; Porkka, L

1985-01-01

Single photon emission computerized tomography (SPECT) was performed thrice in ten patients undergoing open-heart surgery--preoperatively and 2 and 12 weeks postoperatively. The operations were done for ischemic heart disease (5), aortic valvular stenosis (2), aortic valvular insufficiency (1), leaking mitral prosthetic valve (1) and combined aortic and mitral valvular stenosis and insufficiency (1). The healing process in the longitudinally divided sternum was evaluated from the SPECT study. Four conventional static images in two dimensions were registered in anteroposterior, posteroanterior and left and right lateral projections. A tomographic study was done. Quantitative analyses were performed. The ratio of the sternal counts to the counts from a thoracic vertebra was calculated for use as a reference. The activity ratios showed a similar pattern in six cases, with initial increases and at 12 weeks slight decrease compared with the preoperative values. In two cases the activity was still increasing after 12 postoperative weeks. One patient, with sternotomy also one year previously, showed only slightly increased activity. The activity at the areas of the sternal wires was increased in six cases. The study thus revealed differing patterns of isotope uptake, although recovery was uneventful in all patients. The differences may reflect the possibility that the operative course and the preoperative clinical status can influence the healing mechanisms.

Development of a cryopreservation protocol for testicular interstitial cells with the account of temperature intervals for controlled cooling below -60°С.

PubMed

Gurina, T M; Pakhomov, A V; Kyryliuk, A L; Bozhok, G A

2011-04-01

A long course of anticancer therapy may lead to testicular steroidogenesis destruction. Cryopreservation of testicular interstitial cells (TIC) would be a strategy to protect hormonal and fertile potential of pre-pubertal boys treated with chemo - or radiotherapy. The aim of this research was to optimize protocols for freezing of TIC. Essential physical processes associated with the presence of dimethyl sulphoxide (Me(2)SO) in the cryoprotectant solution take place at the temperatures below -60°С. These processes are the eutectic crystallization at the stage of freezing and the recrystallization before the melting of the eutectic mixture at the stage of heating. Both of the processes affect the viability of the cells subjected to cryopreservation. Temperature intervals when these processes take place were determined by the method of thermoplastic deformation for 10% Me(2)SO selected for cryopreservation of TIC. Rat TIC were cryopreserved using five different protocols which varied in cooling rates within the chosen temperature intervals. Post-thaw cell viability and metabolic activity were evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining assays. Leydig cell recovery after cryopreservation was measured by 3-beta-hydroxysteroid dehydrogenase reaction. Based on the obtained results, the authors developed a cryopreservation protocol for TIC which makes it possible to achieve great cell viability due to using controlled cooling rates within the temperature intervals below -60°С. Copyright © 2011 Elsevier Inc. All rights reserved.

Intravital third harmonic generation microscopy of collective melanoma cell invasion

PubMed Central

Weigelin, Bettina; Bakker, Gert-Jan; Friedl, Peter

2012-01-01

Cancer cell invasion is an adaptive process based on cell-intrinsic properties to migrate individually or collectively, and their adaptation to encountered tissue structure acting as barrier or providing guidance. Whereas molecular and physical mechanisms of cancer invasion are well-studied in 3D in vitro models, their topographic relevance, classification and validation toward interstitial tissue organization in vivo remain incomplete. Using combined intravital third and second harmonic generation (THG, SHG), and three-channel fluorescence microscopy in live tumors, we here map B16F10 melanoma invasion into the dermis with up to 600 µm penetration depth and reconstruct both invasion mode and tissue tracks to establish invasion routes and outcome. B16F10 cells preferentially develop adaptive invasion patterns along preformed tracks of complex, multi-interface topography, combining single-cell and collective migration modes, without immediate anatomic tissue remodeling or destruction. The data suggest that the dimensionality (1D, 2D, 3D) of tissue interfaces determines the microanatomy exploited by invading tumor cells, emphasizing non-destructive migration along microchannels coupled to contact guidance as key invasion mechanisms. THG imaging further detected the presence and interstitial dynamics of tumor-associated microparticles with submicron resolution, revealing tumor-imposed conditioning of the microenvironment. These topographic findings establish combined THG, SHG and fluorescence microscopy in intravital tumor biology and provide a template for rational in vitro model development and context-dependent molecular classification of invasion modes and routes. PMID:29607252

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells

PubMed Central

Juliano, Celina E.; Reich, Adrian; Liu, Na; Götzfried, Jessica; Zhong, Mei; Uman, Selen; Reenan, Robert A.; Wessel, Gary M.; Steele, Robert E.; Lin, Haifan

2014-01-01

PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI–piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality. PMID:24367095

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells.

PubMed

Juliano, Celina E; Reich, Adrian; Liu, Na; Götzfried, Jessica; Zhong, Mei; Uman, Selen; Reenan, Robert A; Wessel, Gary M; Steele, Robert E; Lin, Haifan

2014-01-07

PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI-piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality.

Effectiveness, safety and costs of thromboembolic prevention in patients with non-valvular atrial fibrillation: phase I ESC-FA protocol study and baseline characteristics of a cohort from a primary care electronic database

PubMed Central

Vedia Urgell, Cristina; Roso-Llorach, Albert; Morros, Rosa; Capellà, Dolors; Castells, Xavier; Ferreira-González, Ignacio; Troncoso Mariño, Amelia; Diògene, Eduard; Elorza, Josep Mª; Casajuana, Marc; Bolíbar, Bonaventura; Violan, Concepció

2016-01-01

Purpose Atrial fibrillation is the most common arrhythmia. Its management aims to reduce symptoms and to prevent complications through rate and rhythm control, management of concomitant cardiac diseases and prevention of related complications, mainly stroke. The main objective of Effectiveness, Safety and Costs in Atrial Fibrillation (ESC-FA) study is to analyse the drugs used for the management of the disease in real-use conditions, particularly the antithrombotic agents for stroke prevention. The aim of this work is to present the study protocol of phase I of the ESC-FA study and the baseline characteristics of newly diagnosed patients with atrial fibrillation in Catalonia, Spain. Participants The data source is System for the Improvement of Research in Primary Care (SIDIAP) database. The population included are all patients with non-valvular atrial fibrillation diagnosis registered in the electronic health records during 2007–2012. Findings to date A total of 22 585 patients with non-valvular atrial fibrillation were included in the baseline description. Their mean age was 72.8 years and 51.6% were men. The most commonly prescribed antithrombotics were vitamin K antagonists (40.1% of patients) and platelet aggregation inhibitors (32.9%); 25.3% had not been prescribed antithrombotic treatment. Age, gender, comorbidities and co-medication at baseline were similar to those reported for previous studies. Future plans The next phase in the ESC-FA study will involve assessing the effectiveness and safety of antithrombotic treatments, analysing stroke events and bleeding episodes’ rates in our patients (rest of phase I), describing the current management of the disease and its costs in our setting, and assessing how the introduction of new oral anticoagulants changes the stroke prevention in non-valvular atrial fibrillation. PMID:26823179

[The best of valvular heart disease in 2005].

PubMed

de Gevigney, G

2006-01-01

The year 2005 has been rich in publications concerning valvular heart disease. In France, this year has been dominated by the publication of the French Society of Cardiologists' guidelines on the operative and interventional indications for acquired valvular heart disease: discussed and accepted formal indications based on the evidence in the literature. Non-ischaemic mitral insufficiency has been the subject of a major study that showed the high prognostic significance of echographic measuring of the area of the regurgitating orifice; patients with a surface > or =40 mm2 had a worse long-term prognosis and should undergo surgery early. The prognostic significance of BNP in valvular heart disease, such as mitral insufficiency and aortic stenosis, also became apparent. BNP is being used more and more for risk stratification for these conditions. The significance of anti-arrhythmic surgery combined with a mitral procedure has confirmed the harmful effect of atrial fibrillation, before and after the mitral surgery. The first randomised study into the use of statins to slow the progression of aortic stenosis was unfortunately disappointing, despite the various unrandomised studies that had opened a therapeutic pathway for this pathology, for which the prevalence is continually rising due to the ever increasing life expectancy. In mitral stenosis, a randomised study showed the long-term value of mitral commissurotomy in percutaneous mitral valvuloplasty, giving identical long-term results, in terms of mitral area, to those obtained with the classic Inoué balloon. In infectious endocarditis, surveys have confirmed the seriousness of this pathology as well as the slight advances in its prophylaxis. Other studies have confirmed the frequency and the severity of emboli, endocarditis due to Staphylococcus aureus, and the low risk of recurrence for endocarditis with the more and more accepted short course antibiotic treatment for patients undergoing surgery. Of course, this selection of publications is limited and by necessity subjective.

Transcatheter Pulmonary Valve Replacement by Hybrid Approach Using a Novel Polymeric Prosthetic Heart Valve: Proof of Concept in Sheep

PubMed Central

Xu, Tong-yi; Zhang, Zhi-gang; Li, Xin; Han, Lin; Xu, Zhi-yun

2014-01-01

Background Since 2000, transcatheter pulmonary valve replacement has steadily advanced. However, the available prosthetic valves are restricted to bioprosthesis which have defects like poor durability. Polymeric heart valve is thought as a promising alternative to bioprosthesis. In this study, we introduced a novel polymeric transcatheter pulmonary valve and evaluated its feasibility and safety in sheep by a hybrid approach. Methods We designed a novel polymeric trileaflet transcatheter pulmonary valve with a balloon-expandable stent, and the valve leaflets were made of 0.1-mm expanded polytetrafluoroethylene (ePTFE) coated with phosphorylcholine. We chose glutaraldehyde-treated bovine pericardium valves as control. Pulmonary valve stents were implanted in situ by a hybrid transapical approach in 10 healthy sheep (8 for polymeric valve and 2 for bovine pericardium valve), weighing an average of 22.5±2.0 kg. Angiography and cardiac catheter examination were performed after implantation to assess immediate valvular functionality. After 4-week follow-up, angiography, echocardiography, computed tomography, and cardiac catheter examination were used to assess early valvular function. One randomly selected sheep with polymeric valve was euthanized and the explanted valved stent was analyzed macroscopically and microscopically. Findings Implantation was successful in 9 sheep. Angiography at implantation showed all 9 prosthetic valves demonstrated orthotopic position and normal functionality. All 9 sheep survived at 4-week follow-up. Four-week follow-up revealed no evidence of valve stent dislocation or deformation and normal valvular and cardiac functionality. The cardiac catheter examination showed the peak-peak transvalvular pressure gradient of the polymeric valves was 11.9±5.0 mmHg, while that of two bovine pericardium valves were 11 and 17 mmHg. Gross morphology demonstrated good opening and closure characteristics. No thrombus or calcification was seen macroscopically. Conclusions This design of the novel ePTFE transcatheter pulmonary valve is safe and effective to deploy in sheep by hybrid approach, and the early valvular functionality is good. PMID:24926892

Position paper for the evaluation and management of oral status in patients with valvular disease: Groupe de Travail Valvulopathies de la Société Française de Cardiologie, Société Française de Chirurgie Orale, Société Française de Parodontologie et d'Implantologie Orale, Société Française d'Endodontie et Société de Pathologie Infectieuse de Langue Française.

PubMed

Millot, Sarah; Lesclous, Philippe; Colombier, Marie-Laure; Radoi, Loredana; Messeca, Clément; Ballanger, Mathieu; Charrier, Jean-Luc; Tramba, Philippe; Simon, Stéphane; Berrebi, Alain; Doguet, Fabien; Lansac, Emmanuel; Tribouilloy, Christophe; Habib, Gilbert; Duval, Xavier; Iung, Bernard

Oral health is of particular importance in patients with heart valve diseases because of the risk of infective endocarditis. Recommendations for antibiotic prophylaxis before dental procedures have been restricted, but the modalities of oral evaluation and dental care are not detailed in guidelines. Therefore, a multidisciplinary working group reviewed the literature to propose detailed approaches for the evaluation and management of buccodental status in patients with valvular disease. Simple questions asked by a non-dental specialist may draw attention to buccodental diseases. Besides clinical examination, recent imaging techniques are highly sensitive for the detection of inflammatory bone destruction directly related to oral or dental infection foci. The management of buccodental disease before cardiac valvular surgery should be adapted to the timing of the intervention. Simple therapeutic principles can be applied even before urgent intervention. Restorative dentistry and endodontic and periodontal therapy can be performed before elective valvular intervention and during the follow-up of patients at high risk of endocarditis. The detection and treatment of buccodental foci of infection should follow specific rules in patients who present with acute endocarditis. Implant placement is no longer contraindicated in patients at intermediate risk of endocarditis, and can also be performed in selected high-risk patients. The decision for implant placement should follow an analysis of general and local factors increasing the risk of implant failure. The surgical and prosthetic procedures should be performed in optimal safety conditions. It is therefore now possible to safely decrease the number of contraindicated dental procedures in patients at risk of endocarditis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Primary venous insufficiency increases risk of deep vein thrombosis.

PubMed

Shaydakov, Maxim E; Comerota, Anthony J; Lurie, Fedor

2016-04-01

Varicose veins have been recognized as a risk factor for deep vein thrombosis (DVT). However, venous reflux has not carried the same correlation. This study evaluated the association between primary valvular reflux and DVT. We performed a nested case-control study with enrollment of outpatients presenting to the vascular laboratory with signs and symptoms of DVT. All patients had a complete bilateral venous duplex examination evaluating for DVT and superficial and deep venous valvular reflux. Eighty-seven patients with confirmed DVT on venous duplex were selected for the study group. The control group was randomly selected from the same cohort in a 4:1 ratio matched by age and gender (n = 348). Groups were compared for the prevalence of deep and superficial reflux. DVT outpatients were 4.7-times more likely to have primary valvular reflux than symptomatic controls (65.5% vs 29.0%; 95% confidence interval [CI], 2.8-7.7; P < .000001). Deep reflux was 2.1-times more prevalent (36.8% vs 21.6%; odds ratio, 2.12; 95% CI, 1.28-3.51; P = .005) and superficial reflux was 4.6-times more prevalent (43.7% vs 14.4%; odds ratio, 4.62; 95% CI, 2.75-7.77; P < .0000001) in DVT patients than in controls. DVT patients were also 2.1-times more likely to have combined deep and superficial reflux than non-DVT patients (13.8% vs 6.6%, 95% CI, 1.08-4.75; P = .044). The prevalence of primary valvular reflux in patients with DVT is significantly higher than expected. Reflux may be considered as a novel risk factor for DVT. Two-thirds of patients with DVT have pre-existent primary chronic venous disease, which is likely to contribute to post-thrombotic morbidity. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies.

PubMed

Sachdev, Molly; Miller, William C; Ryan, Thomas; Jollis, James G

2002-12-01

Fenfluramine-derivative diet pills were withdrawn from the market in 1997 because of an association with valvular regurgitation, but subsequent estimates of the prevalence of this condition have varied widely. We systematically reviewed evidence regarding the prevalence of valvular disease after fenfluramine exposure. We searched multiple databases with multiple search terms. Conference proceedings from 1997 onward were searched by index. Authors of eligible studies were contacted to identify unpublished works. Selection criteria were liberally determined. Ten of the identified 11 articles met these criteria. Reviewers assessed the studies' methodologic quality by use of a standard form to evaluate selection, attrition, performance, and detection bias. The studies were analyzed in 2 groups on the basis of length of exposure (<90 days or >90 days). The Mantel-Haenszel method was used to summarize data. Quantitative and qualitative tests for heterogeneity were performed. Tests for publication bias were also done. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The pooled prevalence of valvular regurgitation meeting Food and Drug Administration criteria (at least mild aortic regurgitation or at least moderate mitral regurgitation) among patients treated for >90 days was 12.0% compared with 5.9% for the unexposed group (prevalence odds ratio 2.2, 95% CI 1.7-2.7). The combined analyses also identified a small but statistically significant increase in mitral regurgitation not previously identified by individual studies (exposed 3.5%, unexposed 1.8%, prevalence odds ratio 1.6, 95% CI 1.05-2.3). Among patients exposed for <90 days, a trend toward more regurgitation was not statistically significant by either combined Food and Drug Administration criteria (exposed 6.8%, unexposed 5.8%, prevalence odds ratio 1.4, 95% CI 0.8-2.4) or by individual valve. These data indicate that fenfluramine-associated valvular regurgitation is less common than initially reported, but still present in 1 of 8 patients treated for >90 days.

The Relationship between the (In-)Stability of NORs and Their Chromosomal Location: The Example of Cercopithecidae and a Short Review of Other Primates.

PubMed

Gerbault-Seureau, Michèle; Cacheux, Lauriane; Dutrillaux, Bernard

2017-01-01

Amongst Cercopithecidae, the species of the Cercopithecini tribe underwent a very active chromosome evolution, principally by fissions, which increased their chromosome number up to 72. In contrast, all the species of Papionini have fairly similar karyotypes with 42 chromosomes. In animals, nucleolus organizer regions (NORs) are generally considered as instable structures, which frequently vary in size, number, and location at both infra- and interspecific levels. Although in Cercopithecinae the NORs, involved in breaks, exchanges, and translocations, behave like fragile sites in somatic cells, their number and location appear to be very stable between species. Fluorescence in situ hybridization of a 28S rDNA probe on metaphase chromosomes displayed a unique interstitial location in either an acrocentric pair (in 12 species of Cercopithecini) or a metacentric pair (in 6 species of Papionini). A non-exhaustive survey of literature data on NOR location in other primates shows that numerical variations of the NORs principally depend on their location: most multiple NORs are in terminal positions, while almost all unique NORs are in interstitial positions. We propose that this correlation is the consequence of the selection against gametic imbalances involving the chromosomal material distal to the NORs, which is effective when they are interstitially, but not terminally, located. Thus, the consequences of the interstitial NOR instability for reproduction are essentially limited to their size variations, as observed in Cercopithecidae. © 2018 S. Karger AG, Basel.

Architecture of interstitial nodal spaces in the rodent renal inner medulla.

PubMed

Gilbert, Rebecca L; Pannabecker, Thomas L

2013-09-01

Every collecting duct (CD) of the rat inner medulla is uniformly surrounded by about four abutting ascending vasa recta (AVR) running parallel to it. One or two ascending thin limbs (ATLs) lie between and parallel to each abutting AVR pair, opposite the CD. These structures form boundaries of axially running interstitial compartments. Viewed in transverse sections, these compartments appear as four interstitial nodal spaces (INSs) positioned symmetrically around each CD. The axially running compartments are segmented by interstitial cells spaced at regular intervals. The pairing of ATLs and CDs bounded by an abundant supply of AVR carrying reabsorbed water, NaCl, and urea make a strong argument that the mixing of NaCl and urea within the INSs and countercurrent flows play a critical role in generating the inner medullary osmotic gradient. The results of this study fully support that hypothesis. We quantified interactions of all structures comprising INSs along the corticopapillary axis for two rodent species, the Munich-Wistar rat and the kangaroo rat. The results showed remarkable similarities in the configurations of INSs, suggesting that the structural arrangement of INSs is a highly conserved architecture that plays a fundamental role in renal function. The number density of INSs along the corticopapillary axis directly correlated with a loop population that declines exponentially with distance below the outer medullary-inner medullary boundary. The axial configurations were consistent with discrete association between near-bend loop segments and INSs and with upper loop segments lying distant from INSs.

Architecture of interstitial nodal spaces in the rodent renal inner medulla

PubMed Central

Gilbert, Rebecca L.

2013-01-01

Every collecting duct (CD) of the rat inner medulla is uniformly surrounded by about four abutting ascending vasa recta (AVR) running parallel to it. One or two ascending thin limbs (ATLs) lie between and parallel to each abutting AVR pair, opposite the CD. These structures form boundaries of axially running interstitial compartments. Viewed in transverse sections, these compartments appear as four interstitial nodal spaces (INSs) positioned symmetrically around each CD. The axially running compartments are segmented by interstitial cells spaced at regular intervals. The pairing of ATLs and CDs bounded by an abundant supply of AVR carrying reabsorbed water, NaCl, and urea make a strong argument that the mixing of NaCl and urea within the INSs and countercurrent flows play a critical role in generating the inner medullary osmotic gradient. The results of this study fully support that hypothesis. We quantified interactions of all structures comprising INSs along the corticopapillary axis for two rodent species, the Munich-Wistar rat and the kangaroo rat. The results showed remarkable similarities in the configurations of INSs, suggesting that the structural arrangement of INSs is a highly conserved architecture that plays a fundamental role in renal function. The number density of INSs along the corticopapillary axis directly correlated with a loop population that declines exponentially with distance below the outer medullary-inner medullary boundary. The axial configurations were consistent with discrete association between near-bend loop segments and INSs and with upper loop segments lying distant from INSs. PMID:23825077

Progression of renal fibrosis in congenital CKD model rats with reduced number of nephrons.

PubMed

Yasuda, Hidenori; Tochigi, Yuki; Katayama, Kentaro; Suzuki, Hiroetsu

2017-06-14

A congenital reduction in the number of nephrons is a critical risk factor for both onset of chronic kidney disease (CKD) and its progression to end-stage kidney disease (ESKD). Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and show progressive CKD. This study used an immunohistological method to assess glomerular and interstitial pathogenesis in male HPK rats aged 35-210days. CD68 positive-macrophages were found to infiltrate into glomeruli in HPK rats aged 35 and 70days and to infiltrate into interstitial tissue in rats aged 140 and 210days. HPK rats aged 35 and 70days showed glomerular hypertrophy, loss of normal linear immunostaining of podocine, and increased expression of PDGFr-β, TGF-β, collagens, and fibronectin, with all of these alterations gradually deteriorating with age. α-SMA-positive myofibroblasts were rarely detected in glomerular tufts, whereas α-SMA-positive glomerular parietal epithelium (GPE) cells were frequently observed along Bowman's capsular walls. The numbers of PDGFr-β-positive fibroblasts in interstitial tissue were increased in rats aged 35days and older, whereas interstitial fibrosis, characterized by the increased expression of tubular PDGF-BB, the appearance of myofibroblasts doubly positive for PDGFr-β and α-SMA, and increased expression of collagens and fibronectin, were observed in rats aged 70 and older. These results clearly indicate that congenital CKD with only 20% of nephrons cause renal fibrosis in rats. Copyright © 2017 Elsevier GmbH. All rights reserved.

Compared to the amniotic membrane, Wharton's jelly may be a more suitable source of mesenchymal stem cells for cardiovascular tissue engineering and clinical regeneration.

PubMed

Pu, Lei; Meng, Mingyao; Wu, Jian; Zhang, Jing; Hou, Zongliu; Gao, Hui; Xu, Hui; Liu, Boyu; Tang, Weiwei; Jiang, Lihong; Li, Yaxiong

2017-03-21

The success of developing cardiovascular tissue engineering (CTE) grafts greatly needs a readily available cell substitute for endothelial and interstitial cells. Perinatal annexes have been proposed as a valuable source of mesenchymal stem cells (MSCs) for tissue engineering and regenerative medicine. The objective of the present study is to evaluate the potential of human Wharton's jelly MSCs (WJ-MSCs) and amniotic membrane MSCs (AM-MSCs) as a seeding cell in CTE and cardiovascular regenerative medicine. WJ-MSCs/AM-MSCs were isolated and characterized in vitro according to their morphology, proliferation, self-renewal, phenotype, and multipotency. More importantly, the characteristics of hemocompatibility, extracellular matrix deposition, and gene expression and viability of both MSCs were investigated. Fibroblast-like human WJ-MSCs and AM-MSCs were successfully isolated and positively expressed the characteristic markers CD73, CD90, and CD105 but were negative for CD34, CD45, and HLA-DR. Both MSCs shared trilineage differentiation toward the adipogenic, osteogenic, and chondrogenic lineages. The proliferative and self-renewal capacity of WJ-MSCs was significantly higher than that of AM-MSCs (P < 0.001). WJ-MSCs provided comparable properties of antiplatelet adhesion and did not activate the coagulation cascade to endothelial cells. However, aggregated platelets were visualized on the surface of AM-MSCs-derived cell sheets and the intrinsic pathway was activated. Furthermore, WJ-MSCs have superior properties of collagen deposition and higher viability than AM-MSCs during cell sheet formation. This study highlights that WJ-MSCs could act as a functional substitute of endothelial and interstitial cells, which could serve as an appealing and practical single-cell source for CTE and regenerative therapy.

Vitamins E and C - effects on matrix components in the vascular system

USDA-ARS?s Scientific Manuscript database

The connective tissue in the vascular system, consisting mainly of vascular smooth muscle cells (VSMC) and the interstitial extracellular matrix (ECM), plays important roles in the maintenance of an intact vascular wall as well as in the repair of atherosclerotic lesions during disease development. ...

Diffusion of oxygen interstitials in UO2+x using kinetic Monte Carlo simulations: Role of O/M ratio and sensitivity analysis

NASA Astrophysics Data System (ADS)

Behera, Rakesh K.; Watanabe, Taku; Andersson, David A.; Uberuaga, Blas P.; Deo, Chaitanya S.

2016-04-01

Oxygen interstitials in UO2+x significantly affect the thermophysical properties and microstructural evolution of the oxide nuclear fuel. In hyperstoichiometric Urania (UO2+x), these oxygen interstitials form different types of defect clusters, which have different migration behavior. In this study we have used kinetic Monte Carlo (kMC) to evaluate diffusivities of oxygen interstitials accounting for mono- and di-interstitial clusters. Our results indicate that the predicted diffusivities increase significantly at higher non-stoichiometry (x > 0.01) for di-interstitial clusters compared to a mono-interstitial only model. The diffusivities calculated at higher temperatures compare better with experimental values than at lower temperatures (< 973 K). We have discussed the resulting activation energies achieved for diffusion with all the mono- and di-interstitial models. We have carefully performed sensitivity analysis to estimate the effect of input di-interstitial binding energies on the predicted diffusivities and activation energies. While this article only discusses mono- and di-interstitials in evaluating oxygen diffusion response in UO2+x, future improvements to the model will primarily focus on including energetic definitions of larger stable interstitial clusters reported in the literature. The addition of larger clusters to the kMC model is expected to improve the comparison of oxygen transport in UO2+x with experiment.

Electrical Coupling between the Myenteric Interstitial Cells of Cajal and Adjacent Muscle Layers in the Guinea-Pig Gastric Antrum

PubMed Central

Cousins, H M; Edwards, F R; Hickey, H; Hill, C E; Hirst, G D S

2003-01-01

Intracellular recordings were made from short segments of the muscular wall of the guinea-pig gastric antrum. Preparations were impaled using two independent microelectrodes, one positioned in the circular layer and the other either in the longitudinal layer, in the network of myenteric interstitial cells of Cajal (ICCmy) or in the circular layer. Cells in each layer displayed characteristic patterns of rhythmical activity, with the largest signals being generated by ICCmy. Current pulses injected into the circular muscle layer produced electrotonic potentials in each cell layer, indicating that the layers are electrically interconnected. The amplitudes of these electrotonic potentials were largest in the circular layer and smallest in the longitudinal layer. An analysis of electrical coupling between the three layers suggests that although the cells in each layer are well coupled to neighbouring cells, the coupling between either muscle layer and the network of ICCmy is relatively poor. The electrical connections between ICCmy and the circular layer did not rectify. In parallel immunohistochemical studies, the distribution of the connexins Cx40, Cx43 and Cx45 within the antral wall was determined. Only Cx43 was detected; it was widely distributed on ICCmy and throughout the circular smooth muscle layer, being concentrated around ICCIM, but was less abundant in the circular muscle layer immediately adjacent to ICCmy. Although the electrophysiological studies indicate that smooth muscle cells in the longitudinal muscle layer are electrically coupled to each other, none of the connexins examined were detected in this layer. PMID:12844505

Oxygen measurement in interstitially perfused cellularized constructs cultured in a miniaturized bioreactor.

PubMed

Raimondi, Manuela T; Giordano, Carmen; Pietrabissa, Riccardo

2015-12-18

The possibility of developing engineered tissue in vitro and maintaining the cell viability and functionality is primarily related to the possibility of controlling key culture parameters such as oxygen concentration and cell-specific oxygen consumption. We measured these parameters in a three-dimensional (3D) cellularized construct maintained under interstitially perfused culture in a miniaturized bioreactor. MG63 osteosarcoma cells were seeded at high density on a 3D polystyrene scaffold. The 3D scaffolds were sensorized with sensor foils made of a polymer, which fluoresce with intensity proportional to the local oxygen tension. Images of the sensor foil in contact with the cellularized construct were acquired with a video camera every four hours for six culture days and were elaborated with analytical imaging software to obtain oxygen concentration maps. The data collected indicate a globally decreasing oxygen concentration profile, with a total drop of 28% after six days of culture and an average drop of 10.5% between the inlet and outlet of the perfused construct. Moreover, by importing the measured oxygen concentration data and the cell counts in a model of mass transport, we calculated the cell-specific oxygen consumption over the whole culture period. The consumption increased with oxygen availability and ranged from 0.1 to 0.7 µmol/h/106 cells. The sensors used here allowed a non-invasive, contamination-free and non-destructive oxygen measurement over the whole culture period. This study is the basis for optimization of the culture parameters involved in oxygen supply, in order to guarantee maintenance of cell viability in our system.

Changes in the interstitial fluid and the muscle water in rabbits in hemorrhagic shock.

PubMed Central

Wolcott, M W; Malinin, T I; Wu, N M

1976-01-01

Dynamics and changes in the biochemical composition in the interstitial fluid and the muscle water were studied in hemorrhagic shock. The interstitial fluid was collected from implanted perforated capsules. Muscle biopsies were examined with regard to their water content by the steady state magnetic nuclear resonance spectroscopy. The consistent and what appears to be the most significant changes were the fall in the interstitial fluid pressures, the quantitative reduction of muscle water, a sharp fall in the blood and interstitial blood pH, the moderate hyperkalemia and lack of change in blood an interstitial fluid sodium, and the rise in blood glucose levels not accompanied by a rise in the interstitial fluid glucose levels. PMID:11754

The stem cell growth factor receptor KIT is not expressed on interstitial cells in bladder.

PubMed

Gevaert, Thomas; Ridder, Dirk De; Vanstreels, Els; Daelemans, Dirk; Everaerts, Wouter; Aa, Frank Van Der; Pintelon, Isabel; Timmermans, Jean-Pierre; Roskams, Tania; Steiner, Clara; Neuhaus, Jochen

2017-06-01

The mast/stem cell growth factor receptor KIT has long been assumed to be a specific marker for interstitial cells of Cajal (ICC) in the bladder, with possible druggable perspectives. However, several authors have challenged the presence of KIT + ICC in recent years. The aim of this study was therefore to attempt to clarify the conflicting reports on KIT expression in the bladder of human beings, rat, mouse and guinea pig and to elucidate the possible role of antibody-related issues and interspecies differences in this matter. Fresh samples were obtained from human, rat, mouse and guinea pig cystectomies and processed for single/double immunohistochemistry/immunofluorescence. Specific antibodies against KIT, mast cell tryptase (MCT), anoctamin-1 (ANO1) and vimentin were used to characterize the cell types expressing KIT. Gut (jejunum) tissue was used as an external antibody control. Our results revealed KIT expression on mast cells but not on ICC in human, rat, mouse and guinea pig bladder. Parallel immunohistochemistry showed KIT expression on ICC in human, rat, mouse and guinea pig gut, which confirmed the selectivity of the KIT antibody clones. In conclusion, we have shown that KIT + cells in human, rat, mouse and guinea pig bladder are mast cells and not ICC. The present report is important as it opposes the idea that KIT + ICC are present in bladder. In this perspective, functional concepts of KIT + ICC being involved in sensory and/or motor aspects of bladder physiology should be revised. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Cells competition in tumor growth poroelasticity

NASA Astrophysics Data System (ADS)

Fraldi, Massimiliano; Carotenuto, Angelo R.

2018-03-01

Growth of biological tissues has been recently treated within the framework of Continuum Mechanics, by adopting heterogeneous poroelastic models where the interaction between soft matrix and interstitial fluid flow is coupled with inelastic effects ad hoc introduced to simulate the macroscopic volumetric growth determined by cells division, cells growth and extracellular matrix changes occurring at the micro-scale level. These continuum models seem to overcome some limitations intrinsically associated to other alternative approaches based on mass balances in multiphase systems, because the crucial role played by residual stresses accompanying growth and nutrients walkway is preserved. Nevertheless, when these strategies are applied to analyze solid tumors, mass growth is usually assigned in a prescribed form that essentially copies the in vitro measured intrinsic growth rates of the cell species. As a consequence, some important cell-cell dynamics governing mass evolution and invasion rates of cancer cells, as well as their coupling with feedback mechanisms associated to in situ stresses, are inevitably lost and thus the spatial distribution and the evolution with time of the growth inside the tumor -which would be results rather than inputs- are forced to enter in the model simply as data. In order to solve this paradox, it is here proposed an enhanced multi-scale poroelastic model undergoing large deformations and embodying inelastic growth, where the net growth terms directly result from the "interspecific" predator-prey (Volterra/Lotka-like) competition occurring at the micro-scale level between healthy and abnormal cell species. In this way, a system of fully-coupled non-linear PDEs is derived to describe how the fight among cell species to grab the available common resources, stress field, pressure gradients, interstitial fluid flows driving nutrients and inhomogeneous growth all simultaneously interact to decide the tumor fate.

ERYTHROCYTE DERIVED MICROPARTICLES ACTIVATE PULMONARY ENDOTHELIAL CELLS IN A MURINE MODEL OF TRANSFUSION

PubMed Central

Chang, Alex L; Kim, Young; Seitz, Aaron P; Schuster, Rebecca M; Lentsch, Alex B; Pritts, Timothy A

2016-01-01

Erythrocyte-derived microparticles (MPs) are sub-micrometer, biologically active vesicles shed by red blood cells as part of the biochemical changes that occur during storage. We hypothesized that MPs from stored red blood cells would activate endothelial cells. MPs from aged murine packed red blood cells (pRBCs) were isolated and used to treat confluent layers of cultured endothelial cells. Endothelial expression of leukocyte adhesion molecules, ELAM-1 and ICAM-1, and inflammatory mediator, IL-6, were evaluated at 0.5, 6, 12, and 24 hours of treatment. Healthy C57BL/6 mice were transfused with a MP suspension and lung sections were analyzed for adhesion molecules and sequestered interstitial leukocytes. Increased levels of ELAM-1 and ICAM-1 were found on cultured endothelial cells 6 hours after MP stimulation (6.91 vs 4.07 relative fluorescent intensity, RFI, p<0.01, and 5.85 vs 3.55 RFI, p=0.01, respectively). IL-6 in cell culture supernatants was increased after 12 hours of MP stimulation compared to controls (1.24 vs 0.73 ng/ml, p=0.03). In vivo experiments demonstrated that MP injection increased ELAM-1 and ICAM-1 expression at 1 hour (18.56 vs 7.08 RFI, p<0.01, and 23.66 vs 6.87 RFI, p<0.01, respectively) and caused increased density of pulmonary interstitial leukocytes by 4 hours of treatment (69.25 vs 29.25 cells/HPF, p<0.01). This series of experiments supports our hypothesis that erythrocyte-derived MPs are able to activate pulmonary endothelium, leading to the pulmonary sequestration of leukocytes following the transfusion of stored pRBCs. PMID:27792124

The role of T cells in the pathogenesis of primary hypertension

PubMed Central

Quiroz, Yasmir; Johnson, Richard J.; Rodríguez-Iturbe, Bernardo

2012-01-01

Accumulating evidence indicates that T cells play an important role in the pathogenesis of hypertension. Here we review the investigations that have shown that T cells are infiltrating the kidney in hypertension. Interstitial accumulation of immune cells is associated with increments in oxidative stress and renal angiotensin II activity that result in the impairment in pressure natriuresis. The severity of salt-sensitive hypertension is directly correlated with the intensity of immune cell infiltration in the kidney. Reducing the renal infiltration of T cells prevents or ameliorates hypertension and the induction of tubulointerstitial inflammation results in salt-sensitive hypertension. The potential participation of autoimmune mechanisms in the renal infiltration of immune competent cells is discussed. PMID:23036901

Pramipexole in the treatment of Parkinson's disease: new developments.

PubMed

Möller, J Carsten; Oertel, Wolfgang H

2005-09-01

The nonergot dopamine agonist pramipexole is an efficient and safe drug for the treatment of Parkinson's disease. Clinicians may favor pramipexole over other dopamine agonists because of its suggested higher tolerability with respect to peripheral dopaminergic side effects. Importantly, nonergot dopamine agonists such as pramipexole may not cause restrictive valvular heart disease and may therefore represent the first choice in patients with valvular lesions under treatment with ergot dopamine agonists. However, particular caution has to be exercised in younger Parkinson's disease patients with a shorter disease duration regarding the occurrence of sudden onset of sleep. In light of cost-effectiveness and quality-of-life issues, its final significance for the initial treatment of patients with early Parkinson's disease remains to be determined.

Stability and migration of large oxygen clusters in UO(2+x): density functional theory calculations.

PubMed

Andersson, D A; Espinosa-Faller, F J; Uberuaga, B P; Conradson, S D

2012-06-21

Using ab initio molecular dynamics simulations and nudged elastic band calculations we examine the finite temperature stability, transition pathways, and migration mechanisms of large oxygen clusters in UO(2+x). Here we specifically consider the recently proposed split quad-interstitial and cuboctahedral oxygen clusters. It is shown that isolated cuboctahedral clusters may transform into more stable configurations that are closely linked to the split quad-interstitial. The split quad-interstitial is stable with respect to single interstitials occupying the empty octahedral holes of the UO(2) lattice. In order to better understand discrepancies between theory and experiments, the simulated atomic pair distribution functions for the split quad-interstitial structures are analyzed with respect to the distribution function for U(4)O(9) previously obtained from neutron diffraction data. Our nudged elastic band calculations suggest that the split quad-interstitial may migrate by translating one of its constituent di-interstitial clusters via a barrier that is lower than the corresponding barrier for individual interstitials, but higher than the barrier for the most stable di-interstitial cluster.

A case of hirsutism due to bilateral diffuse ovarian Leydig cell hyperplasia in a post-menopausal woman.

PubMed

Ali, F S.M.; Stanaway, S E.R.S.; Zakhour, H D.; Spearing, G; Bowen-Jones, D

2003-11-01

Hyperandrogenism in females usually results from ovarian or adrenal pathology. We present a case of virilizaton due to very rare bilateral ovarian diffuse interstitial proliferation of Leydig cells with no tumour or hilar cell hyperplasia identified. Interestingly, the case was further complicated by the finding of high levels of testosterone in one adrenal vein on selective venous sampling (SVS), resulting in an unnecessary unilateral adrenalectomy. Further sampling found high levels also in the ovarian veins, and the condition was finally cured by bilateral oophorectomy.

[Airway-centered interstitial fibrosis related to exposure to fumes from cleaning products].

PubMed

Serrano, Mario; Molina-Molina, María; Ramírez, José; Sánchez, Marcelo; Xaubet, Antoni

2006-10-01

Airway-centered interstitial fibrosis is a little known clinical entity that has only recently been described in the literature. Its pathology is characterized by bronchial fibrosis and localized interstitial pulmonary fibrosis around the airways. The disease has been associated with inhalation of a variety of substances, environmental or occupational, organic or inorganic. Clinical signs, radiographic manifestations, and lung function in patients with airway-centered interstitial fibrosis are similar to those of patients with idiopathic interstitial pneumonia. We describe a case of airway-centered interstitial fibrosis related to exposure to fumes from cleaning products.

Interstitial Lung Disease Induced by Osimertinib for Epidermal Growth Factor Receptor (EGFR) T790M-positive Non-small Cell Lung Cancer.

PubMed

Matsumoto, Yoshiya; Kawaguchi, Tomoya; Yamamoto, Norio; Sawa, Kenji; Yoshimoto, Naoki; Suzumura, Tomohiro; Watanabe, Tetsuya; Mitsuoka, Shigeki; Asai, Kazuhisa; Kimura, Tatsuo; Yoshimura, Naruo; Kuwae, Yuko; Hirata, Kazuto

2017-09-01

A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration. We diagnosed the patient to have interstitial lung disease induced by osimertinib.

Interstitial Lung Disease Induced by Osimertinib for Epidermal Growth Factor Receptor (EGFR) T790M-positive Non-small Cell Lung Cancer

PubMed Central

Matsumoto, Yoshiya; Kawaguchi, Tomoya; Yamamoto, Norio; Sawa, Kenji; Yoshimoto, Naoki; Suzumura, Tomohiro; Watanabe, Tetsuya; Mitsuoka, Shigeki; Asai, Kazuhisa; Kimura, Tatsuo; Yoshimura, Naruo; Kuwae, Yuko; Hirata, Kazuto

2017-01-01

A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration. We diagnosed the patient to have interstitial lung disease induced by osimertinib. PMID:28794368

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

Whinnery, J.E.; Young, J.T.

Albumin lung-scanning agents have a proven high degree of safety, with the only contraindication to their use being allergic hypersensitivity. We have used these agents to investigate the physiologic effects of high G/sub z/ acceleratory forces on pulmonary perfusion using the miniature swine. Multiple doses of human macroaggregated albumin and human-albumin microspheres were given to a miniature swine at various levels of centrifugal acceleration over a 6-wk period. The dosages given were the same per kilogram as those used for routine clinical human studies. The animal subsequently died from a severe granulomatous interstitial pneumonia. The granulomatous lesions suggest that themore » pathogenesis may have involved a cell-mediated delayed hypersensitivity. This interstitial pneumonia may represent the end point in a chronic hypersensitivity response to the human-albumin lung-scanning agents.« less

Protein vs electrolytes and all of the Starling forces.

PubMed

Peters, R M; Hargens, A R

1981-10-01

Hemodilution-induced reductions of the intravascular protein concentration in patients and experimental animals with intact capillaries do not lead to pulmonary edema, despite significant increases in the amount of extravascular water in the systemic interstitial space. The protective factors are a drop in the extravascular concentration of protein, a rise in interstitial tissue pressure, and an increase in lymph flow. If the capillary endothelium is damaged, protein leaks into the extravascular space, and protein infusion has a diminished effect on fluid exchange across the capillary. Whether capillaries are intact or injured, prevention of increases in capillary hydrostatic pressure is the most important factor in preventing pulmonary edema. Administration of hypertonic fluids may provide a useful method of limiting total fluid infusion and reducing cell swelling after blood loss.

Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

PubMed Central

Zhang, Bo; Hu, Yu; Pang, Zhiqing

2017-01-01

Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

Computer Simulations of the Tumor Vasculature: Applications to Interstitial Fluid Flow, Drug Delivery, and Oxygen Supply.

PubMed

Welter, Michael; Rieger, Heiko

2016-01-01

Tumor vasculature, the blood vessel network supplying a growing tumor with nutrients such as oxygen or glucose, is in many respects different from the hierarchically organized arterio-venous blood vessel network in normal tissues. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature. Integrative models, based on detailed experimental data and physical laws, implement, in silico, the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. This chapter provides an overview over the current status of computer simulations of vascular remodeling during tumor growth including interstitial fluid flow, drug delivery, and oxygen supply within the tumor. The model predictions are compared with experimental and clinical data and a number of longstanding physiological paradigms about tumor vasculature and intratumoral solute transport are critically scrutinized.

Interstitial space and collagen alterations of the developing rat diaphragm

NASA Technical Reports Server (NTRS)

Gosselin, L. E.; Martinez, D. A.; Vailas, A. C.; Sieck, G. C.

1993-01-01

The effect of growth on the relative interstitial space [%total cross-sectional area (CSA)] and collagen content of the rat diaphragm muscle was examined at postnatal ages of 0, 7, 14, and 21 days as well as in adult males. The proportion of interstitial space relative to total muscle CSA was determined by computerized image analysis of lectin-stained cross sections of diaphragm muscle. To assess collagen content and extent of collagen maturation (i.e., cross-linking), high-pressure liquid chromatography analysis was used to measure hydroxyproline concentration and the nonreducible collagen cross-link hydroxylysylpyridinoline (HP), respectively. At birth, interstitial space accounted for approximately 47% of total diaphragm muscle CSA. During postnatal growth, the relative contribution of interstitial space decreased such that by adulthood the interstitial space accounted for approximately 18% of total muscle CSA. The change in relative interstitial space occurred without a concomitant change in hydroxyproline concentration. However, the concentration of HP markedly increased with age such that the adult diaphragm contained approximately 17 times more HP than at birth. These results indicate that during development the relative CSA occupied by interstitial space decreases as muscle fiber size increases. However, the reduction in relative interstitial space is not associated with a change in collagen concentration. Thus collagen density in the interstitial space may increase with age. It is possible that the observed changes in relative interstitial space and collagen influence the passive length-force properties of the diaphragm.

Effects of non-leukocyte-reduced and leukocyte-reduced packed red blood cell transfusions on oxygenation of rat spinotrapezius muscle

PubMed Central

Sundararajan, Sripriya; Dodhy, Sami C.; Pittman, Roland N.; Lewis, Stephen J.

2015-01-01

Leukoreduction of blood used for transfusion alleviates febrile transfusion reactions, graft versus host disease and alloimmunization to leukocyte antigen. However, the actual clinical benefit of leukoreduction in terms of microcirculatory tissue O2 delivery after packed red blood cell (pRBC) transfusion has not been investigated. As such, the aim of this study was to determine the effects of non-leukoreduced (NLR) and leukoreduced (LR) fresh pRBC transfusion on interstitial oxygenation in anesthetized male Sprague-Dawley rats. Interstitial fluid PO2 and arteriolar diameters in spinotrapezius muscle preparations were monitored before and after transfusion with NLR- or LR-pRBCs. The major findings were that (1) transfusion of NLR-pRBCs significantly decreased interstitial oxygenation whereas transfusion of LR-pRBCs did not, and (2) transfusion with LR-pRBCs elicited a substantially greater increase in arterial blood pressure (ABP) than did transfusion with NLR-pRBCs. These changes in PO2 and ABP were not associated with changes in the diameters of resistance arterioles in the spinotrapezius muscle. These data suggest that transfusion of fresh NLR-pRBCs may negatively affect tissue oxygenation via enhanced leukocyte influx and decreased O2 delivery. They also suggest that leukocytes diminish the capability of transfused pRBCs to increase cardiac output. As such, transfusion of LR-pRBCs may be less deleterious on tissue PO2 levels than NLR-pRBCs although a concomitantly greater increase in ABP may accompany transfusion of LR-pRBCs. PMID:24189119

Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity.

PubMed

Green, Jenna; Endale, Mehari; Auer, Herbert; Perl, Anne-Karina T

2016-04-01

Epithelial-mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor α-green fluorescent protein (PDGFRα-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRα kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRα-expressing fibroblasts during alveolar regeneration were observed. Although CD140α(+)CD29(+) cells behaved as myofibroblasts, CD140α(+)CD34(+) appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRα kinase activity using the inhibitor nilotinib and a dominant-active PDGFRα-D842V mutation revealed that PDGFRα was important for matrix fibroblast differentiation. We demonstrated that PDGFRα signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRα independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy.

Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity

PubMed Central

Green, Jenna; Endale, Mehari; Auer, Herbert

2016-01-01

Epithelial–mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor α–green fluorescent protein (PDGFRα-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRα kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRα-expressing fibroblasts during alveolar regeneration were observed. Although CD140α+CD29+ cells behaved as myofibroblasts, CD140α+CD34+ appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRα kinase activity using the inhibitor nilotinib and a dominant-active PDGFRα-D842V mutation revealed that PDGFRα was important for matrix fibroblast differentiation. We demonstrated that PDGFRα signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRα independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy. PMID:26414960

Histopathology and immunophenotype of acrodermatitis chronica atrophicans correlated with ospA and ospC genotypes of Borrelia species.

PubMed

Brandt, Friederike C; Ertas, Beyhan; Falk, Thomas M; Metze, Dieter; Böer-Auer, Almut

2015-10-01

Chronic cutaneous borreliosis (acrodermatitis chronica atrophicans, ACA) is a relatively rare manifestation of borreliosis attributed mainly to Borrelia afzelii. Chronic borreliosis has been associated with ospA and ospC genotypes. Literature on molecular investigations of Borrelia in lesions of ACA is scant. Histopathological and immmunohistochemical features in 22 biopsies of ACA (16 patients) were examined. Paraffin-embedded biopsies were analyzed with polymerase chain reaction (PCR) assays targeting ospA and ospC genes, sequencing and phylogenetic analysis. Genotyping of ospA identified B. afzelii, serotype 2, in 12 of 16 patients. ospC-PCR was positive in seven patients revealing genotypes Af5 (n = 4), Af2 (n = 2) and Af6 (n = 1). Histopathologically, interstitial granulomatous infiltrates (CD68 positive) were common, combined with thickened collagen bundles and band-like infiltrates of CD4 positive T lymphocytes. Plasma cells were sparse/absent in 9 of 22 specimens even on staining with CD138. On CD34-staining, interstitial fibroblasts were often reduced akin to the situation in morphea. With assays targeting ospA and ospC genes we confirmed from paraffin-embedded biopsies that B. afzelii, serotype 2, osp C groups Af5, Af2 and Af6 is the main cause of ACA. Specimens commonly showed a combination of band-like T-cell-rich infiltrates with interstitial granulomatous features, a pattern previously under-recognized in ACA. This finding was particularly typical for lesions infected with ospC genotype Af5. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diabetic cardiomyopathy: Where are we 40 years later?

PubMed Central

Sharma, Vijay; McNeill, John H

2006-01-01

Diabetic cardiomyopathy is a cardiac disease that arises as a result of the diabetic state, independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology is incompletely understood, but appears to be initiated both by hyperglycemia and changes in cardiac metabolism. These changes induce oxidative stress and activate a number of secondary messenger pathways, leading to cardiac hypertrophy, fibrosis and cell death. Alterations in contractile proteins and intracellular ions impair excitation-contraction coupling, while decreased autonomic responsiveness and autonomic neuropathy impair its regulation. Extensive structural abnormalities also occur, which have deleterious mechanical and functional consequences. PMID:16568154

[Computed tomographic semiotics of respiratory tuberculosis in HIV-infected patients].

PubMed

Gavrilov, P V; Lazareva, A S; Malashenkov, E A

2013-01-01

to study the computed tomographic (CT) semiotics of respiratory tuberculosis in HIV-infected patients in relation to the degree of immunosuppression. The study enrolled 74 patients with verified respiratory tuberculosis in the presence of HIV infection. According to the degree of immunosuppression and the Centers for Disease Control (CDC) and Prevention classification (Atlanta, USA, 1993), the patients were divided into 3 groups: (1) CD4 > or = 500 cells/microl (n = 10); 2) CD4 200-499 cells/microl (n = 28); (3) CD4 <200 cells/microl (n = 36). With spiral CT, focal changes with a predominance of clear-cut foci are visualized at a high frequency in the patients with pulmonary tuberculosis in the presence of HIV infection. In progressive immunosuppression, the CT pattern displays atypical syndromes (frosted glass-type foci, interstitial infiltration, and thin-walled cavities) with the lower rate of alveolar infiltration with confluent foci, as well as lung tissue decay. Enlarged intrathoracic lymph nodes are characteristic of 70.0% of the patients with HIV infection and tuberculosis regardless of the level of CD4 cells. As immunosuppression progresses, the CT pattern of respiratory tuberculosis in the presence of HIV infection shows as atypical syndromes (unclearly defined frosted glass-type focal changes, interstitial infiltrations, and thin-walled cavernous masses). A marked polymorphism in changes and a high rate of lymph node involvement are characteristic.

Effects of Electroacupuncture on Interstitial Cells of Cajal (ICC) Ultrastructure and Connexin 43 Protein Expression in the Gastrointestinal Tract of Functional Dyspepsia (FD) Rats

PubMed Central

Zhang, Guoshan; Xie, Shen; Hu, Wei; Liu, Yuer; Liu, Mailan; Liu, Mi; Chang, Xiaorong

2016-01-01

Background Gastrointestinal motility disorder is the main clinical manifestation in functional dyspepsia (FD) patients. Electroacupuncture is effective in improving gastrointestinal motility disorder in FD; however, the underlying mechanism remains unclear. It has been demonstrated that interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract, and the pacemaker potential is transmitted to nearby cells through gap junctions between ICC or ICC and the smooth muscle. Therefore, this study aimed to assess the effects of electroacupuncture on ICC ultrastructure and expression of the gap junction protein connexin 43 (Cx43) in FD rats. Material/Methods The animals were randomized into 3 groups: control, model, and electroacupuncture. Electroacupuncture was applied at Zusanli (ST36) in the electroacupuncture group daily for 10 days, while no electroacupuncture was applied to model group animals. Results Ultrastructure of ICC recovered normally in gastric antrum and small intestine specimens was improved, with Cx43 expression levels in these tissues significantly increased in the electroacupuncture group compared with the model group. Conclusions These findings indicated that electroacupuncture is effective in alleviating ICC damage and reduces Cx43 levels in FD rats, and suggest that ICC and Cx43 are involved in electroacupuncture treatment in rats with FD to improve gastrointestinal motility disorders. PMID:27297942

The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype

PubMed Central

Thayer, Patrick; Balachandran, Kartik; Rathan, Swetha; Yap, Choon Hwai; Arjunon, Sivakkumar; Jo, Hanjoong; Yoganathan, Ajit P.

2017-01-01

Aortic valve interstitial cells (VIC) can exhibit phenotypic characteristics of fibroblasts, myofibroblasts, and smooth muscle cells. Others have proposed that valve cells become activated and exhibit myofibroblast or fibroblast characteristics during disease initiation and progression; however, the cues that modulate this phenotypic change remain unclear. We hypothesize that the mechanical forces experienced by the valve play a role in regulating the native phenotype of the valve and that altered mechanical forces result in an activated phenotype. Using a novel ex vivo cyclic stretch and pressure bioreactor, we subjected porcine aortic valve (AV) leaflets to combinations of normal and pathological stretch and pressure magnitudes. The myofibroblast markers α-SMA and Vimentin, along with the smooth muscle markers Calponin and Caldesmon, were analyzed using immunohistochemistry and immunoblotting. Tissue structure was analyzed using Movat’s pentachrome staining. We report that pathological stretch and pressure inhibited the contractile and possibly myofibroblast phenotypes as indicated by downregulation of the proteins α-SMA, Vimentin, and Calponin. In particular, Calponin downregulation implies depolymerization of actin filaments and possible conversion to a more synthetic (non-contractile) phenotype. This agreed well with the increase in spongiosa and fibrosa thickness observed under elevated pressure and stretch that are typically indicative of increased matrix synthesis. Our study therefore demonstrates how cyclic stretch and pressure may possibly act together to modulate the AVIC phenotype. PMID:21347552

Survival-Related Autophagic Activity Versus Procalcific Death in Cultured Aortic Valve Interstitial Cells Treated With Critical Normophosphatemic-Like Phosphate Concentrations

PubMed Central

Bonetti, Antonella; Della Mora, Alberto; Contin, Magali; Gregoraci, Giorgia; Tubaro, Franco; Marchini, Maurizio; Ortolani, Fulvia

2017-01-01

Valve dystrophic calcification is a common disorder affecting normophosphatemic subjects. Here, cultured aortic valve interstitial cells (AVICs) were treated 3 to 28 days with phosphate (Pi) concentrations spanning the normal range in humans (0.8, 1.3, and 2.0 mM) alone or supplemented with proinflammatory stimuli to assess possible priming of dystrophic-like calcification. Compared with controls, spectrophotometric analyses revealed marked increases in calcium amounts and alkaline phosphatase activity for 2.0-mM-Pi-containing cultures, with enhancing by proinflammatory mediators. Ultrastructurally, AVICs treated with low/middle Pi concentrations showed an enormous endoplasmic reticulum (ER) enclosing organelle debris, so apparently executing a survival-related atypical macroautophagocytosis, consistently with ultracytochemical demonstration of ER-associated acid phosphatase activity and decreases in autophagosomes and immunodetectable MAP1LC3. In contrast, AVICs cultured at 2.0-mM Pi underwent mineralization due to intracellular release and peripheral layering of phospholipid-rich material acting as hydroxyapatite nucleator, as revealed by Cuprolinic Blue and von Kossa ultracytochemical reactions. Lack of immunoblotted caspase-3 cleaved form indicated apoptosis absence for all cultures. In conclusion, fates of cultured AVICs were crucially driven by Pi concentration, suggesting that serum Pi levels just below the upper limit of normophosphatemia in humans may represent a critical watershed between macroautophagy-associated cell restoring and procalcific cell death. PMID:28112549

Ca2+ influx in the endothelial cells is required for the bradykinin-induced endothelium-dependent contraction in the porcine interlobar renal artery

PubMed Central

Ihara, Eikichi; Derkach, Dmitry N; Hirano, Katsuya; Nishimura, Junji; Nawata, Hajime; Kanaide, Hideo

2001-01-01

To determine the mechanism of bradykinin-induced production of endothelium-derived contracting factors, we monitored the changes in cytosolic Ca2+ concentration ([Ca2+]i) in in situ endothelial cells in porcine aortic valvular strips and the changes in [Ca2+]i of smooth muscle cells and force in porcine interlobar renal arterial strips using front-surface fluorometry of fura-2. In the presence of Nω-nitro-l-arginine methyl ester, bradykinin caused an endothelium-dependent transient elevation of [Ca2+]i and contraction in smooth muscle in the interlobar renal artery. This contraction was completely inhibited by a prostaglandin H2/thromboxane A2 receptor antagonist. In the absence of extracellular Ca2+, bradykinin failed to induce contraction. However, replenishing extracellular Ca2+ to 0.75 mm and higher induced an instantaneous contraction. However, replenishing Ca2+per se did not induce any contraction in the absence of bradykinin. Pretreatment with either 10−5m 1-(β-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenethyl)-1H-imidazole hydrochloride (SKF96365) or 0.2 mm Ni2+ abolished the contraction induced by bradykinin in the presence of extracellular Ca2+. Treatment with 10−5m indomethacin completely inhibited the contractile response induced by Ca2+ replenishment, regardless of the timing of its application, before or after the application of bradykinin. In endothelial cells in the valvular strips, bradykinin caused a transient [Ca2+]i elevation in the presence of 1.25 mm extracellular Ca2+, but [Ca2+]i returned to the resting level within 10 min. Neither 10−5m SKF96365 nor 0.2 mm Ni2+ had any effect on the peak [Ca2+]i elevation, but decreased [Ca2+]i in the declining phase. In the absence of extracellular Ca2+, bradykinin induced a transient [Ca2+]i elevation to a level similar to that seen in the presence of 1.25 mm extracellular Ca2+. However, [Ca2+]i then rapidly returned to the prestimulation level within 5 min. Subsequent Ca2+ replenishment to 0.75 mm and higher in the presence of bradykinin elevated [Ca2+]i to significantly higher levels than the resting level seen in the media containing 1.25 mm Ca2+. In conclusion, Ca2+ influx in the endothelial cells is essential for bradykinin to induce endothelium-dependent contraction in the porcine interlobar renal artery. PMID:11483701

Extending the analytical window for water-soluble organic matter in sediments by aqueous Soxhlet extraction

NASA Astrophysics Data System (ADS)

Schmidt, Frauke; Koch, Boris P.; Witt, Matthias; Hinrichs, Kai-Uwe

2014-09-01

Dissolved organic matter (DOM) in marine sediments is a complex mixture of thousands of individual constituents that participate in biogeochemical reactions and serve as substrates for benthic microbes. Knowledge of the molecular composition of DOM is a prerequisite for a comprehensive understanding of the biogeochemical processes in sediments. In this study, interstitial water DOM was extracted with Rhizon samplers from a sediment core from the Black Sea and compared to the corresponding water-extractable organic matter fraction (<0.4 μm) obtained by Soxhlet extraction, which mobilizes labile particulate organic matter and DOM. After solid phase extraction (SPE) of DOM, samples were analyzed for the molecular composition by Fourier Transform Ion-Cyclotron Resonance Mass Spectrometry (FT-ICR MS) with electrospray ionization in negative ion mode. The average SPE extraction yield of the dissolved organic carbon (DOC) in interstitial water was 63%, whereas less than 30% of the DOC in Soxhlet-extracted organic matter was recovered. Nevertheless, Soxhlet extraction yielded up to 4.35% of the total sedimentary organic carbon, which is more than 30-times the organic carbon content of the interstitial water. While interstitial water DOM consisted primarily of carbon-, hydrogen- and oxygen-bearing compounds, Soxhlet extracts yielded more complex FT-ICR mass spectra with more peaks and higher abundances of nitrogen- and sulfur-bearing compounds. The molecular composition of both sample types was affected by the geochemical conditions in the sediment; elevated concentrations of HS- promoted the early diagenetic sulfurization of organic matter. The Soxhlet extracts from shallow sediment contained specific three- and four-nitrogen-bearing molecular formulas that were also detected in bacterial cell extracts and presumably represent proteinaceous molecules. These compounds decreased with increasing sediment depth while one- and two-nitrogen-bearing molecules increased, resulting in a higher similarity of both sample types in the deep sediment. In summary, Soxhlet extraction of sediments accessed a larger and more complex pool of organic matter than present in interstitial water DOM.

Shear-Sensitive Genes in Aortic Valve Endothelium

PubMed Central

Fernández Esmerats, Joan; Heath, Jack

2016-01-01

Abstract Significance: Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction. Recent Advances: While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms—proteins, sugars, and membrane structures—at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-β signaling and Wnt/β-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD. Critical Issues: While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease. Future Directions: Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401–414. PMID:26651130

Coherex WAVECREST I Left Atrial Appendage Occlusion Study

ClinicalTrials.gov

2015-01-13

Non-valvular Paroxysmal, Persistent, or Permanent Atrial Fibrillation; LAA Anatomy Amenable to Treatment by Percutaneous Technique; Anticoagulation Indication for Potential Thrombus Formation in the Left Atrium

Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

PubMed

Lollinga, Wouter T; de Wit, Raymond H; Rahbar, Afsar; Vasse, Gwenda F; Davoudi, Belghis; Diepstra, Arjan; Riezebos-Brilman, Annelies; Harmsen, Martin C; Hillebrands, Jan-Luuk; Söderberg-Naucler, Cecilia; van Son, Willem J; Smit, Martine J; Sanders, Jan-Stephan; van den Born, Jacob

2017-03-01

Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Conserved and Divergent Features of Mesenchymal Progenitor Cell Types within the Cortical Nephrogenic Niche of the Human and Mouse Kidney.

PubMed

Lindström, Nils O; Guo, Jinjin; Kim, Albert D; Tran, Tracy; Guo, Qiuyu; De Sena Brandine, Guilherme; Ransick, Andrew; Parvez, Riana K; Thornton, Matthew E; Basking, Laurence; Grubbs, Brendan; McMahon, Jill A; Smith, Andrew D; McMahon, Andrew P

2018-03-01

Cellular interactions among nephron, interstitial, and collecting duct progenitors drive mammalian kidney development. In mice, Six2 + nephron progenitor cells (NPCs) and Foxd1 + interstitial progenitor cells (IPCs) form largely distinct lineage compartments at the onset of metanephric kidney development. Here, we used the method for analyzing RNA following intracellular sorting (MARIS) approach, single-cell transcriptional profiling, in situ hybridization, and immunolabeling to characterize the presumptive NPC and IPC compartments of the developing human kidney. As in mice, each progenitor population adopts a stereotypical arrangement in the human nephron-forming niche: NPCs capped outgrowing ureteric branch tips, whereas IPCs were sandwiched between the NPCs and the renal capsule. Unlike mouse NPCs, human NPCs displayed a transcriptional profile that overlapped substantially with the IPC transcriptional profile, and key IPC determinants, including FOXD1 , were readily detected within SIX2 + NPCs. Comparative gene expression profiling in human and mouse Six2/SIX2 + NPCs showed broad agreement between the species but also identified species-biased expression of some genes. Notably, some human NPC-enriched genes, including DAPL1 and COL9A2 , are linked to human renal disease. We further explored the cellular diversity of mesenchymal cell types in the human nephrogenic niche through single-cell transcriptional profiling. Data analysis stratified NPCs into two main subpopulations and identified a third group of differentiating cells. These findings were confirmed by section in situ hybridization with novel human NPC markers predicted through the single-cell studies. This study provides a benchmark for the mesenchymal progenitors in the human nephrogenic niche and highlights species-variability in kidney developmental programs. Copyright © 2018 by the American Society of Nephrology.

Extracellular ATP decreases trophoblast invasion, spiral artery remodeling and immune cells in the mesometrial triangle in pregnant rats.

PubMed

Spaans, F; Melgert, B N; Chiang, C; Borghuis, T; Klok, P A; de Vos, P; van Goor, H; Bakker, W W; Faas, M M

2014-08-01

Preeclampsia is characterized by deficient trophoblast invasion and spiral artery remodeling, a process governed by inflammatory cells. High levels of the danger signal extracellular adenosine triphosphate (ATP) have been found in women with preeclampsia and infusion of ATP in pregnant rats induced preeclampsia-like symptoms such as albuminuria and placental ischemia. We hypothesized that ATP inhibits trophoblast invasion and spiral artery remodeling and affects macrophages and natural killer (NK) cells present in the rat mesometrial triangle. Pregnant rats were infused with ATP or saline (control) on day 14 of pregnancy. Rats were sacrificed on day 15, 17 or 20 of pregnancy and placentas with mesometrial triangle were collected. Sections were stained for trophoblast cells, α-smooth muscle actin (spiral artery remodeling), NK cells and various macrophage populations. Expression of various cytokines in the mesometrial triangle was analyzed using real-time RT-PCR. ATP infusion decreased interstitial trophoblast invasion on day 17 and spiral artery remodeling on day 17 and 20, increased activated tartrate resistant acid phosphatase (TRAP)-positive macrophages on day 15, decreased NK cells on day 17 and 20, and decreased inducible nitric oxide synthase (iNOS)-positive and CD206-positive macrophages and TNF-α and IL-33 expression at the end of pregnancy (day 20). Interstitial trophoblast invasion and spiral artery remodeling in the rat mesometrial triangle were decreased by infusion of ATP. These ATP-induced modifications were preceded by an increase in activated TRAP-positive macrophages and coincided with NK cell numbers, suggesting that they are involved. Trophoblast invasion and spiral artery remodeling may be inhibited by ATP-induced activated macrophages and decreased NK cells in the mesometrial triangle in rat pregnancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Telocytes in meninges and choroid plexus.

PubMed

Popescu, B O; Gherghiceanu, M; Kostin, S; Ceafalan, L; Popescu, L M

2012-05-16

Telocytes (TCs) are a recently identified type of interstitial cells present in a wide variety of organs in humans and mammals (www.telocytes.com). They are characterized by a small cell body, but extremely long cell processes - telopodes (Tp), and a specific phenotype. TCs establish close contacts with blood capillaries, nerve fibers and stem cells. We report here identification of TCs by electron microscopy and immunofluorescence in rat meninges and choroid plexus/subventricular zone, in the vicinity of putative stem cells. The presence of TCs in brain areas involved in adult neurogenesis might indicate that they have a role in modulation of neural stem cell fate. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Expression of the oestrogen receptor GPER by testicular peritubular cells is linked to sexual maturation and male fertility.

PubMed

Sandner, F; Welter, H; Schwarzer, J U; Köhn, F M; Urbanski, H F; Mayerhofer, A

2014-09-01

Besides the two nuclear oestrogen receptors (ESR1/ESR2), the G protein-coupled oestrogen receptor (GPER) was described in the human testis but little is known about testicular GPER during development or male infertility. We performed an immunohistochemical analysis using human and rhesus monkey testicular samples. The results obtained in adult primate testes showed GPER in interstitial and vascular cells as well as in smooth muscle-like peritubular cells, which build the wall of seminiferous tubules. Expression of GPER was also found in cultured human testicular peritubular cells (HPTCs) by Western blotting and RT-PCR/sequencing. Furthermore, as seen in time-lapse videos of cultured cells, addition of a specific GPER agonist (G1) significantly reduced the numbers of HTPCs within 24 h. A GPER antagonist (G15) prevented this action, implying a role for GPER related to the control of cell proliferation or cell death of peritubular cells. Peritubular cell functions and their phenotype change, for example, during post-natal development and in the cases of male infertility. The study of non-human primate samples revealed that GPER in peritubular cells was detectable only from the time of puberty onwards, while in samples from infantile and prepubertal monkeys only interstitial cells showed immunopositive staining. In testicular biopsies of men with mixed atrophy, a reduction or loss of immunoreactive GPER was found in peritubular cells surrounding those tubules, in which spermatogenesis was impaired. In other cases of impaired spermatogenesis, namely when the tubular wall was fibrotically remodelled, a complete loss of GPER was seen. Thus, the observed inverse relation between the state of fertility and GPER expression by peritubular cells implies that the regulation of primate testicular peritubular cells by oestrogens is mediated by GPER in both, health and disease. © 2014 American Society of Andrology and European Academy of Andrology.

[Effect of shenluotong decoction on renal interstitial fibrosis in rats with obstructive nephropathy].

PubMed

Wang, Zheng; Liang, Li-juan; Wang, Cong-hui; Wang, Rui; Jiang, Guo-wang; Zhang, Xiao-man; An, Ya-juan; Xu, Qing-you

2014-10-01

To observe the effect of Shenluotong Decoction (SD) on serum levels of aldosterone, monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle protein (α-SMA), and nuclear factor-KB (NF-κB) in obstructive nephropathy rats, and to explore the initial mechanism of SD for inhibiting renal interstitial fibrosis. Totally 48 healthy Wistar rats were randomly divided into the sham-operation group (n =12) and the model group (n =36). Renal interstitial fibrosis rat model was established by unilateral ureteral obstruction (UUO). After successful modeling, 36 rats were randomly divided into the model group, the Chinese medicine group, and the Western medicine group, 12 in each group. Eplerenone was added in the forage at the daily dose of 100 mg/kg for rats in the Western medicine group. Chinese medicine was added in the forage at the daily dose of 26 g/kg for rats in the Chinese medicine group. Equal volume of normal saline was administered to rats in the sham-operation group and the model group. All medication was performed once daily. The obstructive kidneys were extracted ten days after medication. The pathomorphological changes were observed. The contents of serum aldosterone and MCP-1, and the protein or mRNA expression of MCP-1, α-SMA, and NF-KB were detected. Compared with the sham-operation group, infiltration of a large amount of inflammatory cells and collagen deposition significantly increased, serum contents of aldosterone and MCP-1 obviously increased (P < 0.01), the expression of MCP-1 mRNA and protein were significantly up-regulated (P <0.01), the protein expression of α-SMA and NF-KB were significantly enhanced in the model group (P <0.01). Com- pared with the model group, infiltration of inflammatory cells and renal collagen deposition were attenua- ted in the Chinese medicine group and the Western medicine group, the serum MCP-1 level were reduced, and the mRNA and protein expression of MCP-1 were significantly down-regulated (P <0.01), the protein expression of α-SMA and NF-KB were obviously inhibited (P <0. 01). At the same time, serum aldosterone level was reduced in the Chinese medicine group (P <0.01). inflammatory lesions of the renal tissue could promote the progress of interstitial fibrosis in rats with obstructive nephropathy. SD could attenuate interstitial fibrosis through reducing serum contents of aldosterone and MCP-1, down-regulating MCP-1/ NF-KB, and inhibiting the expression of α-SMA.

The role of cardiovascular magnetic resonance in the assessment of severe aortic stenosis and in post-procedural evaluation following transcatheter aortic valve implantation and surgical aortic valve replacement.

PubMed

Musa, Tarique Al; Plein, Sven; Greenwood, John P

2016-06-01

Degenerative aortic stenosis (AS) is the most common valvular disease in the western world with a prevalence expected to double within the next 50 years. International guidelines advocate the use of cardiovascular magnetic resonance (CMR) as an investigative tool, both to guide diagnosis and to direct optimal treatment. CMR is the reference standard for quantifying both left and right ventricular volumes and mass, which is essential to assess the impact of AS upon global cardiac function. Given the ability to image any structure in any plane, CMR offers many other diagnostic strengths including full visualisation of valvular morphology, direct planimetry of orifice area, the quantification of stenotic jets and in particular, accurate quantification of valvular regurgitation. In addition, CMR permits reliable and accurate measurements of the aortic root and arch which can be fundamental to appropriate patient management. There is a growing evidence base to indicate tissue characterisation using CMR provides prognostic information, both in asymptomatic AS patients and those undergoing intervention. Furthermore, a number of current clinical trials will likely raise the importance of CMR in routine patient management. This article will focus on the incremental value of CMR in the assessment of severe AS and the insights it offers following valve replacement.

Interstitial nephritis.

PubMed

Papper, S

1980-01-01

There are many causes of interstitial nephritis other than pyelonephritis. The term interstitial nephritis does not connote a single etiologic or pathogenetic mechanism; it rather arbitrarily places together a wider variety of renal diseases that have a predilection for early and major involvement of the renal interstitium. The prototype of acute interstitial nephritis is acute pyelonephritis. In addition, there is a drug-related acute interstitial disease that is probably of immunological nature and usually reverses with discontinuance of the offending drug. Chronic interstitial nephritis includes many diverse illnesses. Nonobstructive pyelonephritis occurs but its prevalence is debated. Analgesic abuse nephropathy is not rare and is potentially reversible. Papillary necrosis has many causes and a wide spectrum of clinical presentations. Heavy metals, such as lead, cause interstitial nephritis. Balkan nephropathy occurs in an endemic area and although not bacterial in origin is of unknown cause.