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Sample records for prevent neointimal hyperplasia

  1. Valsartan prevents neointimal hyperplasia after carotid artery stenting by suppressing endothelial cell injuries.

    PubMed

    Suzuki, Hidenori; Sano, Takanori; Umeda, Yasuyuki; Yamamoto, Akitaka; Toma, Naoki; Sakaida, Hiroshi; Taki, Waro

    2015-01-01

    Restenosis or neointimal hyperplasia remains an important complication after carotid artery stenting (CAS) for carotid artery stenosis. The purpose of this study was to examine if an anti-hypertensive drug, angiotensin receptor blocker (ARB), prevents post-CAS neointimal hyperplasia during the first 1-year period after CAS, and to clarify the possible mechanisms. Hypertension had been treated with a calcium channel blocker (CCB) and/or an ARB, valsartan, by the preference of the neurosurgeon in charge in our department. At admission to perform CAS, patients were assigned to normotensive, valsartan (hypertensive patients treated with valsartan with/without any kind of CCBs), and non-valsartan (hypertensive patients treated with any kind of CCBs without ARBs) groups. Post-CAS neointimal hyperplasia was evaluated by carotid duplex ultrasound imaging in terms of intima-media thickening (IMT), which was performed at pre-CAS and at 90, 180, 270, and 360 days post-CAS. Biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine), inflammation (C-reactive protein, tenascin-C) and endothelial cell injury (von Willebrand factor [vWF] antigen) were measured at pre-CAS and at 1, 7, and 180 days post-CAS. The non-valsartan group (n  =  8) had a higher incidence of maximum in-stent IMT ≧ 1.1 mm compared with the normotensive group (n  =  6). Valsartan (n  =  9) significantly suppressed plasma vWF levels at 7 days post-CAS and decreased the incidence of maximum in-stent IMT ≧ 1.1 mm compared with the non-valsartan group, although clinical parameters were similar between the two groups. Other biomarkers were not significantly different among the three groups. These findings suggest that valsartan may prevent post-CAS neointimal hyperplasia possibly by suppressing endothelial cell injury.

  2. Prevention of occlusive arterial thrombus formation by a single loading dose of prasugrel suppresses neointimal hyperplasia in mice.

    PubMed

    Ohno, Kousaku; Tomizawa, Atsuyuki; Jakubowski, Joseph A; Mizuno, Makoto; Sugidachi, Atsuhiro

    2015-12-01

    The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Prevention of Neointimal Hyperplasia by Local Application of Lentiviral Vectors Encoding Pin1 shRNA in Pluronic F127.

    PubMed

    Lv, Lei; Shi, Yaxue; Duan, Rundan; Xie, Hui; Zhang, Jiwei; Liang, Wei; Xue, Guanhua; Zhang, Lan; Huang, Xiaozhong

    2015-01-01

    Inhibition of intimal hyperplasia plays an important role in preventing restenosis. Previously, we reported the provocative role of Pin1 in regulating vascular smooth muscle cell (VSMC) proliferation. Here we intended to identify whether locally delivered lentivirus-mediated siPin1 via pluronic F127 (PF127) could inhibit neointimal formation and further explore the potential mechanisms thereof. In vitro studies revealed that lentivirus-mediated siPin1 dispersed in PF127 suppressed proliferation and induced senescence in VSMCs. Reduction of Pin1 expression resulted in a decrease of phospho-Akt (p-Akt) expression level in VSMCs. Reactivation of Akt phosphorylation overcame the siPin1-mediated senescence. In a rat wire injury model, periadventitial delivery of lentivirus-mediated siPin1 via PF127 produced inhibition of intimal hyperplasia 14 days after injury without evidence for toxicity. Furthermore, the reduction of intimal thickness was associated with a decreased amount of PCNA positive cells, decreased telomerase activity and shortened telomere length. Therefore, these results suggest that PF127 delivery of lentivirus-mediated siPin1 to artery may have a therapeutic potential for the treatment of restenosis.

  4. Neointimal hyperplasia associated with synthetic hemodialysis grafts

    PubMed Central

    Li, Li; Terry, Christi M.; Shiu, Yan-Ting E.; Cheung, Alfred K.

    2008-01-01

    Stenosis is a major cause of failure of hemodialysis vascular grafts and is primarily caused by neointimal hyperplasia (NH) at the anastomoses. The objective of this article is to provide a scientific review of the biology underlying this disorder and a critical review of the state-of-the-art investigational preventive strategies in order to stimulate further research in this exciting area. The histology of the NH shows myofibroblasts (that are probably derived from adventitial fibroblasts), extracellular matrices, pro-inflammatory cells including foreign-body giant cells, a variety of growth factors and cytokines, and neovasculature. The contributing factors of the pathogenesis of NH include surgical trauma, bioincompatibility of the synthetic graft, and the various mechanical stresses that result from luminal hypertension and compliance mismatch between the vessel wall and graft. These mechanical stimuli are focal in nature and may have a significant influence on the preferential localization of the NH. Novel mechanical graft designs and local drug delivery strategies show promise in animal models in preventing graft NH development. Successful prevention of graft stenosis would provide a superior alternative to the native fistula as hemodialysis vascular access. PMID:18668026

  5. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia.

    PubMed

    Urao, Norifumi; Okigaki, Mitsuhiko; Yamada, Hiroyuki; Aadachi, Yasushi; Matsuno, Kuniharu; Matsui, Akihiro; Matsunaga, Shinsaku; Tateishi, Kento; Nomura, Tetsuya; Takahashi, Tomosaburo; Tatsumi, Tetsuya; Matsubara, Hiroaki

    2006-06-09

    We investigated whether the mobilization of endothelial progenitor cells (EPCs) by exogenous erythropoietin (Epo) promotes the repair of injured endothelium. Recombinant human Epo was injected (1000 IU/kg for the initial 3 days) after wire injury of the femoral artery of mice. Neointimal formation was inhibited by Epo to 48% of the control (P<0.05) in an NO-dependent manner. Epo induced a 1.4-fold increase in reendothelialized area of day 14 denuded vessels, 55% of which was derived from bone marrow (BM) cells. Epo increased the circulating Sca-1(+)/Flk-1(+) EPCs (2.0-fold, P<0.05) with endothelial properties NO dependently. BM replacement by GFP- or beta-galactosidase-overexpressing cells showed that Epo stimulated both differentiation of BM-derived EPCs and proliferation of resident ECs. BM-derived ECs increased 2.2- to 2.7-fold (P<0.05) in the Epo-induced neoendothelium, where the expression of Epo receptor was upregulated. Epo induced Akt/eNOS phosphorylation and NO synthesis on EPCs and exerted an antiapoptotic action on wire-injured arteries. In conclusion, Epo treatment inhibits the neointimal hyperplasia after arterial injury in an NO-dependent manner by acting on the injured vessels and mobilizing EPCs to the neo-endothelium.

  6. New Developments in Our Understanding of Neointimal Hyperplasia.

    PubMed

    Lee, Timmy; Ul Haq, Naveed

    2015-11-01

    The vascular access remains the lifeline for the hemodialysis patient. The most common etiology of vascular access dysfunction is venous stenosis at the vein-artery anastomosis in arteriovenous fistula and at the vein-graft anastomosis in arteriovenous grafts (AVG). This stenotic lesion is typically characterized on histology as aggressive venous neointimal hyperplasia in both arteriovenous fistula and AVG. In recent years, we have advanced our knowledge and understanding of neointimal hyperplasia in vascular access and begun testing several novel therapies. This article will (1) review recent developments in our understanding of the pathophysiology of neointimal hyperplasia development in AVG and fistula failure, (2) discuss atypical factors leading to neointimal hyperplasia development, (3) highlight key novel therapies that have been evaluated in clinical trials, and (4) discuss future opportunities and challenges to improve our understanding of vascular access dysfunction and translate this knowledge into novel and innovative therapies. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  7. Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.

    PubMed

    Ye, Qing; Pang, Shu; Zhang, Wenjing; Guo, Xiaotong; Wang, Jianli; Zhang, Yongtao; Liu, Yang; Wu, Xiao; Jiang, Fan

    2017-03-01

    RNA polymerase I (Pol I)-dependent rRNA synthesis is a determinant factor in ribosome biogenesis and thus cell proliferation. The importance of dysregulated Pol I activity in cardiovascular disease, however, has not been recognized. Here, we tested the hypothesis that specific inhibition of Pol I might prevent arterial injury-induced neointimal hyperplasia. CX-5461 is a novel selective Pol I inhibitor. Using this tool, we demonstrated that local inhibition of Pol I blocked balloon injury-induced neointima formation in rat carotid arteries in vivo. Neointimal development was associated with augmented rDNA transcriptional activity as evidenced by the increased phosphorylation of upstream binding factor-1. The beneficial effect of CX-5461 was mainly mediated by inducing G2/M cell cycle arrest of proliferating smooth muscle cells without obvious apoptosis. CX-5461 did not induce p53 stabilization but increased p53 phosphorylation and acetylation and activated the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATR) pathway. Inhibition of ATR, but not of ataxia telangiectasia mutated, abolished the cytostatic effect of CX-5461 and p53 phosphorylation. In addition, inhibition of p53 or knockdown of the p53 target GADD45 mimicked the effect of ATR inhibition. In vivo experiments showed that the levels of phospho-p53 and acetyl-p53, and activity of the ataxia telangiectasia mutated/ATR pathway were all augmented in CX-5461-treated vessels. Pol I can be therapeutically targeted to inhibit the growth of neointima, supporting that Pol I is a novel biological target for preventing arterial restenosis. Mechanistically, Pol I inhibition elicited G2/M cell cycle arrest in smooth muscle cells via activation of the ATR-p53 axis. © 2017 American Heart Association, Inc.

  8. Neo-intimal hyperplasia, diabetes and endovascular injury.

    PubMed

    Kruger, Deirdre

    2012-10-01

    Diabetes is a significant major risk factor for peripheral arterial disease (PAD) and critical limb ischaemia (CLI), the latter which is also the most common cause of amputation in these patients. Revascularisation of the lower extremities of such patients is imperative for limb salvage and has become First-line therapy. However, the incidence of restenosis following endovascular stenting is very high and is largely due to neo-intimal hyperplasia (NIH), the regulation of which is for the greater part not understood. This article therefore reviews our understanding on the regulation of NIH following stent-induced vascular injury, and highlights the importance of future studies to investigate whether the profile of vascular progenitor cell differentiation, neo-intimal growth factors and lumen diameters predict the severity of post-stent NIH in the peripheral arteries. Results from future studies will (1) better our understanding of the regulation of NIH in general, (2) determine whether combinations of any of the vascular factors discussed are predictive of the extent of NIH postoperatively, and (3) potentially facilitate future therapeutic targets and/or change preventive strategies.

  9. Severe venous neointimal hyperplasia prior to dialysis access surgery

    PubMed Central

    Lee, Timmy; Chauhan, Vibha; Krishnamoorthy, Mahesh; Wang, Yang; Arend, Lois; Mistry, Meenakshi J.; El-Khatib, Mahmoud; Banerjee, Rupak; Munda, Rino; Roy-Chaudhury, Prabir

    2011-01-01

    Background. Venous neointimal hyperplasia is the most common cause of arteriovenous (AV) fistula and graft dysfunction following dialysis access surgery. However, the pathogenetic impact of pre-existing venous neointimal hyperplasia at the time of AV access creation on final clinical success is currently unknown in the setting of advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The aim of this study was to perform a detailed histological, morphometric, and immunohistochemical analysis of vein specimens in advanced CKD and ESRD patients collected at the time of new vascular access placement. Methods. Vein samples from 12 patients were collected at the time of AV access creation near the site of AV anastomosis. Histological, immunohistochemistry and morphometric studies were performed on these vein samples. Results. Examination of the tissue specimens obtained at the time of surgery showed neointimal hyperplasia in 10 of 12 specimens, ranging from minimal to very severe. The majority of cells within the neointima were myofibroblasts with a minority of contractile smooth muscle cells present. Conclusion. Our work represents a detailed description of the morphometric and cellular phenotypic lesions present in the veins of CKD and ESRD patients, prior to dialysis access placement. These studies (i) suggest the future possibility of a new predictive marker (pre-existing venous neointimal hyperplasia) for AV dialysis access dysfunction and (ii) open the door for the future development of novel local therapies for optimization of the venous substrate on which the dialysis access is created. PMID:21220751

  10. Prevention of vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia by CREB-mediated p21 induction: An insight from a plant polyphenol.

    PubMed

    Sun, Lan; Zhao, Rui; Zhang, Li; Zhang, Weiku; He, GuoRong; Yang, Shengqian; Song, Junke; Du, Guanhua

    2016-03-01

    Cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element (CRE)-binding protein (CREB) signaling cascade negatively regulates platelet-derived growth factor BB (PDGF-BB)-induced smooth muscle cell (SMC) proliferation, which is a critical event in the initiation and development of restenosis and atherosclerotic lesions. Salvianolic acid A (SAA) is one of the most abundant polyphenols extracted from salvia. The aim of this study is to investigate whether SAA exerts an action on PDGF-BB-induced proliferation via cAMP/PKA/CREB mechanism. SAA blunts PDGF-BB-induced human umbilical artery smooth muscle cell (hUASMC) proliferation via p21 induction, as evidenced by its increased mRNA and protein expression levels. The SAA-induced upregulation of p21 involves the cAMP/PKA signaling pathway; a cAMP analog mimicked the effects of SAA and a specific cAMP/PKA inhibitor opposed these effects. SAA also activated CREB, including phosphorylation at Ser133, and induced its nuclear translocation. Deletion and mutational analysis of p21 promoters, co-immunoprecipitation, and western blot analysis showed that CRE is essential for SAA-induced p21 protein expression. Transfection of dominant-negative CREB (mutated Ser133) plasmids into hUASMCs attenuated SAA-stimulated p21 expression. SAA upregulated p21 expression and activated CREB in the neointima of balloon-injured arteries in vivo. Our results indicate that SAA promotes p21 expression in SMCs through the cAMP/PKA/CREB signaling cascade in vitro and prevents injury-induced neointimal hyperplasia.

  11. Therapeutic strategies to combat neointimal hyperplasia in vascular grafts

    PubMed Central

    Collins, Michael J; Li, Xin; Lv, Wei; Yang, Chenzi; Protack, Clinton D; Muto, Akihito; Jadlowiec, Caroline C; Shu, Chang; Dardik, Alan

    2012-01-01

    Neointimal hyperplasia (NIH) in bypass conduits such as veins and prosthetic grafts is an important clinical entity that limits the long-term success of vascular interventions. Although the development of NIH in the conduits shares many of the same features of NIH that develops in native arteries after injury, vascular grafts are exposed to unique circumstances that predispose them to NIH, including surgical trauma related to vein handling, hemodynamic changes creating areas of low flow, and differences in biocompatibility between the conduit and the host environment. Multiple different approaches, including novel surgical techniques and targeted gene therapies, have been developed to target and prevent the causes of NIH. Recently, the PREVENT trials, the first molecular biology trials in vascular surgery aimed at preventing NIH, have failed to produce improved clinical outcomes, highlighting the incomplete knowledge of the pathways leading to NIH in vascular grafts. In this review, we aim to summarize the pathophysiologic pathways that underlie the formation of NIH in both vein and synthetic grafts and discuss current and potential mechanical and molecular approaches under investigation that may limit NIH in vascular grafts. PMID:22651839

  12. Prevention of neointimal hyperplasia in balloon-injured rat carotid artery via small interference RNA mediated downregulation of osteopontin gene.

    PubMed

    Xu, Jian; Sun, Yingxian; Wang, Tairan; Liu, Guinan

    2013-05-01

    The aim of the present study was to take osteopontin (OPN) as molecular target to study its effects on injured intima model of carotid artery in rat using perivascular transfer of OPN-small interference RNA (siRNA). OPN mRNA in cultured VSMCs was quantified by real-time RT-PCR, and OPN-siRNA-002 was determined as the most sensitive sequence and used as transfected siRNA in the subsequent animal experiments. We established rat carotid arterial intima-injured model with balloon-injured method, and then perivascularly transfected OPN-siRNA-002 to study the role of OPN-siRNA in regulating several related genes including proliferating cell nuclear antigen (PCNA), transforming growth factor β1(TGF-β1), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-14 (MMP-14), as well as its role in neointimal formation. OPN mRNA and protein decreased about 50 % with corresponding decrease in intima thickness after transfecting with specific OPN-siRNA-002 compared with Pluronic control group and OPN-SCR-siRNA group on each time point (n = 6, p < 0.001), and this inhibiting effects persisted up to 14 days after balloon injury. PCNA, TGF-β1, MMP-2, and MMP-14 mRNA and protein correlated directly with the respective levels of OPN, suggesting its functions via regulating these downstream factors (n = 6, p < 0.001). OPN may be a potential target gene in reducing the risk for arterial restenosis after vascular intervention.

  13. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae.

    PubMed

    Skartsis, Nikolaos; Martinez, Laisel; Duque, Juan Camilo; Tabbara, Marwan; Velazquez, Omaida C; Asif, Arif; Andreopoulos, Fotios; Salman, Loay H; Vazquez-Padron, Roberto I

    2014-11-01

    Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae.

  14. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

    PubMed Central

    Skartsis, Nikolaos; Martinez, Laisel; Duque, Juan Camilo; Tabbara, Marwan; Velazquez, Omaida C.; Asif, Arif; Andreopoulos, Fotios; Salman, Loay H.

    2014-01-01

    Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. PMID:25186298

  15. Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation.

    PubMed

    MacAskill, Mark G; Watson, David G; Ewart, Marie-Ann; Wadsworth, Roger; Jackson, Andrew; Aitken, Emma; MacKenzie, Graeme; Kingsmore, David; Currie, Susan; Coats, Paul

    2015-08-01

    Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation

    PubMed Central

    MacAskill, Mark G.; Watson, David G.; Ewart, Marie-Ann; Wadsworth, Roger; Jackson, Andrew; Aitken, Emma; MacKenzie, Graeme; Kingsmore, David; Currie, Susan; Coats, Paul

    2015-01-01

    Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~ 60% at 12 months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates. PMID:25866325

  17. Vitamin K antagonism aggravates chronic kidney disease-induced neointimal hyperplasia and calcification in arterialized veins: role of vitamin K treatment?

    PubMed

    Zaragatski, Emma; Grommes, Jochen; Schurgers, Leon J; Langer, Stephan; Kennes, Lieven; Tamm, Miriam; Koeppel, Thomas A; Kranz, Jennifer; Hackhofer, Tina; Arakelyan, Karen; Jacobs, Michael J; Kokozidou, Maria

    2016-03-01

    Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins

  18. Advances and New Frontiers in the Pathophysiology of Venous Neointimal Hyperplasia and Dialysis Access Stenosis

    PubMed Central

    Lee, Timmy; Roy-Chaudhury, Prabir

    2009-01-01

    Hemodialysis vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of this vascular access dysfunction is venous stenosis as a result of venous neointimal hyperplasia within the peri-anastomotic region (AV fistula) or at the graft-vein anastomosis (PTFE grafts). There have been few effective treatments to-date for venous neointimal hyperplasia in part because of the poor understanding of the pathogenesis of venous neointimal hyperplasia. Therefore, this article will (1) describe the pathology of hemodialysis access stenosis in AV fistulas and grafts, (2) review and describe both current and novel concepts in the pathogenesis of neointimal hyperplasia formation, (3) discuss current and future novel therapies for treating venous neointimal hyperplasia, and (4) suggest future research areas in the field of hemodialysis vascular access dysfunction. PMID:19695501

  19. Mig-6 Gene Knockout Induces Neointimal Hyperplasia in the Vascular Smooth Muscle Cell

    PubMed Central

    Lee, Ju Hee; Choung, Sorim; Kim, Ji Min; Lee, Jung Uee; Kim, Koon Soon; Kim, Hyun Jin; Jeong, Jae-Wook; Ku, Bon Jeong

    2014-01-01

    Although advances in vascular interventions can reduce the mortality associated with cardiovascular disease, neointimal hyperplasia remains a clinically significant obstacle limiting the success of current interventions. Identification of signaling pathways involved in migration and proliferation of vascular smooth muscle cells (SMCs) is an important approach for the development of modalities to combat this disease. Herein we investigate the role of an immediate early response gene, mitogen-inducible gene-6 (Mig-6), in the development of neointimal hyperplasia using vascular smooth muscle specific Mig-6 knockout mice. We induced endoluminal injury to one side of femoral artery by balloon dilatation in both Mig-6 knockout and control mice. Four weeks following injury, the artery of Mig-6 knockout mice demonstrated a 5.3-fold increase in the neointima/media ratio compared with control mice (P = 0.04). In addition, Mig-6 knockout vascular SMCs displayed an increase in both cell migration and proliferation compared with wild-type SMCs. Taken together, our data suggest that Mig-6 plays a critical role in the development of atherosclerosis. This finding provides new insight into the development of more effective ways to treat and prevent neointimal hyperplasia, particularly in-stent restenosis after percutaneous vascular intervention. PMID:25574067

  20. Mig-6 gene knockout induces neointimal hyperplasia in the vascular smooth muscle cell.

    PubMed

    Lee, Ju Hee; Choung, Sorim; Kim, Ji Min; Lee, Jung Uee; Kim, Koon Soon; Kim, Hyun Jin; Jeong, Jae-Wook; Ku, Bon Jeong

    2014-01-01

    Although advances in vascular interventions can reduce the mortality associated with cardiovascular disease, neointimal hyperplasia remains a clinically significant obstacle limiting the success of current interventions. Identification of signaling pathways involved in migration and proliferation of vascular smooth muscle cells (SMCs) is an important approach for the development of modalities to combat this disease. Herein we investigate the role of an immediate early response gene, mitogen-inducible gene-6 (Mig-6), in the development of neointimal hyperplasia using vascular smooth muscle specific Mig-6 knockout mice. We induced endoluminal injury to one side of femoral artery by balloon dilatation in both Mig-6 knockout and control mice. Four weeks following injury, the artery of Mig-6 knockout mice demonstrated a 5.3-fold increase in the neointima/media ratio compared with control mice (P = 0.04). In addition, Mig-6 knockout vascular SMCs displayed an increase in both cell migration and proliferation compared with wild-type SMCs. Taken together, our data suggest that Mig-6 plays a critical role in the development of atherosclerosis. This finding provides new insight into the development of more effective ways to treat and prevent neointimal hyperplasia, particularly in-stent restenosis after percutaneous vascular intervention.

  1. Hyperbaric oxygen inhibits venous neointimal hyperplasia following arteriovenous fistulization.

    PubMed

    Li, Zhui; Li, Maoping; Li, Xiangjie; Zhang, Mao; Zhao, Yu; Ren, Wei; Cheng, Jun; Wang, Xuehu

    2017-04-07

    Hypoxia following arteriovenous fistulization results in venous neointimal hyperplasia (VNH), potentially causing early arteriovenous fistula (AVF) dysfunction. In this study, we used hyperbaric oxygen (HBO) in a rabbit model of AVF to determine whether it could ameliorate early AVF failure. Chronic renal failure was induced by adenine in 96 adult rabbits randomly divided into 3 groups (n=32 in each group). The sham + HBO group underwent sham operation and received HBO. The AVF alone group underwent fistulization, but did not receive HBO. The AVF + HBO group underwent fistulization and received HBO. Each group was further divided into 4 subgroups of 8 rabbits each that were euthanized at 1, 7, 14 or 28 days post-operatively. At each time point, blood flow changes in the AVF venous segment were detected using a high-frequency duplex ultrasonography system. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), and hematoxylin and eosin staining were performed to evaluate VNH. Western blot analysis was performed to confirm the expression of hypoxia-inducible factor (HIF)-1α. At 14 and 28 days following HBO treatment, blood flow in the AVF + HBO group was greater than that at day 0. The AVF + HBO group had a smaller ratio of intima to media area, a lower HIF-1α protein expression, and a smaller percentage of PCNA-positive cells in the proximal vein than did the AVF alone group. Our results thus suggest that continuous HBO treatment following AVF significantly inhibits VNH and promotes blood flow. Therefore, early AVF failure may be prevented by the use of HBO therapy.

  2. Eph-B4 activation reduces neointimal hyperplasia in human saphenous vein in vitro

    PubMed Central

    Wong, Daniel J; Lu, Daniel Y; Protack, Clinton D; Kuwahara, Go; Bai, Hualong; Sadaghianloo, Nirvana; Tellides, George; Dardik, Alan

    2014-01-01

    Background Vein bypass is an essential therapy for patients with advanced peripheral and coronary artery disease despite development of neointimal hyperplasia. We have shown that stimulation of the receptor tyrosine kinase Eph-B4 with its ligand Ephrin-B2 prevents neointimal hyperplasia in murine vein grafts. This study determines whether Eph-B4 in human veins is capable of phosphorylation, activation of downstream signaling pathways, and functional to release nitric oxide and prevent neointimal hyperplasia in vitro. Methods Discarded human saphenous veins were taken from the operating room and placed in organ culture without or with Ephrin-B2/Fc (2 μg/ml; 14 days) and the neointima:media ratio was measured in matched veins. Primary human umbilical vein endothelial cells (HUVEC) were treated with Ephrin-B2/Fc (2 μg/ml) and examined with qPCR, Western blot, immunoassays and for release of nitric oxide. Ephrin-B2/Fc (2 μg/ml) was placed in pluronic gel on the adventitia of saphenous veins treated with arterial shear stress for 24 hours in a bioreactor and activated Eph-B4 examined with immunofluorescence. Results The baseline intima:media ratio in saphenous vein rings was 0.456 ± 0.097 which increased to 0.726 ± 0.142 in untreated veins after 14 days in organ culture, but only to 0.630 ± 0.132 in veins treated with Ephrin-B2/Fc (p=.017; n=19). Ephrin-B2/Fc stimulated Akt, eNOS and caveolin-1 phosphorylation and NO release (p=0.007) from HUVEC (n=6). Ephrin-B2/Fc delivered to the adventitia stimulated endothelial Eph-B4 phosphorylation after 24 hours of arterial stress in a bioreactor (n=3). Discussion Eph-B4 is present and functional in adult human saphenous veins, with intact downstream signaling pathways capable of nitric oxide release and prevention of neointimal hyperplasia in vitro. Adventitial delivery of Ephrin-B2/Fc activates endothelial Eph-B4 in saphenous veins treated with arterial shear stress in vitro. These results suggest that stimulation of Eph

  3. Inhibition of neointimal hyperplasia after stent placement with rhenium 188-filled balloon dilation in a canine iliac artery model.

    PubMed

    Kim, Tae-Hyung; Shin, Ji Hoon; Oh, Seung-Jun; Park, In Kook; Woo, Chul-Woong; Han, Kyung Hee; Dong, Kyung-Rae

    2010-07-01

    To evaluate the efficacy of beta-irradiation therapy with rhenium 188 ((188)Re) mercaptoacetyltriglycine (MAG3)-filled balloon dilation to prevent neointimal hyperplasia after stent placement in a canine iliac artery model. A total of 15 stents were implanted into the iliac arteries of eight dogs (one or two stents in each dog). Rhenium 188 MAG3-filled balloon dilation was performed immediately after placement of 10 bare stents-20 Gy in group II (n = 5) and 40 Gy in group III (n = 5)-and conventional balloon dilation was performed immediately after placement of the remaining five bare stents (group I). A follow-up angiogram was obtained 8 weeks after the procedure, and percentage of luminal stenosis was calculated for the proximal and distal ends of each stent. Neointimal thickening (expressed as the neointimal area divided by the sum of neointimal area and media area) was assessed for microscopic examination. All eight dogs survived until they were euthanized 8 weeks after the procedures. The mean luminal stenosis measurements at 8-week follow-up angiography in groups I, II, and III were 26.63%, -0.44%, and 10.53%, respectively. The mean neointimal thickening measurements in groups I, II, and III were 0.77, 0.21, and 0.34, respectively. The mean percentage of luminal stenosis and neointimal thickening differed significantly among the three groups (P < .05). beta-Irradiation with (188)Re-MAG3-filled balloon dilation has the potential to reduce neointimal hyperplasia secondary to stent placement in a canine iliac artery model. A dose of 20 Gy may be preferable versus a dose of 40 Gy to reduce neointimal hyperplasia. Copyright 2010 SIR. Published by Elsevier Inc. All rights reserved.

  4. Transient receptor potential channel M2 contributes to neointimal hyperplasia in vascular walls.

    PubMed

    Ru, Xiaochen; Zheng, Changbo; Zhao, Qiannan; Lan, Hui-Yao; Huang, Yu; Wan, Song; Mori, Yasuo; Yao, Xiaoqiang

    2015-07-01

    A hallmark of atherosclerosis is progressive intimal thickening (namely neointimal hyperplasia), which leads to occlusive vascular diseases. Over-production of reactive oxygen species (ROS) and alteration of Ca2+ signaling are among the key factors contributing to neointimal growth. In the present study, we investigated the role of TRPM2, a ROS-sensitive Ca2+ entry channel, in neointimal hyperplasia. Perivascular cuffs were used to induce neointimal hyperplasia in rat/mouse arteries. Immunostaining showed numerous TRPM2-positive smooth muscle cells in neointimal regions. ROS were over-produced and PCNA-positive proliferating cells were numerous in the neointimal regions. The neointimal hyperplasia was substantially reduced in Trpm2 knockout mice compared with wild-type mice. In the cultured rat/mouse aortic smooth muscle cells, H2O2 treatment was found to stimulate cell proliferation and migration. The effect of H2O2 was reduced by a TRPM2-specific blocking antibody TM2E3 or Trpm2 knockout. The signaling molecules downstream of TRPM2 were found to be Axl and Akt. These data suggest a critical functional role of TRPM2 in the progression of neointimal hyperplasia. The study also highlights the possibility of targeting TRPM2 as a potential therapeutic option for the treatment of occlusive vascular diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall.

    PubMed

    Bahnson, Edward S M; Koo, Nathaniel; Cantu-Medellin, Nadiezhda; Tsui, Aaron Y; Havelka, George E; Vercammen, Janet M; Jiang, Qun; Kelley, Eric E; Kibbe, Melina R

    2015-01-30

    Superoxide (O2(•-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((•)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (•)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (•)NO exerts cell-specific, differential modulation of O2(•-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (•)NO-dependent inhibition of neointimal hyperplasia. In vivo, (•)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (•)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(•-) levels. Lastly, to determine the role of SOD-1 in (•)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (•)NO. Interestingly, (•)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(•-) by (•)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (•)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia. Published by Elsevier Inc.

  6. Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall

    PubMed Central

    Bahnson, Edward S.M.; Koo, Nathaniel; Cantu-Medellin, Nadiezhda; Tsui, Aaron Y.; Havelka, George E.; Vercammen, Janet M.; Jiang, Qun; Kelley, Eric E.; Kibbe, Melina R.

    2014-01-01

    Superoxide (O2•−) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide (•NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether •NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether •NO exerts cell-specific, differential modulation of O2•− levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates •NO-dependent inhibition of neointimal hyperplasia. In vivo, •NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, •NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2•− levels. Lastly, to determine the role of SOD-1 in •NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without •NO. Interestingly, •NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2•− by •NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of •NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia. PMID:25460325

  7. Effect of Nitric Oxide on Neointimal Hyperplasia based on Sex and Hormone Status

    PubMed Central

    Hogg, Melissa E.; Varu, Vinit N.; Vavra, Ashley K.; Popowich, Daniel A.; Banerjee, Monisha N.; Martinez, Janet; Jiang, Qun; Saavedra, Joseph E.; Keefer, Larry K.; Kibbe, Melina R.

    2011-01-01

    Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have only been performed in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete media, male VSMC proliferated at greater rates than female VSMC. In hormone-deplete media, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male versus female VSMC. These findings correlated with greater G0/G1 cell cycle arrest and changes in cell cycle protein expression in male versus female VSMC following exposure to NO. Next, the rat carotid artery injury model was performed to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males versus females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in both sexes in castrated animals. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males than females and in hormonally-intact compared to castrated rats, indicating that the effect of NO in the vasculature may be sex- and hormone-dependent. PMID:21256959

  8. Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status.

    PubMed

    Hogg, Melissa E; Varu, Vinit N; Vavra, Ashley K; Popowich, Daniel A; Banerjee, Monisha N; Martinez, Janet; Jiang, Qun; Saavedra, Joseph E; Keefer, Larry K; Kibbe, Melina R

    2011-05-01

    Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G₀/G₁ cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.

  9. Andrographolide inhibits NF-kappaBeta activation and attenuates neointimal hyperplasia in arterial restenosis.

    PubMed

    Wang, Yu-Jiu; Wang, Jin-Tao; Fan, Quan-Xin; Geng, Jian-Guo

    2007-11-01

    The NF-kappaBeta transcription factors modulate the expression of tissue factor (TF), E-selectin (CD62E) and vascular cell adhesion molecule-1 (VCAM-1), which are essential for thrombosis and inflammation. We have previously shown that andrographolide (Andro) covalently modifies the reduced cysteine(62) of p50 - a major subunit of NF-kappaBeta transcription factors, thus blocking the binding of NF-kappaBeta transcription factors to the promoters of their target genes, preventing NF-kappaBeta activation and inhibiting inflammation in vitro and in vivo. Here we report that Andro, but not its inactive structural analog 4H-Andro, significantly suppressed the proliferation of arterial neointima ( approximately 60% reduction) in a murine model of arterial restenosis. Consistently, p50(-/-) mice manifested attenuated neointimal hyperplasia upon arterial ligation. Notably, the same dosage of Andro did not further reduce neointimal formation in p50(-/-) mice, which implicates the specificity of Andro on p50 for treating experimental arterial restenosis. The upregulation of NF-kappaBeta target genes, including TF, E-selectin and VCAM-1, and the increased deposition of leukocytes (mainly CD68+ macrophages) were clearly detected within the injured arterial walls, all of which were significantly abolished by treatment with Andro or genetic deletion of p50. The expression of TF, E-selectin and VCAM-1 was also markedly upregulated in the patient sample of thrombotic vasculitis, indicating the clinical relevance of NF-kappaBeta activation in the pathogeneses of occlusive arterial diseases. Our data thus indicate that, by the downregulation of the NF-kappaBeta target genes that are critical in thrombosis and inflammation, specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and treating thrombotic arterial diseases, including neointimal hyperplasia in arterial restenosis.

  10. Viscolin Inhibits In Vitro Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia In Vivo

    PubMed Central

    Chen, Chin-Chuan; Liang, Chan-Jung; Leu, Yann-Lii; Chen, Yuh-Lien; Wang, Shu-Huei

    2016-01-01

    Viscolin, an extract of Viscum coloratum, has anti-inflammatory and anti-proliferative properties against harmful stimuli. The aim of the study was to examine the anti-proliferative effects of viscolin on platelet derived growth factor-BB (PDGF)-treated human aortic smooth muscle cells (HASMCs) and identify the underlying mechanism responsible for these effects. Viscolin reduced the PDGF-BB-induced HASMC proliferation and migration in vitro; it also arrested HASMCs in the G0/G1 phase by decreasing the protein expression of Cyclin D1, CDK2, Cyclin E, CDK4, and p21Cip1 as detected by Western blot analysis. These effects may be mediated by reduced PDGF-induced phosphorylation of ERK1/2, JNK, and P38, but not AKT as well as inhibition of PDGF-mediated nuclear factor (NF)-κB p65 and activator protein 1 (AP-1)/c-fos activation. Furthermore, viscolin pre-treatment significantly reduced neointimal hyperplasia of an endothelial-denuded femoral artery in vivo. Taken together, viscolin attenuated PDGF–BB-induced HASMC proliferation in vitro and reduced neointimal hyperplasia in vivo. Thus, viscolin may represent a therapeutic candidate for the prevention and treatment of vascular proliferative diseases. PMID:27977759

  11. Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

    NASA Astrophysics Data System (ADS)

    Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M.; Dardik, Alan

    2017-01-01

    Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

  12. Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

    PubMed Central

    Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M.; Dardik, Alan

    2017-01-01

    Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants. PMID:28071663

  13. Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.

    PubMed

    Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M; Dardik, Alan

    2017-01-10

    Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

  14. Effect of local heating on restenosis and in-stent neointimal hyperplasia in the atherosclerotic rabbit model: a dose-ranging study.

    PubMed

    Brasselet, Camille; Durand, Eric; Addad, Faouzi; Vitry, Fabien; Chatellier, Gilles; Demerens, Corinne; Lemitre, Mathilde; Garnotel, Roselyne; Urbain, Dominique; Bruneval, Patrick; Lafont, Antoine

    2008-02-01

    In-stent restenosis is related to neointimal hyperplasia. Heating reduces neointimal hyperplasia but promotes constrictive remodeling after balloon angioplasty. We aimed to assess the ability of local heating in inhibiting restenosis and in-stent neointimal hyperplasia and its potential side effects on arterial thrombosis. Atherosclerotic-like lesions were induced in iliac rabbit arteries. One month later, both iliac rabbit arteries were stented. In each animal, one artery was randomized to local heating at four temperatures (50, 60, 80, and 100 degrees C). The contra lateral artery was used as control. Angiographic and histomorphometric analysis were performed 42 days after angioplasty. Immunohistochemistry was performed 3, 15, and 42 days after angioplasty. Angiographic significant reduction of in-stent restenosis after moderate heating (50 degrees C) was related to in-stent neointimal hyperplasia trend to be lower after moderate local heating when compared with controls. In contrast, in-stent thrombosis was similar to controls. Higher temperatures (i.e. 80 and 100 degrees C) also reduced in-stent neointimal hyperplasia but were most frequently associated with severe in-stent thrombosis. Local heating was associated with decreased cell proliferation, collagen density, and increased smooth muscle cell apoptosis and heat shock protein expression. Moderate heating represents a promising approach to prevent in-stent restenosis via the limitation of the proliferative response without thrombosis induction.

  15. Nitric oxide is less effective at inhibiting neointimal hyperplasia in spontaneously hypertensive rats.

    PubMed

    Tsihlis, Nick D; Vavra, Ashley K; Martinez, Janet; Lee, Vanessa R; Kibbe, Melina R

    2013-11-30

    Exogenous administration of nitric oxide (NO) markedly decreases neointimal hyperplasia following arterial injury in several animal models. However, the effect of NO on neointimal hyperplasia in hypertension remains unknown. Here, we employ the spontaneously hypertensive rat (SHR) strain, inbred from Wistar Kyoto (WKY) rats, and the carotid artery balloon injury model to assess the effects of NO on neointimal hyperplasia development. 2weeks after arterial injury, we showed that both rat strains developed similar levels of neointimal hyperplasia, but local administration of NO was less effective at inhibiting neointimal hyperplasia in the SHR compared to WKY rats (58% vs. 79%, P<0.001). Interestingly, local administration of NO did not affect systemic blood pressure in either rat strain. Compared to WKY, the SHR displayed more proliferation in the media and adventitia following balloon injury, as measured by BrdU incorporation. The SHR also showed more inflammation in the adventitia after injury, as well as more vasa vasorum, than WKY rats. NO treatment reduced the vasa vasorum in the SHR but not WKY rats. Finally, while NO decreased both injury-induced proliferation and inflammation in the SHR, it did not return these parameters to levels seen in WKY rats. We conclude that NO is less effective at inhibiting neointimal hyperplasia in the SHR than WKY rats. This may be due to increased scavenging of NO in the SHR, leading to diminished bioavailability of NO. These data will help to develop novel NO-based therapies that will be equally effective in both normotensive and hypertensive patient populations. Published by Elsevier Inc.

  16. Nitric Oxide is Less Effective at Inhibiting Neointimal Hyperplasia in Spontaneously Hypertensive Rats

    PubMed Central

    Tsihlis, Nick D.; Vavra, Ashley K.; Martinez, Janet; Lee, Vanessa R.; Kibbe, Melina R.

    2013-01-01

    Exogenous administration of nitric oxide (NO) markedly decreases neointimal hyperplasia following arterial injury in several animal models. However, the effect of NO on neointimal hyperplasia in hypertension remains unknown. Here, we employ the spontaneously hypertensive rat (SHR) strain, inbred from Wistar Kyoto (WKY) rats, and the carotid artery balloon injury model to assess the effects of NO on neointimal hyperplasia development. Two weeks after arterial injury, we showed that both rat strains developed similar levels of neointimal hyperplasia, but local administration of NO was less effective at inhibiting neointimal hyperplasia in the SHR compared to WKY rats (58% vs. 79%, P<0.001). Interestingly, local administration of NO did not affect systemic blood pressure in either rat strain. Compared to WKY, the SHR displayed more proliferation in the media and adventitia following balloon injury, as measured by BrdU incorporation. The SHR also showed more inflammation in the adventitia after injury, as well as more vasa vasorum, than WKY rats. NO treatment reduced the vasa vasorum in the SHR but not WKY rats. Finally, while NO decreased both injury-induced proliferation and inflammation in the SHR, it did not return these parameters to levels seen in WKY rats. We conclude that NO is less effective at inhibiting neointimal hyperplasia in the SHR than WKY rats. This may be due to increased scavenging of NO in the SHR, leading to diminished bioavailability of NO. These data will help to develop novel NO-based therapies that will be equally effective in both normotensive and hypertensive patient populations. PMID:24149190

  17. Effects of wall shear stress in venous neointimal hyperplasia of arteriovenous fistulae.

    PubMed

    Jia, Lan; Wang, Lihua; Wei, Fang; Yu, Haibo; Dong, Hongye; Wang, Bo; Lu, Zhi; Sun, Guijiang; Chen, Haiyan; Meng, Jia; Li, Bo; Zhang, Ruining; Bi, Xueqing; Wang, Zhe; Pang, Haiyan; Jiang, Aili

    2015-05-01

    An arteriovenous fistulae (AVF) is the preferred vascular access for maintenance haemodialysis patients. Its dysfunction is often due to venous stenosis, which is mainly caused by neointimal hyperplasia. Additionally, haemodynamic forces, especially wall shear stress (WSS), as a mechanical stimuli to venous wall have a significant role in neointimal hyperplasia. The purpose of this study was to evaluate the association between WSS and neointimal hyperplasia. An 'end-to-side' AVF was created between the right femoral artery and vein of canines. Canines were killed at 7 and 28 days post-surgery. The velocity and WSS in the three-dimensional computational model of AVF were simulated using computational fluid dynamics (CFDs). The four typical sites of the vein evaluated in this study, chosen according to the haemodynamic analysis, included the arteriovenous anastomosis (A-V), the juxta-anastomotic segment (J-V), the juxta-ligation segment (L-V) and the proximal vein (P-V). The specimens were haematoxylin-eosin stained and the intima-media thickening was then measured. Neointimal hyperplasia was more obvious in the inner wall of the J-V and L-V (low-and-disturbed WSS) sites compared with the P-V and A-V sites, and the outer wall of the L-V and J-V segments (high or laminar WSS) (P < 0.01). In this study, we described the haemodynamic condition in the AVF and found that neointimal hyperplasia predisposed to occur in the inner wall of venous segment near the anastomosis. We also found that not only the neointimal hyperplasia has a strong inverse correlation with WSS levels, but also is related to flow patterns. © 2015 Asian Pacific Society of Nephrology.

  18. Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.

    PubMed

    Gregory, Elaine K; Webb, Antonio R; Vercammen, Janet M; Flynn, Megan E; Ameer, Guillermo A; Kibbe, Melina R

    2014-11-15

    Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data

  19. Periadventitial adipose tissue modulates the effect of PROLI/NO on neointimal hyperplasia.

    PubMed

    Bahnson, Edward S M; Havelka, George E; Koo, Nathaniel C; Jiang, Qun; Kibbe, Melina R

    2016-10-01

    Periadventitial delivery of nitric oxide (NO) inhibits neointimal hyperplasia; however, the effect of periadventitial adipose tissue on the efficacy of NO at inhibiting neointimal hyperplasia has not been studied. The aim of our study was to assess the effect of NO in the presence and absence of periadventitial adipose tissue. We hypothesized that removal of periadventitial adipose tissue will increase neointimal formation and that NO will be more effective at inhibiting neointimal hyperplasia. The effect of NO on 3T3 fibroblasts, adventitial fibroblast (AF), and vascular smooth muscle cell (VSMC) proliferation was assessed by (3)H-thymidine incorporation in adipocyte-conditioned or regular media. The rat carotid artery balloon injury model was performed on male Sprague-Dawley rats. Before balloon injury, periadventitial adipose tissue was removed (excised model) or remained intact (intact model). Treatment groups included injury or injury with periadventitial application of PROLI/NO. Adiponectin receptor (AR) levels were assessed via immunofluorescence. Adipocyte-conditioned media had an antiproliferative effect on 3T3 and AF and a proproliferative effect on VSMC in vitro. Interestingly, NO was less effective at inhibiting 3T3 and AF proliferation and more effective at inhibiting VSMC proliferation in adipocyte-conditioned media. In vivo, the excised group showed increased neointimal hyperplasia 2 wk after surgery compared with the intact group. NO reduced neointimal hyperplasia to a greater extent in the excised group compared with the intact group. Although NO inhibited or had no impact on AR levels in the intact group, NO increased AR levels in media and adventitia of the excised group. These data show that periadventitial adipose tissue plays a role in regulating the arterial injury response and the efficacy of NO treatment in the vasculature. Published by Elsevier Inc.

  20. Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury.

    PubMed

    Pellet-Many, Caroline; Mehta, Vedanta; Fields, Laura; Mahmoud, Marwa; Lowe, Vanessa; Evans, Ian; Ruivo, Jorge; Zachary, Ian

    2015-11-01

    Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation. NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

  1. Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia.

    PubMed

    Tong, Xiaoyong; Khandelwal, Alok R; Qin, Zhexue; Wu, Xiaojuan; Chen, Lili; Ago, Tetsuro; Sadoshima, Junichi; Cohen, Richard A

    2015-12-01

    Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear. Our purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia. Mice overexpressing a human Nox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22α promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs. Downregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Unusually aggressive immature neo-intimal hyperplasia causing in-stent restenosis.

    PubMed

    McCutcheon, Keir; Triantafyllis, Andreas S; Bennett, Johan; Adriaenssens, Tom

    2017-10-10

    This image illustrates a very unusual pattern of early and aggressive immature neo-intimal hyperplasia in a 52-year-old man with unstable angina, two months after deployment of a drug-eluting stent in the proximal left anterior descending artery.

  3. Vanin-1 pantetheinase drives smooth muscle cell activation in post-arterial injury neointimal hyperplasia.

    PubMed

    Dammanahalli, K Jagadeesha; Stevens, Stephanie; Terkeltaub, Robert

    2012-01-01

    The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1(-/-) SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1(-/-) mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization.

  4. Activation of Protein Kinase G (PKG) Reduces Neointimal Hyperplasia, Inhibits Platelet Aggregation, and Facilitates Re-endothelialization

    PubMed Central

    Kim, Ju-Young; Yang, Han-Mo; Lee, Joo-Eun; Kim, Baek-Kyung; Jin, Sooryeonhwa; Lee, Jaewon; Park, Kyung-Woo; Cho, Hyun-Jai; Kwon, Yoo-Wook; Lee, Hae-Young; Kang, Hyun-Jae; Oh, Byung-Hee; Park, Young-Bae; Kim, Hyo-Soo

    2016-01-01

    In spite of its great success in reducing restenosis, drug-eluting stent (DES) has unfavorable aspects such as stent thrombosis and delayed re-endothelialization. We examined the effects of PKG activation by Exisulind on neointimal formation, platelet aggregation, and re-endothelialization. Exisulind significantly reduced VSMCs viability, cell cycle progression, migration, and neointimal hyperplasia after vascular injury in rat carotid arteries. Interestingly, in contrast to the effect on VSMC viability, Exisulind did not reduce the viability of endothelial cells. Increased PKG activity by Exisulind inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-negative PKG reversed the effects of Exisulind, resulting in the increased viability of VSMCs and neointimal formation. In addition, Exisulind facilitated the differentiation of peripheral blood mononuclear cells to endothelial lineage via PKG pathway, while inhibiting to VSMCs lineage, which was correlated with the enhanced re-endothelialization in vivo. Finally, Exisulind reduced platelet aggregation, which was mediated via PKG activation. This study demonstrated that Exisulind inhibits neointimal formation and platelet aggregation while increasing re-endothelialization via PKG pathway. These findings suggest that Exisulind could be a promising candidate drug of DES for the prevention of restenosis without other complications. PMID:27833146

  5. Use of a tacrolimus-eluting stent to inhibit neointimal hyperplasia in a porcine coronary model.

    PubMed

    Huang, Yanming; Salu, Koen; Wang, Lan; Liu, Xiaoshun; Li, Shengqiao; Lorenz, Gunter; Wnendt, Stephan; Verbeken, Eric; Bosmans, Johan; Van de Werf, Frans; De Scheerder, Ivan

    2005-03-01

    In-stent restenosis remains an unresolved problem which occurs in 5-20% of patients undergoing coronary stenting within the first 3-6 months. Neointimal formation is the main contributor to in-stent restenosis. Stent-induced arterial injury and peri-strut inflammation are involved in the process of neointimal formation by activating cytokines and growth factors which induce smooth muscle cell dedifferentiation, migration, and proliferation. Histopathological studies found that neointimal hyperplasia is principally composed of smooth muscle cells, inflammatory cells, and extracellular matrix. Stent-based delivery of anti-proliferative and/or anti-inflammatory agents have shown beneficial effects on neointimal hyperplasia in experimental studies and clinical trials. Tacrolimus (FK506) is a water-insoluble macrolide immunosuppressant discovered in 1984. It has been widely used in reducing the incidence and severity of allograft rejection after organ transplantation. It has also been used to treat other inflammatory conditions such as atopic dermatitis. In this study, we evaluated the efficacy of stent-based delivery of tacrolimus on inflammation and neointimal formation in an overstretched coronary stent model.

  6. Deficiency of Long Pentraxin PTX3 Promoted Neointimal Hyperplasia after Vascular Injury.

    PubMed

    Ishino, Mitsunori; Shishido, Tetsuro; Suzuki, Satoshi; Katoh, Shigehiko; Sasaki, Toshiki; Funayama, Akira; Netsu, Shunsuke; Hasegawa, Hiromasa; Honda, Shintaro; Takahashi, Hiroki; Arimoto, Takanori; Miyashita, Takehiko; Miyamoto, Takuya; Watanabe, Tetsu; Takeishi, Yasuchika; Kubota, Isao

    2015-01-01

    Pentraxin 3 (PTX3) is a novel marker for the primary local activation of innate immunity and inflammatory responses. Although clinical and experimental evidence suggests that PTX3 is associated with atherosclerosis, the relationship between PTX3 and vascular remodeling after wall injury remains to be determined. We investigated the effects of PTX3 on neointimal hyperplasia following wire vascular injury. PTX3 systemic knockout (PTX3-KO) mice and wild-type littermate (WT) mice were subjected to wire-mediated endovascular injury. At four weeks after wire-mediated injury, the areas of neointimal and medial hyperplasia were evaluated. The PTX3-KO mice exhibited higher hyperplasia/media ratios than the WT mice after wire injury, and the degree of Mac-3-positive macrophage accumulation was significantly higher in the PTX3-KO mice than in the WT mice. Furthermore, the PTX3-KO mice showed a much greater increase in the number of PCNA-stained cells in the vascular wall than that observed in the WT mice. A deficiency of PTX3 results in deteriorated neointimal hyperplasia after vascular injury via the effects of macrophage accumulation and vascular smooth muscle cell proliferation and migration.

  7. Vasohibin prevents arterial neointimal formation through angiogenesis inhibition

    SciTech Connect

    Yamashita, Hiroshi; Abe, Mayumi; Watanabe, Kazuhide; Shimizu, Kazue; Moriya, Takuya; Sato, Akira; Satomi, Susumu; Ohta, Hideki; Sonoda, Hikaru; Sato, Yasufumi . E-mail: y-sato@idac.tohoku.ac.jp

    2006-07-07

    Vasohibin is a VEGF-inducible angiogenesis inhibitor in vascular endothelium. Here we examined the presence of vasohibin in human arterial wall, and found it in endothelium of adventitial microvessels in atherosclerotic lesion. Adventitial angiogenesis is involved in the progression of neointimal formation. Even in the presence of endogenous angiogenesis inhibitors, pathological angiogenesis persists. However, the supplementation of exogenous angiogenesis inhibitors can prevent pathological angiogenesis. We evaluated the potential role of vasohibin in neointimal formation. Adenovirus-mediated human vasohibin gene transfer in mouse liver resulted in the release of vasohibin in plasma and exhibited anti-angiogenic effects at remote sites. This gene transfer inhibited adventitial angiogenesis, macrophage infiltration, and neointimal formation after cuff placement on mouse femoral artery. Vasohibin exhibited no direct effect on migration and proliferation of smooth muscle cells. Thus, vasohibin has an activity to prevent neointimal formation by inhibiting adventitial angiogenesis.

  8. Methotrexate loaded SAE coated coronary stents reduce neointimal hyperplasia in a porcine coronary model

    PubMed Central

    Huang, Y; Salu, K; Liu, X; Li, S; Wang, L; Verbeken, E; Bosmans, J; De Scheerder, I

    2004-01-01

    Objective: To evaluate the effect of stent based methotrexate delivery on neointimal hyperplasia. Methods: Stainless steel coronary stents and biological polymer coated (SAE) stents were randomly implanted in coronary arteries of pigs with a stent to artery ratio of 1.1:1. The pigs were killed after five days (10 stents) or four weeks (20 stents). Second, stainless steel coronary stents were dip coated in a 10 mg/ml methotrexate–SAE polymer solution, resulting in a total load of 150 μg methotrexate/stent. SAE coated stents and methotrexate loaded stents were randomly implanted in porcine coronary arteries with a stent to artery ratio of 1.2:1 and followed up to four weeks. Results: SAE coated stents and bare stents elicited a similar tissue response at five days. At four weeks, neointimal hyperplasia induced by the coated stents was less pronounced than with the bare stents (1.32 (0.66) v 1.73 (0.93) mm2, p > 0.05). In vitro drug release studies showed that 50% of the methotrexate was released in 24 hours, and all drug was released within four weeks. No impact on vascular smooth muscle cell proliferation or viability was observed in in vitro cell cultures. At four weeks the arteries with methotrexate loaded stents had decreased peristrut inflammation and neointimal hyperplasia (1.22 (0.34) v 2.25 (1.28) mm2, p < 0.01). Conclusions: SAE coating had an excellent biocompatibility with vascular tissue. Stent based delivery of methotrexate in the SAE coating effectively reduced neointimal hyperplasia in a porcine coronary stent model, potentially due to reduced peristrut inflammation. PMID:14729797

  9. Human Umbilical Cord Blood Endothelial Progenitor Cells Decrease Vein Graft Neointimal Hyperplasia in SCID Mice

    PubMed Central

    Zhu, Shoukang; Malhotra, Anuj; Zhang, Lisheng; Deng, Shanming; Zhang, Taifang; Freedman, Neil J.; Storms, Robert; Peppel, Karsten; Goldschmidt-Clermont, Pascal J.; Dong, Chunming

    2014-01-01

    Aims Vein graft endothelial damage is a key step in the development of neointimal hyperplasia, leading to vein graft failure. We sought to determine whether exogenous endothelial progenitor cells could promote vein graft re-endothelialization, and thereby ameliorate neointimal hyperplasia. Methods and Results Carotid artery interposition grafting was performed with syngeneic inferior vena cavae in mice with severe combined immunodeficiency (SCID). Lineage-negative human umbilical cord blood (hUCB) cells (or medium alone) were injected into vein-grafted mice intraoperatively and 2 weeks postoperatively. In vein grafts from hUCB cell-injected mice, we found human HLA-expressing endothelial cells, as well as increased levels of VEGF and FGF-2. Furthermore, hUCB cells secreted VEGF and FGF-2 in vitro. The markedly enhanced endothelial regeneration, likely resulting from both direct engraftment and paracrine actions of hUCB cells, inhibited inflammatory response, diminished intimal cell proliferation, and reduced neointimal hyperplasia in the vein grafts. Conclusions hUCB cells may accelerate vein graft re-endothelialization via both direct differentiation into endothelial cells and release of paracrine factors to enhance endothelial regeneration and reduce inflammation. These data highlight a potential therapeutic role for cellular therapy in vessel injury. PMID:20451204

  10. PDGF-D contributes to neointimal hyperplasia in rat model of vessel injury

    SciTech Connect

    Chen Jingzhou; Han Yu; Lin Chunxia; Zhen Yisong; Song Xiaodong; Teng Siyong; Chen Chen; Chen Yu; Zhang Yinhui; Hui Rutai . E-mail: huirutai@sglab.org

    2005-04-15

    In this study, we determined the role of PDGF-D, a new member of the PDGF family, in a rat model of balloon injured artery made with a 2F catheter in Sprague-Dawley male rats. PDGF-D expression was studied in the injured and control segments of abdominal aorta. The function of PDGF-D was evaluated in rat vascular smooth muscle cells stably transfected with PDGF-D gene. We found that in normal abdominal aorta, PDGF-D was highly expressed in adventia, moderate in endothelia, and unidentified in media. Stable transfection of PDGF-D gene into vascular smooth muscle cells increased the cell migration by 2.2-fold, and the proliferation by 2.3-fold, respectively, and MMP-2 production and activity as well. These results support the fact that PDGF-D is involved in the formation of neointimal hyperplasia induced by balloon catheter injury and may serve as a target in preventing vascular restenosis after coronary angioplasty.

  11. Upregulated TRPC1 Channel in Vascular Injury In Vivo and Its Role in Human Neointimal Hyperplasia

    PubMed Central

    Kumar, B.; Dreja, K.; Shah, S.S.; Cheong, A.; Xu, S.-Z.; Sukumar, P.; Naylor, J.; Forte, A.; Cipollaro, M.; McHugh, D.; Kingston, P.A.; Heagerty, A.M.; Munsch, C.M.; Bergdahl, A.; Hultgårdh-Nilsson, A.; Gomez, M.F.; Porter, K.E.; Hellstrand, P.; Beech, D.J.

    2008-01-01

    Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure. PMID:16439693

  12. Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury.

    PubMed

    Yang, Lei; Sakurai, Takayuki; Kamiyoshi, Akiko; Ichikawa-Shindo, Yuka; Kawate, Hisaka; Yoshizawa, Takahiro; Koyama, Teruhide; Iesato, Yasuhiro; Uetake, Ryuichi; Yamauchi, Akihiro; Tanaka, Megumu; Toriyama, Yuichi; Igarashi, Kyoko; Shindo, Takayuki

    2013-06-01

    Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule. We compared the effect of CGRP deficiency on neointimal formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointimal formation after vascular injury was markedly enhanced in CGRP-/- mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointimal formation in CGRP-/-mice. In vitro analysis showed that CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

  13. Short-term effects of double-layer autologous vein graft on restraint of excessive distension and alleviation of neointimal hyperplasia in a porcine saphenous vein graft model.

    PubMed

    Ji, Qiang; Mei, Yunqing; Wang, Xisheng; Feng, Jing; Cai, Jianzhi; Sun, Yifeng; Dewei, Wusha; Wang, Chunping; Chi, Liangjie

    2011-03-01

    Although the use of external vein graft support seems a promising approach to prevent neointimal hyperplasia and wall thickening in vein grafts, its extensive clinical application still has a long way to go. The aim of this study was to evaluate short-term effects of self-designed double-layer autologous saphenous vein graft on restraining excessive distension of vein graft and alleviating neointimal hyperplasia in a porcine model. Left and right hind femoral arteries of 24 white pigs were randomly divided into an experimental group (double-layer vein graft) and a control group (single-layer vein graft). After 1 h of implantation, then 1, 2, and 4 weeks later, the mean inner diameter of the vein grafts in the experimental group measured by Doppler-ultrasound was 2.7 ± 0.1, 2.8 ± 0.1, 2.9 ± 0.1, and 3.1 ± 0.1 mm, respectively; mean peak blood flow velocity measured by Doppler-ultrasound was 96.7 ± 12.8, 93.7 ± 11.5, 89.4 ± 9.6 and 84.6 ± 10.1 cm/s, respectively, while the mean neointimal thicknesses were 47.1 ± 7.7, 93.7 ± 15.1, and 177.4 ± 25.5 μm at 1, 2 and 4 weeks, respectively. As compared to the control group, inner diameter and neointimal thickness of vein grafts in the experimental group were significantly lower, while mean peak blood flow velocity was significantly higher at 1, 2, and 4 weeks after implantation. The proliferation index in the experimental group was also significantly lower within 4 weeks after implantation. The self-designed double-layer autologous saphenous vein graft restrains early excessive distension of vein graft and alleviates early neointimal hyperplasia.

  14. Patient-Specific, Multi-Scale Modeling of Neointimal Hyperplasia in Vein Grafts

    PubMed Central

    Donadoni, Francesca; Pichardo-Almarza, Cesar; Bartlett, Matthew; Dardik, Alan; Homer-Vanniasinkam, Shervanthi; Díaz-Zuccarini, Vanessa

    2017-01-01

    Neointimal hyperplasia is amongst the major causes of failure of bypass grafts. The disease progression varies from patient to patient due to a range of different factors. In this paper, a mathematical model will be used to understand neointimal hyperplasia in individual patients, combining information from biological experiments and patient-specific data to analyze some aspects of the disease, particularly with regard to mechanical stimuli due to shear stresses on the vessel wall. By combining a biochemical model of cell growth and a patient-specific computational fluid dynamics analysis of blood flow in the lumen, remodeling of the blood vessel is studied by means of a novel computational framework. The framework was used to analyze two vein graft bypasses from one patient: a femoro-popliteal and a femoro-distal bypass. The remodeling of the vessel wall and analysis of the flow for each case was then compared to clinical data and discussed as a potential tool for a better understanding of the disease. Simulation results from this first computational approach showed an overall agreement on the locations of hyperplasia in these patients and demonstrated the potential of using new integrative modeling tools to understand disease progression. PMID:28458640

  15. Neointimal hyperplasia persists at six months after sirolimus-eluting stent implantation in diabetic porcine

    PubMed Central

    Zhang, Qi; Lu, Lin; Pu, LiJin; Zhang, RuiYan; Shen, Jie; Zhu, ZhengBing; Hu, Jian; Yang, ZhenKun; Chen, QiuJin; Shen, WeiFeng

    2007-01-01

    Background Observational clinical studies have shown that patients with diabetes have less favorable results after percutaneous coronary intervention compared with the non-diabetic counterparts, but its mechanism remains unclear. The aim of this study was to examine the changes of neointimal hyperplasia after sirolimus-eluting stent (SES) implantation in a diabetic porcine model, and to evaluate the impact of aortic inflammation on this proliferative process. Methods Diabetic porcine model was created with an intravenous administration of a single dose of streptozotocin in 15 Chinese Guizhou minipigs (diabetic group); each of them received 2 SES (Firebird, Microport Co, China) implanted into 2 separated major epicardial coronary arteries. Fifteen non-diabetic minipigs with SES implantation served as controls (control group). At 6 months, the degree of neointimal hyperplasia was determined by repeat coronary angiography, intravascular ultrasound (IVUS) and histological examination. Tumor necrosis factor (TNF)-α protein level in the aortic intima was evaluated by Western blotting, and TNF-α, interleukin (IL)-1β and IL-6 mRNA levels were assayed by reverse transcription and polymerase chain reaction. Results The distribution of stented vessels, diameter of reference vessels, and post-procedural minimal lumen diameter were comparable between the two groups. At 6-month follow-up, the degree of in-stent restenosis (40.4 ± 24.0% vs. 20.2 ± 17.7%, p < 0.05), late lumen loss (0.33 ± 0.19 mm vs. 0.10 ± 0.09 mm, p < 0.001) by quantitative angiography, percentage of intimal hyperplasia in the stented area (26.7 ± 19.2% vs. 7.3 ± 6.1%, p < 0.001) by IVUS, and neointimal area (1.59 ± 0.76 mm2 vs. 0.41 ± 0.18 mm2, p < 0.05) by histological examination were significantly exacerbated in the diabetic group than those in the controls. Significant increases in TNF-α protein and TNF-α, IL-1β and IL-6 mRNA levels were observed in aortic intima in the diabetic group

  16. Oral mycophenolate mofetil prevents in-stent intimal hyperplasia without edge effect.

    PubMed

    Ilkay, Erdogan; Tirikli, Latif; Ozercan, Ibrahim; Yavuzkir, Mustafa; Karaca, Ilgin; Rahman, Ali; Arslan, Nadi

    2006-01-01

    Neointimal hyperplasia is in the forefront in in-stent restenosis. Prevention of in-stent restenosis is possible by reducing and inhibiting the hyperplasia of smooth muscle cells. The authors planned this study to test the hypothesis that when administered orally, mycophenolate mofetil (MMF) could inhibit in-stent neointimal hyperplasia. The study included 14 New Zealand rabbits. The rabbits were allocated to 2 different groups: Group 1 included 7 rabbits that were given MMF, 40 mg/kg/day by oral route. Group 2 included 7 rabbits that were not given MMF after the stenting. Sampling materials were taken before and after stenting by incising the artery so as to cover a 5-mm area. The samples taken from the edge of the stent in Group 1 showed focal neointimal cell proliferation, but it was less than that from the control group. Neointimal thickness was 0.048 +/-0.009 mm and neointimal area was 0.0925 +/-0.019 mm(2). Apparent neointimal cell proliferation and thickening of the intimal layer were observed in Group 2. Neointimal thickness at the stent edge was 0.147 +/-0.051 mm and the neointimal area was 0.154 +/-0.023 mm(2). The differences between groups in terms of neointimal thickness and neointimal area were statistically significant (p=0.001 for thickness and p=0.001 for area). In-stent artery samples of Group 1 showed that some subjects had no neointimal cell proliferation, while others had very limited focal intimal thickening. Neointimal thickening was 0.071 +/-0.003 mm and neointimal area was 0.073 +/-0.003 mm(2). In Group 2 apparent, and mostly focal, neointimal cell proliferation and formation of intimal layer were observed in the stent. Neointimal thickening was 0.154 +/-0.069 mm and neointimal area was 0.279 +/-0.059 mm(2). The comparison between groups showed significant differences (p=0.011 for thickness and p=0.001 for area). It was established in the third month that endothelialization was completed in both groups. Oral MMF decreased in-stent intimal

  17. Neointimal hyperplasia in allogeneic and autologous venous grafts is not different in nature.

    PubMed

    Busch, Albert; Hartmann, Elena; Wagner, Nicole; Ergün, Süleyman; Kickuth, Ralph; Kellersmann, Richard; Lorenz, Udo

    2015-07-01

    Neointimal hyperplasia, transplant rejection and thus immunogenicity of allografts are possible reasons for poorer patency rates in cryopreserved venous allografts for peripheral bypass surgery in comparison with autologous venous grafts. To expand the limited knowledge from human allografts, we histologically investigated allogeneic and autologous venous grafts in arterial location. Specimens of allogeneic and autologous venous graft stenosis, harvested 6 months after bypass implantation, were immunohistochemically characterized. Examination of the lesions showed a uniform morphological pattern. A continuous endothelial layer, tissue fibrosis and a thickened neointima with monocytes and dedifferentiated vascular smooth muscle cells were seen in both conduits with very low cell turnover and the absence of acute and chronic inflammation. Neoangiogenesis with CD34-positive endothelium was abundant in the vessel media. The morphological patterns of allogeneic and autologous neointima formation are similar. Consequently, neointimal hyperplasia in venous grafts may reflect a uniform physiological host response of non-immunological factors with the reasons for poorer clinical outcome of cryopreserved allografts yet to be elucidated.

  18. Neointimal hyperplasia in a thin-strut cobalt-chromium stent: insights from detailed 3-D intravascular ultrasound analysis.

    PubMed

    Otake, Hiromasa; Ako, Junya; Waseda, Katsuhisa; Sakurai, Ryota; Hirohata, Atsushi; Kaneda, Hideaki; Hasegawa, Takao; Honda, Yasuhiro; Fitzgerald, Peter J

    2010-11-05

    The effect of current generation cobalt-chromium stents on neointimal proliferation has not been fully elucidated. IVUS images of 137 patients treated with a single thin-strut cobalt-chromium stent (Driver: DRI, n=74) or stainless steel stent (Multilink plus: ML, n=63) were selected. Although % neointima volume (neointimal volume divided by stent volume) were comparable, DRI showed significantly smaller maximum %cross-sectional narrowing (%CSN: neointimal area divided by stent area) (P=0.006) with significantly less %CSN>60 (percent stent length with %CSN>60%) than ML (P=0.04). In conclusion, the amount of neointimal hyperplasia after DRI implantation was comparable to that after ML. However, current generation cobalt-chromium DRI may show less and shorter severe narrowing than the stainless steel ML.

  19. DNA aptamer raised against advanced glycation end products inhibits neointimal hyperplasia in balloon-injured rat carotid arteries.

    PubMed

    Ojima, Ayako; Oda, Eriko; Higashimoto, Yuichiro; Matsui, Takanori; Yamagishi, Sho-ichi

    2014-02-15

    Advanced glycation end products (AGE) and their receptor (RAGE) interaction elicit inflammatory and proliferative reactions in arteries, thus playing a role in cardiovascular disease. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. However, effects of AGE-aptamer on vascular injury remain unknown. In this study, we examined whether and how AGE-aptamer inhibits neointimal hyperplasia in balloon-injured rat carotid arteries. Male Wistar rats (weighting ca. 400 g at 11 weeks old) were anesthetized with sodium pentobarbital. The left common carotid artery was balloon-injured 3 times with 2F Fogaty catheter inserted through the femoral artery. Then the rats received continuous intraperitoneal infusion (3 μg/day) of either AGE-aptamer or control-aptamer by an osmotic mini pump for 2 weeks. 14 days after the procedure, the left common carotid arteries were excised for morphometric, immunohistochemical and western blot analyses. Compared with control-aptamer, AGE-aptamer significantly suppressed neointima formation after balloon injury and reduced AGE accumulation, oxidative stress generation, proliferation cell nuclear antigen-positive area, macrophage infiltration, RAGE and platelet-derived growth factor-BB (PDGF-BB) expression levels in balloon-injured carotid arteries. The present study suggests that AGE-aptamer could prevent balloon injury-induced neointimal hyperplasia by reducing PDGF-BB and macrophage infiltration via suppression of the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for suppressing neointima formation after balloon angioplasty. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Novel short-duration heating balloon dilatation with uniform temperature distribution: the heating conditions to suppress neo-intimal hyperplasia.

    PubMed

    Kunio, M; Shimazaki, N; Arai, T; Sakurada, M

    2011-01-01

    We investigate the relation between the influences on smooth muscle cells and the chronic performances of our novel short-duration heating balloon dilatation to reveal the heating conditions which can suppress the neo-intimal hyperplasia after our heating dilatations. The temperature of prototype balloon catheter surface was measured during short-duration heating balloon dilatation ex vivo. There existed 2 °C temperature variations in the long direction of prototype balloon catheter at a maximum. The neo-intimal hyperplasia occupancy rate after our short-duration heating dilatations were measured in vivo porcine study. The neo-intimal hyperplasia was suppressed most at 75 °C in balloon peak temperature in vivo. The estimated dead rate of smooth muscle cells at this condition was about 13% by the Arrhenius equation. We think that the suppression of neo-intimal hyperplasia was obtained after our short-duration heating dilatation due to the proper decrease of smooth muscle cells by heating and no thermal damages to the adventitia and surrounding tissues.

  1. Insights into the Effect of Nitric Oxide and its Metabolites Nitrite and Nitrate at Inhibiting Neointimal Hyperplasia

    PubMed Central

    Vavra, Ashley K.; Havelka, George E.; Martinez, Janet; Lee, Vanessa R.; Fu, Bo; Jiang, Qun; Keefer, Larry K.; Kibbe, Melina R.

    2011-01-01

    Objective Periadventitial delivery of the nitric oxide (NO) donor PROLI/NO following arterial injury effectively inhibits neointimal hyperplasia. Given the short half-life of NO release from PROLI/NO, our goal was to determine if inhibition of neointimal hyperplasia by PROLI/NO was due to NO, or its metabolites nitrite and nitrate. Methods and Results In vitro, the NO donor DETA/NO inhibited proliferation of rat aortic vascular smooth muscle cells (RASMC), but neither nitrite nor nitrate did. In vivo, following rat carotid artery balloon injury or injury plus the molar equivalents of PROLI/NO, nitrite, or nitrate (n=8–11/group), PROLI/NO was found to provide superior inhibition of neointimal hyperplasia (82% inhibition of intimal area, and 44% inhibition of medial area, p<0.001). Only modest inhibition was noted with nitrite or nitrate (45% and 41% inhibition of intimal area, and 31% and 29% inhibition of medial area, respectively, p<0.001). No effects on blood pressure were noted with any treatment groups. In vivo, only PROLI/NO inhibited cellular proliferation and increased arterial lumen area compared to injury alone (p<0.001). However, all three treatments inhibited inflammation (p<0.001). Conclusions PROLI/NO was more effective at inhibiting neointimal hyperplasia following arterial injury than nitrite or nitrate. However, modest inhibition of neointimal hyperplasia was observed with nitrite and nitrate, likely secondary to anti-inflammatory actions. In conclusion, we have demonstrated that the efficacy of NO donors is primarily due to NO production and not its metabolites, nitrite and nitrate. PMID:21554972

  2. Sulodexide may alleviate neointimal hyperplasia by inhibiting angiopoietin‑2 in an arteriovenous fistula model.

    PubMed

    Lei, Yan; Zheng, Zhihua; Wang, Ying; Liu, Yuyun; Liu, Rongjun; Xu, Qingdong; Yu, Xueqing

    2013-03-01

    The present study was undertaken to confirm whether sulodexide aleviates neointimal hyperplasia by regulating angiopoietin/Tie in a rat femoral arteriovenous fistula (AVF) model. Sprague Dawley rats were divided into four groups: sham, model, treatment and treatment control. An arteriovenous shunt model was created in the model and treatment groups. Sulodexide was subcutaneously administered (10 mg/kg/day) 6 times per week for 8 weeks in the treatment and treatment control groups. Histology and immunofluorescence were analyzed and the protein expression of angiopoietin‑1, angiopoietin‑2, Tie‑2, p‑ERK and total‑ERK were tested by ELISA and/or western blotting after 8 weeks. HE staining revealed that sulodexide was able to partially alleviate intimal hyperplasia of remodeled veins in the AVF model. Additionally, sulodexide was able to decrease angiopoietin‑2 and Tie‑2 expression while increasing angiopoietin‑1 expression in AVF tissue. Sulodexide was also able to decrease ERK phosphorylation which was increased in the model. Serum levels of soluble Tie-2 (sTie‑2) were also significantly decreased by sulodexide compared with the model. Immunofluorescent analysis also confirmed that sulodexide was able to decrease angiopoietin‑2 expression, possibly partially by inhibiting endothelial cell proliferation. Sulodexide may alleviate venous intimal hyperplasia by regulating the angiopoietin/Tie system, which may play a significant role in assisting remodeled veins to cope with their new biomechanical environment, but whether the angiopoietin/Tie system is beneficial or not requires further study.

  3. Age-related changes in monocytes exacerbate neointimal hyperplasia after vascular injury

    PubMed Central

    Martinez, Laisel; Gomez, Camilo; Vazquez-Padron, Roberto I.

    2015-01-01

    Neointimal hyperplasia is the leading cause of restenosis after endovascular interventions. It is characterized by the accumulation of myofibroblast-like cells and extracellular matrix in the innermost layer of the wall and is exacerbated by inflammation. Monocytes from either young or aged rats were applied perivascularly to injured vascular walls of young recipient animals. Monocytes from aged rats, but not young donors, increased neointima thickness. Accordingly, the gene expression profiles of CD11b+ monocytes from aged rats showed significant up-regulation of genes involved in cellular adhesion, lipid degradation, cytotoxicity, differentiation, and inflammation. These included cadherin 13 (Cdh13), colony stimulating factor 1 (Csf1), chemokine C-X-C motif ligand 1 (Cxcl1), endothelial cell-selective adhesion molecule (Esam), and interferon gamma (Ifng). In conclusion, our results suggest that the increased inflammatory and adhesive profile of monocytes contributes to pathological wall remodeling in aged-related vascular diseases. PMID:25965835

  4. Role of Metabolic Environment on Nitric Oxide Mediated Inhibition of Neointimal Hyperplasia in Type 1 and Type 2 Diabetes

    PubMed Central

    Wang, Zheng; Martinez, Janet; Jiang, Qun; Kibbe, Melina R.

    2014-01-01

    Nitric oxide (NO) is well known to inhibit neointimal hyperplasia following arterial injury. Previously, we reported that NO was more effective at inhibiting neointimal hyperplasia in a type 2 diabetic environment than control. We also found that NO was ineffective in an uncontrolled type 1 diabetic environment; however, insulin restored the efficacy of NO. Thus, the goal of this study was to more closely evaluate the effect of insulin and glucose on the efficacy of NO at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments using different doses of insulin as well as pioglitazone. Type 1 diabetes was induced in male Lean Zucker (LZ) rats with streptozotocin (60mg/kg IP). Groups included control, moderate glucose control, and tight glucose control. Zucker Diabetic Fatty (ZDF) rats fed Purina 5008 chow were used as a type 2 diabetic model. Groups included no therapy, insulin therapy, or pioglitazone therapy. After 4 weeks of maintaining group assignments, the carotid artery injury model was performed. Treatment groups included: control, injury, and injury plus NO. 2 weeks following arterial injury, in the type 1 diabetic rats, NO most effectively reduced the neointimal area in the moderate and tightly controlled groups (81% and 88% vs. 33%, respectively, p=0.01). In type 2 diabetic rats, the metabolic environment had no impact on the efficacy of NO (81%–82% reduction for all groups). Thus, in this study, we show NO is effective at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments. A greater understanding of how the metabolic environment may impact the efficacy of NO may lead to the development of more effective NO-based therapies for patients with diabetes. PMID:24333562

  5. Role of metabolic environment on nitric oxide mediated inhibition of neointimal hyperplasia in type 1 and type 2 diabetes.

    PubMed

    Rodriguez, Monica P; Emond, Zachary M; Wang, Zheng; Martinez, Janet; Jiang, Qun; Kibbe, Melina R

    2014-01-30

    Nitric oxide (NO) is well known to inhibit neointimal hyperplasia following arterial injury. Previously, we reported that NO was more effective at inhibiting neointimal hyperplasia in a type 2 diabetic environment than control. We also found that NO was ineffective in an uncontrolled type 1 diabetic environment; however, insulin restored the efficacy of NO. Thus, the goal of this study was to more closely evaluate the effect of insulin and glucose on the efficacy of NO at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments using different doses of insulin as well as pioglitazone. Type 1 diabetes was induced in male lean Zucker (LZ) rats with streptozotocin (60 mg/kg IP). Groups included control, moderate glucose control, and tight glucose control. Zucker diabetic fatty (ZDF) rats fed Purina 5008 chow were used as a type 2 diabetic model. Groups included no therapy, insulin therapy, or pioglitazone therapy. After 4 weeks of maintaining group assignments, the carotid artery injury model was performed. Treatment groups included: control, injury and injury plus NO. 2 weeks following arterial injury, in the type 1 diabetic rats, NO most effectively reduced the neointimal area in the moderate and tightly controlled groups (81% and 88% vs. 33%, respectively, p=0.01). In type 2 diabetic rats, the metabolic environment had no impact on the efficacy of NO (81-82% reduction for all groups). Thus, in this study, we show NO is effective at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments. A greater understanding of how the metabolic environment may impact the efficacy of NO may lead to the development of more effective NO-based therapies for patients with diabetes.

  6. Leukotriene-C4 synthase, a critical enzyme in the activation of store-independent Orai1/Orai3 channels, is required for neointimal hyperplasia.

    PubMed

    Zhang, Wei; Zhang, Xuexin; González-Cobos, José C; Stolwijk, Judith A; Matrougui, Khalid; Trebak, Mohamed

    2015-02-20

    Leukotriene-C4 synthase (LTC4S) generates LTC4 from arachidonic acid metabolism. LTC4 is a proinflammatory factor that acts on plasma membrane cysteinyl leukotriene receptors. Recently, however, we showed that LTC4 was also a cytosolic second messenger that activated store-independent LTC4-regulated Ca(2+) (LRC) channels encoded by Orai1/Orai3 heteromultimers in vascular smooth muscle cells (VSMCs). We showed that Orai3 and LRC currents were up-regulated in medial and neointimal VSMCs after vascular injury and that Orai3 knockdown inhibited LRC currents and neointimal hyperplasia. However, the role of LTC4S in neointima formation remains unknown. Here we show that LTC4S knockdown inhibited LRC currents in VSMCs. We performed in vivo experiments where rat left carotid arteries were injured using balloon angioplasty to cause neointimal hyperplasia. Neointima formation was associated with up-regulation of LTC4S protein expression in VSMCs. Inhibition of LTC4S expression in injured carotids by lentiviral particles encoding shRNA inhibited neointima formation and inward and outward vessel remodeling. LRC current activation did not cause nuclear factor for activated T cells (NFAT) nuclear translocation in VSMCs. Surprisingly, knockdown of either LTC4S or Orai3 yielded more robust and sustained Akt1 and Akt2 phosphorylation on Ser-473/Ser-474 upon serum stimulation. LTC4S and Orai3 knockdown inhibited VSMC migration in vitro with no effect on proliferation. Akt activity was suppressed in neointimal and medial VSMCs from injured vessels at 2 weeks postinjury but was restored when the up-regulation of either LTC4S or Orai3 was prevented by shRNA. We conclude that LTC4S and Orai3 altered Akt signaling to promote VSMC migration and neointima formation.

  7. Chemerin Stimulates Vascular Smooth Muscle Cell Proliferation and Carotid Neointimal Hyperplasia by Activating Mitogen-Activated Protein Kinase Signaling

    PubMed Central

    Xiong, Wei; Luo, Yu; Wu, Lin; Liu, Feng; Liu, Huadong; Li, Jianghua; Liao, Bihong; Dong, Shaohong

    2016-01-01

    Vascular neointimal hyperplasia and remodeling arising from local inflammation are characteristic pathogeneses of proliferative cardiovascular diseases, such as atherosclerosis and post angioplasty restenosis. The molecular mechanisms behind these pathological processes have not been fully determined. The adipokine chemerin is associated with obesity, metabolism, and control of inflammation. Recently, chemerin has gained increased attention as it was found to play a critical role in the development of cardiovascular diseases. In this study, we investigated the effects of chemerin on the regulation of vascular smooth muscle cells and carotid neointimal formation after angioplasty. We found that circulating chemerin levels increased after carotid balloon injury, and that knockdown of chemerin significantly inhibited the proliferative aspects of vascular smooth muscle cells induced by platelet-derived growth factor-BB and pro-inflammatory chemokines in vitro as well as prohibited carotid neointimal hyperplasia and pro-inflammatory chemokines in vivo after angioplasty. Additionally, inhibition of chemerin down-regulated the expression of several proteins, including phosphorylated p38 mitogen-activated protein kinase, phosphorylated extracellular signal regulated kinase 1/2, nuclear factor-kappa B p65, and proliferation cell nuclear antigen. The novel finding of this study is that chemerin stimulated vascular smooth muscle cells proliferation and carotid intimal hyperplasia through activation of the mitogen-activated protein kinase signaling pathway, which may lead to vascular inflammation and remodeling, and is relevant to proliferative cardiovascular diseases. PMID:27792753

  8. Comparison of neointimal hyperplasia with drug-eluting stents versus bare metal stents in patients undergoing intracoronary bone-marrow mononuclear cell transplantation following acute myocardial infarction.

    PubMed

    Villa, Adolfo; Arnold, Roman; Sánchez, Pedro L; Gimeno, Federico; Ramos, Benigno; Cantero, Teresa; Fernández, Maria Eugenia; Sanz, Ricardo; Gutiérrez, Oliver; Mota, Pedro; García-Frade, Javier; San Román, José Alberto; Fernández-Avilés, Francisco

    2009-06-15

    The aims of this study were to assess the safety of drug-eluting stent (DES) use and to compare the incidence of in-stent restenosis (ISR) and neointimal hyperplasia formation according to the type of stent implanted (DES vs bare-metal stents [BMS]) in patients who underwent intracoronary bone marrow mononuclear cell transplantation after acute ST elevation myocardial infarction. Fifty-nine patients with successfully revascularized ST elevation myocardial infarction (37 using BMS and 22 using DES) underwent paired angiographic examinations at baseline and 6 to 9 months after the intracoronary injection of 91 million +/- 56 million autologous bone marrow mononuclear cells. A subgroup of 30 patients also underwent serial intravascular ultrasound examinations. Off-line angiographic assessment showed 4 cases of binary ISR, primarily in BMS (3 cases), and no major adverse cardiac events were associated with stent type (mean follow-up period 41 +/- 10 months). At follow-up, angiographic late luminal loss was significantly lower in patients with DES than in those patients with BMS (0.35 +/- 0.66 vs 0.71 +/- 0.38 mm, p = 0.011). Multivariate analysis identified the use of DES (beta = -0.32, 95% confidence interval [CI] -0.57 to -0.26, p = 0.03) and a smaller baseline reference vessel diameter (beta = 0.29, 95% CI 0.04 to 0.54, p = 0.02) as independent predictors of lower late loss. Moreover, intravascular ultrasound showed a significant reduction of in-stent neointimal hyperplasia formation related to DES use compared with BMS use (Delta neointimal hyperplasia volume 5.4 mm(3) [95% CI 2.7 to 28.1] vs 35.9 mm(3) [95% CI 22.0 to 43.6], p = 0.035). In conclusion, these findings suggest that the use of DES is safe and may prevent ISR and neointimal hyperplasia formation in patients who undergo intracoronary bone marrow mononuclear cell transplantation after a successfully revascularized ST elevation myocardial infarction.

  9. Sphingosine-1-phosphate receptor 3 promotes neointimal hyperplasia in mouse iliac-femoral arteries

    PubMed Central

    Shimizu, Takuya; De Wispelaere, Allison; Winkler, Martin; D’Souza, Travis; Caylor, Jacob; Chen, Lihua; Dastvan, Frank; Deou, Jessie; Cho, Aesim; Larena-Avellaneda, Axel; Reidy, Michael; Daum, Guenter

    2012-01-01

    Objective The objective of this study is to define a role for S1PR3 in intimal hyperplasia. Methods and Results A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 is higher in these arteries when compared to carotid arteries. At 28 days after surgery, wild-type arteries form significantly larger lesions than S1PR3-null arteries. BrdU labeling experiments demonstrate that upon injury, wild-type arteries exhibit higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro is low, we expressed S1PR3 in S1PR3-null SMCs using retroviral-mediated gene transfer to study S1PR3 effects on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, respond to S1P stimulation with activation of Rac, Erk and Akt. SMCs expressing S1PR3 also grow migrate more. Conclusion In humans and mice, S1PR3 expression is higher in iliac-femoral arteries compared to carotid arteries. S1PR3 promotes neointimal hyperplasia upon denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt and Rac. PMID:22308044

  10. Nobiletin Inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in a rat carotid artery injury model.

    PubMed

    Guan, Siyu; Tang, Qizhu; Liu, Wenwei; Zhu, Rui; Li, Bin

    2014-12-01

    Preclinical Research The abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of neointimal hyperplasia after vascular injury. Nobiletin, a citrus bioflavonoid, exhibits anti-inflammatory and anti-oxidative activities. The present study evalutaed whether nobiletin could inhibit platelet-derived growth factor (PDGF)-BB- stimulated VSMC proliferation and migration and decrease neointimal hyperplasia in a rat carotid artery injury model. Cultured VSMCs from rat thoracic aortas were treated with nobiletin before being stimulated with 20 ng/ml PDGF-BB, and rats were subjected to carotid artery injury. Nobiletin inhibited PDGF-BB-induced VSMC proliferation and migration, attenuated reactive oxygen species (ROS) production and reduced phosphorylation of ERK1/2 and the expression of nuclear NF-κB p65 in PDGF-BB-stimulated VSMCs. Nobiletin decreased the intima area and the ratio of neointima to media in balloon-injured rat carotid arteries. Serum levels of TNF-α and IL-6 in nobiletin-treated rats were decreased. These results indicated that nobiletin could be a potential protective agent for the prevention and treatment of restenosis after angioplasty.

  11. Hydrogen-rich saline attenuates vascular smooth muscle cell proliferation and neointimal hyperplasia by inhibiting reactive oxygen species production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways.

    PubMed

    Chen, Yali; Jiang, Jinyao; Miao, Huibing; Chen, Xingjuan; Sun, Xuejun; Li, Yongjun

    2013-03-01

    Hydrogen-rich saline has been reported to prevent neointimal hyperplasia induced by carotid balloon injury. The purpose of the present study was to further investigate the molecular mechanisms underlying this phenomenon. Daily injection of a hydrogen-rich saline solution (HRSS) in rats was employed to study the effect of hydrogen on balloon injury-induced neointimal hyperplasia and the neointima/media ratio was assessed. HRSS significantly decreased the neointima area and neointima/media ratio in a dose-dependent manner. In vitro effects of hydrogen on fetal bovine serum (FBS)-induced vascular smooth muscle cell (VSMC) proliferation were also investigated. Hydrogen-rich medium (HRM) inhibited rat VSMC proliferation and migration induced by 10% FBS. FBS-induced reactive oxygen species (ROS) production and activation of intracellular Ras, MEK1/2, ERK1/2, proliferative cell nuclear antigen (PCNA), Akt were significantly inhibited by HRM. In addition, HRM blocked FBS-induced progression from the G0/G1 to the S-phase and increased the apoptosis rate of VSMCs. These results showed that hydrogen-rich saline was able to attenuate FBS-induced VSMC proliferation and neointimal hyperplasia by inhibiting ROS production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways. Thus, HRSS may have potential therapeutic relevance for the prevention of human restenosis.

  12. The effect of locally administered anti-growth factor antibodies on neointimal hyperplasia formation in expanded polytetrafluoroethylene grafts.

    PubMed

    Sapienza, Paolo; di Marzo, Luca; Cucina, Alessandra; Borrelli, Valeria; Mosiello, Giovanni; Basile, Ursula; Iacovitti, Simonetta; Cavallaro, Antonino

    2009-01-01

    The selective blockage of platelet-derived growth factor BB (PDGF-BB), basic fibroblast growth factor (bFGF), and transforming growth factor beta1 (TGF-beta1) by specific antibodies coated into expanded polytetrafluoroethylene (ePTFE) grafts may diminish neointimal hyperplasia. Sixty pigs were divided into two groups (n = 30 each) and then further divided into five subgroups. Group 1 had a bilateral iliac artery ePTFE interposition graft precoated with Matrigel. Three subgroups (A, B, and C) received a specific monoclonal antibody against PDGF-BB, bFGF, or TGF-beta1. One (D) received all antibodies, and one served as control (nonimmune immunoglobulin G [IgG] isotypes) (E). Group 2 had a bilateral iliac artery endothelial cell (EC)-seeded ePTFE interposition graft precoated with Matrigel. Three subgroups (A, B, and C) received a specific antibody against PDGF-BB, bFGF, or TGF-beta1. One (D) received all antibodies, and one served as control (nonimmune IgG isotypes) (E). Light microscopy and immunohistochemical stain showed that neointimal hyperplasia formation was significantly reduced in subgroups D compared to the others (p < 0.05). In subgroups D, the different precoating influenced neointimal hyperplasia formation. It was more pronounced in the prosthesis precoated with EC and Matrigel (p < 0.05). In organ culture, the amount of PDGF-BB, bFGF, and TGF-beta1 release was reduced in subgroup D animals compared to the others (p < 0.05). In subgroups D, the release of PDGF-BB, bFGF, and TGF-beta1 depended on ePTFE seeding. A higher amount of these growth factors was released in the prostheses precoated with EC and Matrigel (p < 0.05), and the bromodeoxyuridine labeling index confirmed higher incorporation in this subgroup (p < 0.001). The combined use of locally administered anti-PDGF-BB, bFGF, and TGF-beta1 monoclonal antibodies reduces neointimal hyperplasia formation.

  13. MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ)

    PubMed Central

    Liu, Yong Feng; Spinelli, Amy; Sun, Li-Yan; Jiang, Miao; Singer, Diane V.; Ginnan, Roman; Saddouk, Fatima Z.; Van Riper, Dee; Singer, Harold A.

    2016-01-01

    The multifunctional Ca2+/calmodulin-dependent protein kinase II δ-isoform (CaMKIIδ) promotes vascular smooth muscle (VSM) proliferation, migration, and injury-induced vascular wall neointima formation. The objective of this study was to test if microRNA-30 (miR-30) family members are endogenous regulators of CaMKIIδ expression following vascular injury and whether ectopic expression of miR-30 can inhibit CaMKIIδ-dependent VSM cell function and neointimal VSM hyperplasia induced by vascular injury. The CaMKIIδ 3′UTR contains a consensus miR-30 binding sequence that is highly conserved across species. A significant decrease in miR-30 family members and increase in CaMKIIδ2 protein expression, with no change in CaMKIIδ mRNA expression, was observed in medial layers of VSM 7 days post-injury. In vitro, overexpression of miR-30c or miR-30e inhibited CaMKIIδ2 protein expression by ~50% in cultured rat aortic VSM cells, and inhibited VSM cell proliferation and migration. In vivo, lenti-viral delivery of miR-30c into injured rat carotid arteries prevented the injury-induced increase in CaMKIIδ2. Furthermore, neointima formation was dramatically inhibited by lenti-viral delivery of miR-30c in the injured medial smooth muscle. These studies define a novel mechanism for regulating CaMKIIδ expression in VSM and provide a new potential therapeutic strategy to reduce progression of vascular proliferative diseases, including atherosclerosis and restenosis. PMID:27199283

  14. MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca(2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ).

    PubMed

    Liu, Yong Feng; Spinelli, Amy; Sun, Li-Yan; Jiang, Miao; Singer, Diane V; Ginnan, Roman; Saddouk, Fatima Z; Van Riper, Dee; Singer, Harold A

    2016-05-20

    The multifunctional Ca(2+)/calmodulin-dependent protein kinase II δ-isoform (CaMKIIδ) promotes vascular smooth muscle (VSM) proliferation, migration, and injury-induced vascular wall neointima formation. The objective of this study was to test if microRNA-30 (miR-30) family members are endogenous regulators of CaMKIIδ expression following vascular injury and whether ectopic expression of miR-30 can inhibit CaMKIIδ-dependent VSM cell function and neointimal VSM hyperplasia induced by vascular injury. The CaMKIIδ 3'UTR contains a consensus miR-30 binding sequence that is highly conserved across species. A significant decrease in miR-30 family members and increase in CaMKIIδ2 protein expression, with no change in CaMKIIδ mRNA expression, was observed in medial layers of VSM 7 days post-injury. In vitro, overexpression of miR-30c or miR-30e inhibited CaMKIIδ2 protein expression by ~50% in cultured rat aortic VSM cells, and inhibited VSM cell proliferation and migration. In vivo, lenti-viral delivery of miR-30c into injured rat carotid arteries prevented the injury-induced increase in CaMKIIδ2. Furthermore, neointima formation was dramatically inhibited by lenti-viral delivery of miR-30c in the injured medial smooth muscle. These studies define a novel mechanism for regulating CaMKIIδ expression in VSM and provide a new potential therapeutic strategy to reduce progression of vascular proliferative diseases, including atherosclerosis and restenosis.

  15. Tacrolimus-Eluting Suture Inhibits Neointimal Hyperplasia: An Experimental In Vivo Study in Rats.

    PubMed

    Ak, K; Ak, E; Dericioglu, O; Canak, T; Akbuga, J; Ozkan, N; Cetinel, S; Isbir, S; Arsan, S; Cobanoglu, A

    2017-03-01

    Neointimal hyperplasia (NIH) remains one of the leading causes of graft failure after vascular anastomoses. Cytotoxic drugs, such as rapamycin and tacrolimus, have been shown to inhibit the development of NIH. In this study, the aim was to test the impact of a sustained releasing tacrolimus-chitosan-eluting suture on the development of NIH in a rat model. After tacrolimus-chitosan coating of a 7/0 polyvinylidene difluoride (PVDF) Trofilen(®) suture, the tacrolimus concentration on the coated suture and in vitro release trials were performed spectrophotometrically. Twelve Wistar rats were included. After midline laparotomy, a 7-8 mm longitudinal aortotomy in the infrarenal aorta was made and then closed by a bare 7/0 PVDF (group C, n = 6) and a 7/0 tacrolimus-chitosan coated PVDF suture (0.65 μg/cm tacrolimus [0.9 wt%] + 1.82 μg/cm chitosan [2.28 wt%]) (group T, n = 6). After 1 month, rats were sacrificed and aortotomy sites were examined histologically by ratio of intimal area (including neointima) and immunohistochemically by α-smooth muscle actin (ASMA) and proliferating cell nuclear antigen (PCNA) immunostaining. The PCNA positive cells were indexed to total cell number and expressed as percentage. In vitro tacrolimus release tests for a 7/0 tacrolimus-chitosan coated PVDF suture were confirmed for 1 month without an initial burst release. Endothelialisation over the aortotomy line occurred in both groups. The area of neointima was significantly reduced in group T compared with group C (ratio 0.22 ± 0.12 vs. 0.42 ± 0.11; p = .017) 1 month post-operatively. Likewise, the percentage of PCNA immunostaining significantly decreased in group C compared with group T (3.83 ± 2.85% vs. 11.17 ± 7.78%; p = .026). The cells constituting NIH were positive for ASMA immunostaining. Tacrolimus-chitosan-eluting suture is shown to be an effective way to reduce NIH without interfering with normal endothelialisation. Copyright © 2016 European

  16. In vitro studies of heparin-coated magnetic nanoparticles for potential use in the treatment of neointimal hyperplasia

    NASA Astrophysics Data System (ADS)

    Hargett, Andrew

    Purpose: Though recent decades have developed a myriad of treatments in response to atherosclerosis, prevalence remains high and complications, especially restenosis, may occur. Restenosis following stents is often caused by excessive vascular smooth muscle cell (VSMCS) migration and proliferation into the intima, known as neointimal hyperplasia. The shear number of angioplasty and stent procedures throughout the world makes this a major concern of all endovascular surgery. Our lab has proposed the pairing of heparin and magnetic nanoparticles for targeted drug delivery to the stent location. Utilizing the high surface area of nanoparticles, we hope to deliver higher heparin dosing to inhibit VSMC proliferation without systemic effects. This study evaluates synthesis of these particles as well as preliminary in vitro controls on relevant cell lines found within the vasculature system. Materials and Methods: Heparin-coated iron oxide nanoparticles were synthesized and characterized according to size (TEM), hydrodynamic diameter (DLS), zeta potential, iron concentration, and heparin loading (DMMB assay). Assays were then performed using these particles as experimental conditions on VSMCs, Endothelial Cells (PECs), and Fibroblasts (3T3s) for determination of cell uptake (Prussian Blue, TEM), effects on proliferation (MTS assay), cytotoxicity (Live/Dead assay), and phenotype changes (immunofluorescent staining). Experimental conditions were assessed against control nanoparticles without heparin and raw heparin in solution for dosage effects. Results: Particles were successfully synthesized, loaded with heparin, and characterized to validate each step of synthesis. Proliferation and cytotoxicity cell assays determined heparin-coated nanoparticles to be more potent in effects at lower concentrations of heparin when compared to raw heparin in solution. Immunostaining of VSMCs demonstrated a relatively higher tendency towards nonproliferative phenotypes following

  17. Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia.

    PubMed Central

    Newman, K D; Dunn, P F; Owens, J W; Schulick, A H; Virmani, R; Sukhova, G; Libby, P; Dichek, D A

    1995-01-01

    Adenovirus vectors are capable of high efficiency in vivo arterial gene transfer, and are currently in use as therapeutic agents in animal models of vascular disease. However, despite substantial data on the ability of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading frames that are translated in vivo, no study has examined the effect of adenovirus vectors alone on the arterial phenotype. In a rabbit model of gene transfer into a normal artery, we examined potential vascular cell activation, inflammation, and neointimal proliferation resulting from exposure to replication-defective adenovirus. Exposure of normal arteries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in arterial smooth muscle cells; (c) neointimal hyperplasia. These findings were present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic effects on the arterial wall and cause significant pathology. Interpretation of experimental protocols that use adenovirus vectors to address either biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors. Images PMID:8675667

  18. Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery.

    PubMed

    Ferrer, Lucas M; Monroy, Alexandra M; Lopez-Pastrana, Jahaira; Nanayakkara, Gayani; Cueto, Ramon; Li, Ya-Feng; Li, Xinyuan; Wang, Hong; Yang, Xiao-Feng; Choi, Eric T

    2016-04-01

    To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase(-/-) mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase(-/-) mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvβ3 integrin was reduced in caspase(-/-) tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvβ3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.

  19. Effect of isoflavone on balloon catheter-induced neointimal hyperplasia in ovariectomised rabbit carotid artery.

    PubMed

    Zhang, Gai-Ying; Qiu, Ren-Feng; Sun, Ying-Chun; Wang, Le-Xin

    2013-02-01

    This study was designed to investigate the effects of phytoestrogen isoflavone on balloon catheter-induced hyperplasia of carotid artery. Forty-eight female New Zealand rabbits were randomly divided into four groups: control (balloon-induced carotid artery injury only); ovariectomy control (ovariectomy and carotid artery injury), oestrogen (ovariectomy, carotid artery injury and nilestriol, 5mg/kg daily for 28 days), and isoflavone (ovariectomy, carotid artery injury and isoflavone 120 mg/kg daily for 28 days). The arterial wall thickness was assessed by coloured ultrasonography, and the oestrogen-α and oestrogen-β receptors in the abdominal aorta were measured by Western blotting. The medial layer thickness in the isoflavone group was less than in the ovariectomy control group (0.28±0.03 vs. 0.35±0.04 mm, p<0.01), and the intimal/medial layer (I/M) ratio is the isoflavone group was also less than in the ovariectomy control group (16.85±3.79 vs. 48.94±8.92, p<0.01). There was no statistically significant difference in the medial layer thickness or I/M ratio between the isoflavone and the oestrogen groups. The optical density of the oestrogen-α receptors in the isoflavone group (0.317±0.002) was less than in the oestrogen (0.633±0.002) or ovariectomy control group (0.590±0.001, p<0.01). The optical density of the oestrogen-β receptors in the isoflavone group (1.350±0.002) and the ovariectomy control group (1.2033±0.002) was less than in the oestrogen group (1.7699±0.003, p<0.01). Isoflavone therapy in the ovariectomised rabbit model attenuated balloon catheter-induced intimal and medial layer hyperplasia in the carotid arteries. Down-regulation of the oestrogen-α receptors may be involved in the hyperplasia-preventative effect. Copyright © 2012. Published by Elsevier B.V.

  20. Ginsenoside Rb₁ inhibits the carotid neointimal hyperplasia induced by balloon injury in rats via suppressing the phenotype modulation of vascular smooth muscle cells.

    PubMed

    Zhang, Shu; Deng, Jiang; Gao, Yang; Yang, Dan-li; Gong, Qi-hai; Huang, Xie-nan

    2012-06-15

    This study aims to investigate the effects of ginsenoside Rb(1) on vascular intimal hyperplasia in rats and explore the mechanisms. The rat vascular neointimal hyperplasia model was made by rubbing the endothelia of carotid artery with a balloon and Rb(1) (10 and 30 mg/kg/day) was given the day after surgery for 14 consecutive days. The neointimal hyperplasia level and the degree of vascular smooth muscle cells (VSMCs) proliferation were evaluated by histopathology and by calculating the proliferating cell nuclear antigen (PCNA) positive expression percentage; protein expressions of PCNA, phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2), smooth muscle α-actin (SM α-actin), and the mRNA expressions of proto-oncogene c-myc, SM α-actin, SM-emb (embryonic smooth muscle myosin heavy chain) and p38 MAPK were detected by immunohistochemistry and Real Time RT-PCR, respectively. Compared with the endothelia rubbing model group, Rb(1) 10 and 30 mg/kg/day medication significantly ameliorated the neointimal hyperplasia (P<0.05), and decreased the positive expression percentage of PCNA(P<0.05). Rb(1) medication also significantly decreased the elevated protein expression of pERK1/2 and the mRNA expression of c-myc(P<0.05), and tended to reduce the expression of p38 MAPK mRNA. Endothelial rubbing increased the SM-emb mRNA expression, but decreased the expression of SM α-actin mRNA which was reversed by Rb(1) (P<0.05). The results indicate that Rb(1) inhibits the vascular neointimal hyperplasia induced by balloon-injury in rats via suppressing the VSMC proliferation, which may be involved in part the inhibition of pERK1/2 protein and related to its inhibition on VSMC phenotype modulation.

  1. Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model

    PubMed Central

    Izuhara, Masayasu; Kuwabara, Yasuhide; Saito, Naritatsu; Yamamoto, Erika; Hakuno, Daihiko; Nakashima, Yasuhiro; Horie, Takahiro; Baba, Osamu; Nishiga, Masataka; Nakao, Tetsushi; Nishino, Tomohiro; Nakazeki, Fumiko; Ide, Yuya; Kimura, Masahiro; Kimura, Takeshi; Ono, Koh

    2017-01-01

    Background Despite recent progress with drug-eluting stents, restenosis and thrombosis after endovascular intervention are still major limitations in the treatment of cardiovascular diseases. These problems are possibly caused by inappropriate inhibition of neointimal formation and retardation of re-endothelialization on the surface of the stents. miR-126 has been shown to have the potential to enhance vascular endothelial cell proliferation. Methods and results We designed and constructed a 27-nt double strand RNA (dsRNA) conjugated to cholesterol, which has high membrane permeability, and formed mature miR-126 after transfection. For site-specific induction of miR-126, we utilized poly (DL-lactide-co-glycolide) nanoparticles (NPs). miR-126-dsRNA-containing NPs (miR-126 NPs) significantly reduced the protein expression of a previously identified miR-126 target, SPRED1, in human umbilical vascular endothelial cells (HUVECs), and miR-126 NPs enhanced the proliferation and migration of HUVECs. On the other hand, miR-126 NPs reduced the proliferation and migration of vascular smooth muscle cells, via the suppression of IRS-1. Finally, we developed a stent system that eluted miR-126. This delivery system exhibited significant inhibition of neointimal formation in a rabbit model of restenosis. Conclusions miR-126 NP-conjugated stents significantly inhibited the development of neointimal hyperplasia in rabbits. The present study may indicate the possibility of a novel therapeutic option to prevent restenosis after angioplasty. PMID:28253326

  2. Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury.

    PubMed

    Wu, Bian; Mottola, Giorgio; Chatterjee, Anuran; Lance, Kevin D; Chen, Mian; Siguenza, Iris O; Desai, Tejal A; Conte, Michael S

    2017-01-01

    Lipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury. Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury. RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and

  3. The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

    PubMed Central

    Brahmbhatt, Akshaar; NievesTorres, Evelyn; Yang, Binxia; Edwards, William D.; Roy Chaudhury, Prabir; Lee, Min Kyun; Kong, Hyunjoon; Mukhopadhyay, Debabrata; Kumar, Rajiv; Misra, Sanjay

    2014-01-01

    Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1−/− mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1−/− mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune-histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with

  4. Neointimal Hyperplasia in Low-Profile Nitinol Stents, Palmaz Stents, and Wallstents: A Comparative Experimental Study

    SciTech Connect

    Schuermann, Karl; Vorwerk, Dierk; Kulisch, Arthur; Stroehmer-Kulisch, Eva; Biesterfeld, Stefan; Stopinski, Tadeusz; Guenther, Rolf W.

    1996-04-15

    Purpose: To compare neointima formation following insertion of low-profile Nitinol stents, Palmaz stents, and Wallstents. Methods: Nitinol stents, Palmaz stents, and Wallstents similar in size were transfemorally inserted into the iliac arteries of 12 sheep. Four stents per sheep were deployed; the position of the stents was varied so that each type of stent was placed in each position (right or left, proximal or distal) with equal frequency. Stent patency was followed by angiography. Six sheep were euthanized after 1 month, and the remaining six after 6 months. Iliac arteries were removed en bloc and prepared for histological examination. Neointimal and medial thickness were measured by light microscopy, and measurements were analyzed statistically. Results: Mean neointimal thickness both over (NO) and between (NB) the stent struts was greater in Wallstents (NO = 0.341 mm, NB = 0.368 mm) than in the Nitinol (NO = 0.260 mm, NB = 0.220 mm) and Palmaz stents (NO = 0.199 mm, NB = 0.204 mm), but differences were not significant (p> 0.05). Medial atrophy in the area between the stent struts was greater in Wallstents compared with Nitinol and Palmaz stents (p < 0.007 and p < 0.02, respectively); in the area under the stent struts there was a significant difference only between Palmaz stents and Wallstents (p < 0.02). Conclusion: Under defined experimental conditions, none of the three types of stent appears to be preferable to the others regarding neointima formation in the short- to mid-term follow-up period.

  5. The Effect of Short-term Intra-arterial Delivery of Paclitaxel on Neointimal Hyperplasia and the Local Thrombotic Environment after Angioplasty

    SciTech Connect

    Yajun, E; He Nengshu Fan Hailun

    2013-08-01

    PurposeTo evaluate the effects of short-term intra-arterial delivery of paclitaxel on neointimal hyperplasia and the local thrombotic environment after angioplasty.MethodsAn experimental common carotid artery injury model was established in 60 rats, which were divided into experimental groups (40 rats) and controls (20 rats). Local intra-arterial administration of paclitaxel was applied at 2 doses (90 and 180 {mu}g/30 {mu}l), and the effects of short-term delivery of paclitaxel on neointimal hyperplasia and the expression of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated at days 15 and 30 by hematoxylin and eosin staining and immunohistochemistry.ResultsAt 15 and 30 days after injury, neointimal thickness and area, the ratio of intimal area to medial area and the stenotic rate were all significantly decreased in the group provided the high concentrations (180 {mu}g/30 {mu}l) of paclitaxel for 2 min or 10 min and in the group provided the low concentration (90 {mu}g/30 {mu}l) of paclitaxel for 10 min (p < 0.05). At 30 days after injury, there were no significant changes in TF expression among all experimental groups. PAI-1 expression increased in the neointima of the high concentration 10 min group (p < 0.05), while t-PA expression decreased in the neointima of the high concentration 2 min group (p < 0.05).ConclusionIn the rat common carotid artery injury model, the short-term delivery of paclitaxel could effectively inhibit neointimal hyperplasia in the long term, with very little influence on the local expression of TF and PAI-1.

  6. MicroRNA-24 Attenuates Neointimal Hyperplasia in the Diabetic Rat Carotid Artery Injury Model by Inhibiting Wnt4 Signaling Pathway.

    PubMed

    Yang, Jian; Fan, Zhixing; Yang, Jun; Ding, Jiawang; Yang, Chaojun; Chen, Lihua

    2016-05-24

    The long-term stimulation of hyperglycemia greatly increases the incidence of vascular restenosis (RS) after angioplasty. Neointimal hyperplasia after vascular injury is the pathological cause of RS, but its mechanism has not been elucidated. MicroRNA-24 (miR-24) has low expression in the injured carotid arteries of diabetic rats. However, the role of miR-24 in the vascular system is unknown. In this study, we explore whether over-expression of miR-24 could attenuate neointimal formation in streptozotocin (STZ)-induced diabetic rats. Adenovirus (Ad-miR-24-GFP) was used to deliver the miR-24 gene to injured carotid arteries in diabetic rats. The level of neointimal hyperplasia was examined by hematoxylin-eosin (HE) staining. Vascular smooth muscle cell (VSMC) proliferation in the neointima was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA). The mRNA levels of miR-24, PCNA, wingless-type MMTV integration site family member 4 (Wnt4), disheveled-1 (Dvl-1), β-catenin and cell cycle-associated molecules (Cyclin D1, p21) were determined by Quantitative Real-Time PCR (qRT-PCR). PCNA, Wnt4, Dvl-1, β-catenin, Cyclin D1 and p21 protein levels were measured by Western blotting analysis. STZ administration decreased plasma insulin and increased fasting blood glucose in Sprague-Dawley (SD) rats. The expression of miR-24 was decreased in the carotid artery after a balloon injury in diabetic rats, and adenoviral transfection (Ad-miR-24-GFP) increased the expression of miR-24. Over-expression of miR-24 suppressed VSMC proliferation and neointimal hyperplasia in diabetic rats at 14 days. Furthermore, compared with Sham group, the mRNA and protein levels of PCNA, Wnt4, Dvl-1, β-catenin, and Cyclin D1 were strikingly up-regulated in the carotid arteries of diabetic rats after a balloon injury. Interestingly, up-regulation of miR-24 significantly reduced the mRNA and protein levels of these above molecules. In contrast, the change trend in p21 mRNA and

  7. Role of cAMP-Phosphodiesterase 1C Signaling in Regulating Growth Factor Receptor Stability, Vascular Smooth Muscle Cell Growth, Migration, and Neointimal Hyperplasia

    PubMed Central

    Cai, Yujun; Nagel, David J.; Zhou, Qian; Cygnar, Katherine D.; Zhao, Haiqing; Li, Faqian; Pi, Xinchun; Knight, Peter A.; Yan, Chen

    2015-01-01

    Objective Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, post-angioplasty restenosis, vein graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs). Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases. Methods & Results We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. Additionally, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1C deficiency or PDE1 inhibition attenuated SMC proliferation and migration. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of growth factor receptors, such as PDGF-receptor-beta (PDGFRβ) known to be important in pathological vascular remodeling. PDE1C interacts with LDL-receptor-related-protein-1 (LRP1) and PDGFRβ, thus regulating PDGFRβ endocytosis and lysosome-dependent degradation in an LRP1-dependent manner. A transmembrane-adenylyl-cyclase (tmAC)-cAMP-PKA cascade modulated by PDE1C is critical in regulating PDGFRβ degradation. Conclusion These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome dependent PDGFRβ protein degradation via LRP1. PMID:25608528

  8. Over-expression of neuron-derived orphan receptor-1 (NOR-1) exacerbates neointimal hyperplasia after vascular injury.

    PubMed

    Rodríguez-Calvo, Ricardo; Guadall, Anna; Calvayrac, Olivier; Navarro, María A; Alonso, Judith; Ferrán, Beatriz; de Diego, Alicia; Muniesa, Pedro; Osada, Jesús; Rodríguez, Cristina; Martínez-González, José

    2013-05-15

    We have previously shown that NOR-1 (NR4A3) modulates the proliferation and survival of vascular cells in culture. However, in genetically modified animal models, somewhat conflicting results have been reported concerning the involvement of NOR-1 in neointimal formation after vascular injury. The aim of this study was to generate a transgenic mouse model over-expressing NOR-1 in smooth muscle cells (SMCs) and assess the consequence of a gain of function of this receptor on intimal hyperplasia after vascular injury. The transgene construct (SM22-NOR1) was prepared by ligating the full-length human NOR-1 cDNA (hNOR-1) and a mouse SM22α minimal promoter able to drive NOR-1 expression to SMC. Two founders were generated and two stable transgenic mouse lines (TgNOR-1) were established by backcrossing the transgene-carrying founders with C57BL/6J mice. Real-time PCR and immunohistochemistry confirmed that hNOR-1 was mainly targeted to vascular beds such as aorta and carotid arteries, and was similar in both transgenic lines. Vascular SMC from transgenic animals exhibit increased NOR-1 transcriptional activity (assessed by electrophoretic mobility shift assay and luciferase assays), increased mitogenic activity (determined by [(3)H]-thymidine incorporation; 1.58-fold induction, P < 0.001) and increased expression of embryonic smooth muscle myosin heavy chain (SMemb) than wild-type cells from control littermates. Using the carotid artery ligation model, we show that neointima formation was increased in transgenic versus wild-type mice (2.36-fold induction, P < 0.01). Our in vivo data support a role for NOR-1 in VSMC proliferation and vascular remodelling. This NOR-1 transgenic mouse could be a useful model to study fibroproliferative vascular diseases.

  9. Association of Serum HMGB2 Levels With In-Stent Restenosis: HMGB2 Promotes Neointimal Hyperplasia in Mice With Femoral Artery Injury and Proliferation and Migration of VSMCs.

    PubMed

    He, Yu Hu; Wang, Xiao Qun; Zhang, Jian; Liu, Zhu Hui; Pan, Wen Qi; Shen, Ying; Zhu, Zheng Bin; Wang, Ling Jie; Yan, Xiao Xiang; Yang, Ke; Zhang, Rui Yan; Shen, Wei Feng; Ding, Feng Hua; Lu, Lin

    2017-04-01

    In a previous study, we established diabetic and nondiabetic minipig models with coronary artery in-stent restenosis (ISR). Mass spectrometry showed that high-mobility group box (HMGB) 2 level was higher in ISR than in non-ISR tissue from diabetic minipigs. We here investigated whether serum HMGB2 levels were related to ISR in coronary artery disease patients. The effect of HMGB2 was evaluated in mice with femoral artery wire injury and in human aortic smooth muscle cells. From 2513 patients undergoing coronary artery intervention and follow-up angiography at ≈1 year, 262 patients were diagnosed with ISR, and 298 patients with no ISR were randomly included as controls. Serum HMGB2 levels were significantly higher in patients with ISR than in those without ISR and were associated with ISR severity. Multivariable logistic regression analysis showed that HMGB2 level was independently associated with ISR. In experiments, HMGB2 expression was increased in vascular tissue after injury. Perivascular HMGB2 administration promoted injury-induced neointimal hyperplasia in C57Bl/6 mice compared with in the control, whereas such pathophysiological features were attenuated in Hmgb2(-/-) mice. Mechanistically, HMGB2 enhanced neointimal hyperplasia in mice and proliferation and migration in human aortic smooth muscle cells by inducing reactive oxygen species through increased p47phox phosphorylation. Knocking down p47phox, however, inhibited HMGB2-induced effects in human aortic smooth muscle cells. Finally, HMGB2-induced effects were significantly declined in receptor of advanced glycation end products knockdown or deficient cells, but not in Toll-like receptor 4 knockdown or deficient cells. Serum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation. © 2017 American Heart Association, Inc.

  10. Hypoxia induces a phenotypic switch of fibroblasts to myofibroblasts through a MMP-2/TIMP mediated pathway: Implications for venous neointimal hyperplasia in hemodialysis access

    PubMed Central

    Misra, Sanjay; Fu, Alex A.; Misra, Khamal D.; Shergill, Uday M.; Leof, Edward B; Mukhopadhyay, Debabrata

    2010-01-01

    Purpose Hemodialysis grafts fail because of venous neointimal hyperplasia formation caused by adventitial fibroblasts which have become myofibroblasts (α-smooth muscle actin positive cells) and migrate to the neointima. There is increased expression of hypoxia inducible factor-1 alpha (HIF-1α in venous neointimal hyperplasia formation in experimental animal model and clinical samples. We hypothesized that under hypoxic stimulus (HIF-1α fibroblasts will convert to myofibroblasts through a matrix metalloproteinase-2 (MMP-2) mediated pathway. Materials and methods Murine AKR-2B fibroblasts were made hypoxic or normoxic for 24, 48, and 72 hours. Protein expression for HIF-1α, α-smooth muscle actin, MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed to determine the kinetic changes of these proteins. Immunostaining for α-smooth muscle actin, collagen, and fibronectin was performed. Results At all time points, there was significantly increased expression of HIF-1α in the hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was significantly increased expression α-smooth muscle actin at all time points which peaked by 48 hours in hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was a significant increase in the expression of active MMP-2 by 48-72 hours and a significant increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) by 48-72 hours by hypoxic fibroblasts (P<0.05). By 72 hours, there was significant increase in TIMP-2 expression (P<0.05). Immunohistochemical analysis demonstrated increased expression for α-smooth muscle actin, collagen, and fibronectin as the length of hypoxia increased. Conclusions Under hypoxia, fibroblasts will convert to myofibroblasts through a MMP-2 mediated pathway which may provide insight into the mechanism of venous neointimal hyperplasia. PMID:20434368

  11. Endogenously Generated Omega‐3 Fatty Acids Attenuate Vascular Inflammation and Neointimal Hyperplasia by Interaction With Free Fatty Acid Receptor 4 in Mice

    PubMed Central

    Li, Xinzhi; Ballantyne, Laurel L.; Che, Xinghui; Mewburn, Jeffrey D.; Kang, Jing X.; Barkley, Robert M.; Murphy, Robert C.; Yu, Ying; Funk, Colin D.

    2015-01-01

    Background Omega‐3 polyunsaturated fatty acids (ω3 PUFAs) suppress inflammation through activation of free fatty acid receptor 4 (FFAR4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR4 activation by ω3 PUFAs in the process of vascular inflammation and neointimal hyperplasia in mice. Methods and Results We used mice with disruption of FFAR4 (Ffar4−/−), along with a strain that synthesizes high levels of ω3 PUFAs (fat‐1) and a group of crossed mice (Ffar4−/−/fat‐1), to elucidate the role of FFAR4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR4 in vascular‐associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFAs endogenously generated in fat‐1 mice (n=9), but not in compound Ffar4−/−/fat‐1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl3. Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl3 injury in fat‐1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4−/−/fat‐1 mice. Conclusions These results indicate that ω3 PUFAs mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR4 in mice. Moreover, the ω3 PUFA–FFAR4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration. PMID:25845931

  12. Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice.

    PubMed

    Li, Xinzhi; Ballantyne, Laurel L; Che, Xinghui; Mewburn, Jeffrey D; Kang, Jing X; Barkley, Robert M; Murphy, Robert C; Yu, Ying; Funk, Colin D

    2015-04-06

    Omega-3 polyunsaturated fatty acids (ω3 PUFAs) suppress inflammation through activation of free fatty acid receptor 4 (FFAR4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR4 activation by ω3 PUFAs in the process of vascular inflammation and neointimal hyperplasia in mice. We used mice with disruption of FFAR4 (Ffar4(-/-)), along with a strain that synthesizes high levels of ω3 PUFAs (fat-1) and a group of crossed mice (Ffar4(-/-)/fat-1), to elucidate the role of FFAR4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR4 in vascular-associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFAs endogenously generated in fat-1 mice (n=9), but not in compound Ffar4(-/-)/fat-1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl3. Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl3 injury in fat-1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4(-/-)/fat-1 mice. These results indicate that ω3 PUFAs mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR4 in mice. Moreover, the ω3 PUFA-FFAR4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  13. Neointimal hyperplasia and calcification in medium sized arteries in adult patients with chronic kidney disease.

    PubMed

    Chitalia, Nihil; Ross, Louise; Krishnamoorthy, Mahesh; Kapustin, Alexander; Shanahan, Catherine M; Kaski, Juan Carlos; Roy-Chaudhury, Prabir; Chemla, Eric; Banerjee, Debasish

    2015-01-01

    The nature of arterial changes resulting in cardiovascular events and dialysis vascular access failures in adult predialysis patients is not well known. This study examined intimal changes, calcium deposition, and consequent stiffness in brachial and radial arteries of adult CKD patients. Ten brachial-artery and seven radial-artery specimens were obtained during fistula creation from nine predialysis and eight dialysis-dependent, nondiabetic patients; and age-gender matched controls undergoing coronary bypass grafts (6 radial) or kidney donation (6 renal). Arterial stiffness was measured at baseline. Vessel histology, morphometric analysis of intima-media, and direct quantification of calcium load was performed using standard techniques. Both predialysis and dialysis patients demonstrated significant arterial intimal hyperplasia with intima:media ratio higher than controls (0.13 ± 0.12 vs. 0.02 ± 0.05, p = 0.01). Calcium deposition was demonstrated on histology and the calcium content in patients was higher than controls (34.68 ± 26.86 vs. 10.95 ± 9.18 μg/μg, p = 0.003). The blood vessel calcium content correlated with arterial stiffness (r = 0.64, p = 0.018). This study for the first time describes, and suggests mechanistic linkage between, intimal hyperplasia, pathological calcium deposition, and increased functional arterial stiffness in dialysis and predialysis patients. Our research could serve as a unique window into the in vivo status of the uremic vasculature impacting fistula maturation and cardiovascular disease.

  14. Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations.

    PubMed

    Fu, Chunhua; Yu, Peng; Tao, Ming; Gupta, Tushar; Moldawer, Lyle L; Berceli, Scott A; Jiang, Zhihua

    2012-10-01

    To evaluate direct versus indirect monocyte chemoattractant protein (MCP)-1/CCR2 signaling and to identify the cellular producers and effectors for MCP-1 during neointimal hyperplasia (NIH) development in vein grafts. Genomic analysis revealed an overrepresentation of 13 inflammatory pathways in wild-type vein grafts compared with CCR2 knockout vein grafts. Further investigation with various vein graft-host combinations of MCP-1- and CCR2-deficient mice was used to modify the genotype of cells both inside (graft-intrinsic group) and outside (graft-extrinsic group) the vein wall. CCR2 deficiency inhibited NIH only when present in cells extrinsic to the graft wall, and MCP-1 deficiency required its effectiveness in cells both intrinsic and extrinsic to the graft wall to suppress NIH. Deletion of either MCP-1 or CCR2 was equally effective in inhibiting NIH. CCR2 deficiency in the predominant neointimal cell population had no impact on NIH. Direct MCP-1 stimulation of primary neointimal smooth muscle cells had minimal influence on cell proliferation and matrix turnover, confirming an indirect mechanism of action. MCP-1/CCR2 axis accelerates NIH via its signaling in graft-extrinsic cells, particularly circulating inflammatory cells, with cells both intrinsic and extrinsic to the graft wall being critical MCP-1 producers. These findings underscore the importance of systemic treatment for anti-MCP-1/CCR2 therapies.

  15. Inhibition of neointimal hyperplasia in a rabbit vein graft model following non-viral transfection with human iNOS cDNA

    PubMed Central

    Meng, Q-H; Irvine, S; Tagalakis, A D; McAnulty, R J; McEwan, J R; Hart, S L

    2013-01-01

    Vein graft failure caused by neointimal hyperplasia (IH) after coronary artery bypass grafting with saphenous veins is a major clinical problem. The lack of safe and efficient vectors for vascular gene transfer has significantly hindered progress in this field. We have developed a Receptor-Targeted Nanocomplex (RTN) vector system for this purpose and assessed its therapeutic efficacy in a rabbit vein graft model of bypass grafting. Adventitial delivery of β-Galactosidase showed widespread transfection throughout the vein wall on day 7, estimated at about 10% of cells in the adventitia and media. Vein grafts were then transfected with a plasmid encoding inducible nitric oxide synthase (iNOS) and engrafted into the carotid artery. Fluorescent immunohistochemistry analysis of samples from rabbits killed at 7 days after surgery showed that mostly endothelial cells and macrophages were transfected. Morphometric analysis of vein graft samples from the 28-day groups showed approximately a 50% reduction of neointimal thickness and 64% reduction of neointimal area in the iNOS-treated group compared with the surgery control groups. This study demonstrates efficacy of iNOS gene delivery by the RTN formulation in reducing IH in the rabbit model of vein graft disease. PMID:23636244

  16. IL-19 Reduces Ligation-Mediated Neointimal Hyperplasia by Reducing Vascular Smooth Muscle Cell Activation

    PubMed Central

    Ellison, Stephen; Gabunia, Khatuna; Richards, James M.; Kelemen, Sheri E.; England, Ross N.; Rudic, Dan; Azuma, Yasu-Taka; Munroy, M. Alexandra; Eguchi, Satoru; Autieri, Michael V.

    2015-01-01

    We tested the hypothesis that IL-19, a putative member of the type 2 helper T-cell family of anti-inflammatory interleukins, can attenuate intimal hyperplasia and modulate the vascular smooth muscle cell (VSMC) response to injury. Ligated carotid artery of IL-19 knockout (KO) mice demonstrated a significantly higher neointima/intima ratio compared with wild-type (WT) mice (P = 0.04). More important, the increased neointima/intima ratio in the KO could be reversed by injection of 10 ng/g per day recombinant IL-19 into the KO mouse (P = 0.04). VSMCs explanted from IL-19 KO mice proliferated significantly more rapidly than WT. This could be inhibited by addition of IL-19 to KO VSMCs (P = 0.04 and P < 0.01). IL-19 KO VSMCs migrated more rapidly compared with WT (P < 0.01). Interestingly, there was no type 1 helper T-cell polarization in the KO mouse, but there was significantly greater leukocyte infiltrate in the ligated artery in these mice compared with WT. IL-19 KO VSMCs expressed significantly greater levels of inflammatory mRNA, including IL-1β, tumor necrosis factor α, and monocyte chemoattractant protein-1 in response to tumor necrosis factor α stimulation (P < 0.01 for all). KO VSMCs expressed greater adhesion molecule expression and adherence to monocytes. Together, these data indicate that IL-19 is a previously unrecognized counterregulatory factor for VSMCs, and its expression is an important protective mechanism in regulation of vascular restenosis. PMID:24814101

  17. The microRNA miR-34c inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by targeting stem cell factor.

    PubMed

    Choe, Nakwon; Kwon, Jin-Sook; Kim, Yong Sook; Eom, Gwang Hyeon; Ahn, Young Keun; Baik, Yung Hong; Park, Hyun-Young; Kook, Hyun

    2015-06-01

    The fine balance between proliferation and differentiation of vascular smooth muscle cells (VSMCs) is indispensable for the maintenance of healthy blood vessels, whereas an increase in proliferation participates in pathologic cardiovascular events such as atherosclerosis and restenosis. Here we report that microRNA-34c (miR-34c) targets stem cell factor (SCF) to inhibit VSMC proliferation and neointimal hyperplasia. In an animal model, miR-34c was significantly increased in the rat carotid artery after catheter injury. Transient transfection of miR-34c to either VSMCs or A10 cells inhibited cell survival by inducing apoptosis, which was accompanied by an increase in expression of p21, p27, and Bax. Transfection of miR-34c also attenuated VSMC migration. Bioinformatics showed that SCF is a target candidate of miR-34c. miR-34c down-regulated luciferase activity driven by a vector containing the 3'-untranslated region of SCF in a sequence-specific manner. Forced expression of SCF in A10 cells induced proliferation and migration, whereas knocking-down of SCF reduced cell survival and migration. miR-34c antagomir-induced VSMC proliferation was blocked by SCF siRNA. Delivery of miR-34c to rat carotid artery attenuated the expression of SCF and blocked neointimal hyperplasia. These results suggest that miR-34c is a new modulator of VSMC proliferation and that it inhibits neointima formation by regulating SCF.

  18. Deficiency of endothelial CXCR4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice.

    PubMed

    Noels, Heidi; Zhou, Baixue; Tilstam, Pathricia V; Theelen, Wendy; Li, Xiaofeng; Pawig, Lukas; Schmitz, Corinna; Akhtar, Shamima; Simsekyilmaz, Sakine; Shagdarsuren, Erdenechimeg; Schober, Andreas; Adams, Ralf H; Bernhagen, Jürgen; Liehn, Elisa A; Döring, Yvonne; Weber, Christian

    2014-06-01

    The Cxcl12/Cxcr4 chemokine ligand/receptor axis mediates the mobilization of smooth muscle cell progenitors, driving injury-induced neointimal hyperplasia. This study aimed to investigate the role of endothelial Cxcr4 in neointima formation. β-Galactosidase staining using bone marrow x kinase (Bmx)-CreER(T2) reporter mice and double immunofluorescence revealed an efficient and endothelial-specific deletion of Cxcr4 in Bmx-CreER(T2+) compared with Bmx-CreER(T2-) Cxcr4-floxed apolipoprotein E-deficient (Apoe(-/-)) mice (referred to as Cxcr4(EC-KO)ApoE(-/-) and Cxcr4(EC-WT) ApoE(-/-), respectively). Endothelial Cxcr4 deficiency significantly increased wire injury-induced neointima formation in carotid arteries from Cxcr4(EC-KO)ApoE(-/-) mice. The lesions displayed a higher number of macrophages, whereas the smooth muscle cell and collagen content were reduced. This was associated with a significant reduction in reendothelialization and endothelial cell proliferation in injured Cxcr4(EC-KO)ApoE(-/-) carotids compared with Cxcr4(EC-WT)ApoE(-/-) controls. Furthermore, stimulation of human aortic endothelial cells with chemokine (C-X-C motif) ligand 12 (CXCL12) significantly enhanced their wound-healing capacity in an in vitro scratch assay, an effect that could be reversed with the CXCR4 antagonist AMD3100. Also, flow cytometric analysis showed a reduced mobilization of Sca1(+)Flk1(+)Cd31(+) and of Lin(-)Sca1(+) progenitors in Cxcr4(EC-KO) ApoE(-/-) mice after vascular injury, although Cxcr4 surface expression was unaltered. No differences could be detected in plasma concentrations of Cxcl12, vascular endothelial growth factor, sphingosine 1-phosphate, or Flt3 (fms-related tyrosine kinase 3) ligand, all cytokines with an established role in progenitor cell mobilization. Nonetheless, double immunofluorescence revealed a significant reduction in local endothelial Cxcl12 staining in injured carotids from Cxcr4(EC-KO)ApoE(-/-) mice. Endothelial Cxcr4 is crucial for

  19. Deep sea water prevents balloon angioplasty-induced hyperplasia through MMP-2: an in vitro and in vivo study.

    PubMed

    Li, Pei-Chuan; Pan, Chun-Hsu; Sheu, Ming-Jyh; Wu, Chin-Ching; Ma, Wei-Fen; Wu, Chieh-Hsi

    2014-01-01

    Major facts about the development of restenosis include vascular smooth muscle cells (VSMCs) proliferation and migration. A previous study showed that in vitro treatment with magnesium chloride has the potential to affect the proliferation and migration of VSMCs. Magnesium is the major element in deep sea water (DSW) and is a biologically active mineral. It is unclear whether DSW intake can prevent abnormal proliferation and migration of VSMCs as well as balloon angioplasty-induced neointimal hyperplasia. Thus, we attempted to evaluate the anti-restenotic effects of DSW and its possible molecular mechanisms. Several concentrations of DSW, based on the dietary recommendations (RDA) for magnesium, were applied to a model of balloon angioplasty in SD rats. The results showed that DSW intake markedly increased magnesium content within the vascular wall and reduced the development of neointimal hyperplasia. The immunohistochemical analysis also showed that the expression of proteins associated with cell proliferation and migration were decreased in the balloon angioplasty groups with DSW supplement. Furthermore, in vitro treatment with DSW has a dose-dependent inhibitory effect on serum-stimulated proliferation and migration of VSMCs, whose effects might be mediated by modulation of mitogen-activated protein kinase (MAPK) signaling and of the activity of matrix metalloproteinase-2 (MMP-2). Our study suggested that DSW intake can help prevent neointimal hyperplasia (or restenosis), whose effects may be partially regulated by magnesium and other minerals.

  20. The laser driven short-term heating balloon catheter: Relation between the chronic neointimal hyperplasia formation and thermal damage to arterial smooth muscle cells.

    PubMed

    Shimazaki, Natsumi; Hayashi, Tomoaki; Kunio, Mie; Igami, Yuka; Arai, Tsunenori; Sakurada, Masami

    2010-01-01

    We proposed a novel laser-driven short-term heating angioplasty to realize restenosis-suppressive angioplasty for peripheral artery disease. In this study, we investigated the chronic intimal hyperplasia formation after the short-term heating dilatation in vivo, as well as the thermal damage calculation on arterial smooth muscle cells (SMCs). The prototype short-term heating balloon catheter with 5.0, 5.5, 6.0 mm φ in balloon diameter and 25 mm in balloon length were employed. The short-term heating dilatation was performed in porcine iliac arteries with dilatation conditions of 75°C (N=4) and 65°C (N=5) as peak balloon temperature, 18 ± 4s as heating duration, 3.5 atm as balloon dilatation pressure. Four weeks after the balloon dilatation, the balloon-dilated artery segments were extracted and were stained with HE and picrosirius red for histological observation. In the case of 75°C as the peak balloon temperature, neointimal hyperplasia formation was significantly reduced. In this case, the SMCs density in the artery media measured from the HE-stained specimen was 20% lower than that in the reference artery. According to the thermal damage calculation, it was estimated that the SMCs lethality in artery media after the short-term heating angioplasty was 20% in the case of 75°C as the peak balloon temperature. We demonstrated that the short-term heating dilatation reduced the number of SMCs in artery media. We think this SMCs reduction might contribute to the suppression of chronic neointimal hyperplasia.

  1. Inhibitory effect of sustained perivascular delivery of paclitaxel on neointimal hyperplasia in the jugular vein after open cutdown central venous catheter placement in rats

    PubMed Central

    Kim, Seongyup; Kim, Younglim; Hwang, Ji Woong

    2017-01-01

    Purpose Inhibitory effect of paclitaxel on neointimal hyperplasia after open cutdown has not been elucidated. Methods For the control group (n = 16), silicone 2.7-Fr catheters were placed via the right external jugular vein with the cutdown method. For the treatment group (n = 16), a mixture of 0.65 mg of paclitaxel and 1 mL of fibrin glue was infiltrated around the exposed vein after cutdown. After scheduled intervals (1, 2, 4, and 8 weeks), the vein segment was harvested and morphometric analysis was performed on cross-sections. Results Proliferation of smooth muscle cell (SMC) was strongly suppressed in the treatment group, and the ratio of neointima to vein wall was significantly reduced in the treatment group (8 weeks; 0.63 ± 0.08 vs. 0.2 ± 0.08, P < 0.05). Luminal patency was significantly more preserved in the treatment group, and the luminal area was significantly wider in the paclitaxel-treated group compared to the control group (8 weeks; 1.91 ± 0.43 mm2 vs. 5.1 ± 0.43 mm2, P < 0.05). Mean SMC counts measured at 1 and 2 weeks after cutdown were significantly lower in the treatment group (2 weeks; 115 ± 22 vs. 62 ± 22). Paclitaxel was undetectable in systemic circulation (<10 ng/mL). Conclusion Sustained perivascular delivery of paclitaxel with fibrin glue was effective in inhibiting neointimal hyperplasia in rat jugular vein after open cutdown. PMID:28203557

  2. Crucial role of nuclear factor-kappaB in neointimal hyperplasia of the mouse carotid artery after interruption of blood flow.

    PubMed

    Squadrito, Francesco; Deodato, Barbara; Bova, Antonio; Marini, Herbert; Saporito, Francesco; Calò, Margherita; Giacca, Mauro; Minutoli, Letteria; Venuti, Francesco S; Caputi, Achille P; Altavilla, Domenica

    2003-02-01

    We used a molecular genetics approach to investigate the role of nuclear factor-kappaB (NF-kappaB) in neointimal hyperplasia induced by flow interruption of carotid artery in mice. Wild type mice (WT mice) and mice rendered deficient in p105, the precursor of p50, one of the components of the multimeric transcription factor NF-kappaB (NF-kappaB knockout mice; KO mice), were subjected to a complete ligation of the left common carotid artery. Morphometric analysis of the structural alteration caused by the disruption of the arterial blood flow was performed 14 days after surgery. Furthermore the expression of intercellular adhesion molecule-1 (ICAM-1) in injured arteries was evaluated 4 days after artery ligation by the means of reverse transcriptase polymerase chain reaction (RT-PCR) and quantification of the ICAM-1 protein levels. In a separate experiment normal mice were randomly assigned to receive a recombinant adeno-associated virus (rAAV) encoding the gene for the NF-kappaB inhibitory protein IkappaBalpha (rAAV-IkappaBalpha), or the beta-galactosidase gene (rAAV-LacZ), both at a dose of 10(11) copies and 2 weeks later were subjected to the complete ligation of the left carotid artery. NF-kappaB activity (studied by means of electrophoretic mobility shift assay-EMSA), IkappaBalpha expression (evaluated by Western blot analysis) ICAM-1 evaluation (RT-PCR and quantification of the protein levels) and a morphometric analysis were evaluated in the injured arteries. Disruption of the arterial blood flow caused a marked neointimal hyperplasia. The mean intimal area was 0.023+/-0.002 mm(2) in wild type mice compared with 0.002+/-0.001 mm(2) in NF-kappaB knockout mice. ICAM-1 expression was 1.7+/-0.8 relative amount of ICAM-1 mRNA in wild type mice compared with 0.4+/-0.06 relative amount of ICAM-1 mRNA in NF-kappaB knockout mice. ICAM-1 protein levels were also significantly reduced in NF-kappaB knockout mice. Injured arteries treated with rAAV-IkappaBalpha had a

  3. Promoting endothelial recovery and reducing neointimal hyperplasia using sequential-like release of acetylsalicylic acid and paclitaxel-loaded biodegradable stents.

    PubMed

    Lee, Cheng-Hung; Yu, Chia-Ying; Chang, Shang-Hung; Hung, Kuo-Chun; Liu, Shih-Jung; Wang, Chao-Jan; Hsu, Ming-Yi; Hsieh, I-Chang; Chen, Wei-Jan; Ko, Yu-Shien; Wen, Ming-Shien

    2014-01-01

    This work reports on the development of a biodegradable dual-drug-eluting stent with sequential-like and sustainable drug-release of anti-platelet acetylsalicylic acid and anti-smooth muscle cell (SMC) proliferative paclitaxel. To fabricate the biodegradable stents, poly-L-lactide strips are first cut from a solvent-casted film. They are rolled onto the surface of a metal pin to form spiral stents. The stents are then consecutively covered by acetylsalicylic acid and paclitaxel-loaded polylactide-polyglycolide nanofibers via electrospinning. Biodegradable stents exhibit mechanical properties that are superior to those of metallic stents. Biodegradable stents sequentially release high concentrations of acetylsalicylic acid and paclitaxel for more than 30 and 60 days, respectively. In vitro, the eluted drugs promote endothelial cell numbers on days 3 and 7, and reduce the proliferation of SMCs in weeks 2, 4, and 8. The stents markedly inhibit the adhesion of platelets on days 3, 7, and 14 relative to a non-drug-eluting stent. In vivo, the implanted stent is intact, and no stent thrombosis is observed in the stent-implanted vessels without the administration of daily oral acetylsalicylic acid. Promotion of endothelial recovery and inhibition of neointimal hyperplasia are also observed on the stented vessels. The work demonstrates the efficiency and safety of the biodegradable dual-drug-eluting stents with sequential and sustainable drug release to diseased arteries.

  4. Promoting endothelial recovery and reducing neointimal hyperplasia using sequential-like release of acetylsalicylic acid and paclitaxel-loaded biodegradable stents

    PubMed Central

    Lee, Cheng-Hung; Yu, Chia-Ying; Chang, Shang-Hung; Hung, Kuo-Chun; Liu, Shih-Jung; Wang, Chao-Jan; Hsu, Ming-Yi; Hsieh, I-Chang; Chen, Wei-Jan; Ko, Yu-Shien; Wen, Ming-Shien

    2014-01-01

    Introduction This work reports on the development of a biodegradable dual-drug-eluting stent with sequential-like and sustainable drug-release of anti-platelet acetylsalicylic acid and anti-smooth muscle cell (SMC) proliferative paclitaxel. Methods To fabricate the biodegradable stents, poly-L-lactide strips are first cut from a solvent-casted film. They are rolled onto the surface of a metal pin to form spiral stents. The stents are then consecutively covered by acetylsalicylic acid and paclitaxel-loaded polylactide-polyglycolide nanofibers via electrospinning. Results Biodegradable stents exhibit mechanical properties that are superior to those of metallic stents. Biodegradable stents sequentially release high concentrations of acetylsalicylic acid and paclitaxel for more than 30 and 60 days, respectively. In vitro, the eluted drugs promote endothelial cell numbers on days 3 and 7, and reduce the proliferation of SMCs in weeks 2, 4, and 8. The stents markedly inhibit the adhesion of platelets on days 3, 7, and 14 relative to a non-drug-eluting stent. In vivo, the implanted stent is intact, and no stent thrombosis is observed in the stent-implanted vessels without the administration of daily oral acetylsalicylic acid. Promotion of endothelial recovery and inhibition of neointimal hyperplasia are also observed on the stented vessels. Conclusion The work demonstrates the efficiency and safety of the biodegradable dual-drug-eluting stents with sequential and sustainable drug release to diseased arteries. PMID:25206303

  5. Inhibition of neo-intimal hyperplasia in porcine coronary arteries utilizing a novel paclitaxel-coated scoring balloon catheter.

    PubMed

    Cremers, Bodo; Schmitmeier, Stephanie; Clever, Yvonne P; Gershony, Gary; Speck, Ulrich; Scheller, Bruno

    2014-12-01

    Scoring balloons are particularly useful in the acute treatment of fibro-calcific, bifurcation and in-stent restenosis lesions but have not been shown to affect the restenosis rate. Conventional balloons coated with paclitaxel have recently been shown to reduce restenosis rates in certain lesion subsets, but are associated with suboptimal acute results. A novel paclitaxel-coated scoring balloon was developed to overcome these limitations. AngioSculpt(®) scoring balloons (SB) were coated with paclitaxel admixed with a specific excipient. Four in vitro and in vivo studies were performed: (a) loss of the drug during passage to the lesion, (b) transfer of the drug to the vessel wall; (c) inhibition of neo-intimal proliferation in porcine coronary arteries as compared to uncoated SB and the Paccocath™, and (d) evaluation of the dose-response to 1.5-12 μg of paclitaxel/mm(2) . Drug loss during delivery to the lesion was 17% ± 8%, and transfer to the vessel wall was 9% ± 4% of dose on unused balloons. The paclitaxel-coated SB resulted in a lower late lumen loss of 0.27 ± 0.24 mm compared to 1.4 ± 0.7 mm with the uncoated SB (P = 0.001). Histomorphometry revealed larger luminal areas of 6.8 ± 1.6 mm(2) (paclitaxel-coated SB) and 5.8 ± 1.7 mm(2) (Paccocath) as compared to the uncoated SB (2.3 ± 1.5 mm(2) ; P = 0.001). No coating related adverse effects were observed on follow-up angiography or histologic examination at the treatment site or downstream myocardium. A novel paclitaxel-coated SB leads to a significant inhibition of neointimal proliferation in the porcine coronary model. © 2013 Wiley Periodicals, Inc.

  6. Neointimal Hyperplasia after Silverhawk Atherectomy versus Percutaneous Transluminal Angioplasty (PTA) in Femoropopliteal Stent Reobstructions: A Controlled, Randomized Pilot Trial

    SciTech Connect

    Brodmann, Marianne Rief, Peter; Froehlich, Harald; Dorr, Andreas; Gary, Thomas; Eller, Philipp; Hafner, Franz; Deutschmann, Hannes; Seinost, Gerald; Pilger, Ernst

    2013-02-15

    Due to intimal hyperplasia instent reobstruction in the femoropopliteal arterial segment is still an unsolved problem. Different techniques have been discussed in case of reintervention to guarantee longlasting patency rate. We conducted a randomized, controlled, pilot trial comparing Silverhawk atherectomy with percutaneous transluminal angioplasty (PTA) in patients with a first instent reobstruction in the femoropopliteal arterial segment, to evaluate intima media thickness (IMT) within the treated segment, as a parameter of recurrence of intimal hyperplasia. In a total 19 patients were included: 9 patients in the atherectomy device and 10 patients in the PTA arm. IMT within the treated segment was statistically significantly elevated in all patients treated with the Silverhawk device versus the patients treated with PTA. The obvious differentiation in elevation of IMT in nonfavor for patients treated with the Silverhawk device started at month 2 (max IMT SH 0.178 mm vs. IMT PTA 0.1 mm, p = 0.001) with a spike at month 5 (max IMT SH 0.206 mm vs. IMT PTA 0.145 mm, p = 0.003) and a decline once again at month 6 (max IMT SH 0.177 mm vs. IMT PTA 0.121 mm, p = 0.02). The values for mean IMT performed the same way. Although Silverhawk atherectomy provides good results at first sight, in the midterm follow-up of treatment of first instent restenosis it did not perform better than PTA as it showed elevated reoccurrence of intimal media hyperplasia.

  7. Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia.

    PubMed

    González-Cobos, José C; Zhang, Xuexin; Zhang, Wei; Ruhle, Brian; Motiani, Rajender K; Schindl, Rainer; Muik, Martin; Spinelli, Amy M; Bisaillon, Jonathan M; Shinde, Arti V; Fahrner, Marc; Singer, Harold A; Matrougui, Khalid; Barroso, Margarida; Romanin, Christoph; Trebak, Mohamed

    2013-03-29

    Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store-operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown. The goal of this study was to determine the agonist-evoked Ca(2+) entry pathway contributed by Orai3; Orai3 potential upregulation and role during neointima formation after balloon injury of rat carotid arteries. Ca(2+) imaging and patch-clamp recordings showed that although the platelet-derived growth factor activates the canonical Ca(2+) release-activated Ca(2+) channels via store depletion in VSMC, the pathophysiological agonist thrombin activates a distinct Ca(2+)-selective channel contributed by Orai1, Orai3, and stromal interacting molecule1 in the same cells. Unexpectedly, Ca(2+) store depletion is not required for activation of Orai1/3 channel by thrombin. Rather, the signal for Orai1/3 channel activation is cytosolic leukotrieneC4 produced downstream thrombin receptor stimulation through the catalytic activity of leukotrieneC4 synthase. Importantly, Orai3 is upregulated in an animal model of VSMC neointimal remodeling, and in vivo Orai3 knockdown inhibits neointima formation. These results demonstrate that distinct native Ca(2+)-selective Orai channels are activated by different agonists/pathways and uncover a mechanism whereby leukotrieneC4 acts through hitherto unknown intracrine mode to elicit store-independent Ca(2+) signaling that promotes vascular occlusive disease. Orai3 and Orai3-containing channels provide novel targets for control of VSMC remodeling during vascular injury or disease.

  8. Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats

    PubMed Central

    Wang, Hongfeng; Weihrauch, Dorothee; Kersten, Judy R.; Toth, Jeffrey M.; Passerini, Anthony G.; Rajamani, Anita; Schrepfer, Sonja

    2015-01-01

    Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-β (TGF-β) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-β expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. The study supports an important role for AGE-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM. PMID:26254329

  9. A Preliminary Study of the Therapeutic Role of Human Early Fetal Aorta-derived Endothelial Progenitor Cells in Inhibiting Carotid Artery Neointimal Hyperplasia.

    PubMed

    Xu, Rong-Wei; Zhang, Wen-Jian; Zhang, Jian-Bin; Wen, Jian-Yan; Wang, Meng; Liu, Hong-Lin; Pan, Lin; Yu, Chang-An; Lou, Jin-Ning; Liu, Peng

    2015-12-20

    Endothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells (EPCs) derived from human early fetal aortas in rat injured arteries. The carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas (<14 weeks) were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry. Green fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control (P < 0.05) and the residual lumen area was larger (P < 0.05). After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human von Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment. EPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury.

  10. A Preliminary Study of the Therapeutic Role of Human Early Fetal Aorta-derived Endothelial Progenitor Cells in Inhibiting Carotid Artery Neointimal Hyperplasia

    PubMed Central

    Xu, Rong-Wei; Zhang, Wen-Jian; Zhang, Jian-Bin; Wen, Jian-Yan; Wang, Meng; Liu, Hong-Lin; Pan, Lin; Yu, Chang-An; Lou, Jin-Ning; Liu, Peng

    2015-01-01

    Background: Endothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells (EPCs) derived from human early fetal aortas in rat injured arteries. Methods: The carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas (<14 weeks) were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry. Results: Green fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control (P < 0.05) and the residual lumen area was larger (P < 0.05). After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human von Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment. Conclusion: EPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury. PMID:26668152

  11. Mir-22-3p Inhibits Arterial Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia by Targeting HMGB1 in Arteriosclerosis Obliterans.

    PubMed

    Huang, Shui-Chuan; Wang, Mian; Wu, Wei-Bin; Wang, Rui; Cui, Jin; Li, Wen; Li, Zi-Lun; Li, Wen; Wang, Shen-Ming

    2017-08-22

    Aberrant vascular smooth muscle cell (VSMC) proliferation and migration contribute to the development of vascular pathologies, such as atherosclerosis and post-angioplasty restenosis. The aim of this study was to determine whether miR-22-3p plays a role in regulating human artery vascular smooth muscle cell (HASMC) function and neointima formation. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to detect miR-22-3p expression in human arteries. Cell Counting Kit-8 (CCK-8) and EdU assays were performed to assess cell proliferation, and transwell and wound closure assays were performed to assess cell migration. Moreover, luciferase reporter assays were performed to identify the target genes of miR-22-3p. Finally, a rat carotid artery balloon-injury model was used to determine the role of miR-22-3p in neointima formation. MiR-22-3p expression was downregulated in arteriosclerosis obliterans (ASO) arteries compared with normal arteries, as well as in platelet-derived growth factor-BB (PDGF-BB)-stimulated HASMCs compared with control cells. MiR-22-3p overexpression had anti-proliferative and anti-migratory effects and dual-luciferase assay showed that high mobility group box-1 (HMGB1) is a direct target of miR-22-3p in HASMCs. Furthermore, miR-22-3p expression was negatively correlated with HMGB1 expression in ASO tissue specimens. Finally, LV-miR-22-3p-mediated miR-22-3p upregulation significantly suppressed neointimal hyperplasia specifically by reducing HMGB1 expression in vivo. Our results indicate that miR-22-3p is a key molecule in regulating HASMC proliferation and migration by targeting HMGB1 and that miR-22-3p and HMGB1 may be therapeutic targets in the treatment of human ASO. © 2017 The Author(s). Published by S. Karger AG, Basel.

  12. Hyperplasia

    MedlinePlus

    Hyperplasia is increased cell production in a normal tissue or organ. Hyperplasia may be a sign of abnormal or precancerous changes. This is called pathologic hyperplasia. It can also be due to the growth ...

  13. Safety and biocompatibility of a novel self-expanding nitinol carotid stent with hybrid cell design in a porcine model of neointimal hyperplasia.

    PubMed

    Janas, Adam; Milewski, Krzysztof; Buszman, Piotr P; Nowakowski, Przemysław; Jelonek, Michał; Orlik, Bartłomiej; Krauze, Agata; Samborski, Stefan; Beaudry, Diane; Lecelrc, Guy; Król, Marek; Lapointe, Jean Martin; Wojakowski, Wojciech; Turek, Anna; Kiesz, Radosław S; Buszman, Paweł E

    2015-01-01

    Stent design may influence the outcomes, suggesting that adverse event rates vary according to free cell area and cell design. Open cell design technology of self-expandable stents, dedicated for carotid revascularisation has better deliverability, although closed cell technology is expected to cause fewer thromboembolic events. To evaluate the feasibility and vascular response of novel, hybrid cell, self-expandable nitinol stents (MER®, Balton, Poland) implanted into porcine carotid arteries. Hybrid cell design combines open and closed cell technology. All tested stents were implanted with 10% overstretch into 10 carotid segments of Polish domestic pigs. Control angiography was obtained immediately before and after vascular interventions as well as 28 days after the procedure. Thereafter, animals were sacrificed, and the treated segments were harvested and evaluated in the independent histopathology laboratory. All stents were easily introduced and implanted, showing good angiographic acute outcome. At 28 days, in the angiography, all vessels were patent with no signs of thrombi or excessive neointimal formation, with the late lumen loss of -0.11 ± 0.3 mm and percentage diameter stenosis 10.18 ± 8.1%. There was a 10% increase in the vessel reference diameter when compared to baseline (4.57 ± 0.5 vs. 4.96 ± 0.3 mm, p < 0.01). In the histopathology, mean area stenosis was 17.4% and mean intimal thickness was 0.20 mm. At histopathology, the mean injury, inflammation, and fibrin scores were low. Endothelialisation was complete in all stents, and neointimal tissue appeared moderately mature as shown by the moderate mean neointimal smooth muscle score. Nonetheless, histopathology shows one stent affected by peri-strut granulomas and one stent affected by marked mineralisation. The novel Polish self-expandable nitinol carotid stent with hybrid cell technology shows optimal biocompatibility and a vascular healing profile, and therefore may be introduced for first

  14. A small molecule PAI-1 functional inhibitor attenuates neointimal hyperplasia and vascular smooth muscle cell survival by promoting PAI-1 cleavage.

    PubMed

    Simone, Tessa M; Higgins, Stephen P; Archambeault, Jaclyn; Higgins, Craig E; Ginnan, Roman G; Singer, Harold; Higgins, Paul J

    2015-05-01

    Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo. In contrast to the active full-length serine protease inhibitor (SERPIN), elastase-cleaved PAI-1 (similar to tiplaxtinin) also promoted VSMC apoptosis in vitro and similarly reduced neointimal formation in vivo. The mechanism through which cleaved PAI-1 (CL-PAI-1) stimulates apoptosis appears to involve the TNF-α family member TWEAK (TNF-α weak inducer of apoptosis) and it's cognate receptor, fibroblast growth factor (FGF)-inducible 14 (FN14). CL-PAI-1 sensitizes cells to TWEAK-stimulated apoptosis while full-length PAI-1 did not, presumably due to its ability to down-regulate FN14 in a low density lipoprotein receptor-related protein 1 (LRP1)-dependent mechanism. It appears that prolonged exposure of VSMCs to CL-PAI-1 induces apoptosis by augmenting TWEAK/FN14 pro-apoptotic signaling. This work identifies a critical, anti-stenotic, role for a functionally-inactive (at least with regard to its protease inhibitory function) cleaved SERPIN. Therapies that promote the conversion of full-length to cleaved PAI-1 may have translational implications.

  15. Lithium Chloride Inhibits Vascular Smooth Muscle Cell Proliferation and Migration and Alleviates Injury-Induced Neointimal Hyperplasia via Induction of PGC-1α

    PubMed Central

    Wang, Danfeng; Wu, Jun; Liang, Tingming; Liu, Chang

    2013-01-01

    The proliferation and migration of vascular smooth muscle cells (VSMCs) contributes importantly to the development of in-stent restenosis. Lithium has recently been shown to have beneficial effects on the cardiovascular system, but its actions in VSMCs and the direct molecular target responsible for its action remains unknown. On the other hand, PGC-1α is a transcriptional coactivator which negatively regulates the pathological activation of VSMCs. Therefore, the purpose of the present study is to determine if lithium chloride (LiCl) retards VSMC proliferation and migration and if PGC-1α mediates the effects of lithium on VSMCs. We found that pretreatment of LiCl increased PGC-1α protein expression and nuclear translocation in a dose-dependent manner. MTT and EdU incorporation assays indicated that LiCl inhibited serum-induced VSMC proliferation. Similarly, deceleration of VSMC migration was confirmed by wound healing and transwell assays. LiCl also suppressed ROS generation and cell cycle progression. At the molecular level, LiCl reduced the protein expression levels or phosphorylation of key regulators involved in the cell cycle re-entry, adhesion, inflammation and motility. In addition, in vivo administration of LiCl alleviated the pathophysiological changes in balloon injury-induced neointima hyperplasia. More importantly, knockdown of PGC-1α by siRNA significantly attenuated the beneficial effects of LiCl on VSMCs both in vitro and in vivo. Taken together, our results suggest that LiCl has great potentials in the prevention and treatment of cardiovascular diseases related to VSMC abnormal proliferation and migration. In addition, PGC-1α may serve as a promising drug target to regulate cardiovascular physiological homeostasis. PMID:23383200

  16. Early growth response gene-1 decoy oligonucleotides inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia of autogenous vein graft in rabbits.

    PubMed

    Wang, Xisheng; Mei, Yunqing; Ji, Qiang; Feng, Jing; Cai, Jianzhi; Xie, Shiliang

    2015-07-01

    The excess proliferation of vascular smooth muscle cells (VSMCs) and the development of intimal hyperplasia is a hallmark of vein graft failure. This study aimed to verify that a single intraoperative transfection of early growth response gene-1 (Egr-1) decoy oligonucleotide (ODN) can suppress vein graft proliferation of VSMCs and intimal hyperplasia. In a rabbit model, jugular veins were treated with Egr-1 decoy ODN, scrambled decoy ODN, Fugene6, or were left untreated, then grafted to the carotid artery. The vein graft samples were obtained 48 h, 1, 2 or 3 weeks after surgery. The thickness of the intima and intima/media ratio in the grafts was analysed by haematoxylin-eosin (HE) staining. The expression of the Egr-1 decoy ODN transfected in the vein was analysed using fluorescent microscopy. Egr-1 mRNA was measured using reverse transcription-polymerase chain reaction. The expression of Egr-1 protein was analysed by Western blot and immunohistochemistry. Transfection efficiency of the ODN was confirmed by 4', 6-diamidino-2-phenylindole staining. In the grafts treated with Egr-1 decoy ODN, our study achieved statistically significant inhibition of intimal hyperplasia by ∼58% at 3 weeks. Transfection of Egr-1 decoy ODNs decreased the protein expression of Egr-1 and Egr-1 mRNA. We confirmed that gene therapy using in vivo transfection of an Egr-1 decoy ODN significantly inhibits proliferation of VSMC and intimal hyperplasia of vein grafts in a rabbit model. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  17. Cinacalcet HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD

    PubMed Central

    Miller, Gerald; Davis, James; Shatzen, Edward; Colloton, Matthew; Martin, David

    2012-01-01

    Background. Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT. Methods. We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT. Results. Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium. Conclusions. The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH. PMID:22036941

  18. Cinacalcet HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD.

    PubMed

    Miller, Gerald; Davis, James; Shatzen, Edward; Colloton, Matthew; Martin, David; Henley, Charles M

    2012-06-01

    Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT. We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT. Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium. The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.

  19. AdipoRon, an adiponectin receptor agonist, attenuates PDGF-induced VSMC proliferation through inhibition of mTOR signaling independent of AMPK: Implications toward suppression of neointimal hyperplasia.

    PubMed

    Fairaq, Arwa; Shawky, Noha M; Osman, Islam; Pichavaram, Prahalathan; Segar, Lakshman

    2017-02-22

    Hypoadiponectinemia is associated with an increased risk of coronary artery disease. Although adiponectin replenishment mitigates neointimal hyperplasia and atherosclerosis in mouse models, adiponectin therapy has been hampered in a clinical setting due to its large molecular size. Recent studies demonstrate that AdipoRon (a small-molecule adiponectin receptor agonist) improves glycemic control in type 2 diabetic mice and attenuates postischemic cardiac injury in adiponectin-deficient mice, in part, through activation of AMP-activated protein kinase (AMPK). To date, it remains unknown as to whether AdipoRon regulates vascular smooth muscle cell (VSMC) proliferation, which plays a major role in neointima formation. In the present study, oral administration of AdipoRon (50mg/kg) in C57BL/6J mice significantly diminished arterial injury-induced neointima formation by ∼57%. Under in vitro conditions, AdipoRon treatment led to significant inhibition of platelet-derived growth factor (PDGF)-induced VSMC proliferation, DNA synthesis, and cyclin D1 expression. While AdipoRon induced a rapid and sustained activation of AMPK, it also diminished basal and PDGF-induced phosphorylation of mTOR and its downstream targets, including p70S6K/S6 and 4E-BP1. However, siRNA-mediated AMPK downregulation showed persistent inhibition of p70S6K/S6 and 4E-BP1 phosphorylation, indicating AMPK-independent effects for AdipoRon inhibition of mTOR signaling. In addition, AdipoRon treatment resulted in a sustained and transient decrease in PDGF-induced phosphorylation of Akt and ERK, respectively. Furthermore, PDGF receptor-β tyrosine phosphorylation, which controls the phosphorylation state of Akt and ERK, was diminished upon AdipoRon treatment. Together, the present findings suggest that orally-administered AdipoRon has the potential to limit restenosis after angioplasty by targeting mTOR signaling independent of AMPK activation.

  20. Prevention of neointimal formation by a serine protease inhibitor, FUT-175, after carotid balloon injury in rats.

    PubMed

    Sawada, M; Yanamoto, H; Nagata, I; Hashimoto, N; Nakahara, I; Akiyama, Y; Kikuchi, H; Macdonald, R L

    1999-03-01

    In vivo and vitro studies revealed the activation of thrombin and the complement system in vascular lesion formation during the process of atherosclerosis, along with pathological proliferation of smooth muscle cells. We examined the effect of the synthetic serine protease inhibitor FUT-175 (developed as a potent inhibitor of thrombin and the complement system) on vascular lesions using balloon dilatation-induced neointimal formation in the carotid artery of rats. Sprague-Dawley (SD) rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mL of saline for 7 consecutive days. The control group (n=8) was similarly treated with 1 mL of saline for 7 days. The injections were started immediately after balloon injury. Two weeks after the injury, the left carotid arteries were perfusion-fixed, and the areas of the neointimal and medial layer were analyzed under a microscope. A morphometric analysis revealed that there were significant differences in the intima-media ratio between the 4 groups treated with vehicle (saline) or a low, medium, or high dose of FUT-175 (1.45+/-0.11, 1.08+/-0.06, 0.71+/-0.04, or 0.32+/-0.04, respectively). This suppression was achieved in a dose-dependent manner by the administration of FUT-175 after balloon injury. In the histological study, it was demonstrated that FUT-175 suppresses the production of platelet-derived growth factor (PDGF)-BB in the neointima and the medial smooth muscle cell layer. After balloon injury activated proteases that were inhibited by FUT-175 were demonstrated to have an essential role in the development of the pathological thickening of the arterial wall.

  1. Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia.

    PubMed

    Longchamp, Alban; Allagnat, Florent; Alonso, Florian; Kuppler, Christopher; Dubuis, Céline; Ozaki, Charles-Keith; Mitchell, James R; Berceli, Scott; Corpataux, Jean-Marc; Déglise, Sébastien; Haefliger, Jacques-Antoine

    2015-01-01

    Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment.

  2. Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia

    PubMed Central

    Longchamp, Alban; Allagnat, Florent; Alonso, Florian; Kuppler, Christopher; Dubuis, Céline; Ozaki, Charles-Keith; Mitchell, James R.; Berceli, Scott; Corpataux, Jean-Marc

    2015-01-01

    Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment. PMID:26398895

  3. Use of levonorgestrel-releasing intrauterine system in the prevention and treatment of endometrial hyperplasia.

    PubMed

    Ewies, Ayman A A; Alfhaily, Fadi

    2012-11-01

    Endometrial hyperplasia is a commonly seen gynecological condition that affects women of all age groups. Whereas hysterectomy is the most preferred treatment option for complex endometrial hyperplasia with atypia, there is no consensus regarding the first-line management of women with hyperplasia without cytological atypia. Oral progestogen therapy was used with some success. Nonetheless, it may be plausible to argue that women with endometrial hyperplasia need continuous treatment and high level of compliance to ensure complete regression, which may not be guaranteed with oral therapy. Observational studies suggested that levonorgestrel-releasing intrauterine system (LNG-IUS) has been successfully used to treat endometrial hyperplasia without cytological atypia and selected cases of atypical endometrial hyperplasia. Furthermore, there is strong evidence from randomized controlled trials that LNG-IUS prevents the development of endometrial hyperplasia in exogenous estrogen users; however, its protective role and safety in tamoxifen-treated breast cancer survivors remain uncertain. This article evaluates the current evidence for the use of LNG-IUS, releasing 20 μg of LNG per day, in the prevention and treatment of endometrial hyperplasia.

  4. Prevention of Bronchial Hyperplasia by EGFR Pathway Inhibitors in an Organotypic Culture Model

    PubMed Central

    Lee, Jangsoon; Ryu, Seung-Hee; Kang, Shin Myung; Chung, Wen-Cheng; Gold, Kathryn Ann; Kim, Edward S.; Hittelman, Walter N.; Hong, Waun Ki; Koo, Ja Seok

    2011-01-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. The current study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured using the 3-dimensional organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands EGF, transforming growth factor-alpha, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MEK inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we demonstrated that bronchial hyperplasia can be modeled in vitro using primary NHTBE cells maintained in a 3-dimensional (3-D) organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role. PMID:21505178

  5. Smooth Muscle Cell–targeted RNA Aptamer Inhibits Neointimal Formation

    PubMed Central

    Thiel, William H; Esposito, Carla L; Dickey, David D; Dassie, Justin P; Long, Matthew E; Adam, Joshua; Streeter, Jennifer; Schickling, Brandon; Takapoo, Maysam; Flenker, Katie S; Klesney-Tait, Julia; Franciscis, Vittorio de; Miller, Francis J; Giangrande, Paloma H

    2016-01-01

    Inhibition of vascular smooth muscle cell (VSMC) proliferation by drug eluting stents has markedly reduced intimal hyperplasia and subsequent in-stent restenosis. However, the effects of antiproliferative drugs on endothelial cells (EC) contribute to delayed re-endothelialization and late stent thrombosis. Cell-targeted therapies to inhibit VSMC remodeling while maintaining EC health are necessary to allow vascular healing while preventing restenosis. We describe an RNA aptamer (Apt 14) that functions as a smart drug by preferentially targeting VSMCs as compared to ECs and other myocytes. Furthermore, Apt 14 inhibits phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) and VSMC migration in response to multiple agonists by a mechanism that involves inhibition of platelet-derived growth factor receptor (PDGFR)-β phosphorylation. In a murine model of carotid injury, treatment of vessels with Apt 14 reduces neointimal formation to levels similar to those observed with paclitaxel. Importantly, we confirm that Apt 14 cross-reacts with rodent and human VSMCs, exhibits a half-life of ~300 hours in human serum, and does not elicit immune activation of human peripheral blood mononuclear cells. We describe a VSMC-targeted RNA aptamer that blocks cell migration and inhibits intimal formation. These findings provide the foundation for the translation of cell-targeted RNA therapeutics to vascular disease. PMID:26732878

  6. Parathyroid hyperplasia

    MedlinePlus

    Enlarged parathyroid glands; Osteoporosis - parathyroid hyperplasia; Bone thinning - parathyroid hyperplasia; Osteopenia - parathyroid hyperplasia; High calcium level - parathyroid hyperplasia; Chronic kidney disease - parathyroid hyperplasia; ...

  7. Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway

    PubMed Central

    Son, Dong Ju; Jung, Jae Chul; Hong, Jin Tae

    2016-01-01

    Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs. PMID:27218463

  8. Induction or prevention of intimal hyperplasia by photodynamic therapy in a porcine model

    NASA Astrophysics Data System (ADS)

    Sobeh, Mohammed S.; Greenwald, Stephen E.; Ham, Robert J.; Phypers, Barrie J.; Cross, Frank W.; Hsiang, York N.

    1995-05-01

    Photodynamic therapy (PDT) has been proposed as a treatment for intimal hyperplasia (IH). We studied the effect of PDT on the development of IH following endothelial injury, using the photosensitizer Metatetrahydroxyphenyl-chlorin (m-THPC) and 652 nm illumination. 9 mini- pigs were used in 3 groups of 3. Pigs in the first group (balloon alone; BA) were anaesthetized and the lower 4 cm of abdominal aorta was denuded using a balloon catheter through the right femoral artery. In the second group (light alone; LA) the procedure was repeated, followed by illumination of the denuded area at an energy density of 20 Jcm-2 using a transparent PDT catheter. In the third group pigs were sensitized and an intravenous injection of 0.3 mg/kg of m-THPC 4 hours prior to balloon injury and illumination (PDT Group). Animals were allowed to recover for 8 weeks before being killed and perfusion fixed with 10% formal saline. 5 sections were cut from the treated segments and stained for elastin. Specimens were measured by a computerized morphometry system and the areas of the lumen (L), intima (I) and media (M) were measured. The degree of intimal hyperplasia was expressed as (a) I/M; (b) I/(I+M) and (c) I/(I+L) to take account of changes that could have occurred to the media and the overall diameter of the vessel. We found that when compared to BA controls, the lumenal area was decreased by 46% in LA group and increased by 44% in PDT group. The changes in the medical areas were minimal. These results show that both light alone and PDT produced more intimal hyperplasia than balloon injury alone (P < 0.002 for both groups, Student's t test). When allowance is made for the large increase in lumenal area associated with PDT the degree of intimal hyperplasia I/(I+L) was significantly reduced in PDT treated vessels when compared to those treated with light and balloon alone in spite of the greater absolute area of the intima in the PDT group. We conclude that PDT under the above conditions

  9. Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis.

    PubMed

    Mancini, Maria L; Lien, Evan C; Toker, Alex

    2016-04-05

    One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1(E17K).

  10. Pre-existing smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions

    PubMed Central

    Yang, Pu; Hong, Michael S.; Fu, Chunhua; Schmit, Bradley M.; Su, Yunchao; Berceli, Scott A.; Jiang, Zhihua

    2015-01-01

    Background With the diverse origin of neointimal cells, previous studies have documented differences of neointimal cell-lineage composition across models, but the animal-to-animal difference has not attracted much attention though the cellular heterogeneity may impact neointimal growth and its response to therapeutic interventions. Methods The R26R+;Myh11-CreER+ and R26R+;Scl-CreER+ mice were utilized to attach LacZ tags to the pre-existing smooth muscle cells (SMCs) and endothelial cells (ECs), respectively. Neointimal lesions were created via complete ligation of the common carotid artery (CCA) and transluminal injury to the femoral artery (FA). Results LacZ-tagged SMCs were physically relocated from media to neointima and changed to a de-differentiated phenotype in both CCA and FA lesions. The content of SMCs in the neointimal tissue, however, varied widely among specimens, ranging from 5–70% and 0–85%, with an average at low levels of 27% and 29% in CCA (n=15) and FA (n=15) lesions, respectively. Bone marrow cells, while able to home to the injured arteries, did not differentiate fully into SMCs after either type of injury. Pre-existing ECs were located in the sub-endothelial region and produced mesenchymal marker α-actin, indicating endothelial-mesenchymal-transition (EndoMT), however, EC-derived cells represented only 7% and 3% of the total neointimal cell pool of CCA (n=7) and FA (n=7) lesions, respectively. ECs located on the luminal surface exhibited little evidence for EndoMT. Conclusion Neointimal hyperplasia proceeds with a wide range of variation in its cellular composition between individual lesions. Relative to ECs, SMCs are major contributors to the lesion-to-lesion heterogeneity in neointimal cell-lineage composition. PMID:26387788

  11. Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by Inducing HIF-1alpha.

    PubMed

    Cho, Young-Suk; Lee, Kyung-Hoon; Park, Jong-Wan

    2010-04-01

    Epidermal keratinocytes overgrow in response to ultraviolet-B (UVB), which may be associated with skin photoaging and cancer development. Recently, we found that HIF-1alpha controls the keratinocyte cell cycle and thereby contributes to epidermal homeostasis. A further study demonstrated that HIF-1alpha is down-regulated by UVB and that this process is involved in UVB-induced skin hyperplasia. Therefore, we hypothesized that the forced expression of HIF-1alpha in keratinocytes would prevent UVB-induced keratinocyte overgrowth. Among several agents known to induce HIF-1alpha, pyrithione-zinc (Py-Zn) overcame the UVB suppression of HIF-1alpha in cultured keratinocytes. Mechanistically, Py-Zn blocked the degradation of HIF-1alpha protein in keratinocytes, while it did not affect the synthesis of HIF-1alpha. Moreover, the p21 cell cycle inhibitor was down-regulated after UVB exposure, but was robustly induced by Py-Zn. In mice repeatedly irradiated with UVB, the epidermis became hyperplastic and HIF-1alpha disappeared from nuclei of epidermal keratinocytes. However, a cream containing Py-Zn effectively prevented the skin thickening and up-regulated HIF-1alpha to the normal level. These results suggest that Py-Zn is a potential agent to prevent UVB-induced photoaging and skin cancer development. This work also provides insight into a molecular target for treatment of UVB-induced skin diseases.

  12. Low-dose UVB irradiation prevents MMP2-induced skin hyperplasia by inhibiting inflammation and ROS.

    PubMed

    Dang, Lin; Wang, Yan; Xue, Yadong; He, Lei; Li, Yuzhen; Xiong, Jikui

    2015-09-01

    Skin cancer is one of the most common types of malignancy in the world. UV radiation is known as the primary environmental carcinogen responsible for skin cancer development. However, UV radiation is a ubiquitous substance existing in the environment and the physiological effect of UV radiation is consistently ignored. Therefore, in the present study, the physiological effect of UV radiation on inhibition of skin cancer was investigated. Normal mouse skin was processing by no pre-radiation or pre-radiation of low-dose UV before a medium or high dose of UV radiation. We found that the low-dose pre-radiated mouse skin tissue exhibited low skin inflammation, skin ROS production and consequently low skin epithelial hyperplasia after the medium-dose UV radiation compared with the no pre-radiated mouse. However, this inhibition was not indicated in the high-dose UV radiation group after low-dose pre-radiation. Furthermore, western blot analysis and gelatin zymography showed low expression and activation of MMP2 in the skin tissues processed following medium-dose radiation, but not in tissues treated with high-dose radiation after a low-dose pre-radiation. Further investigation of MMP2 inhibitors of TIMP2/TIMP4 showed an upregulated TIMP2 expression, but not TIMP4. Collectively, these data indicate that low-dose pre-radiation attenuates the skin inflammation and ROS production induced by medium-dose UV radiation and also elevates TIMP2 to withstand MMP2, therefore suppressing skin hyperplasia. The present study indicates a novel concept or prophylactic function of moderate UV radiation as a preventative strategy.

  13. Preventive effects of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats.

    PubMed

    Bisson, Jean-François; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

    2007-12-01

    Plant extracts are useful in the management of benign prostatic hyperplasia (BPH). This study investigates whether ACTICOA (Barry Callebaut France, Louviers, France) powder (AP), a cocoa polyphenolic extract, could prevent prostate hyperplasia induced by testosterone propionate (TP) in rats. Male Wistar-Unilever rats were randomly divided in four groups of 12 rats: one negative control group receiving subcutaneous injections of corn oil and treated with vehicle and three groups injected subcutaneously with TP and treated with the vehicle (positive control) or AP at 24 (AP24) and 48 (AP48) mg/kg/day. Treatments were given orally and started 2 weeks before the induction of prostate hyperplasia. The influence of TP and AP on body weights and food and water consumption of rats was examined. On day 36, rats were sacrificed, and the prostates were removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. TP significantly influenced the body weight gain of the rats and their food and water consumption, while AP at both doses tested reduced significantly these differences. TP significantly increased prostate size ratio (P < .001), and this induced increase was significantly inhibited in AP-treated rats in comparison with positive controls (P < .001) in a dose-dependent manner. We conclude that AP can prevent TP-induced prostate hyperplasia and therefore may be beneficial in the management of BPH.

  14. Preventive effects of lignan extract from flax hulls on experimentally induced benign prostate hyperplasia.

    PubMed

    Bisson, Jean-François; Hidalgo, Sophie; Simons, Rudy; Verbruggen, Marian

    2014-06-01

    Consumption of diet rich in lignans may decrease the risk of some chronic hormonal conditions such as benign prostatic hyperplasia (BPH). This study investigated whether a lignan-rich extract from flaxseed hulls, LinumLife EXTRA (LLE), could prevent BPH using the testosterone propionate (TP)-induced BPH rat model. Male Wistar-Unilever rats were randomly divided into four groups of 12 rats each: a negative control group fed with control diet and receiving daily subcutaneous injections of corn oil without TP, and three groups fed with control diet (positive control), diet containing 0.5% LLE (LLE 0.5) or 1.0% LLE (LLE 1.0) and receiving daily subcutaneous injections of TP in corn oil. Treatments with diets started 2 weeks before the induction of BPH and were carried out for 5 consecutive weeks. The influence of TP and LLE on body weight (BW), food and water consumptions, and enterolactone (ENL) levels in serum and urine of rats was examined at the end of the 5-week treatment period. TP significantly diminished the mean body weight gain (MBWG) of positive control rats and their food and water consumptions while LLE reduced significantly this MBWG reduction in a dose-dependent manner. The lignan-rich extract significantly inhibited TP-induced prostate size ratio (prostate weight/rat BW) increase in comparison with positive controls (P<.001). This effect was dose dependent. Higher serum and urine levels of ENL correlated well with the dose of extract provided to rats. It was concluded that the lignan-rich flaxseed hull extract prevented the TP-induced BPH indicating it might be beneficial in the prevention of BPH.

  15. Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice.

    PubMed

    Arcidiacono, Maria Vittoria; Yang, Jing; Fernandez, Elvira; Dusso, Adriana

    2015-03-01

    In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia. A dominant-negative human EGFR mutant, which forms non-functional heterodimers with full-length endogenous EGFR, was successfully targeted to the parathyroid glands (PTGs) of FVB/N mice, using the 5' regulatory sequence of the PTH promoter. The parathyroid phenotype and serum chemistries of wild-type (WT) and transgenic mice were examined after 14 weeks of either sham operation or 75% renal mass reduction (NX). Both genotypes had similar morphology and body weight, and NX-induction enhanced similarly serum blood urea nitrogen compared with sham-operated controls. However, despite similar serum calcium, phosphate and FGF23 levels in NX mice of both genotypes, parathyroid EGFR inactivation sufficed to completely prevent the marked increases in PTG enlargement, serum PTH and in parathyroid levels of transforming growth factor-α, a powerful EGFR-activator, and the VDR reductions observed in WT mice. In CKD, parathyroid EGFR activation is essential for parathyroid hyperplasia and VDR loss, rendering this transgenic mouse a unique tool to scrutinize the pathogenesis of parathyroid and multiple organ dysfunction of CKD progression unrelated to parathyroid hyperplasia. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  16. Neointimal hyperplasia and endothelial function after percutaneous coronary intervention

    PubMed Central

    Sorop, O.; van Beusekom, H.M.M.; van der Giessen, W.J.

    2006-01-01

    Percutaneous coronary revascularisation has become much safer and efficacious since its introduction more than 25 years ago. Currently, the need for surgical backup is small and the rate of late complications is lower than 10%. Further improvements are being studied, especially directed towards more biocompatible stents, using pharmacological principles with wider therapeutic windows and enhancing the vascular healing response/reendothelialisation. This article reviews several activities within the ICIN theme group `Vessel Wall'. ImagesFigure 1 PMID:25696566

  17. Prevention of intimal hyperplasia using short-period vascular heating without surrounding tissue injury: in vitro/in vivo experiments and thermal conduction calculation

    NASA Astrophysics Data System (ADS)

    Suga, Eriko; Kaneko, Kenji; Futami, Hikaru; Yamashita, Erika; Arai, Tsunenori

    2005-04-01

    We have been proposed novel short-term (<10s) heating balloon using the combination of light-heat conversion mechanism and heated contrast medium irrigation in the balloon to improve dilatation characteristics of balloon angioplasty. Our new balloon angioplasty had suppressed intimal hyperplasia in rabbit model. We designed following experiments to understand the mechanism of suppression of intimal hyperplasia in our new thermal balloon angioplasty. We also aimed to obtain the suitable heating condition in our angioplasty to suppress intimal hyperplasia. We studied influence of the short-term heating on smooth muscle cells (SMCs) lethality in vitro. We investigated number of SMCs reduction in media in order to prevent intimal hyperplasia. We applied to our heating balloon dilatation to chronic rabbit model using normal iliac artery to study relation between heating condition and hyperplasia suppression. We estimated temperature history of the rabbit vascular wall by thermal conduction calculation. We related the estimated temperature history to the hyperplasia suppression effect in the chronic rabbit model. Finally, we obtained the relation between number of SMCs decreases and intimal hyperplasia suppression. We obtained that the short-term heating with 10s laser irradiation corresponding to estimated temperature of 50°C in the media and prevented intimal hyperplasia in the rabbit chronic model. In this case, we estimated about 30 percents of SMCs cellular lethality in media.

  18. The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells

    PubMed Central

    Smirnova, Natalia F.; Fontaine, Coralie; Buscato, Mélissa; Lupieri, Adrien; Vinel, Alexia; Valera, Marie-Cécile; Guillaume, Maeva; Malet, Nicole; Foidart, Jean-Michel; Raymond-Letron, Isabelle; Lenfant, Francoise; Gourdy, Pierre; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.; Laffargue, Muriel; Arnal, Jean-Francois

    2015-01-01

    Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor α (ERα) via 2 activation functions, AF1 and AF2, and can also activate membrane ERα. The role of E2 on the endothelium relies on membrane ERα activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood. Objective: The aim of this study was to determine which cellular target and which ERα subfunction are involved in the preventive action of E2 on neointimal hyperplasia. Methods and Results: To trigger neointimal hyperplasia of VSMC, we used a mouse model of femoral arterial injury. Cre-Lox models were used to distinguish between the endothelial- and the VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ERα agonists and transgenic mice in which the ERαAF1 function had been specifically invalidated. We found that (1) the selective inactivation of ERα in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ERα has no effect; (2) the selective activation of membrane ERα does not prevent neointimal hyperplasia; and (3) ERαAF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. Conclusions: Altogether, ERαAF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ERα largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ERα subfunctions and helps to delineate the spectrum of action of selective ER modulators. PMID:26316608

  19. From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures.

    PubMed

    Boruban, Melih C; Altundag, Kadri; Kilic, Gokhan S; Blankstein, Josef

    2008-04-01

    Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy

  20. Targeted nitric oxide delivery by supramolecular nanofibers for the prevention of restenosis after arterial injury

    DOE PAGES

    Bahnson, Edward S. M.; Kassam, Hussein A.; Moyer, Tyson J.; ...

    2016-01-21

    Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. Here we sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. As a result, structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescentmore » detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. In conclusion, we successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases« less

  1. Targeted nitric oxide delivery by supramolecular nanofibers for the prevention of restenosis after arterial injury

    SciTech Connect

    Bahnson, Edward S. M.; Kassam, Hussein A.; Moyer, Tyson J.; Jiang, Wulin; Morgan, Courtney E.; Vercammen, Janet M.; Jiang, Qun; Flynn, Megan E.; Stupp, Samuel I.; Kibbe, Melina R.

    2016-01-21

    Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. Here we sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. As a result, structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. In conclusion, we successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases

  2. Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury

    PubMed Central

    Bahnson, Edward S.M.; Kassam, Hussein A.; Moyer, Tyson J.; Jiang, Wulin; Morgan, Courtney E.; Vercammen, Janet M.; Jiang, Qun; Flynn, Megan E.; Stupp, Samuel I.

    2016-01-01

    Abstract Aims: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. Results: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. Innovation: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. Conclusion: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases. Antioxid. Redox Signal. 27, 401–418. PMID:26593400

  3. MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia

    PubMed Central

    Evans, Brian C.; Hocking, Kyle M.; Osgood, Michael J.; Voskresensky, Igor; Dmowska, Julia; Kilchrist, Kameron V.; Brophy, Colleen M.; Duvall, Craig L.

    2017-01-01

    Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)–activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3′,5′-monophosphate) element–binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i–treated grafts. The decrease in IH in MK2i-NP–treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure. PMID:26062847

  4. Low molecular weight fucoidan prevents intimal hyperplasia in rat injured thoracic aorta through the modulation of matrix metalloproteinase-2 expression.

    PubMed

    Hlawaty, Hanna; Suffee, Nadine; Sutton, Angela; Oudar, Olivier; Haddad, Oualid; Ollivier, Veronique; Laguillier-Morizot, Christelle; Gattegno, Liliane; Letourneur, Didier; Charnaux, Nathalie

    2011-01-15

    The therapeutic potential of low molecular-weight fucoidan (LMWF), a sulfated polysaccharide extracted from brown seaweed was investigated on vascular smooth muscle cell (VSMC) and human vascular endothelial cell (HUV-EC-C) proliferation and migration in vitro and in a rat model of intimal hyperplasia. Sprague-Dawley rats were subjected to balloon injury in the thoracic aorta followed by two weeks' treatment with either LMWF (5mg/kg/day) or vehicle. Morphological analysis and proliferating cell nuclear antigen immunostaining at day 14 indicated that LMWF prevented intimal hyperplasia in rat thoracic aorta as compared with vehicle (neo-intima area, 3±0.50mm(2) versus 5±0.30mm(2), P<0.01). In situ zymography showed that LMWF significantly decreased the activity of matrix metalloproteinase (MMP)-2 in the neo-intima compared to vehicle. The in vitro study demonstrated that 10μg/ml LMWF increased HUV-EC-C migration by 45±5% but reduced VSMC migration by 40±3%. LMWF also increased MMP-2 mRNA expression in HUV-EC-Cs and reduced it in VSMCs. MMP-2 level in the conditioned medium from cells incubated with 10μg/ml LMWF was 5.4-fold higher in HUV-EC-Cs, but 6-fold lower in VSMCs than in untreated control cells. Furthermore, decreasing MMP-2 expression in HUV-EC-Cs or VSMCs by RNA interference resulted in reduced LMWF-induced effects on cell migration. In conclusion, LMWF increased HUV-EC-C migration and decreased VSMC migration in vitro. In vivo, this natural compound reduced the intimal hyperplasia in the rat aortic wall after balloon injury. Therefore, LMWF could be of interest for the prevention of intimal hyperplasia.

  5. Modelling ultrasound-induced mild hyperthermia of hyperplasia in vascular grafts

    PubMed Central

    2011-01-01

    Background Expanded polytetrafluoroethylene (ePTFE) vascular grafts frequently develop occlusive neointimal hyperplasia as a result of myofibroblast over-growth, leading to graft failure. ePTFE exhibits higher ultrasound attenuation than native soft tissues. We modelled the selective absorption of ultrasound by ePTFE, and explored the feasibility of preventing hyperplasia in ePTFE grafts by ultrasound heating. Specifically, we simulated the temperature profiles of implanted grafts and nearby soft tissues and blood under ultrasound exposure. The goal was to determine whether ultrasound exposure of an ePTFE graft can generate temperatures sufficient to prevent cell growth on the graft without damaging nearby soft tissues and blood. Methods Ultrasound beams from two transducers (1.5 and 3.2 MHz) were simulated in two graft/tissue models, with and without an intra-graft cellular layer mimicking hyperplasia, using the finite-difference time-domain (FDTD) method. The resulting power deposition patterns were used as a heat source for the Pennes bioheat equation in a COMSOL® Multiphysics heat transfer model. 50°C is known to cause cell death and therefore the transducer powers were adjusted to produce a 13°C temperature rise from 37°C in the ePTFE. Results Simulations showed that both the frequency of the transducers and the presence of hyperplasia significantly affect the power deposition patterns and subsequent temperature profiles on the grafts and nearby tissues. While neither transducer significantly raised the temperature of the blood, the 1.5-MHz transducer was less focused and heated larger volumes of the graft and nearby soft tissues than the 3.2-MHz transducer. The presence of hyperplasia had little effect on the blood's temperature, but further increased the temperature of the graft and nearby soft tissues in response to either transducer. Skin cooling and blood flow play a significant role in preventing overheating of the native tissues. Conclusions

  6. Angioscopic Evaluation of Neointimal Coverage of Coronary Stents.

    PubMed

    Uchida, Yasumi; Uchida, Yasuto

    2010-10-01

    Drug-eluting stents (DES) reduce coronary restenosis significantly; however, late stent thrombosis (LST) occurs, which requires long-term antiplatelet therapy. Angioscopic grading of neointimal coverage of coronary stent struts was established, and it was revealed that neointimal formation is incomplete and prevalence of LST is higher in DES when compared to bare-metal stents. It was also observed that the neointima is thicker and LST is less frequent in paclitaxel-eluting and zotarolimus-eluting stents than in sirolimus-eluting stents. Many new stents were devised and they are now under experimental or clinical investigations to overcome the shortcomings of the stents that have been employed clinically. Endothelial cells are highly anti-thrombotic. Neo-endothelial cell damage is considered to be caused by friction between the cells and stent struts due to the thin neointima between them which might act as a cushion. Therefore, development of a DES that causes an appropriate thickness (around 100 μm) of the neointima is a potential option with which to prevent neo-endothelial cell damage and consequent LST while preventing restenosis.

  7. Role of the Renin–Angiotensin System in the Pathogenesis of Intimal Hyperplasia: Therapeutic Potential for Prevention of Vein Graft Failure?

    PubMed Central

    Osgood, Michael J.; Harrison, David G.; Sexton, Kevin W.; Hocking, Kyle M.; Voskresensky, Igor V.; Komalavilas, Padmini; Cheung-Flynn, Joyce; Guzman, Raul J.; Brophy, Colleen M.

    2014-01-01

    The saphenous vein remains the most widely used conduit for peripheral and coronary revascularization despite a high rate of vein graft failure. The most common cause of vein graft failure is intimal hyperplasia. No agents have been proven to be successful for the prevention of intimal hyperplasia in human subjects. The rennin–angiotensin system is essential in the regulation of vascular tone and blood pressure in physiologic conditions. However, this system mediates cardiovascular remodeling in pathophysiologic states. Angiotensin II is becoming increasingly recognized as a potential mediator of intimal hyperplasia. Drugs modulating the renin–angiotensin system include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs are powerful inhibitors of atherosclerosis and cardiovascular remodeling, and they are first-line agents for management of several medical conditions based on class I evidence that they delay progression of cardiovascular disease and improve survival. Several experimental models have demonstrated that these agents are capable of inhibiting intimal hyperplasia. However, there are no data supporting their role in prevention of intimal hyperplasia in patients with vein grafts. This review summarizes the physiology of the rennin–angiotensin system, the role of angiotensin II in the pathogenesis of cardiovascular remodeling, the medical indications for these agents, and the experimental data supporting an important role of the rennin–angiotensin system in the pathogenesis of intimal hyperplasia. PMID:22445245

  8. Tongxinluo inhibits neointimal formation by regulating the expression and post-translational modification of KLF5 in macrophages

    PubMed Central

    Jiang, Wen; Zheng, Bin; Zhang, Xin-Hua; Yue, Ling-Yan; Liu, Chan; Ma, Dong; Yang, Zhan; Wen, Jin-Kun

    2016-01-01

    Neointimal hyperplasia is a common pathological characteristic in diverse vascular remodeling diseases. The inflammatory response that follows vascular injury plays an important role in intimal hyperplasia. Tongxinluo (TXL), a traditional Chinese medicine, can ameliorate neointimal formation via suppressing vascular inflammatory response induced by vascular injury. However, the mechanisms underlying anti-inflammatory and anti-intimal hyperplasia of TXL are still not fully understood. The aim of present study was to examine whether the expression and post-translational modification of KLF5 were involved in the vasoprotective effects of TXL. In vivo, TXL inhibited neointimal formation induced by carotid artery injury. In vitro, TNF-α treatment of macrophages resulted in the increased proliferation and migration, but the effects of TNF-α on macrophages were blocked by TXL treatment. Next, KLF5 expression was up-regulated by carotid artery injury in vivo, as well as by exposure of macrophages to TNF-α in vitro, whereas TXL treatment abrogated the up-regulation of KLF5 by TNF-α or vascular injury. Intimal hyperplasia was strongly reduced in macrophage-specific KLF5 knockout (KLF5ly-/-) mice, indicating that TXL inhibits intimal hyperplasia by suppression of KLF5 expression. Furthermore, besides down-regulating KLF5 expression in macrophages, TXL also regulated KLF5 stability by ubiquitination and sumoylation of KLF5. Finally, TNF-α induced KLF5 sumoylation via PI3K/Akt signaling, whereas TXL inhibited Akt phosphorylation induced by TNF-α. We conclude that the multiple ingredients in TXL may act on different targets, which in turn generates a range of actions that manifest as a comprehensively vasoprotective effect. PMID:27904679

  9. Preventing Progression in Men with Mild Symptoms of Benign Prostatic Hyperplasia: A Potential Role for Phytotherapy

    PubMed Central

    Fong, Yan Kit; Marihart, Sibylle; Harik, Mike; Djavan, Bob

    2004-01-01

    Prevalence of benign prostate hyperplasia (BPH) is increasing with the aging population worldwide. Throughout the 20th century, men with minimally symptomatic BPH were generally advised to defer treatment. Treatment deferral or watchful waiting has always appeared reasonable because mild lower urinary tract symptoms suggestive of bladder outlet obstruction are not bothersome and are often regarded as part of the aging process, progression is usually slow, and symptoms often regress spontaneously. This review examines the evidence of the natural history of BPH, highlighting the group of patients with mild symptoms, the risk factors for progression, and the potential role of phytotherapy in this group of men. PMID:16985600

  10. Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model.

    PubMed

    Kipshidze, Nicholas N; Kim, Han Soo; Iversen, Patrick; Yazdi, Hamid A; Bhargava, Balram; New, Gishel; Mehran, Roxana; Tio, Fermin; Haudenschild, Christian; Dangas, George; Stone, Gregg W; Iyer, Sriram; Roubin, Gary S; Leon, Martin B; Moses, Jeffrey W

    2002-05-15

    We evaluated the long-term influence of intramural delivery of advanced c-myc neutrally charged antisense oligonucleotides (Resten-NG) on neointimal hyperplasia after stenting in a pig model. Neointimal hyperplasia after percutaneous coronary interventions is one of the key components of the restenotic process. The c-myc is a critical cell division cycle protein involved in the formation of neointima. In short-term experiments, different doses (from 500 microg to 5 mg) of Resten-NG or saline were delivered to the stent implantation site with an infiltrator delivery system (Interventional Technologies, San Diego, California). Animals were euthanized at 2, 6 and 18 h after interventions, and excised vessels were analyzed for c-myc expression by Western blot. In long-term experiments, either saline or a dose of 1, 5 or 10 mg of Resten-NG was delivered in the same fashion, and animals were euthanized at 28 days after the intervention. Western blot analysis demonstrated inhibition of c-myc expression and was dose dependent. Morphometry showed that the intimal area was 3.88 +/- 1.04 mm(2) in the control. There was statistically significant reduction of intimal areas in the 5 and 10 mg groups (2.01 +/- 0.66 and 1.95 +/- 0.91, respectively, p < 0.001) but no significant reduction in the 1 mg group (2.81 +/- 0.56, p > 0.5) in comparison with control. This study demonstrated that intramural delivery of advanced c-myc neutrally charged antisense morpholino compound completely inhibits c-myc expression and dramatically reduces neointimal formation in a dose dependent fashion in a porcine coronary stent restenosis model, while allowing for complete vascular healing.

  11. Preventive effect of Pueraria mirifica on testosterone-induced prostatic hyperplasia in Sprague Dawley rats.

    PubMed

    Masrudin, S S; Mohamad, J

    2015-12-01

    Pueraria mirifica (PM) extract contains phytoestrogen daidzein and genistein. In this study, we investigated the protective effect of PM extract, daidzein and genistein on a testosterone-induced prostatic hyperplasia in rats. Testosterone was administered at 3 mg kg(-1) to rats followed by the PM extract, daidzein and genistein for a period of 30 days with finasteride as positive control. The testosterone level was increased, indicating inhibition of 5α-reductase converting testosterone to dihydrotestosterone. This was confirmed by prostate-specific antigen level that significantly decreased when treated with PM extract, daidzein and genistein. The PM extract, daidzein and genistein reduced the increase in the prostate/body weight ratio in testosterone-induced rats. This gives indication that PM extract, daidzein and genistein possessed protective activity for the treatment of benign prostatic hyperplasia. The analysis of histoarchitechture of the prostate has also shown that there was a significant improvement in prostatic cells of the testosterone-induced rats when treated with PM extract, daidzein and genistein.

  12. A successful experimental model for intimal hyperplasia prevention using a resveratrol-delivering balloon.

    PubMed

    Tolva, Valerio; Mazzola, Silvia; Zerbi, Pietro; Casana, Renato; Albertini, Mariangela; Calvillo, Laura; Selmin, Francesca; Cilurzo, Francesco

    2016-03-01

    Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. Resveratrol (RSV) has demonstrated a beneficial effect on restenosis from angioplasty. Unfortunately, the physicochemical characteristics of RSV reduce the practicality of its immediate clinical application. This work proposes an experimental model aiming to setup an intravessel, elutable, RSV-containing compound. A 140 μg/mL RSV sterile injectable solution with a suitable viscosity for intravascular administration by drug-delivery catheter (RSV-c) was prepared. This solution was locally administered in the common iliac artery of adult male New Zealand White rabbits using a dedicated device (Genie; Acrostak, Geneva, Switzerland) after the induction of intimal hyperplasia by traumatic angioplasty. The RSV concentrations in the wall artery were determined, and the thickness of the harvested iliac arteries was measured over a 1-month period. The Genie catheter was applied in rabbit vessels, and the local delivery resulted in an effective reduction in restenosis after plain angioplasty. Notably, RSV-c forced into the artery wall by balloon expansion might accumulate in the interstitial areas or within cells, avoiding the washout of solutions. Magnification micrographs showed intimal proliferation was significantly inhibited when RSV-c was applied. Moreover, no adverse events were documented in in vitro or in vivo studies. RSV can be advantageously administered in the arterial walls by a drug-delivery catheter to reduce the risk of restenosis. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  13. Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61.

    PubMed

    Hao, Feng; Zhang, Fuqiang; Wu, Daniel Dongwei; An, Dong; Shi, Jing; Li, Guohong; Xu, Xuemin; Cui, Mei-Zhen

    2016-12-01

    Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA1-/-, LPA2-/-, and LPA3-/-) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA1 deficiency, but not LPA2 or LPA3 deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1 deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1 is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA1-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention. Copyright © 2016 the American Physiological Society.

  14. Lymphofollicular hyperplasia

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001377.htm Lymphofollicular hyperplasia To use the sharing features on this page, please enable JavaScript. Lymphofollicular hyperplasia is an increase in the size of the ...

  15. Contribution of Vascular Cells to Neointimal Formation

    PubMed Central

    Yuan, Falei; Wang, Dong; Xu, Kang; Wang, Jixian; Zhang, Zhijun; Yang, Li; Yang, Guo-Yuan; Li, Song

    2017-01-01

    The de-differentiation and proliferation of smooth muscle cells (SMCs) are widely accepted as the major contributor to vascular remodeling. However, recent studies indicate that vascular stem cells (VSCs) also play an important role, but their relative contribution remains to be elucidated. In this study, we used genetic lineage tracing approach to further investigate the contribution of SMCs and VSCs to neointimal thickening in response to endothelium denudation injury or artery ligation. In vitro and in vivo analysis of MYH11-cre/Rosa-loxP-RFP mouse artery showed that SMCs proliferated at a much slower rate than non-SMCs. Upon denudation or ligation injury, two distinct types of neointima were identified: Type-I neointimal cells mainly involved SMCs, while Type II mainly involved non-SMCs. Using Sox10-cre/Rosa-loxP-LacZ mice, we found that Sox10+ cells were one of the cell sources in neointima. In addition, lineage tracing using Tie2-cre/Rosa-LoxP-RFP showed that endothelial cells also contributed to the neointimal formation, but rarely transdifferentiated into mesenchymal lineages. These results provide a novel insight into the contribution of vascular cells to neointima formation, and have significant impact on the development of more effective therapies that target specific vascular cell types. PMID:28060852

  16. Metabolic Syndrome and Benign Prostatic Hyperplasia: Evidence of a Potential Relationship, Hypothesized Etiology, and Prevention

    PubMed Central

    Briganti, Alberto; Suardi, Nazareno; Castiglione, Fabio; Gallina, Andrea; Capitanio, Umberto; Montorsi, Francesco

    2011-01-01

    Benign prostatic hyperplasia (BPH) is highly prevalent in older men and causes substantial adverse effects on health. The pathogenesis of this disease is not totally clear. Recent reports have suggested a possible relationship between metabolic syndrome (MetS) and BPH. Single components of MetS (obesity, dyslipidemia, hypertension, and insulin resistance) as well as the syndrome itself may predispose patients to a higher risk of BPH and lower urinary tract symptoms (LUTS). This may stem from changes in insulin resistance, increased autonomic activity, impaired nitrergic innervation, increased Rho kinase activity, pro-inflammatory status, and changes in sex hormones that occur in association with MetS. However, the exact underlying mechanisms that regulate the potential relationship between MetS and BPH/LUTS still need to be clarified. Increased physical activity and dietary strategies may help in decreasing the incidence of MetS and its impact on BPH/LUTS. However, differences in the definitions used to address the examined predictors and endpoints preclude the possibility of arriving at definitive conclusions. PMID:21927696

  17. Preventing female virilisation in congenital adrenal hyperplasia: The controversial role of antenatal dexamethasone.

    PubMed

    Heland, Sarah; Hewitt, Jacqueline K; McGillivray, George; Walker, Susan P

    2016-06-01

    Congenital adrenal hyperplasia (CAH) refers to a group of recessively inherited disorders of cortisol production, which in the classical form results in virilisation of female fetuses. Since the 1980s, antenatal treatment with dexamethasone has been recommended in high-risk pregnancies to minimise the risk of virilising the female genitalia of affected fetuses. To be effective, this treatment requires implementation in early pregnancy, prior to the commencement of autonomous fetal adrenal androgen synthesis. Using this approach, seven of eight high-risk pregnancies are treated unnecessarily, prior to establishing the fetal gender or the confirmed diagnosis of a genetically affected pregnancy. In the face of ongoing concerns regarding potential adverse maternal-fetal effects of antenatal dexamethasone exposure, a review of this practice has been advocated by expert advisory groups. In this review, we summarise current controversies, potential improvements and future directions in the management of pregnancies at risk of CAH. In high-risk families, recent genomic advances include early prenatal diagnosis utilising noninvasive genetic techniques to minimise unnecessary dexamethasone exposure to unaffected fetuses. In affected pregnancies when families elect for antenatal treatment, optimal antenatal dosing regimens need to be defined and a standardised treatment and follow-up protocol are recommended. Establishment of a national registry with standardised follow-up will allow future families to be better informed of the risks and benefits of both treated and untreated fetal CAH.

  18. The prevention and treatment effects of tanshinone IIA on oestrogen/androgen-induced benign prostatic hyperplasia in rats.

    PubMed

    Wang, Chao; Du, Xiaoling; Yang, Rui; Liu, Jie; Xu, Da; Shi, Jiandang; Chen, Linfeng; Shao, Rui; Fan, Guanwei; Gao, Xiumei; Tian, Guo; Zhu, Yan; Zhang, Ju

    2015-01-01

    Benign prostatic hyperplasia (BPH) is one of the major diseases of the urinary system in elderly men. Tanshinone IIA (Tan IIA) is the active ingredient extracted from the traditional Chinese medicine Salvia, and it has effects of anti-oxidation, anti-inflammation, vascular smooth muscle relaxation and tumour growth inhibition. The present study aimed to investigate the therapeutic potential of Tan IIA in the prevention and treatment of BPH. In a rat model of oestradiol/testosterone-induced BPH, Tan IIA inhibited the increase in the thickness of the peri-glandular smooth muscle layer, suppressed the expression of proliferating cell nuclear antigen (PCNA) in both prostate epithelial cells and stromal cells, downregulated the expression of androgen receptor (AR), oestrogen receptor α (ERα), cyclin B1 (CCNB1) and cyclin D1 (CCND1), and effectively prevented the development of the disorder. In vitro, Tan IIA inhibited the proliferation of human prostate stromal cell line WPMY-1 and epithelial cell line RWPE-1 in a dose- and time-dependent manner. In WPMY-1 cells, Tan IIA treatment arrested the cell cycle at the G2/M phase and downregulated the expression of CCNB1. However, in RWPE-1 cells, Tan IIA treatment arrested cell cycle at the G0/G1 phase and reduced the expression of CCND1. Tan IIA also reduced the expression of ERα and AR in WPMY-1 and RWPE-1 cells. These results suggest that Tan IIA can inhibit the growth of prostate stromal and epithelial cells both in vivo and in vitro by a mechanism that may involve arresting the cell cycle and downregulating ERα and AR expression.

  19. Inhibition of vein graft intimal hyperplasia by periadventitial application of hyaluronic acid-carboxymethyl cellulose: an experimental study.

    PubMed

    Bahcivan, Muzaffer; Yucel, Semih; Kefeli, Mehmet; Gol, M Kamil; Can, Bilge; Keceligil, Hasan Tahsin

    2008-04-01

    Placement of an external support has been reported to prevent intimal hyperplasia of vein grafts. In this study, we investigated the effect of HA/CMC on intimal hyperplasia in a rabbit model. Right jugular vein to common carotid artery bypass grafting was performed in 24 female New Zealand white rabbits (2.5-3.0 kg). Animals were divided into two groups: control group (n=12) and HA/CMC group (n=12). Absorbable membrane barrier was wrapped around vein grafts in HA/CMC group. In control group, no material was applied following venous graft bypass. At 1 month, in the vein grafts supported with the HA/CMC membrane neointimal thickening was significantly less (109 microm [IQR, 78-166]) compared to the unsupported control grafts (220 microm [IQR; 101-312]; p<0.001). Medial thickening in the HA/CMC group (128 microm [IQR, 101-181]) compared to unsheathed control grafts (182 microm [IQR, 131-255] p<0.001) was also significantly less. Periadventitial placement of HA/CMC as an absorbable membrane inhibits intimal hyperplasia of vein bypass grafts in a rabbit model.

  20. Inhibition of neointimal formation by trans-resveratrol: role of phosphatidyl inositol 3-kinase-dependent Nrf2 activation in heme oxygenase-1 induction.

    PubMed

    Kim, Jung Woo; Lim, Sung Chul; Lee, Moo Yeol; Lee, Jeong Woon; Oh, Won Keun; Kim, Sang Kyum; Kang, Keon Wook

    2010-10-01

    Neointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitory effects on proliferation and migration of vascular smooth muscle cells has been reported, its activity on neointimal formation is still unclear. Oral administration of trans-resveratrol significantly suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. In cultured vascular smooth muscle cells, trans-resveratrol inhibited platelet-derived growth factor-stimulated DNA synthesis and cell proliferation with down-regulation of cyclin D and pRB. Moreover, platelet-derived growth factor-induced production of reactive oxygen species was inhibited by trans-resveratrol and the compound induced heme oxygenase-1 (HO-1). The anti-proliferative activity of trans-resveratrol was reversed by an HO-1 inhibitor, ZnPPIX. Subcellular fractionation and reporter gene analyses revealed that trans-resveratrol increased the level of nuclear Nrf2 and antioxidant response element reporter activity, and that these were essential for the induction of HO-1. Trans-resveratrol also enhanced the activities of phosphatidyl inositol 3-kinase and extracellular signal regulated kinase, and phosphatidyl inositol 3-kinase was required for Nrf2/antioxidant response element-dependent HO-1 induction. These data have significant implications for the elucidation of the pharmacological mechanism by which trans-resveratrol prevents vascular occlusive diseases.

  1. Inhibition of cell surface expression of endothelial adhesion molecules by ursolic acid prevents intimal hyperplasia of venous bypass grafts in rats

    PubMed Central

    Zeller, Iris; Wiedemann, Dominik; Schwaiger, Stefan; Stelzmüller, Marlies; Kreutmayer, Simone; Leberfing, Oliver; Stuppner, Hermann; Bernhard, David

    2012-01-01

    OBJECTIVES Despite rapid progress in surgical techniques, there is still a significant lack of surgery-supportive pharmacological treatments. The aim of this study was to test the hypothesis that ursolic acid (UA) may prevent intimal hyperplasia of venous bypass grafts. METHODS The hypothesis was tested by means of primary cell isolation and culture followed by real-time polymerase chain reaction, western blotting, fluorescence microscopy and fluorescence-activated cell sorting analyses, as well as an in vivo rat model for intimal hyperplasia of venous bypass grafts and immunohistochemistry and histochemistry. RESULTS The local application of UA significantly inhibited intimal hyperplasia in vivo (intimal thickness control: 25 μm, UA group: 18 μM–8 weeks after surgery). The UA treatment of grafts significantly resulted in reduced endothelial vascular cell adhesion molecule-1 (VCAM-1) expression, reduced infiltration of the grafts vessel wall by CD45-positive cells and increased smooth muscle cell (SMC) death. In in vitro condition, it could be shown that UA inhibits VCAM-1 expression downstream of NFκB and is likely to interfere with VCAM-1 protein synthesis in endothelial cells. Quantification of cell death in vascular smooth muscle cells treated with UA indicated that UA is a potent inducer of SMC apoptosis. CONCLUSIONS Our results suggest that UA-mediated inhibition of endothelial VCAM-1 expression reduces the infiltration of venous bypass grafts by CD45-positive cells and inhibits intimal hyperplasia. Apoptosis induction in SMCs may be another method in which UA reduces intimal thickening. UA may constitute a surgery-supportive pharmacon that reduces intimal hyperplasia of vein grafts. PMID:22551965

  2. Endometrial Hyperplasia

    MedlinePlus

    ... menopause (in women who have not had a hysterectomy ) Irregular menstrual periods, especially associated with polycystic ovary ... atypical hyperplasia, the risk of cancer is increased. Hysterectomy usually is the best treatment option if you ...

  3. Preventive effects of D-004, a lipid extract from Cuban royal palm (Roystonea regia) fruits, on testosterone-induced prostate hyperplasia in intact and castrated rodents.

    PubMed

    Arruzazabala, M L; Carbajal, D; Más, R; Molina, V; Rodríguez, E; González, V

    2004-01-01

    Benign prostatic hyperplasia (BPH) is the noncancerous, uncontrolled growth of prostate gland cells and stroma that can cause difficulty urinating. Fruit lipid extracts from saw palmetto, a palm from the Arecaceae family, are used for BPH management. The Cuban royal palm, Roystonea regia, is also a member of the Arecaceae family and therefore it was appropriate to investigate the protective effects of Roystonea regia fruit lipid extracts on prostatic hyperplasia. The aim of this study was to investigate whether D-004, a lipid extract from Roystonea regia fruits, prevented testosterone-induced PH in castrated and intact rodents. Two series of experiments were performed. The first one was conducted in castrated and intact rats, distributed into five groups of 10 rats per group. The negative control group was injected with soy oil and treated orally with vehicle, while the four testosterone-injected groups were treated with vehicle (positive control), D-004 100, 200 and 400 mg/kg, respectively. The other experiment was conducted in castrated and intact mice. These were distributed into four groups of 10 mice per group: a negative control group and three testosterone-injected groups, of which one was a positive control, while two received D-004 200 and 400 mg/kg, respectively. At study completion, the rodents were sacrificed and prostates removed and weighed. D-004 at doses of 100, 200 and 400 mg/kg significantly and dose-dependently prevented prostate enlargement in intact and castrated rats and mice. The percentage inhibitions obtained in mice were greater: 77% and 84% for intact and castrated mice, respectively. D-004 therapy did not affect body weight. It is concluded that D-004 administered orally significantly prevented testosterone-induced prostate enlargement in both intact and castrated rodents, indicating that an endogenous supply of testosterone is not necessary to observe such an effect The results of the present investigation support further studies of D

  4. Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction.

    PubMed

    See, Vincent Y; DeNofrio, David; Goldberg, Lee; Chang, Gene; Sasseen, Brett; Kolansky, Daniel M; Pickering, Faith; Kao, Andrew; Loh, Evan; Wilensky, Robert L

    2003-07-01

    Following cardiac transplantation, accelerated coronary disease limits long-term survival. Because statins may reduce the progression of the disease in part by their anti-inflammatory effects, this study was designed to assess if atorvastatin prevented neointimal hyperplasia and endothelial dysfunction independently of baseline cholesterol levels. Patients were randomized to usual therapy (n = 13) or to 10 to 20 mg of atorvastatin (n = 12). Control subjects received niacin when their low-density lipoprotein (LDL) cholesterol levels were >130 mg/dl (n = 4). Neointimal hyperplasia by intracoronary ultrasonography, endothelial dependent vascular reactivity, and coronary flow reserve were measured at baseline and 1 year. Control group total cholesterol (203 +/- 11 to 200 +/- 13 mg/dl) and LDL (116 +/- 10 to 119 +/- 11 mg/dl) remained stable, whereas there was a nonsignificant reduction at 12 months in the atorvastatin group (total cholesterol 216 +/- 28 to 178 +/- 21 mg/dl; LDL 126 +/- 17 to 100 +/- 18 mg/dl). At 2 to 3 months there was a significant increase in total cholesterol and LDL cholesterol that was reduced with atorvastatin. At 1 year, patients taking atorvastatin showed a decrease in new or progressing lesions (2.5 +/- 1.7 vs 4.2 +/- 1.8 lesions/patient, p = 0.02), progression of maximal intimal thickness (0.12 +/- 0.07 vs 0.52 +/- 0.17 mm, p = 0.04), and percent area stenosis (5.9 +/- 2.2% vs 19.0 +/- 5.5%, p = 0.04). Atorvastatin ameliorated progressive endothelial dysfunction, whereas coronary flow reserve was unchanged in both groups. Atorvastatin administered to patients with normal or mild hypercholesterolemia in the initial year after transplant reduced the initial increase in LDL cholesterol, and, by doing so, prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels.

  5. Effect on Intimal Hyperplasia of Dexamethasone Released from Coated Metal Stents Compared with Non-Coated Stents in Canine Femoral Arteries

    SciTech Connect

    Strecker, Ernst-Peter; Gabelmann, Andreas; Boos, Irene; Lucas, Christopher; Xu, Zhongying; Haberstroh, Joerg; Freudenberg, Nicolaus; Stricker, Helmut; Langer, Mathias; Betz, Eberhard

    1998-11-15

    Purpose: Polymer-coated, dexamethasone (DXM)-releasing stents were tested in order to assess the efficacy of DXM released locally for the prevention of stent restenosis due to intimal hyperplasia. Methods: Strecker stents coated with a biodegradable membrane containing DXM were implanted percutaneously into the femoral artery in 14 dogs. The contralateral artery received a conventional non-coated stent serving as control. The drugs are eluted by degradation of the carrier membrane. Follow-up intraarterial digital subtraction angiography (DSA) was obtained at 3, 6, 9, 12, and 24 weeks with subsequent autopsy. Specimens for gross and microscopic pathology were obtained and histomorphometry was performed. Results: Four of 14 DXM-coated stents showed thrombotic occlusion within the first 3 weeks; ten DXM-coated stents remained patent. At follow-up DSA, DXM-coated stents showed a significantly wider lumen than the non-coated stents. At morphometry there was less intimal hyperplasia over DXM-coated stents than over non-coated stents (p < 0.05). Conclusion: DXM-coated stents reduce neointimal hyperplasia in dogs when compared with non-coated stents.

  6. Efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the prevention of the atypical endometrial hyperplasia and endometrial cancer: retrospective data from selected obese menopausal symptomatic women.

    PubMed

    Morelli, Michele; Di Cello, Annalisa; Venturella, Roberta; Mocciaro, Rita; D'Alessandro, Pietro; Zullo, Fulvio

    2013-02-01

    The aim of this retrospective study was to evaluate the efficacy of levonorgestrel intrauterine system-releasing (LNG-IUS) insertion in preventing atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in symptomatic postmenopausal overweight/obese women. A total of 34 overweight/obese postmenopausal women, presenting abnormal uterine bleeding (AUB) and endometrial hyperplasia (EH), and who were submitted to LNG-IUS insertion, were identified from registry data. Endometrial histology at LNG-IUS insertion showed simple EH in 20 cases (58.8%), complex EH in 14 cases (41.2%). At 36 months, 91% of patients showed no recurrence of AUB and a significant reduction in the mean endometrial thickness (from 8.2 ± 2.2 to 3.2 ± 1.5 mm, p < 0.05) was observed. Histologic regression of EH was observed in 27 (79.4%) and 33 (97.5%) cases at 12 and 36 months, respectively. None of the women in which EH persisted, reported cellular atypia or cancer progression at 12 and 36 months of follow-up. LNG-IUS represents an effective treatment option to manage postmenopausal obese women affected by AUB and EH. The device seems to be able to prevent the onset of AH and EC in women at high risk. Further prospective controlled studies in a well selected group of women are needed.

  7. [Congenital Adrenal Hyperplasia in Adults].

    PubMed

    Vrbíková, Jana

    2016-01-01

    Congenital adrenal hyperplasia is a life-long disease requiring an integrated therapy. It may negatively influence the quality of life. In childhood, the main problems of the care of these patients involve sex determination and ensuring optimum growth and puberty. The therapeutic goals for adults are the prevention of Addisonian crisis and ensuring the best possible quality of life, including fertility.Key words: androgens - cardiovascular risk - congenital adrenal hyperplasia - bone density - testicular rest tumors.

  8. Endometrial hyperplasia.

    PubMed

    Mills, Anne M; Longacre, Teri A

    2010-11-01

    Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification.

  9. Hyperplasia (Ductal or Lobular)

    MedlinePlus

    ... is also known as epithelial hyperplasia or proliferative breast disease. It’s an overgrowth of the cells that line the ducts or the milk glands (lobules). Hyperplasia may be called either ductal hyperplasia ( ...

  10. Involvement of c-Jun NH2 terminal kinase and p38MAPK in rapamycin-mediated inhibition of neointimal formation in rat carotid arteries.

    PubMed

    Omura, Takashi; Yoshiyama, Minoru; Izumi, Yasukatsu; Kim, Shokei; Matsumoto, Ryo; Enomoto, Soichiro; Kusuyama, Takanori; Nishiya, Daisuke; Nakamura, Yasuhiro; Akioka, Kaname; Iwao, Hiroshi; Takeuchi, Kazuhide; Yoshikawa, Junichi

    2005-10-01

    Rapamycin-coated stents in coronary artery lesions have recently been shown to be effective in inhibiting neointimal formation. However, little is known about the effects of rapamycin on mitogen-activated protein kinase (MAPK), which is an important signal for neointimal formation. Therefore, we examined the effects of rapamycin on MAPK and transcriptional factors in cultured human coronary artery smooth muscle cells (CASMC) and in balloon-injured rat carotid arteries. Activation of ERK, JNK, p38MAPK, AP-1, and NF-kB in coronary artery smooth muscle cells was increased by 2% fetal bovine serum. Ten nmol/L of rapamycin prevented the activation of JNK, p38MAPK, AP-1, and NF-kB (65%, 65%, 67%, and 26% respectively, P<0.01). In an in vivo study, remarkable neointimal formation was observed 14 days after injury. Coating Pluronic gel with 20 and 50 mug rapamycin around the injured artery significantly decreased the intimal area/medial area ratio, compared with vehicle (0.75 vs. 1.2, P<0.01). Rapamycin prevented the increase in activation of JNK, p38MAPK, AP-1, and NF-kB in injured artery (42%, 70%, 75%, and 60% respectively, P<0.05). Neointimal formation after balloon injury is inhibited by rapamycin, which is partially mediated by inhibition of JNK and p38MAPK, followed by AP-1 and NF-kB.

  11. Crucial Role of Hyaluronan in Neointimal Formation after Vascular Injury

    PubMed Central

    Kashima, Yuichiro; Takahashi, Masafumi; Shiba, Yuji; Itano, Naoki; Izawa, Atsushi; Koyama, Jun; Nakayama, Jun; Taniguchi, Shun'ichiro; Kimata, Koji; Ikeda, Uichi

    2013-01-01

    Background Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy. Methods and Results HA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced VSMC activation, including migration, proliferation, and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22α mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22α mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS. Conclusion VSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease. PMID:23484050

  12. Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury

    SciTech Connect

    Shishido, Tetsuro . E-mail: Tetsuro_Shishido@URMC.Rochester.edu; Nozaki, Naoki; Takahashi, Hiroki; Arimoto, Takanori; Niizeki, Takeshi; Koyama, Yo; Abe, Jun-ichi; Takeishi, Yasuchika; Kubota, Isao

    2006-07-14

    Background: It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo. Methods and results: Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-{alpha}, interleukin-1{beta} (IL-1{beta}), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury. Conclusions: These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.

  13. Chronic in vitro shear stress stimulates endothelial cell retention on prosthetic vascular grafts and reduces subsequent in vivo neointimal thickness.

    PubMed

    Dardik, A; Liu, A; Ballermann, B J

    1999-01-01

    The absence of endothelial cells at the luminal surface of a prosthetic vascular graft potentiates thrombosis and neointimal hyperplasia, which are common causes of graft failure in humans. This study tested the hypothesis that pretreatment with chronic in vitro shear stress enhances subsequent endothelial cell retention on vascular grafts implanted in vivo. Cultured endothelial cells derived from Fischer 344 rat aorta were seeded onto the luminal surface of 1.5-mm internal diameter polyurethane vascular grafts. The seeded grafts were treated for 3 days with 1 dyne/cm2 shear stress and then for an additional 3 days with 1 or 25 dyne/cm2 shear stress in vitro. The grafts then were implanted as aortic interposition grafts into syngeneic rats in vivo. Grafts that were similarly seeded with endothelial cells but not treated with shear stress and grafts that were not seeded with endothelial cells served as controls. The surgical hemostasis time was monitored. Endothelial cell identity, density, and graft patency rate were evaluated 24 hours after implantation. Endothelial cell identity in vivo was confirmed with cells transduced in vitro with beta-galactosidase complementary DNA in a replication-deficient adenoviral vector. Histologic, scanning electron microscopic, and immunohistochemical analyses were performed 1 week and 3 months after implantation to establish cell identity and to measure neointimal thickness. The pretreatment with 25 dyne/cm2 but not with 0 or 1 dyne/cm2 shear stress resulted in the retention of fully confluent endothelial cell monolayers on the grafts 24 hours after implantation in vivo. Retention of seeded endothelial cells was confirmed by the observation that beta-galactosidase transduced cells were retained as a monolayer 24 hours after implantation in vivo. In the grafts with adherent endothelial cells that were pretreated with shear stress, immediate graft thrombosis was inhibited and surgical hemostasis time was significantly prolonged

  14. Effect of drug-coated balloon on stent restenosis, neointimal proliferation, and coronary dissection: an optical coherence tomography analysis.

    PubMed

    Fukushima, Taku; Ashikaga, Takashi; Yoshikawa, Shunji; Hatano, Yu; Ueshima, Daisuke; Yamamoto, Takanobu; Yasuhiro, Maejima; Isobe, Mitsuaki

    2017-09-11

    The aim of this study was to assess the acute and mid-term effects of drug-coated balloon (DCB) in terms of the healing process of non-flow-limiting dissections and changes in the neointimal area after DCB treatment using frequency domain optical coherence tomography (FD-OCT). Thirty-six consecutive patients with in-stent restenosis pretreated with a scoring balloon were evaluated (19 and 17 patients with and without a DCB, respectively). FD-OCT was performed before and after each procedure during percutaneous coronary intervention and at 6 months of follow-up. Clinical characteristics and baseline FD-OCT findings were comparable between the two groups. No patient required stent implantation because of low-pressure DCB-related dissections. In the acute phase, the DCB distributed paclitaxel to the vessel wall without increasing dissections. The DCB did not reduce the neointimal area by itself. At 6 months, more dissections healed in the DCB group (-4.5±2.3 vs. -2.7±1.3, P=0.02). The DCB group showed less change in the neointimal area (-0.04±0.92 vs. 1.06±1.57 mm, P=0.03). The low-pressure DCB was not intended to expand the lumen, but instead to attach paclitaxel to the vessel wall by using FD-OCT examination. The DCB reduced the number of dissections and prevented neointimal proliferation during the mid-term follow-up.

  15. Gene Therapy Inhibiting Neointimal Vascular Lesion: In vivo Transfer of Endothelial Cell Nitric Oxide Synthase Gene

    NASA Astrophysics Data System (ADS)

    von der Leyen, Heiko E.; Gibbons, Gary H.; Morishita, Ryuichi; Lewis, Neil P.; Zhang, Lunan; Nakajima, Masatoshi; Kaneda, Yasufumi; Cooke, John P.; Dzau, Victor J.

    1995-02-01

    It is postulated that vascular disease involves a disturbance in the homeostatic balance of factors regulating vascular tone and structure. Recent developments in gene transfer techniques have emerged as an exciting therapeutic option to treat vascular disease. Several studies have established the feasibility of direct in vivo gene transfer into the vasculature by using reporter genes such as β-galactosidase or luciferase. To date no study has documented therapeutic effects with in vivo gene transfer of a cDNA encoding a functional enzyme. This study tests the hypothesis that endothelium-derived nitric oxide is an endogenous inhibitor of vascular lesion formation. After denudation by balloon injury of the endothelium of rat carotid arteries, we restored endothelial cell nitric oxide synthase (ec-NOS) expression in the vessel wall by using the highly efficient Sendai virus/liposome in vivo gene transfer technique. ec-NOS gene transfection not only restored NO production to levels seen in normal untreated vessels but also increased vascular reactivity of the injured vessel. Neointima formation at day 14 after balloon injury was inhibited by 70%. These findings provide direct evidence that NO is an endogenous inhibitor of vascular lesion formation in vivo (by inhibiting smooth muscle cell proliferation and migration) and suggest the possibility of ec-NOS transfection as a potential therapeutic approach to treat neointimal hyperplasia.

  16. Favorable effect of optimal lipid-lowering therapy on neointimal tissue characteristics after drug-eluting stent implantation: qualitative optical coherence tomographic analysis.

    PubMed

    Jang, Ji-Yong; Kim, Jung-Sun; Shin, Dong-Ho; Kim, Byeong-Keuk; Ko, Young-Guk; Choi, Donghoon; Jang, Yangsoo; Hong, Myeong-Ki

    2015-10-01

    Serial follow-up optical coherence tomography (OCT) was used to evaluate the effect of optimal lipid-lowering therapy on qualitative changes in neointimal tissue characteristics after drug-eluting stent (DES) implantation. DES-treated patients (n = 218) who received statin therapy were examined with serial follow-up OCT. First and second follow-up OCT evaluations were performed approximately 6 and 18 months after the index procedure, respectively. Patients were divided into two groups, based on the level of low-density lipoprotein-cholesterol (LDL-C), which was measured at the second follow-up. The optimal lipid-lowering group (n = 121) had an LDL-C reduction of ≥50% or an LDL-C level ≤70 mg/dL, and the conventional group (n = 97). Neointimal characteristics were qualitatively categorized as homogeneous or non-homogeneous patterns using OCT. The non-homogeneous group included heterogeneous, layered, or neoatherosclerosis patterns. Qualitative changes in neointimal tissue characteristics between the first and second follow-up OCT examinations were assessed. Between the first and second follow-up OCT procedures, the neointimal cross-sectional area increased more substantially in the conventional group (0.4 mm(2) vs. 0.2 mm(2) in the optimal lipid-lowering group, p = 0.01). The neointimal pattern changed from homogeneous to non-homogeneous less often in the optimal lipid-lowering group (1.3%, 1/77, p < 0.001) than in the conventional group (15.3%, 11/72, p = 0.44). Optimal LDL-C reduction was an independent predictor for the prevention of neointimal pattern change from homogeneous to non-homogeneous (odds ratio: 0.05, 95% confidence interval: 0.01∼0.46, p = 0.008). Our findings suggest that an intensive reduction in LDL-C levels can prevent non-homogeneous changes in the neointima and increases in neointimal cross-sectional area compared with conventional LDL-C controls. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Verrucous Hyperplasia

    PubMed Central

    Grover, Sonal; Jha, Mihir; Sharma, Bhushan; Kapoor, Shekhar; Mittal, Kumud; Parakkat, Nithin K.; Shivappa, Anil B.; Kaur, Ravleen

    2017-01-01

    Verrucous hyperplasia (VH) is a rare exophytic oral mucosal lesion which can transform into verrucous carcinoma (VC), its malignant but clinically similar counterpart. These entities can be distinguished by the lack of invasive growth in VH cases; as such, it is essential to include a margin with adequate depth when performing a biopsy of the epithelium of the lesion. We report an 80-year-old male patient who presented to the Bapuji Dental College & Hospital, Davangere, Karanataka, India, in 2011 with a warty whitish-pink growth on the inside of his cheek. The patient was treated with wide surgical excision of the lesion and a diagnosis of VH was made based on histopathological features. There was no evidence of recurrence at a five-year follow-up. This report highlights the histological variations, pathogenesis and differential diagnosis of VH. PMID:28417036

  18. Design and Rationale of the PREVENT III Clinical Trial: Edifoligide for the Prevention of Infrainguinal Vein Graft Failure

    PubMed Central

    Conte, Michael S.; Lorenz, Todd J.; Bandyk, Dennis F.; Clowes, Alexander W.; Moneta, Gregory L.; Seely, B. Lynn

    2006-01-01

    Surgical bypass of peripheral arterial occlusive disease with autologous vein grafts provides an effective means of restoring blood flow to the lower extremity, and has been a standard therapy for patients with disabling claudication or critical limb ischemia (CLI). However, failure rates may run as high as 50% within 5 years. These graft failures occur as a result of neointimal hyperplasia, a ubiquitous biologic response of blood vessel walls to injury, which is characterized by the migration and proliferation of smooth muscle cells (SMC). The E2F family of transcription factors regulates the expression of genes controlling SMC proliferation. Edifoligide (E2F Decoy) is a novel therapy that inhibits E2F function, thus attenuating neointimal hyperplasia. Its use in conjunction with a patented drug delivery pressurization chamber is under investigation. Using this system, edifoligide is administered to vein grafts in a single, ex vivo treatment following vein harvest and before implantation, resulting in minimal systemic drug exposure and excellent patient compliance. This Phase 3, randomized, double-blind, multicenter clinical trial is designed to evaluate the safety and efficacy of edifoligide in a population of approximately 1400 patients with CLI undergoing infrainguinal bypass for peripheral arterial disease (PAD). The primary outcome measure will be the time to occurrence of non-technical graft failure resulting in either graft revision or major amputation at 12 months after enrollment. A governing Clinical Events Classification committee (CEC) will adjudicate each graft failure to determine its etiology. The PREVENT III trial is the largest multicenter trial ever performed in patients receiving autologous vein bypass grafts for CLI. This landmark study will determine if edifoligide is safe and effective at preventing vein graft failure in patients undergoing lower extremity bypass, but it also provides a unique opportunity to observe current treatment

  19. Suppression of neointimal hyperplasia by photodynamic therapy: in vitro and in vivo results

    NASA Astrophysics Data System (ADS)

    Sobeh, Mohammed S.; Chan, Philip; Greenwald, Stephen E.; Ham, Robert J.; Wood, Alan J.; Cross, Frank W.; Hsiang, York N.

    1994-07-01

    Proliferation of vascular smooth muscle cells (VSMCs) is the pathophysiogical basis of the restenoses which occur in 30-55% of patients undergone revascularisation. Prophylactic measures including pharmacotherapy, endovascular stenting and anti-gene therapy have so far failed to contain this problem. Photodynamic therapy (PDT) may selectively suppress VSMCs and decrease restenosis rates. We report 2 studies; the first examines the effect of PDT on an in-vitro model of NIH and the second involves using endoluminal ablation of an in-vivo model of experimental NIH of the rabbit's aorta.

  20. Intimal hyperplasia: slow but deadly.

    PubMed

    Mills, B; Robb, T; Larson, D F

    2012-11-01

    Intimal hyperplasia is the leading cause of long-term failure in coronary artery bypass vein grafting, coronary artery stenting, angioplasty, arteriovenous fistula for dialysis, and allograft transplantation. Intimal hyperplasia is a product of vascular smooth muscle cell proliferation, migration through the internal elastic lamina, and deposition of extracellular matrix proteins driven by growth factors in the vasculature. This vascular pathology results in a progressive diminution of the vessel lumen and serves as a site for thrombosis and atherosclerotic lesions. A key cell type in the initiation of intimal hyperplasia is the vascular endothelial cell, which appears to have down-stream effects on the vascular smooth muscle proliferation and migration. Currently, the only means available for prevention of intimal hyperplasia is through inhibition of mammalian target of rapamycin (mTOR) with the immunosuppressant rapamycin. mTOR integrates up-stream signals from growth factors such as IL-2 and senses the cellular nutrient and energy levels and redox status. This presentation will discuss the potential means of preserving the vascular endothelial cell and, thereby, reducing the development of intimal hyperplasia in our open-heart surgical patients.

  1. Attenuated proliferation and trans-differentiation of prostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia.

    PubMed

    Zenzmaier, Christoph; Sampson, Natalie; Pernkopf, Dominik; Plas, Eugen; Untergasser, Gerold; Berger, Peter

    2010-08-01

    Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast trans-differentiation. To evaluate the potential of phosphodiesterase type 5 (PDE5) inhibitors like tadalafil for prevention and treatment of BPH, we analyzed the role of the nitric oxide/cyclic GMP (cGMP)/PDE5 pathway for cellular proliferation and TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation in primary prostate stromal cells. Inhibition by tadalafil of PDE5, which is mainly expressed in the stromal compartment of the prostate, reduced proliferation of primary prostate stromal cells and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was confirmed by inhibition of the cGMP-dependent protein kinase G by its inhibitor KT2358. Moreover, tadalafil strongly attenuated TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation. The inhibitory effect on trans-differentiation was also observed after small interfering RNA-mediated PDE5 knockdown. As confirmed by the MAPK kinase 1 inhibitor PD98059, this effect was mediated via MAPK kinase 1 signaling. We conclude that BPH patients might benefit from adjuvant therapies with PDE5 inhibitors that inhibit stromal enlargement due to cell proliferation, as well as TGFbeta1-induced trans-differentiation processes.

  2. Interference of IP-10 expression inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in carotid artery: a new insight in the prevention of restenosis.

    PubMed

    Zuojun, Hu; Lingyu, Hu; Wei, He; Henghui, Yin; Chonggang, Zhang; Jingsong, Wang; Mian, Wang; Yong, Liu; Shenming, Wang

    2012-01-01

    After vascular angioplasty, vascular smooth muscle cell (VSMC) proliferation causes atherosclerosis and intimal hyperplasia leading to restenosis. Interferon-γ-inducible protein (IP)-10 plays a role in atherogenesis, but the mechanism remains unclear. We evaluated the role of IP-10 in intimal hyperplasia and restenosis. IP-10 expression was determined in arterial specimens from 20 arteriosclerotic obliteration patients and 6 healthy individuals. VSMCs were stimulated in vitro with IFN-γ and transfected with IP-10 siRNA. Silencing was verified with RT-PCR/Western blot; cell proliferation rate was detected by methyl-thiazol-tetrazolium. The carotid artery model of atherosclerosis injury was established with IP-10 siRNA. IP-10 expression was detected at 1 and 4 weeks using RT-PCR and immunohistochemistry. Artery morphology was assessed with hematoxylin-and-eosin staining, and intimal hyperplasia was evaluated by electron microscopy. IP-10 was overexpressed in arteriosclerotic obliteration group compared with control group (P < 0.05). IP-10 expression in transfected group was significantly lower than in untransfected group. The intima-to-media ratio of transfected group at 4 weeks was lower than that of untransfected group (P < 0.01). The transfected group exhibited more regular intimal structure and less hyperplasia under electron microscopy. We, therefore, concluded that IP-10 played an important role in intimal hyperplasia as siRNA-mediated IP-10 silencing inhibited aberrant VSMCs hyperplasia and reduced restenosis.

  3. Serum Adiponectin, C-peptide and Leptin and Risk of Symptomatic Benign Prostatic Hyperplasia: Results From the Prostate Cancer Prevention Trial

    PubMed Central

    Schenk, Jeannette M.; Kristal, Alan R.; Neuhouser, Marian L.; Tangen, Catherine M.; White, Emily; Lin, Daniel W.; Thompson, Ian M.

    2010-01-01

    Background Recent epidemiologic studies have identified obesity as a risk factor for benign prostatic hyperplasia (BPH). We examined whether adiponectin, leptin and C-peptide were associated with incident, symptomatic BPH and whether these factors mediate the relationship between obesity and BPH risk. Methods Data are from Prostate Cancer Prevention Trial placebo arm participants who were free of BPH at baseline. Incident BPH (n=698) was defined as treatment, two International Prostate Symptom Score (IPSS) values >14, or an increase of ≥5 in IPSS from baseline documented on at least two occasions plus at least one score ≥12. Controls (n=709) were selected from men reporting no BPH treatment or IPSS >7 during the seven-year trial. Baseline serum was analyzed for adiponectin, C-peptide, and leptin concentrations. Results Neither C-peptide nor leptin was associated with BPH risk. The odds ratio [95% CI] contrasting highest to lowest quartiles of adiponectin was 0.65[0.47, 0.87] ptrend=0.004. Findings differed between levels of physical activity: there was a strong inverse association between adiponectin and BPH among moderately/very active men OR=0.43[0.29, 0.63], and no association among sedentary/minimally active men OR=0.92[0.65, 1.30] pinteraction=0.005. Adiponectin concentrations explained only a moderate amount of the relationship between obesity and BPH risk. Conclusions High adiponectin concentrations were associated with reduced risk of incident, symptomatic BPH. This association was limited to moderately/very active men; suggesting the relationship between obesity and BPH involves a complex interaction between factors affecting glucose uptake and insulin sensitivity. However, adiponectin is likely not the only mechanism through which obesity affects BPH risk. PMID:19475640

  4. Complete vascular healing and sustained suppression of neointimal thickening after local delivery of advanced c-myc antisense at six months follow-up in a rabbit balloon injury model

    SciTech Connect

    Kipshidze, Nicholas; Iversen, Patrick; Keane, Eamon; Stein, David; Chawla, Paramjith; Skrinska, Victor; Shankar, Latha Raja; Mehran, Roxana; Chekanov, Valerie; Dangas, George; Komorowski, Richard; Haudenschild, Christian; Khanna, Ashwani; Leon, Martin; Keelan, Michael H.; Moses, Jeffrey

    2002-03-01

    Background: Neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA) is one of the major components of the process of restenosis. We evaluated the long-term impact of local delivery of c-myc neutrally charged antisense oligonucleotides (Resten-NG) upon neointimal formation following PTCA in a rabbit model.Methods:PTCA was performed in the iliac arteries of 10 New Zealand white rabbits at 8 atm for 30 s, three times. An infusion of 500 {mu}g Resten-NG (n=6) or saline (n=4) was delivered to the site at 2 atm via the outer balloon pores of the transport{sup TM} catheter over 2 min. The diet was supplemented with 0.25% cholesterol for 10 days before and 6 months following PTCA.Results:After 6 months, animals were sacrificed and vessels were fixed in formalin, processed and stained with hematoxylin, eosin, and movat. Histological analysis revealed complete vascular healing in both groups of animals. Planimetry showed that intimal areas were 1.71{+-}0.25 and 0.65{+-}0.36 mm{sup 2} in the control and antisense delivery groups, respectively (P<.05).Conclusion:We conclude that local delivery of Resten-NG significantly inhibited neointimal thickening following PTCA in a rabbit for up to 6 months.

  5. Acaricide treatment prevents adrenocortical hyperplasia as a long-term stress reaction to psoroptic mange in cattle.

    PubMed

    Blutke, A; Börjes, P; Herbach, N; Pfister, K; Hamel, D; Rehbein, S; Wanke, R

    2015-01-15

    -treated bulls was due to a selective increase of the volume of the zona fasciculata in the adrenal cortex. Compared to uninfested controls and P. ovis-infested, IVM LAI-treated bulls, the number of epithelial cells in the zona fasciculata was significantly increased in P. ovis-infested, saline-treated bulls, while the zona fasciculata cell volumes did not differ between the three groups of cattle. While the single point determination of serum cortisol concentrations did not reveal significant differences between the three groups of cattle at tissue sampling, the hyperplastic growth of the adrenal cortex in the P. ovis-infested, saline-treated bulls provides morphologic evidence that a chronic stress reaction is one consequence of mange mite infestations that can be prevented by efficacious acaricidal treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Improved Patency of Transjugular Intrahepatic Portosystemic Shunt: The Efficacy of Cilostazol for the Prevention of Pseudointimal Hyperplasia in Swine TIPS Models

    SciTech Connect

    Park, Sang Woo Cha, In Ho; Kim, Chul Hwan; Jeon, Hae Jeong; Park, Jeong Hee; Hong, Suk Joo; Lee, In Sik

    2007-07-15

    Purpose. To investigate the efficacy of oral administration of cilostazol to inhibit pseudointimal/intimal hyperplasia in swine TIPS models. Methods. Successful TIPS creation was carried out in 11 of 12 healthy young pigs (20-25 kg). In the treatment group (n = 6), both cilostazol and aspirin were administered daily, from the first day of TIPS creation. The control group (n = 5) was administered only aspirin. The animals were followed-up for 2 weeks and then killed. The specimen (including portal vein, hepatic parenchymal tract, hepatic vein, and inferior vena cava) and stents were carefully bisected in a longitudinal fashion. The control group was compared with the treatment group by means of a gross and histologic evaluation of the degree of pseudointimal/intimal hyperplasia in the shunt. Results. At the gross evaluation, the control group showed considerably more pseudointimal/intimal hyperplasia than the treatment group. Using microscopic evaluation, there was a statistically significant difference (p < 0.05) in the mean maximum pseudointimal/intimal hyperplasia thickness between the control group (2.97 {+-} 0.33 mm) and treatment group (0.73 {+-} 0.27 mm). Conclusion. Oral administration of cilostazol may have been effective in reducing pseudointimal/intimal hyperplasia in swine TIPS models.

  7. improved patency of transjugular intrahepatic portosystemic shunt: the efficacy of cilostazol for the prevention of pseudointimal hyperplasia in swine TIPS models.

    PubMed

    Park, Sang Woo; Cha, In Ho; Kim, Chul Hwan; Jeon, Hae Jeong; Park, Jeong Hee; Hong, Suk Joo; Lee, In Sik

    2007-01-01

    To investigate the efficacy of oral administration of cilostazol to inhibit pseudointimal/intimal hyperplasia in swine TIPS models. Successful TIPS creation was carried out in 11 of 12 healthy young pigs (20-25 kg). In the treatment group (n = 6), both cilostazol and aspirin were administered daily, from the first day of TIPS creation. The control group (n = 5) was administered only aspirin. The animals were followed-up for 2 weeks and then killed. The specimen (including portal vein, hepatic parenchymal tract, hepatic vein, and inferior vena cava) and stents were carefully bisected in a longitudinal fashion. The control group was compared with the treatment group by means of a gross and histologic evaluation of the degree of pseudointimal/intimal hyperplasia in the shunt. At the gross evaluation, the control group showed considerably more pseudointimal/intimal hyperplasia than the treatment group. Using microscopic evaluation, there was a statistically significant difference (p < 0.05) in the mean maximum pseudointimal/intimal hyperplasia thickness between the control group (2.97 +/- 0.33 mm) and treatment group (0.73 +/- 0.27 mm). Oral administration of cilostazol may have been effective in reducing pseudointimal/intimal hyperplasia in swine TIPS models.

  8. Modulation of protein expression and activity by radiation: Relevance to intracoronary radiation for the prevention of restenosis

    SciTech Connect

    Vodovotz, Yoram; Mitchell, James B.; Lucia, M. Scott; McKinney, Leslie; Kollum, Marc; Cottin, Yves; Chan, Rosanna C.; Barcellos-Hoff, Mary Helen; Waksman, Ron

    2001-08-25

    Restenosis is a common complication of percutaneous transluminal coronary angioplasty. Recent studies have demonstrated a striking reduction in the neointimal hyperplasia characteristic of restenosis following intracoronary radiation (IR), but the mechanisms by which radiation reduces neointima formation following balloon overstretch injury are not elucidated fully. In addition to direct antimitotic effects mediated via oxygen free radicals, ionizing radiation can induce the expression of numerous genes and thereby mediate indirect effects. Additionally, IR prevents restenosis at the cost of decreased healing and increased thrombosis, and we suggest that these adverse reactions can be modulated by adjunct pharmacology or gene-based strategies. This review discusses several genes and proteins modulated by radiation in the context of arterial injury, and their possible therapeutic relevance.

  9. Ceramide 1-phosphate induces neointimal formation via cell proliferation and cell cycle progression upstream of ERK1/2 in vascular smooth muscle cells

    SciTech Connect

    Kim, Tack-Joong; Kang, Yeo-Jin; Lim, Yong; Lee, Hyoung-Woo; Bae, Kiho; Lee, Youn-Sun; Yoo, Jae-Myung; Yoo, Hwan-Soo; Yun, Yeo-Pyo

    2011-08-15

    Ceramide 1-phosphate (C1P) is a novel bioactive sphingolipid formed by ceramide kinase (CERK)-catalyzed phosphorylation of ceramide. It has been implicated in the regulation of such vital pathophysiological functions as phagocytosis and inflammation, but there have been no reports ascribing a biological function to CERK in vascular disorders. Here the potential role of CERK/C1P in neointimal formation was investigated using rat aortic vascular smooth muscle cells (VSMCs) in primary culture and a rat carotid injury model. Exogenous C8-C1P stimulated cell proliferation, DNA synthesis, and cell cycle progression of rat aortic VSMCs in primary culture. In addition, wild-type CERK-transfected rat aortic VSMCs induced a marked increase in rat aortic VSMC proliferation and [{sup 3}H]-thymidine incorporation when compared to empty vector transfectant. C8-C1P markedly activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) within 5 min, and the activation could be prevented by U0126, a MEK inhibitor. Also, K1, a CERK inhibitor, decreased the ERK1/2 phosphorylation and cell proliferation on platelet-derived growth factor (PDGF)-stimulated rat aortic VSMCs. CERK expression and C1P levels were found to be potently increased during neointimal formation using a rat carotid injury model. However, ceramide levels decreased during the neointimal formation process. These findings suggest that C1P can induce neointimal formation via cell proliferation through the regulation of the ERK1/2 protein in rat aortic VSMCs and that CERK/C1P may regulate VSMC proliferation as an important pathogenic marker in the development of cardiovascular disorders.

  10. Benign prostate hyperplasia (BPH) - resources

    MedlinePlus

    Resources - benign prostatic hyperplasia (BPH); Prostate enlargement resources; BPH resources ... organizations provide information on benign prostatic hyperplasia ( prostate enlargement ): National Kidney and Urologic Diseases Information Clearinghouse -- www. ...

  11. Management of adolescents with congenital adrenal hyperplasia.

    PubMed

    Merke, Deborah P; Poppas, Dix P

    2013-12-01

    The management of congenital adrenal hyperplasia involves suppression of adrenal androgen production, in addition to treatment of adrenal insufficiency. Management of adolescents with congenital adrenal hyperplasia is especially challenging because changes in the hormonal milieu during puberty can lead to inadequate suppression of adrenal androgens, psychosocial issues often affect adherence to medical therapy, and sexual function plays a major part in adolescence and young adulthood. For these reasons, treatment regimen reassessment is indicated during adolescence. Patients with non-classic congenital adrenal hyperplasia require reassessment regarding the need for glucocorticoid drug treatment. No clinical trials have compared various regimens for classic congenital adrenal hyperplasia in adults, thus therapy is individualised and based on the prevention of adverse outcomes. Extensive patient education is key during transition from paediatric care to adult care and should include education of females with classic congenital adrenal hyperplasia regarding their genital anatomy and surgical history. Common issues for these patients include urinary incontinence, vaginal stenosis, clitoral pain, and cosmetic concerns; for males with classic congenital adrenal hyperplasia, common issues include testicular adrenal rest tumours. Transition from paediatric to adult care is most successful when phased over many years. Education of health-care providers on how to successfully transition patients is greatly needed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Management of adolescents with congenital adrenal hyperplasia

    PubMed Central

    Merke, Deborah P; Poppas, Dix P

    2014-01-01

    The management of congenital adrenal hyperplasia involves suppression of adrenal androgen production, in addition to treatment of adrenal insufficiency. Management of adolescents with congenital adrenal hyperplasia is especially challenging because changes in the hormonal milieu during puberty can lead to inadequate suppression of adrenal androgens, psychosocial issues often affect adherence to medical therapy, and sexual function plays a major part in adolescence and young adulthood. For these reasons, treatment regimen reassessment is indicated during adolescence. Patients with non-classic congenital adrenal hyperplasia require reassessment regarding the need for glucocorticoid drug treatment. No clinical trials have compared various regimens for classic congenital adrenal hyperplasia in adults, thus therapy is individualised and based on the prevention of adverse outcomes. Extensive patient education is key during transition from paediatric care to adult care and should include education of females with classic congenital adrenal hyperplasia regarding their genital anatomy and surgical history. Common issues for these patients include urinary incontinence, vaginal stenosis, clitoral pain, and cosmetic concerns; for males with classic congenital adrenal hyperplasia, common issues include testicular adrenal rest tumours. Transition from paediatric to adult care is most successful when phased over many years. Education of health-care providers on how to successfully transition patients is greatly needed. PMID:24622419

  13. Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study.

    PubMed

    Taniguchi, Norimasa; Nakamura, Takeshi; Sawada, Takahisa; Matsubara, Kinya; Furukawa, Keizo; Hadase, Mitsuyoshi; Nakahara, Yoshifumi; Nakamura, Takashi; Matsubara, Hiroaki

    2010-11-01

    Erythropoietin (EPO) enhances re-endothelialization and anti-apoptotic action. Larger clinical studies to examine the effects of high-dose EPO are in progress in patients with acute myocardial infarction (AMI). The aim of this multi-center pilot study was to investigate the effect of `low-dose EPO' (6,000 IU during percutaneous coronary intervention (PCI), 24 h and 48 h) in 35 patients with a first ST-elevated AMI undergoing PCI who was randomly assigned to EPO or placebo (saline) treatment. Neointimal volume, cardiac function and infarct size were examined in the acute phase and 6 months later (ClinicalTrials.gov identifier: NCT00423020). No significant regression in in-stent neointimal volume was observed, whereas left ventricular (LV) ejection fraction was significantly improved (49.2% to 55.7%, P=0.003) and LV end-systolic volume was decreased in the EPO group (47.7 ml to 39.0 ml, P=0.036). LV end-diastolic volume tended to be reduced from 90.2% to 84.5% (P=0.159), whereas in the control group it was inversely increased (91.7% to 93.7%, P=0.385). Infarction sizes were significantly reduced by 38.5% (P=0.003) but not in the control group (23.7%, P=0.051). Hemoglobin, peak creatine kinase values, and CD34(+)/CD133(+)/CD45(dim) endothelial progenitors showed no significant changes. No adverse events were observed during study periods. This is a first study demonstrating that short-term `low-dose' EPO to PCI-treated AMI patients did not prevent neointimal hyperplasia but rather improved cardiac function and infarct size without any clinical adverse effects.

  14. Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β

    PubMed Central

    Papke, Christina L.; Cao, Jiumei; Kwartler, Callie S.; Villamizar, Carlos; Byanova, Katerina L.; Lim, Soon-Mi; Sreenivasappa, Harini; Fischer, Grant; Pham, John; Rees, Meredith; Wang, Miranda; Chaponnier, Christine; Gabbiani, Giulio; Khakoo, Aarif Y.; Chandra, Joya; Trache, Andreea; Zimmer, Warren; Milewicz, Dianna M.

    2013-01-01

    Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2−/− mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-β). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-β activation and Acta2−/− SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations. PMID:23591991

  15. Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β.

    PubMed

    Papke, Christina L; Cao, Jiumei; Kwartler, Callie S; Villamizar, Carlos; Byanova, Katerina L; Lim, Soon-Mi; Sreenivasappa, Harini; Fischer, Grant; Pham, John; Rees, Meredith; Wang, Miranda; Chaponnier, Christine; Gabbiani, Giulio; Khakoo, Aarif Y; Chandra, Joya; Trache, Andreea; Zimmer, Warren; Milewicz, Dianna M

    2013-08-01

    Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-β). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-β activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

  16. Neointimal calcification after stenting and chronic kidney disease.

    PubMed

    Kawase, Yoshiaki; Honye, Junko; Ota, Hideaki; Miyake, Taiji; Kamikawa, Shigeshi; Kondo, Hiroki; Okubo, Munenori; Tsuchiya, Kunihiko; Matsuo, Hitoshi; Jang, Ik-Kyung; Ueno, Katsumi

    2013-01-01

    The timing and incidence of neointimal calcification after stenting (NIC) is largely unknown. The purpose of our study was to elucidate the characteristics of NIC. The presence of NIC in patients who underwent intravascular ultrasound between June 30, 2009 and June 30, 2012 was analyzed. The patients were divided into two groups based on the follow-up period: < 365 days or ≥ 365 days. A total of 181 images were analyzed. Those with NIC had a lower estimated glomerular filtration rate [51 (6-60) versus 61 (52-72) mL/minute/1.73 m²; P < 0.01] and longer time after stenting [3198 (1710-3684) versus 211 (180-516) days; P < 0.01] compared to those without NIC. NIC during short-term follow-up was observed only in patients who were on hemodialysis. On the other hand, NIC in the long-term follow-up was observed only in patients with bare metal stents. The development of NIC was related to renal function and time after stenting. NIC in the short-term and the long-term follow-up was observed only in patients who were on hemodialysis and who were implanted with a bare metal stent, respectively.

  17. A novel biodegradable external mesh stent improved long-term patency of vein grafts by inhibiting intimal-medial hyperplasia in an experimental canine model.

    PubMed

    Sato, Atsuhiko; Kawamoto, Shunsuke; Watanabe, Mika; Suzuki, Yusuke; Takahashi, Goro; Masaki, Naoki; Kumagai, Kiichiro; Saijo, Yoshifumi; Tabayashi, Koichi; Saiki, Yoshikatsu

    2016-01-01

    Increased hemodynamic stress on vein grafts used in the arterial system is associated with vein graft disease. We determined whether a novel biodegradable external mesh stent could inhibit medial-intimal hyperplasia by suppressing hemodynamic stress on vein grafts and improve long-term patency. Twenty-four beagles underwent bilateral femoral interposition grafting using reversed femoral veins. Vein grafts were externally supported by a novel poly L-lactide-ε-caprolactone copolymer (P(LA/CL)) biodegradable mesh stent or a nonabsorbable mesh stent. Vein grafts with no reinforcement were used as controls. The grafts were harvested 6 and 12 months after implantation for morphometric and immunohistochemical assessment. The endoluminal circumferential vein graft length was smaller in the P(LA/CL) and nonabsorbable groups (17.2 ± 2.9 and 19.0 ± 0.3 mm, respectively), than that in the control group (25.0 ± 2.6 mm, P < 0.01) at 12 months. The mean intimal-medial thickness was thinner in P(LA/CL) and nonabsorbable stent groups (0.18 ± 0.05 and 0.16 ± 0.05 mm, respectively), than that in the control group (0.30 ± 0.08 mm, P < 0.01). Differences in the intimal-medial thickness among the groups were associated with the magnitude of cellular proliferating activity. The graft patency ratio (100 %) was higher in the P(LA/CL) group than that in the nonabsorbable and control groups (72.2 and 63.6%, respectively, P < 0.05). The biodegradable P(LA/CL) external mesh stent improved vein graft patency for 12 months and prevented vein graft dilatation and intimal hyperplasia associated with suppressed neointimal layer cellular proliferating activity.

  18. Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia.

    PubMed

    Zhang, Li; Chen, Qishan; An, Weiwei; Yang, Feng; Maguire, Eithne Margaret; Chen, Dan; Zhang, Cheng; Wen, Guanmei; Yang, Mei; Dai, Bin; Luong, Le Anh; Zhu, Jianhua; Xu, Qingbo; Xiao, Qingzhong

    2017-09-14

    hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) plays a variety of roles in gene expression. However, little is known about the functional involvement of hnRNPA1 in vascular smooth muscle cell (VSMC) function and neointima hyperplasia. In this study, we have attempted to investigate the functional roles of hnRNPA1 in the contexts of VSMC function, injury-induced vessel remodeling, and human atherosclerotic lesions, as well as discern the molecular mechanisms involved. APPROACH AND RESULTS: hnRNPA1 expression levels were consistently modulated during VSMC phenotype switching and neointimal lesion formation induced by wire injury. Functional studies showed that VSMC-specific gene expression, proliferation, and migration were regulated by hnRNPA1. Our data show that hnRNPA1 exerts its effects on VSMC functions through modulation of IQGAP1 (IQ motif containing GTPase activating protein 1). Mechanistically, hnRNPA1 regulates IQGAP1 mRNA degradation through 2 mechanisms: upregulating microRNA-124 (miR-124) and binding to AU-rich element of IQGAP1 gene. Further evidence suggests that hnRNPA1 upregulates miR-124 by modulating miR-124 biogenesis and that IQGAP1 is the authentic target gene of miR-124. Importantly, ectopic overexpression of hnRNPA1 greatly reduced VSMC proliferation and inhibited neointima formation in wire-injured carotid arteries. Finally, lower expression levels of hnRNPA1 and miR-124, while higher expression levels of IQGAP1, were observed in human atherosclerotic lesions. Our data show that hnRNPA1 is a critical regulator of VSMC function and behavior in the context of neointima hyperplasia, and the hnRNPA1/miR-124/IQGAP1 regulatory axis represents a novel therapeutic target for the prevention of cardiovascular diseases. © 2017 The Authors.

  19. Local Administration of NF-{kappa} B Decoy Oligonucleotides to Prevent Restenosis after Balloon Angioplasty: An Experimental Study in New Zealand White Rabbits

    SciTech Connect

    Kalinowski, Marc Viehofer, Kerstin; Hamann, Christine; Barry, James J.; Kleb, Beate; Klose, Klaus Jochen; Wagner, Hans-Joachim; Alfke, Heiko

    2005-04-15

    Purpose. To evaluate the efficacy of NF-{kappa} B oligonucleotides (ODN) administered by local administration with the channeled balloon catheter to prevent restenosis after balloon angioplasty in restenotic iliac arteries of New Zealand white rabbits. Materials and Methods. In vitro, 8000 rabbit vascular smooth muscle cells (rVSMC) where transfected with a liposomal carrier (TfX50) with 100 ng of decoy and scrambled ODN. Inhibition of proliferation was measured using a MTT assay after 24 hours in comparison to control. In vivo, 22 male New Zealand White rabbits were fed a 1% cholesterol diet and received denudation of both common iliac arteries with a 3 mm balloon catheter to induce an arterial stenosis. Four weeks after stenosis induction, local application of NF-{kappa} B in two different concentrations (1 {mu}g: n = 14; 10 {mu}g: n = 8) was performed randomly on one common iliac artery. Scrambled oligonucleotides without specific binding capacities were injected into the contralateral side. The channeled balloon catheter allows simultaneous balloon dilation (8 atm) of the stenosis and local application of a drug solution (2 atm). Four weeks after local drug delivery the animals were killed and the vessels were excised and computerized morphometric measurements were performed. Results. NF-{kappa} B decoy ODN but not scrambled ODN inhibited proliferation of rVSMC in vitro. Following local ODN application in the animals, no acute vascular complications were seen. NF-{kappa} B ODN resulted in a statistically non significant reduction of neointimal area compared to the control group. The neointimal area was 0.97 mm{sup 2} using 1 {mu}g NF-{kappa} B ODN compared to 0.98 mm{sup 2} in the control group. The higher dose resulted in a neointimal area of 0.97 mm{sup 2} compared to 1.07mm{sup 2} at the control side. Conclusions. Local drug delivery of NF-{kappa} B ODN using the 'channeled balloon' catheter could not reduce neointimal hyperplasia in stenostic rabbit iliac

  20. Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation.

    PubMed

    Huo, Yan; Yi, Bing; Chen, Ming; Wang, Nadan; Chen, Pengguo; Guo, Cheng; Sun, Jianxin

    2014-12-15

    Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83 μM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation-induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

    PubMed Central

    Kim, Yu-Mee; Haghighat, Leila; Spiekerkoetter, Edda; Sawada, Hirofumi; Alvira, Cristina M.; Wang, Lingli; Acharya, Swati; Rodriguez-Colon, Gabriela; Orton, Andrew; Zhao, Mingming; Rabinovitch, Marlene

    2011-01-01

    Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastase-specific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease. PMID:21763677

  2. Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing

    PubMed Central

    Granada, Juan F; Stenoien, Mark; Buszman, Piotr P; Tellez, Armando; Langanki, Dan; Kaluza, Greg L; Leon, Martin B; Gray, William; Jaff, Michael R; Schwartz, Robert S

    2014-01-01

    Background The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown. Methods and results The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3 µg/mm2) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245 ng/mg; p=NS). At 24 h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28 days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7 days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group. Conclusions The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing. PMID:25332821

  3. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.

    PubMed Central

    Marks, D S; Vita, J A; Folts, J D; Keaney, J F; Welch, G N; Loscalzo, J

    1995-01-01

    Endothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S-nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO-BSA) on neointimal responses in an animal model of vascular injury. Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < or = 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO-BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < or = 0.001). Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty. Images PMID:8675628

  4. Cryoplasty for the Prevention of Arterial Restenosis

    SciTech Connect

    Wildgruber, Moritz G.; Berger, Hermann J.

    2008-11-15

    Restenosis after percutaneous transluminal angioplasty remains the limiting factor for the long-term benefit of endovascular therapies of peripheral arterial occlusive disease. Despite a variety of modifications and adjuncts to angioplasty such as bare metal stents, covered stents, and drug-eluting stents as well as a number of new technologies like laser angioplasty and cutting balloon angioplasty, restenosis rates have not been significantly affected and remain inferior to those for surgery for long lesions in the femoropopliteal segment. Cryoplasty, which combines balloon angioplasty with the application of cryothermal energy to the vessel wall, was suggested as a promising approach to prevent the formation of neointimal hyperplasia after angioplasty procedures. This review discusses the basic principles of cryoplasty, summarizes the current data on restenosis rates after cryoplasty treatment, and evaluates cryoplasty as a new treatment method to solve the problems associated with restenosis development. The results of the clinical studies suggest that cryoplasty is a feasible and safe technique in the treatment of femoropopliteal disease, however, they have failed to prove any superiority of cryoplasty over conventional angioplasty.

  5. INCIDENCE OF ENDOMETRIAL HYPERPLASIA

    PubMed Central

    REED, Susan D.; NEWTON, Katherine M.; CLINTON, Walter L.; EPPLEIN, Meira; GARCIA, Rochelle; ALLISON, Kimberly; VOIGT, Lynda F.; Weiss, Noel S.

    2009-01-01

    Objective Estimate age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. Study design Women ages 18–90 years with endometrial pathology specimens (1985–2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. Results Endometrial hyperplasia peak incidence was: simple-142/100,000 woman-years, complex-213/100,000 woman-years, both in the early 50s; and atypical-56/100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. Conclusions Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence. PMID:19393600

  6. Can angiotensin receptor antagonists prevent restenosis after stent placement?

    PubMed

    Peters, Stefan

    2002-01-01

    Restenosis rates after coronary stent implantation in complex lesions are between 30 and 50%. Neointimal hyperplasia promoted by complex interaction between cellular and acellular elements, such as cytokines and growth factors, is thought to be the primary process responsible for restenosis. The risk of in-stent restenosis is increased in patients with a history of restenosis after percutaneous transluminal coronary angioplasty, in long lesions, in total occlusions, in patients with diabetes mellitus, in small vessels, in the proximal parts of the left anterior descending coronary artery and in cases of stent oversizing. In-stent restenosis represents a serious economic burden on society because treatment strategies include expensive approaches such as cutting-balloon angioplasty, rotational atherectomy and brachytherapy. A number of pharmacological agents, including ACE inhibitors, have been unsuccessful in preventing restenosis. Alternative procedures such as brachytherapy, radioactive stents and drug-eluting stents are under evaluation. Although sirolimus- or paclitaxel-eluting stents have been associated with very low restenosis rates over durations of 6 to 12 months, the long-term efficacy and tolerability of this approach is currently being investigated. Although ACE inhibitors have failed in reducing restenosis rates, the selective angiotensin II type 1 (AT(1)) receptor antagonist valsartan has shown encouraging results in the single-center Valsartan for Prevention of Restenosis after Stenting of Type B2/C lesions trial (ValPREST). The ValPREST trial is the first randomized, placebo-controlled study to have evaluated the effect of an angiotensin receptor antagonist on in-stent restenosis in a moderate number of patients. Compared with ACE inhibitors, angiotensin receptor blockers exert additional effects on the pathophysiological processes which lead to restenosis. Angiotensin receptor antagonists may affect several mechanisms involved in neointimal

  7. Ultrasound-induced thermal therapy of hyperplasia in ringed expanded polytetrafluoroethylene (eptfe) access grafts

    NASA Astrophysics Data System (ADS)

    Query, Michael Earl

    Hemodialysis vascular access, the interface between a dialysis patient and a dialysis machine, is quite literally the lifeblood of a patient's health. Vascular access dysfunction is the leading cause of hospitalization in hemodialysis patients. The occlusive growth of neointimal hyperplasia (NH) in expanded polytetrafluoroethylene (ePTFE) ringed grafts is the primary cause of failure. To further develop a proposed thermal ultrasound treatment to reduce or prevent NH in arteriovenous vascular grafts, the acoustic properties of ePTFE were studied in water and alcohol solutions. Previous reports of ePTFE acoustic properties are critiqued. It was found that the acoustic transmission and attenuation through ePTFE, and therefore the potential for an ultrasound-based therapy for NH, are heavily dependent on the medium in which the graft is immersed, suggesting that the acoustic properties of implanted grafts will change as grafts mature in vivo. The acoustic impedance and attenuation of water-soaked ePTFE were 0.478 +/- 1.43 x 10-2 MRayl and 1.78 +/- 0.111 Np/cm*MHz, respectively, while the acoustic impedance and attenuation of ePTFE in alcohol were 1.49 +/- 0.149 MRayl and 0.77 +/- 1.1 x 10-2 Np/cm*MHz, respectively. The use of focused ultrasound to heat implanted ringed ePTFE grafts was numerically modeled from 1.35- and 1.443-MHz transducers for in vitro geometries. Power deposition and heating, in turn, differed by an order of magnitude between various graft acoustic properties. Graft rings were predicted to be substantial absorbing and scattering features. In vitro phantom models were constructed: one with and one without thermocouples. At 1 W of acoustic power, the maximum temperature rise was 8˚ C. The thermocouple model containing a water-soaked graft did not experience heating in the far graft wall. The MRTI model confirmed that the graft rings are an absorbing/scattering feature. Heating was not prevented in the presence of water flow through the graft. Water

  8. Late Stent Expansion and Neointimal Proliferation of Oversized Nitinol Stents in Peripheral Arteries

    SciTech Connect

    Zhao, Hugh Q. Nikanorov, Alexander; Virmani, Renu; Jones, Russell; Pacheco, Erica; Schwartz, Lewis B.

    2009-07-15

    For peripheral endovascular intervention, self-expanding (SE) stents are commonly oversized in relation to target arteries to assure optimal wall apposition and prevent migration. However, the consequences of oversizing have not been well studied. The purpose of this study was to examine the effects of SE stent oversizing (OS) with respect to the kinetics of late stent expansion and the long-term histological effects of OS. Pairs of overlapped 8 x 28-mm Nitinol SE stents were implanted into the iliofemoral arteries of 14 Yucatan swine. Due to variations in target artery size, the stent-to-artery ratio ranged from 1.2:1 to 1.9:1. Lumen and stent diameters were assessed by quantitative angiography at the time of implantation. Following angiographic assessment at 6 months, stented arteries were perfusion-fixed, sectioned, and stained for histological analysis. Immediately following implantation, the stents were found to be expanded to a range of 4.7-7.1 mm, largely conforming to the diameter of the recipient target artery. The stents continued to expand over time, however, and all stents had enlarged to nearly their 8-mm nominal diameter by 6 months. The histological effects of OS were profound, with marked increases in injury and luminal area stenosis, including a statistically significant linear correlation between stent-to-artery ratio and area stenosis. In this experimental model of peripheral endovascular intervention, oversized Nitinol SE stents are constrained by their target artery diameter upon implantation but expand to their nominal diameter within 6 months. Severe OS (stent-to-artery ratio >1.4:1) results in a profound long-term histological response including exuberant neointimal proliferation and luminal stenosis.

  9. [Focal epithelial hyperplasia].

    PubMed

    Vera-Iglesias, E; García-Arpa, M; Sánchez-Caminero, P; Romero-Aguilera, G; Cortina de la Calle, P

    2007-11-01

    Focal epithelial hyperplasia is a rare disease of the oral mucosa caused by the human papilloma virus (HPV). It appears as a benign epithelial growth, usually in the mucosa of the lower lip. It is mainly associated with HPV serotypes 13 and 32 and there is a clear racial predilection for the disease in Native Americans and Eskimos. We describe the case of a 17-year-old girl from Ecuador with multiple papular lesions in both lips that were clinically and histologically consistent with focal epithelial hyperplasia. Analysis by polymerase chain reaction detected HPV serotype 13.

  10. Congenital Adrenal Hyperplasia

    PubMed Central

    Speiser, Phyllis W.

    2015-01-01

    Congenital adrenal hyperplasia associated with deficiency of steroid 21-hydroxylase is the most common inborn error in adrenal function and the most common cause of adrenal insufficiency in the pediatric age group. As patients now survive into adulthood, adult health-care providers must also be familiar with this condition. Over the past several years, F1000 has published numerous commentaries updating research and practical guidelines for this condition. The purposes of this review are to summarize basic information defining congenital adrenal hyperplasia and to highlight current knowledge and controversies in management. PMID:26339484

  11. Nanoporous CREG-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

    PubMed Central

    Sun, Mingyu; Tao, Jie; Yan, Chenghui; Kang, Jian; Li, Shaohua

    2013-01-01

    Background The goal of this study was to evaluate the efficacy of a nanoporous CREG-eluting stent (CREGES) in inhibiting neointimal formation in a porcine coronary model. Methods In vitro proliferation assays were performed using isolated human endothelial and smooth muscle cells to investigate the cell-specific pharmacokinetic effects of CREG and sirolimus. We implanted CREGES, control sirolimus-eluting stents (SES) or bare metal stents (BMS) into pig coronary arteries. Histology and immunohistochemistry were performed to assess the efficacy of CREGES in inhibiting neointimal formation. Results CREG and sirolimus inhibited in vitro vascular smooth muscle cell proliferation to a similar degree. Interestingly, human endothelial cell proliferation was only significantly inhibited by sirolimus and was increased by CREG. CREGES attenuated neointimal formation after 4 weeks in porcine coronary model compared with BMS. No differences were found in the injury and inflammation scores among the groups. Scanning electron microscopy and CD31 staining by immunohistochemistry demonstrated an accelerated reendothelialization in the CREGES group compared with the SES or BMS control groups. Conclusions The current study suggests that CREGES reduces neointimal formation, promotes reendothelialization in porcine coronary stent model. PMID:23573278

  12. Preoperative Venous Intimal Hyperplasia, Postoperative Arteriovenous Fistula Stenosis, and Clinical Fistula Outcomes

    PubMed Central

    Robbin, Michelle L.; Young, Carlton J.; Deierhoi, Mark H.; Goodman, Jeremy; Hanaway, Michael; Lockhart, Mark E.; Litovsky, Silvio

    2013-01-01

    Summary Background and objectives Arteriovenous fistulas often fail to mature, and nonmaturation has been attributed to postoperative stenosis caused by aggressive neointimal hyperplasia. Preexisting intimal hyperplasia in the native veins of uremic patients may predispose to postoperative arteriovenous fistula stenosis and arteriovenous fistula nonmaturation. Design, setting, participants, & measurements This work explored the relationship between preexisting venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical arteriovenous fistula outcomes in 145 patients. Venous specimens obtained during arteriovenous fistula creation were quantified for maximal intimal thickness (median thickness=22.3 μm). Postoperative ultrasounds at 4–6 weeks were evaluated for arteriovenous fistula stenosis. Arteriovenous fistula maturation within 6 months of creation was determined clinically. Results Postoperative arteriovenous fistula stenosis was equally frequent in patients with preexisting venous intimal hyperplasia (thickness>22.3 μm) and patients without hyperplasia (46% versus 53%; P=0.49). Arteriovenous fistula nonmaturation occurred in 30% of patients with postoperative stenosis versus 7% of those patients without stenosis (hazard ratio, 4.33; 95% confidence interval, 1.55 to 12.06; P=0.001). The annual frequency of interventions to maintain arteriovenous fistula patency for dialysis after maturation was higher in patients with postoperative stenosis than patients without stenosis (0.83 [95% confidence interval, 0.58 to 1.14] versus 0.42 [95% confidence interval, 0.28 to 0.62]; P=0.008). Conclusions Preexisting venous intimal hyperplasia does not predispose to postoperative arteriovenous fistula stenosis. Postoperative arteriovenous fistula stenosis is associated with a higher arteriovenous fistula nonmaturation rate. Arteriovenous fistulas with hemodynamically significant stenosis frequently mature without an intervention. Postoperative

  13. Subareolar Sclerosing Ductal Hyperplasia.

    PubMed

    Cheng, Esther; D'Alfonso, Timothy M; Arafah, Maria; Marrero Rolon, Rebecca; Ginter, Paula S; Hoda, Syed A

    2017-02-01

    Subareolar sclerosing duct hyperplasia (SSDH) remains to be fully characterized nearly 20 years after initial description. Thirty-five SSDH cases diagnosed over a 16-year period (January 2000 to December 2015) were reviewed. All patients were female (mean age = 59 years, range = 18-80) who had presented with a unilateral solitary lesion (left 22, right 13) with a mean size of 1.3 cm (range = 0.4-3.0 cm), and showed florid and papillary epithelial hyperplasia with dense sclerosis without involvement of nipple or areolar epidermis. Significant lesions concurrent within SSDH included low-grade adenosquamous carcinoma (n = 1), ductal carcinoma in situ (DCIS; n = 1), lobular carcinoma in situ (LCIS; n = 1), and atypical ductal hyperplasia (ADH; n = 13). No case of SSDH recurred in a mean follow-up of 44 months (range = 6-189). Subsequent significant lesions occurred in 6 patients: DCIS (n = 3; ipsilateral 2, contralateral 1), ipsilateral ADH (n = 2), and ipsilateral atypical lobular hyperplasia (n = 1). Long-term follow-up for patients with SSDH is indicated as DCIS can occur subsequently in either breast.

  14. Congenital adrenal hyperplasia

    MedlinePlus

    ... or inappropriately). Congenital adrenal hyperplasia can affect both boys and girls. About 1 in 10,000 to 18,000 ... penis but normal testes Well-developed muscles Both boys and girls will be tall as children, but much shorter ...

  15. Atypical adenomatous hyperplasia

    Cancer.gov

    Focal and diffuse lesions involving alveoli and terminal bronchioles and consisting of relatively uniform atypical cuboidal to columnar cells with dense chromatin. Degrees of cellular hypertrophy and hyperchromasia are variable. Cellular and nuclear atypia are the distinctive features as compared with hyperplasia. Their relevance to human AAH and mouse adenomas remains to be determined.

  16. Oral focal epithelial hyperplasia.

    PubMed

    Bassioukas, K; Danielides, V; Georgiou, I; Photos, E; Zagorianakou, P; Skevas, A

    2000-01-01

    Focal epithelial hyperplasia (FEH) or Heck disease, is a rare viral infection of the oral mucosa caused by HPV 13 or HPV 32. In Caucasians there have been only a few cases reported. We present the first case in Greece in a young Caucasian girl in which HPV 13 was detected with PCR analysis. The patient was successfully treated with CO2 laser.

  17. Oral focal epithelial hyperplasia.

    PubMed

    López-Jornet, Pía; Camacho-Alonso, Fabio; Berdugo, Lucero

    2010-01-01

    Focal epithelial hyperplasia (FEH) is a benign, asymptomatic disease. It appears as papules, principally on the lower lip, although it can also be found on the retro-commissural mucosa and tongue and, less frequently, on the upper lip, gingiva and palate. FEH is caused by human papillomavirus subtype 13 or 32. The condition occurs in many populations and ethnic groups. We present the clinical case of a 31-year-old male with lesions that clinically and histologically corresponded to FEH.

  18. Pathologic pancreatic endocrine cell hyperplasia

    PubMed Central

    Ouyang, Debra; Dhall, Deepti; Yu, Run

    2011-01-01

    Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known. β cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy, which is commonly caused by mutations in the islet ATP-sensitive potassium channel, and to non-insulinoma pancreatogenous hypoglycemia in adults, which may or may not be associated with bariatric surgery. α cell hyperplasia may cause glucagonoma syndrome or induce pancreatic neuroendocrine tumors. An inactivating mutation of the glucagon receptor causes α cell hyperplasia and asymptomatic hyperglucagonemia. Pancreatic polypeptide cell hyperplasia has been described without a clearly-characterized clinical syndrome and hyperplasia of other endocrine cells inside the pancreas has not been reported to our knowledge. Based on morphological evidence, the main pathogenetic mechanism for pancreatic endocrine cell hyperplasia is increased endocrine cell neogenesis from exocrine ductal epithelium. Pancreatic endocrine cell hyperplasia should be considered in the diagnosis and management of hypoglycemia, elevated islet hormone levels, and pancreatic neuroendocrine tumors. Further studies of pathologic pancreatic endocrine cell hyperplasia will likely yield insights into the pathogenesis and treatment of diabetes and pancreatic neuroendocrine tumors. PMID:21245985

  19. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling

    PubMed Central

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M.; Kirkby, Nicholas S.; van de Putte, Elisabeth E. Fransen; Christen, Sibylle; Kimmitt, Robert A.; Moorhouse, Rebecca; Castellan, Raphael F.P.; Kotelevtsev, Yuri V.; Kuc, Rhoda E.; Davenport, Anthony P.; Dhaun, Neeraj; Webb, David J.

    2017-01-01

    The role of smooth muscle endothelinB (ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETB receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETB receptors were selectively deleted from smooth muscle by crossing floxed ETB mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ETB deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ETB was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ETB-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ETB-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ETB knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ETB blockade–mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ETB-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ETB knockout mice. In the absence of other pathology, ETB receptors in vascular smooth muscle make a small but significant contribution to ETB-dependent regulation of BP. These ETB receptors have no effect on vascular contraction or neointimal remodeling. PMID:28028193

  20. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.

    PubMed

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M; Kirkby, Nicholas S; van de Putte, Elisabeth E Fransen; Christen, Sibylle; Kimmitt, Robert A; Moorhouse, Rebecca; Castellan, Raphael F P; Kotelevtsev, Yuri V; Kuc, Rhoda E; Davenport, Anthony P; Dhaun, Neeraj; Webb, David J; Hadoke, Patrick W F

    2017-02-01

    The role of smooth muscle endothelinB (ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETB receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETB receptors were selectively deleted from smooth muscle by crossing floxed ETB mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ETB deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ETB was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ETB-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ETB-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ETB knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ETB blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ETB-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ETB knockout mice. In the absence of other pathology, ETB receptors in vascular smooth muscle make a small but significant contribution to ETB-dependent regulation of BP. These ETB receptors have no effect on vascular contraction or neointimal remodeling. © 2016 The Authors.

  1. [Focal epithelial hyperplasia].

    PubMed

    Delgado, Yolanda; Torrelo, Antonio; Colmenero, Isabel; Zambrano, Antonio

    2005-12-01

    Focal epithelial hyperplasia (FEH) is a benign proliferation of the oral mucosa with well defined clinical and histological characteristics. It has been associated with infection of the oral mucosa by types 13 and 32 of the human papillomavirus (HPV), and to a lesser extent, with other types. Its clinical course is variable, although it usually persists for months or years; cases with spontaneous resolution have been described, as have others with prolonged persistence. We present the case of an Ecuadorian boy whose visit was motivated by lesions in the oral mucosa consistent with a diagnosis of FEH, which were confirmed in the histological study, and in which HPV type 13 DNA was identified.

  2. Oncocytic hyperplasia of the larynx.

    PubMed

    Thawley, S E; Berlin, B P; Berkowitz, W P

    1977-07-01

    Oncocytic hyperplasia of the larynx is rare. The lesion most commonly arises from the false vocal chord. A distinction arises between oncocytomas of the salivary glands which are considered to be neoplasms and extrasalivary oncocytic lesions which are secondary to hyperplasia. Oncocytic lesions of the larynx are benign and treatment is excision. They may be multiple, but recurrences are rare.

  3. The N-Glycoform of sRAGE is the Key Determinant for Its Therapeutic Efficacy to Attenuate Injury-elicited Arterial Inflammation and Neointimal Growth

    PubMed Central

    Tae, Hyun-Jin; Kim, Ji Min; Park, Sungha; Tomiya, Noboru; Li, Geng; Wei, Wen; Petrashevskaya, Natalia; Ahmet, Ismayil; Pang, John; Cruschwitz, Stefanie; Riebe, Rebecca A.; Zhang, Yinghua; Morrell, Christopher H.; Browe, David; Lee, Yuan Chuan; Xiao, Rui-ping; Talan, Mark I.; Lakatta, Edward G.; Lin, Li

    2013-01-01

    Signaling of the receptor for advanced glycation end products (RAGE) has been implicated in the development of injury-elicited vascular complications. Soluble RAGE (sRAGE) acts as a decoy of RAGE, and has been used to treat pathological vascular conditions in animal models. However, previous studies using sRAGE produced in insect Sf9 cells (sRAGESf9) used a high dose and multiple injections to achieve the therapeutic outcome. Here, we explore whether modulation of sRAGE N-glycoform impacts its bioactivity and augments its therapeutic efficacy. We first profiled carbohydrate components of sRAGECHO to show that a majority of its N-glycans belong to sialylated complex-types that are not shared by sRAGESf9. In cell-based NF-κB activation and vascular smooth muscle cell (VSMC) migration assays, sRAGECHO exhibited a significantly higher bioactivity relative to sRAGESf9 to inhibit RAGE alarmin ligand-induced NF-κB activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGECHO is translated to higher in vivo therapeutic efficacy in a rat carotid artery balloon injury model. Consistent with the observed higher bioactivity in cell assays, sRAGECHO significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGECHO reduced neointimal hyperplasia by over 70%, whereas the same dose of sRAGESf9 showed no effect. The administered sRAGECHO is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGECHO may offset an inflammatory circuit and reduce the ensuing tissue remodeling. Our findings showed that the N-glycoform of sRAGE is the key determinant underlying its bioactivity, and thus is an important glycobioengineering target to develop a highly potent therapeutic sRAGE for future clinical applications. PMID:24132651

  4. Congenital adrenal hyperplasia.

    PubMed

    Merke, Deborah P; Bornstein, Stefan R

    Congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase is a disorder of the adrenal cortex characterised by cortisol deficiency, with or without aldosterone deficiency, and androgen excess. Patients with the most severe form also have abnormalities of the adrenal medulla and epinephrine deficiency. The severe classic form occurs in one in 15,000 births worldwide, and the mild non-classic form is a common cause of hyperandrogenism. Neonatal screening for CAH and gene-specific prenatal diagnosis are now possible. Standard hormone replacement fails to achieve normal growth and development for many children with CAH, and adults can experience iatrogenic Cushing's syndrome, hyperandrogenism, infertility, or the development of the metabolic syndrome. This Seminar reviews the epidemiology, genetics, pathophysiology, diagnosis, and management of CAH, and provides an overview of clinical challenges and future therapies.

  5. Extensive focal epithelial hyperplasia.

    PubMed

    Hashemipour, Maryam Alsadat; Shoryabi, Ali; Adhami, Shahrzad; Mehrabizadeh Honarmand, Hoda

    2010-01-01

    Heck's disease or focal epithelial hyperplasia is a benign contagious disease caused by human papillomavirus types 13 or 32. It occurs with low frequency in the Iranian population. This condition is characterized by the occurrence of multiple, small papules or nodules in the oral cavity, especially on the labial and buccal mucosa and tongue. In some populations, up to 39% of children are affected. Conservative surgical excision of lesions may be performed for diagnostic or aesthetic purposes. The risk of recurrence after this therapy is minimal, and there seems to be no malignant transformation potential. In the present work, we presented the clinical case of a 12-year-old Iranian girl with oral lesions that clinically and histologically correspond to Heck's disease.

  6. Novel role of Egr-1 in nicotine-related neointimal formation

    PubMed Central

    Vazquez-Padron, Roberto I.; Mateu, Dania; Rodriguez-Menocal, Luis; Wei, Yuntao; Webster, Keith A.; Pham, Si M.

    2010-01-01

    Aims The aim of this study was to investigate the mechanisms by which nicotine increases vascular smooth muscle cell (VSMC) proliferation and post-injury neointimal formation. Methods and results Vascular injury was inflicted in the right iliac artery of nicotine-treated and control rats. Nicotine increased post-injury VSMC proliferation (Ki67+ cells) and neointimal formation (neointima/media ratio, 0.42 ± 0.23 vs. 0.14 ± 0.07, P= 0.02). To determine the mechanisms by which nicotine exacerbates VSMC proliferation, cultured cells were exposed to nicotine, and signalling pathways leading to cell proliferation were studied. Nicotine activated extracellular signal-regulated kinase (ERK) 1/2 in a dose- and time-dependent manner. The blockade of this signalling axis abolished nicotine-mediated proliferation. Functional nicotinic acetylcholine receptors and Ca2+ influx were necessary for ERK1/2 activation and nicotine-induced mitogenesis in VSMCs. Downstream to ERK1/2, nicotine induced the phosphorylation of Ets-like gene 1 in a timely co-ordinated manner with the up-regulation of the atherogenic transcription factor, early growth response 1 (Egr-1). The treatment of balloon-injured arteries with a lentivirus vector carrying a short hairpin RNA against Egr-1 abolished the deleterious effect of nicotine on vascular remodelling. Conclusion Nicotine acts through its receptors in VSMC to activate the ERK–Egr-1 signaling cascade that induces cell proliferation and exacerbates post-injury neointimal development. PMID:20615913

  7. Amlodipine-induced gingival hyperplasia.

    PubMed

    Lafzi, Ardeshir; Farahani, Ramin Mostofi Zadeh; Shoja, Mohammad Ali Mohajjel

    2006-11-01

    Drug-induced gingival hyperplasia is a serious concern both for the patient and the clinician. A 45 year-old Caucasian male patient with hypertension, who received amlodipine (10 mg/day, single dose orally) for two months, sought medical attention because of the new-onset gingival enlargement. On clinical examination a generalized and firm overgrowth of the gingival throughout the maxilla and the mandible were evident. The lack of gingival inflammation and purulent discharge were other features of the clinical scenario. Histological assessment of the biopsy specimen revealed the hyperplasia of connective tissue, epithelial acanthosis, and elongated rete ridges along with few inflammatory cells. The histological and the clinical evidences were consistent with amlodipine-induced gingival hyperplasia. We believe that the present report indicates the most rapidly developed case of amlodipine-induced gingival hyperplasia reported to date. The related literature is reviewed and the underlying pathogenic mechanisms of this rare side-effect are discussed here.

  8. Congenital lipoid adrenal hyperplasia

    PubMed Central

    2014-01-01

    Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most fatal form of CAH, as it disrupts adrenal and gonadal steroidogenesis. Most cases of lipoid CAH are caused by recessive mutations in the gene encoding steroidogenic acute regulatory protein (StAR). Affected patients typically present with signs of severe adrenal failure in early infancy and 46,XY genetic males are phenotypic females due to disrupted testicular androgen secretion. The StAR p.Q258X mutation accounts for about 70% of affected alleles in most patients of Japanese and Korean ancestry. However, it is more prevalent (92.3%) in the Korean population. Recently, some patients have been showed that they had late and mild clinical findings. These cases and studies constitute a new entity of 'nonclassic lipoid CAH'. The cholesterol side-chain cleavage enzyme, P450scc (CYP11A1), plays an essential role converting cholesterol to pregnenolone. Although progesterone production from the fetally derived placenta is necessary to maintain a pregnancy to term, some patients with P450scc mutations have recently been reported. P450scc mutations can also cause lipoid CAH and establish a recently recognized human endocrine disorder. PMID:25654062

  9. C-cell hyperplasia.

    PubMed

    Guyétant, S; Bléchet, C; Saint-André, J-P

    2006-06-01

    Routine calcitonin assay programs and recent studies on the natural history of familial medullary thyroid carcinoma (MTC) have greatly added to our understanding of C-cell hyperplasia (CCH) and refined its classification. This article is an update on CCH physiopathology related to clinical presentation. With this combined approach, two types of CCH that differ by their physiological characteristics can be identified: neoplastic CCH and reactive (also called physiological) CCH. Neoplastic CCH is caused by a germline mutation of the RET protooncogene in a multiple endocrine neoplasia type 2 (MEN 2) syndrome. It progresses to MTC following a time line that depends on the RET mutation involved. CCH may actually be a misnomer for a neoplastic condition that some authors have proposed to call "in situ-MTC". Reactive CCH is considered to be caused by a stimulus that is external to the C-cell, and its premalignant potential is not documented. Many situations such as hypercalcemia, hyperparathyroidy, chronic lymphocytic thyroiditis or follicular tumors have been associated with reactive CCH, the pathogenesis of which remains unclear. But C-cell density in normal patients is subject to important variability, and several studies have demonstrated the dramatic male predominance in physiological CCH when hypercalcitoninemia was a random discovery. These data suggest that a number of conditions which were previously associated with reactive CCH might be purely fortuitous. Our clinical/pathological confrontation contributes to appropriately distinguishing between various CCH types, and in turn to identify the best way of managing patients.

  10. Benign prostatic hyperplasia

    PubMed Central

    2006-01-01

    Introduction Symptomatic benign prostatic hyperplasia (BPH) may affect up to 30% of men in their early 70s, causing urinary symptoms of bladder outlet obstruction. Symptoms can improve without treatment, but the usual course is a slow progression of symptoms, with acute urinary retention occurring in 1-2% of men with BPH per year. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical, surgical, and herbal treatments? We searched: Medline, Embase, The Cochrane Library and other important databases up to May 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: 5 alpha-reductase inhibitors, alpha-blockers, beta-sitosterol plant extract, less-invasive surgical techniques, pygeum africanum, rye grass pollen extract, saw palmetto plant extracts, transurethral microwave thermotherapy, transurethral needle ablation, and transurethral resection.

  11. Pharmacotherapy for benign prostatic hyperplasia.

    PubMed Central

    Narayan, P; Indudhara, R

    1994-01-01

    Benign prostatic hyperplasia is a benign neoplasm of the prostate seen in men of advancing age. Microscopic evidence of the disorder is seen in about 70% of men by 70 years of age, whereas symptoms requiring some form of surgical intervention occur in 30% of men during their lifetime. Although the exact cause of benign prostatic hyperplasia is not clear, it is well recognized that high levels of intraprostatic androgens are required for the maintenance of prostatic growth. In recent years, extensive surveys of patients undergoing transurethral resection of the prostate reveal an 18% incidence of morbidity that has essentially not changed in the past 30 years. This procedure is also the second highest reimbursed surgical therapy under Medicare. These findings have resulted in an intensive search for alternative therapies for prostatic hyperplasia. An alternative that has now been well defined is the use of alpha-adrenergic blockers to relax the prostatic urethra. This is based on findings that a major component of benign prostatic hyperplasia symptoms is spasm of the prostatic urethra and bladder neck, which is mediated by the alpha-adrenergic nerves. A second approach is to block androgens involved in maintaining prostate growth. Several such drugs are now available for clinical use, and we discuss their side effects and use. We also include the newer recommendations on evaluating benign prostatic hyperplasia that are cost-effective yet comprehensive. Images PMID:7528957

  12. Reduction of Intimal Hyperplasia with Re-188-labeled Stents in a Rabbit Model at 7 and 26 Weeks: An Experimental Study

    SciTech Connect

    Tepe, Gunnar Dietrich, Tobias; Grafen, Franziska; Brehme, Ute; Muschick, Peter; Dinkelborg, Ludger M.; Greschniok, Annette; Claussen, Claus D.; Duda, Stephan H.

    2005-06-15

    The aim of this study was to analyze the feasibility of {sup 188}Re-labeled stents to reduce neointimal formation in a rabbit atherosclerosis model and to test the long-term effects at 7 and 26 weeks. Fifty-nine male New Zealand White rabbits were fed a 0.5% cholesterol diet for 4 weeks before balloon angioplasty and insertion of Palmaz stents in the infrarenal aorta. The animals were sacrificed 7 and 26 weeks after stent implantation. Control stents were compared with {sup 188}Re stents: (dose 1) 11.3 {+-} 1.8 MBq; (dose 2) 37.3 {+-} 4.2 MBq, and (dose 3) 80.1 {+-} 7.8 MBq. Each activity group consisted of a short-term (7 weeks) and a long-term group (26 weeks), resulting in a total of eight study groups. No thrombotic occlusion was observed. The neointimal formation in the control group was 2.11 [95% confidence interval (CI): 0.68-6.52] mm{sup 2} at 7 weeks and 2.10 (0.62-7.11) at 26 weeks. In the treatment groups, neointima reduction was detectable at 7 weeks [dose 1: 0.33 (0.09-1.22) mm{sup 2}; dose 2: 0.17 (0.05-0.57) mm{sup 2}; dose 3: 0.03 (0.01-0.13) mm{sup 2}]. After 26 weeks, a catch-up of neointimal formation in the radioactive groups was most obvious in the low-dose group [dose 1: 0.80 (0.28-2.29) mm{sup 2}; dose 2: 0.18([0.06-0.52) mm{sup 2}; dose 3: 0.50 (0.17-1.42) mm{sup 2}]. Compared to the long-term control group, neointimal reduction was still >60%. No induction of neointimal formation was observed at the edges of the stents. Radiation resulted in delayed re-endothelialization. {sup 188}Re stents were capable to reduce intimal hyperplasia and did not cause thrombosis. The edge effect, which was the major limitation of {sup 32}P stents, was not observed in {sup 188}Re stents.

  13. BET Bromodomain Blockade Mitigates Intimal Hyperplasia in Rat Carotid Arteries.

    PubMed

    Wang, Bowen; Zhang, Mengxue; Takayama, Toshio; Shi, Xudong; Roenneburg, Drew Alan; Craig Kent, K; Guo, Lian-Wang

    2015-11-01

    Intimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic "readers" including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known. We investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model. While BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(-), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(-), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced. Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  14. BET Bromodomain Blockade Mitigates Intimal Hyperplasia in Rat Carotid Arteries.

    PubMed

    Wang, Bowen; Zhang, Mengxue; Takayama, Toshio; Shi, Xudong; Roenneburg, Drew Alan; Kent, K Craig; Guo, Lian-Wang

    2015-11-01

    Intimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic "readers" including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known. We investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model. While BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(-), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(-), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced. Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.

  15. Myometrial dysplasia (atypical myometrial hyperplasia).

    PubMed

    Cramer, Stewart F; Newcomb, Patricia M; Bonfiglio, Thomas A

    2007-04-01

    Although precursor lesions are well known for cervical and endometrial neoplasms, precursor lesions are not currently recognized for the most common tumor of the uterus-leiomyomas. Myometrial hyperplasia has been recently described and evaluated by morphometry, but its relationship to uterine leiomyomas has not been systematically explored. Myometrial dysplasia (atypical myometrial hyperplasia) has not been previously recognized. We herein report a case of myometrial dysplasia with immunostains for proliferation marker MIB-1 (Ki-67) and for p53. The paradoxical rarity of myometrial dysplasia is considered in comparison to the striking frequency of uterine leiomyomas.

  16. Thymic hyperplasia in Graves' disease.

    PubMed

    Kotwal, Narendra; Singh, Yashpal; Menon, Anil; Behera, Vineet

    2013-05-01

    Graves' disease is an autoimmune thyroid condition characterized by the production of autoantibodies against the thyrotropin receptor. It is known to be associated with autoimmune conditions such as myasthenia gravis, Addison's disease, type 1 diabetes mellitus, and vitiligo. We present a case of rare autoimmune association of Graves' disease with thymic hyperplasia which regressed after treatment with antithyroid drugs. Exact pathophysiology of thymic hyperplasia in Graves' is not well understood; it is likely to be the result of rather than the cause of Graves' disease.

  17. Focal epithelial hyperplasia: Case report.

    PubMed

    Puriene, Alina; Rimkevicius, Arunas; Gaigalas, Mindaugas

    2011-01-01

    The purpose of the present article is to present a 15 year-old patient with focal epithelial hyperplasia and to review the references on the subject-related etiological, pathological, diagnostic and treatment aspects. Focal epithelial hyperplasia is a rare human papilloma virus (HPV) related to oral lesion with very low frequency within our population. Surgical treatment with a biopsy was performed, acanthosis and parakeratosis are consistent histopathological features, since the patient had no history of sexual contact and HIV infection, the virus was probably acquired from environmental sources.

  18. Therapeutic options for management of endometrial hyperplasia.

    PubMed

    Chandra, Vishal; Kim, Jong Joo; Benbrook, Doris Mangiaracina; Dwivedi, Anila; Rai, Rajani

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

  19. Therapeutic options for management of endometrial hyperplasia

    PubMed Central

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH. PMID:26463434

  20. Automatic detection of stent struts with thick neointimal growth in intravascular optical coherence tomography image sequences

    NASA Astrophysics Data System (ADS)

    Xu, Chenyang; Schmitt, Joseph M.; Akasaka, Takashi; Kubo, Takashi; Huang, Kun

    2011-10-01

    To assist cardiologists investigating neointimal tissue growth on stents during follow-up with optical coherence tomography (OCT), we developed an automatic algorithm to locate deeply buried stent struts and to quantify the restenosis burden. The technique is based on an improved steerable filter for computing the local ridge strength and orientation. It also uses an ellipsoid fitting algorithm and continuity criteria to obtain globally optimal stent localization. The restenosis burden calculations were compared to manual assessment of OCT coronary artery image data obtained from in vivo human clinical studies. Compared to manual assessment by expert readers, the algorithm operated with > 97% accuracy in the measurement of mean and maximum restenosis burden. The results indicated that the technique yielded comparable accuracy in measuring restenosis burden, and significantly reduced user interaction time.

  1. Use of rosiglitazone before and after vascular injury in hypercholesterolemic rabbits: Assessment of neointimal formation

    PubMed Central

    Alessi, Alexandre; França Neto, Olímpio Ribeiro; Brofman, Paulo Roberto Slud; Prim, Camila; Noronha, Lucia; Silva, Ruy Fernando Kuenzer Caetano; Baroncini, Liz Andréa Villela; Précoma, Dalton Bertolim

    2008-01-01

    Objectives To analyse the effects of rosiglitazone administered at different times on neointimal formation in hypercholesterolemic rabbits following vascular injury. Methods Thirty-nine rabbits on a hypercholesterolemic diet were included. The animals underwent balloon catheter injury to the right iliac artery on day 14. They were divided into three groups as follows: control group, 13 rabbits without rosiglitazone; group I, 13 rabbits treated with rosiglitazone (3 mg/Kg body weight/day) for 28 days after the vascular injury; and group II, 13 rabbits treated with rosiglitazone (3 mg/Kg body weight/day) during all the experiment (42 days). Histological analysis was done by an experienced pathologist who was unaware of the rosiglitazone treatment. Histomorphometric parameters were performed by calculation of the luminal and intimal layer area, and intima/media layer area ratio (the area of the intimal layer divided by the area of the medial layer). Results Intimal area was significantly lower in group II vs. CG (p = 0.024) and group I (p = 0.006). Luminal layer area was higher in group II vs. CG (p < 0.0001) and group I (p < 0.0001). Intima/media layer area ratio was equal between CG and group I. Intima/media layer ratio area was significantly lower in group II vs. control group (p < 0.021) and group I (p < 0.003). There was a significant reduction of 65% and 71% in intima/media layer area ratio in group II vs. control group and group I, respectively. Conclusion Pretreatment with rosiglitazone in hypercholesterolemic rabbits submitted to vascular injury significantly reduces neointimal formation. PMID:18752684

  2. [Regenerative nodular hyperplasia in HIV].

    PubMed

    González, Ramiro Javier Romo; Chaves, Emiliano; Mullen, Eduardo; Copello, Hercilia

    2011-12-01

    Nodular regenerative hyperplasia of the liver is a rare condition. We describe here the case of a patient with HIV who presented with a clinical syndrome of portal hypertension. After multiple evaluations the diagnosis was recognized by the histology. The findings were attributed to the prolonged use of didanosine.

  3. Rare presentation of sebaceous hyperplasia

    PubMed Central

    Lester, Rachael A; Torgerson, Rochelle R; Sandhu, Nicole P

    2014-01-01

    A 23-year-old woman presented with an 8-month history of asymptomatic thickening of the central areola bilaterally and oily nipple discharge. On examination, there were yellowish-pink papules coalescing into plaques bilaterally. Biopsy showed ectopic sebaceous glands (Montgomery tubercles), known as bilateral areolar sebaceous hyperplasia. PMID:24759166

  4. [Frequency of Kongenital Adrenal Hyperplasia (author's transl)].

    PubMed

    Müller, W; Prader, M; Kofler, J; Glatzl, J; Geir, W

    1979-01-01

    The frequency of homozygous congenital adrenal hyperplasia in Tyrol is found to be 1 : 8991, the gene-frequency for congenital adrenal hyperplasia 1 : 95 and the frequency of heterozygous congenital adrenal hyperplasia 1 : 48. Our data is compared on a numerical and statistical base with that in Zürich and Munich with regard to the frequency of congenital adrenal hyperplasia, to its distribution with and without salt loss and to its sex-distribution. According to our study one may assume a frequency of homozygous congenital adrenal hyperplasia in Tyrol, Zürich and Munich of 1 : 7000--10,000.

  5. [Role of cytokine-matrix metalloproteinase axis on promoting vascular neointima hyperplasia in mice].

    PubMed

    Liu, Y; Ning, W H; Shen, X H; Guo, D L; Guo, L

    2016-11-24

    Objective: To observe the effects of tumor necrosis factor-α (TNF-α) and platelet derived growth factor (PDGF) on vascular neointimal hyperplasia on matrix metalloproteinase 9/2 gene knockout (MMP9/2(-/-)) mice and explore related mechanisms. Methods: Mice of control group, MMP9(-/-) group, MMP2(-/-) group and MMP9/2(-/-) group were studied. Femoral artery was injured by transluminal wire, the mRNA expression levels of TNF-α and PDGF on femoral artery were detected by RT-PCR; the protein expression of MMP9 and MMP2 were assessed by Western blot on day 0, 1, 3, 7, 14 and 28 post injury. Mice in control group received TNF-α(5 ng/ml, 0.10 ml), TNF-α(0.05 ml)+ MMP inhibitor SB-3CT(0.50 ng/ml, 0.05 ml) injection, or PDGF-bb (10 ng/ml, 0.10 ml)and PDGF-bb(0.05 ml)+ SB-3CT(0.05 ml)injection around injured artery, intimal hyperplasia at 2 and 4 weeks after injury was observed. Intimal hyperplasia at 2 and 4 weeks after injury was also observed in MMP9/2(-/-) mice. TNF-α(5 ng/ml, 0.10 ml)was injected to MMP2(-/-) mice, PDGF-bb (0.1 ml) was injected to MMP9(-/-) mice around injured artery, intimal hyperplasia at 2 and 4 weeks after injury was observed. The degree of neointimal hyperplasia were observed by the Elastica-van Gieson staining and the area of neointima and media of the arteries were measured by SigmaPlot and intima ratio was calculated. Vascular smooth muscle cell (VSMC) mediums of MMP9(-/-) and MMP2(-/-) mice were stimulated by TNF-α and PDGF-bb, respectively, and migration assay, and proliferation assay were performed, relative migration and proliferation cells numbers were counted. Results: (1) mRNA expression of TNF-α (235.33±23.68) and PDGF-bb (3.30±0.56) in femoral arteries peaked at 1 day after injury, while MMP9 or MMP2 protein expression peaked at 7 or 28 days after injury. (2)In control mice, TNF-α intervention significantly enhanced intimal hyperplasia at 2 weeks after injury (2.21±0.05 vs. 1.55±0.03 in blank control group, P<0.05), while

  6. Frequency of Vascular Inflammation and Impact on Neointimal Proliferation of Drug Eluting Stents in Porcine Coronary Arteries

    PubMed Central

    Yeh, Jong Shiuan; Oh, Seung Jin; Hsueh, Chun Mei

    2016-01-01

    Background We aimed to describe the frequency of vascular inflammatory reactions with second generation drug eluting stents (DES) compared to first generation DES, and analyze the impact on inflammation and neointimal proliferation in a porcine coronary model. Methods A total of 26 stents (7 multi-link VISION, 6 CYPHER, 6 TAXUS and 7 XIENCE V) were deployed in the coronary arteries of 10 domestic swine for 28 days, after which each stent was harvested and processed (divided into 8 or 9 segments) for histomorphometric analysis. Results A total of 202 histological segments [146 DES and 56 bare metal stents (BMS)] were included in this study. The mean neointimal thickness was significantly reduced in the DES group compared to the BMS group. The DES group had higher injury scores (DES = 0.99 ± 0.79 versus BMS = 0.67 ± 0.44, p < 0.004), inflammatory scores (DES = 2.09 ± 1.54 versus BMS = 0.64 ± 0.98, p < 0.001) and presence of para-strut granulomas (DES = 35% versus BMS = 2%, p < 0.001). In logistic regression analysis, the presence of para-strut granulomas correlated with an area of stenosis > 50% (RR: 6.11, 95% CI: 2.97 to 12.59, p = 0.001). In the DES group, the second generation stents had a lower neointimal area (XIENCE V: 1.64 ± 0.90 mm2) compared to the first generation stents (TAXUS: 2.36 ± 1.56 mm2, p = 0.005; CYPHER 2.78 ± 1.82 mm2, p = 0.001). The XIENCE V stents had lower inflammatory scores and lower frequency of para-strut granulomas compared to the first generation stents. Conclusions Second generation DES had a lower incidence of vascular inflammatory reactions compared to first generation DES. This biological phenomenon appears to influence the patterns of neointimal formation. PMID:27713606

  7. Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type 1 (PAI-1).

    PubMed

    Schneider, David J; Hayes, Michael; Wadsworth, Marilyn; Taatjes, Heidi; Rincón, Mercedes; Taatjes, Douglas J; Sobel, Burton E

    2004-08-01

    Rupture of vulnerable atheroma often underlies acute coronary syndromes. Vulnerable plaques exhibit a paucity of vascular smooth muscle cells (VSMCs) in the cap. Therefore, decreased VSMC migration into the neointima may predispose to vulnerability. The balance between cell surface plasminogen activator activity and its inhibition [mediated primarily by plasminogen activator inhibitor type 1 (PAI-1)] modulates migration of diverse types of cells. We sought to determine whether increased expression of PAI-1 would decrease migration of VSMCs in vitro and neointimal cellularity in vivo in apolipoprotein E knockout (ApoE(-/-)) mice fed a high-fat diet. Increased vessel wall expression of PAI-1 in transgenic mice was induced with the SM22alpha promoter. VSMC migration through Matrigel in vitro was quantified with laser scanning cytometry. Expression of PAI-1 was increased threefold in the aortic wall of SM22-PAI transgene-positive mice. Neointimal cellularity of vascular lesions was decreased by 26% (p=0.01; n=5 each) in ApoE(-/-) mice with the SM22-PAI transgene compared with ApoE(-/-) mice. VSMCs explanted from transgene-positive mice exhibited twofold greater expression of PAI-1 and their migration was attenuated by 27% (p=0.03). Accordingly, increased expression of PAI-1 protein by VSMCs reduces their migration in vitro and their contribution to neointimal cellularity in vivo.

  8. Roscovitine attenuates intimal hyperplasia via inhibiting NF-κB and STAT3 activation induced by TNF-α in vascular smooth muscle cells.

    PubMed

    He, Ming; Wang, Chao; Sun, Jia-Huan; Liu, Yu; Wang, Hong; Zhao, Jing-Shan; Li, Yun-Feng; Chang, Hong; Hou, Jian-Ming; Song, Jun-Na; Li, Ai-Ying; Ji, En-Sheng

    2017-08-01

    Roscovitine is a selective CDK inhibitor originally designed as anti-cancer agent, which has also been shown to inhibit proliferation in vascular smooth muscle cells (VSMCs). However, its effect on vascular remodeling and its mechanism of action remain unknown. In our study, we created a new intimal hyperplasia model in male Sprague-Dawley rats by trypsin digestion method, which cause to vascular injury as well as the model of rat carotid balloon angioplasty. Roscovitine administration led to a significant reduction in neointimal formation and VSMCs proliferation after injury in rats. Western blot analysis revealed that, in response to vascular injury, TNF-α stimulation induced p65 and STAT3 phosphorylation and promoted translocation of these molecules into the nucleus. p65 can physically associate with STAT3 and bind to TNF-α-regulated target promoters, such as MCP-1 and ICAM-1, to initiate gene transcription. Roscovitine can interrupt activation of NF-κB and reduce expression of TNF-α-induced proinflammatory gene, thus inhibiting intimal hyperplasia. These findings provide a novel mechanism to explain the roscovitine-mediated inhibition of intimal hyperplasia induced by proinflammatory pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Phytotherapeutic Agents for Benign Prostatic Hyperplasia: An Overview.

    PubMed

    Passi, Neelima Dhingra

    2016-06-20

    Benign prostatic hyperplasia (BPH) the most common condition in aging men is the non malignant enlargement of the prostate gland with increase in numbers of both epithelial and stromal cells within the periurethal transition zone of the prostate. Sources of symptoms in patient with BPH appear to be both static and dynamic component. Management of BPH has undergone a rapid evolution over the past decade to aid men with lower urinary tract symptoms attributed to bladder outlet obstruction. Treatment of clinical BPH aims to improve symptoms, prevent urinary tract infections, avoid renal insult, relief obstruction and improve bladder emptying.Prostate cancer patients and those with benign prostatic hyperplasia are increasingly exploring the use of plant derived non-nutritive compounds with protective or disease preventive properties, especially due to long term side effects of pharmacological treatment and risk of mortality associated with surgical procedures. Phytotherapeutic preparations are plant extracts with different components obtained by different extraction procedures. Numerous mechanisms of action have been postulated for mono and combination plant extracts. This article give a brief account of rationale and efficacy of various existing phytotherapeutic agents in the management of benign prostatic hyperplasia, including the herbs which hold the potential promise are also mentioned , although much research is still required.

  10. Real-Time Electrical Bioimpedance Characterization of Neointimal Tissue for Stent Applications.

    PubMed

    Rivas-Marchena, David; Olmo, Alberto; Miguel, José A; Martínez, Mar; Huertas, Gloria; Yúfera, Alberto

    2017-07-28

    To follow up the restenosis in arteries stented during an angioplasty is an important current clinical problem. A new approach to monitor the growth of neointimal tissue inside the stent is proposed on the basis of electrical impedance spectroscopy (EIS) sensors and the oscillation-based test (OBT) circuit technique. A mathematical model was developed to analytically describe the histological composition of the neointima, employing its conductivity and permittivity data. The bioimpedance model was validated against a finite element analysis (FEA) using COMSOL Multiphysics software. A satisfactory correlation between the analytical model and FEA simulation was achieved in most cases, detecting some deviations introduced by the thin "double layer" that separates the neointima and the blood. It is hereby shown how to apply conformal transformations to obtain bioimpedance electrical models for stack-layered tissues over coplanar electrodes. Particularly, this can be applied to characterize the neointima in real-time. This technique is either suitable as a main mechanism for restenosis follow-up or it can be combined with proposed intelligent stents for blood pressure measurements to auto-calibrate the sensibility loss caused by the adherence of the tissue on the micro-electro-mechanical sensors (MEMSs).

  11. Quantitative 3-Dimensional Imaging of Murine Neointimal and Atherosclerotic Lesions by Optical Projection Tomography

    PubMed Central

    Kirkby, Nicholas S.; Low, Lucinda; Seckl, Jonathan R.; Walker, Brian R.; Webb, David J.; Hadoke, Patrick W. F.

    2011-01-01

    Objective Traditional methods for the analysis of vascular lesion formation are labour intensive to perform - restricting study to ‘snapshots’ within each vessel. This study was undertaken to determine the suitability of optical projection tomographic (OPT) imaging for the 3-dimensional representation and quantification of intimal lesions in mouse arteries. Methods and Results Vascular injury was induced by wire-insertion or ligation of the mouse femoral artery or administration of an atherogenic diet to apoE-deficient mice. Lesion formation was examined by OPT imaging of autofluorescent emission. Lesions could be clearly identified and distinguished from the underlying vascular wall. Planimetric measurements of lesion area correlated well with those made from histological sections subsequently produced from the same vessels (wire-injury: R2 = 0.92; ligation-injury: R2 = 0.89; atherosclerosis: R2 = 0.85), confirming both the accuracy of this methodology and its non-destructive nature. It was also possible to record volumetric measurements of lesion and lumen and these were highly reproducible between scans (coefficient of variation = 5.36%, 11.39% and 4.79% for wire- and ligation-injury and atherosclerosis, respectively). Conclusions These data demonstrate the eminent suitability of OPT for imaging of atherosclerotic and neointimal lesion formation, providing a much needed means for the routine 3-dimensional analysis of vascular morphology in studies of this type. PMID:21379578

  12. Human recombinant activated protein C-coated stent for the prevention of restenosis in porcine coronary arteries.

    PubMed

    Lukovic, Dominika; Nyolczas, Noemi; Hemetsberger, Rayyan; Pavo, Imre J; Pósa, Aniko; Behnisch, Boris; Horak, Gerhard; Zlabinger, Katrin; Gyöngyösi, Mariann

    2015-10-01

    Activated protein C (APC), an endogenous protein, inhibits inflammation and thrombosis and interrupts the coagulation cascade. Here, we investigated the effect of human recombinant APC on the development of neointimal hyperplasia in porcine coronary arteries. Yukon Choice bare metal stents were coated with 2.6 µg APC/mm(2). Under general anesthesia, APC-coated and bare stents were implanted in the left anterior descending and circumflex coronary arteries of 10 domestic pigs. During the 4-week follow-up, animals were treated with dual antiplatelet therapy and neointimal hyperplasia was evaluated via histology. Scanning electron microscopy indicated successful but unequal coating of stents with APC; nearly complete drug release occurred within 4 h. Enzyme-linked immunosorbent assay revealed that intracoronary stent implantation rapidly increased the levels of monocyte chemoattractant protein-1, an effect that was inhibited by APC release from the coated stent. Fibrin deposition and adventitial inflammation were significantly decreased 1 month after implanting APC-coated stents versus bare stents, paralleled by significantly smaller neointimal area (0.98 ± 0.92 vs. 1.44 ± 0.91 mm(2), P = 0.028), higher lumen area (3.47 ± 0.94 vs. 3.06 ± 0.91 mm(2), P = 0.046), and lower stenosis area (22.2 ± 21.2% vs. 32.1 ± 20.1%, P = 0.034). Endothelialization was complete with APC-coated but not bare (90%) stents. P-selectin immunostaining revealed significantly fewer activated endothelial cells in the neointima in the APC group (4.6 ± 1.9 vs. 11.6 ± 4.1%, P < 0.001). Thus, short exposure of coronary arteries to APC reduced inflammatory responses, neointimal proliferation, and in-stent restenosis, offering a promising therapy to improve clinical outcomes of coronary stenting. However, coating stents with APC for prolonged, controlled drug release remains technically challenging.

  13. Pituicytoma Coexisting With Corticotroph Hyperplasia

    PubMed Central

    Guo, Xiaopeng; Fu, Hanhui; Kong, Xiangyi; Gao, Lu; Wang, Wenze; Ma, Wenbin; Yao, Yong; Wang, Renzhi; Xing, Bing

    2016-01-01

    Abstract Pituicytoma is a rare, low-grade glial neoplasm that arises in the neurohypophysis or infundibulum and usually presents as pituitary gland enlargement. They are often misdiagnosed as pituitary adenomas. Causes have varied for high serum adrenocorticotropic hormone level reported in a few patients with pituicytoma. We report a rare case of pituicytoma accompanied by corticotroph hyperplasia—a challenging diagnosis guided by clinical presentations, radiological signs, and biopsy. We present a case of pituicytoma with corticotroph hyperplasia in a 46-year-old woman with typical Cushing syndrome. Magnetic resonance imaging revealed a lesion in the sellar area with equal T1 and T2 signals and marked homogeneous enhancement. We present detailed analysis of the patient's disease course and review pertinent literature. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary. The patient underwent a surgical exploration and tumor resection through a trans-sphenoidal approach. Pathologic results revealed pituicytoma and corticotroph hyperplasia. As adrenocorticotropic hormone and cortisol levels did not decrease to normal, the patient received radiotherapy and recovered uneventfully. No recurrence was found over 8 years of follow-up. Pituicytoma is a rare type of sellar tumor. Pituicytomas in patients with Cushing syndrome are rarer still. To our knowledge, this is the first report of Cushing syndrome caused by corticotroph hyperplasia in a pituicytoma patient. PMID:26962837

  14. Focal epithelial hyperplasia: Heck disease.

    PubMed

    Cohen, P R; Hebert, A A; Adler-Storthz, K

    1993-09-01

    Two sisters of Mexican ancestry had focal epithelial hyperplasia (FEH). The lesions on the oral mucosa of the older child were initially misinterpreted as representing sexual abuse. Microscopic evaluation of a hematoxylin and eosin-stained section from a lower lip papule demonstrated the histologic features of FEH. Although human papillomavirus (HPV) type 13 and HPV32 have been most consistently present in FEH lesions, types 6, 11, 13, and 32 were not detected in the paraffin-embedded tissue specimen of our patient using an in situ hybridization technique. The lesions persisted or recurred during management using destructive modalities; subsequently, they completely resolved spontaneously.

  15. Benign Prostatic Hyperplasia: An Overview

    PubMed Central

    Roehrborn, Claus G

    2005-01-01

    Despite the deceptively simple description of benign prostatic hyperplasia (BPH), the actual relationship between BPH, lower urinary tract symptoms (LUTS), benign prostatic enlargement, and bladder outlet obstruction is complex and requires a solid understanding of the definitional issues involved. The etiology of BPH and LUTS is still poorly understood, but the hormonal hypothesis has many arguments in its favor. There are many medical and minimally invasive treatment options available for affected patients. In the intermediate and long term, minimally invasive treatment options are superior to medical therapy in terms of symptom and flow rate improvement; tissue ablative surgical treatment options are superior to both minimally invasive and medical therapy. PMID:16985902

  16. Prevention

    MedlinePlus

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  17. Nodular extramammary Paget disease with fibroepitheliomatous hyperplasia.

    PubMed

    Kim, Joung Soo; Jeong, Myeong Gil; Kang, Ho Song; Yu, Hee Joon

    2014-12-01

    Extramammary Paget disease (EMPD) is a rare skin condition usually found in the anogenital region. Histologically, EMPD may be associated with varying degrees of epidermal hyperplasia classified as squamous, papillomatous, or fibroepitheliomatous. We report a case of EMPD in a 90-year-old man who presented with well-demarcated plaques and a nodule in the pubic area with fibroepitheliomatous hyperplasia.

  18. Hyperplasia in glands with hormone excess.

    PubMed

    Marx, Stephen J

    2016-01-01

    Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.

  19. Oral verrucous hyperplasia: a case report.

    PubMed

    Navaneetham, Anuradha; Dayanand Saraswathi, M C; Santosh, B S

    2014-09-01

    Oral verrucous hyperplasia is a whitish or pinkinsh elevated pre malignant lesion which occurs rarely. Its is also considered to be an early form of verrucous carcinoma. We have reported a case of verrucous hyperplasia which was diagnosed and treated with buccal fat pad as graft.

  20. The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

    PubMed Central

    Charron, Thierry; Nili, Nafiseh; Strauss, Bradley H

    2006-01-01

    Percutaneous coronary intervention is the preferred revascularization approach for most patients with coronary artery disease. However, this strategy is limited by renarrowing of the vessel by neointimal hyperplasia within the stent lumen (in-stent restenosis). Vascular smooth muscle cell proliferation is a major component in this healing process. This process is mediated by multiple cytokines and growth factors, which share a common pathway in inducing cell proliferation: the cell cycle. The cell cycle is highly regulated by numerous mechanisms ensuring orderly and coordinated cell division. The present review discusses current concepts related to regulation of the cell cycle and new therapeutic options that target aspects of the cell cycle. PMID:16498512

  1. Imaging Characteristics of Pathologically Proven Thymic Hyperplasia: Identifying Features That Can Differentiate True From Lymphoid Hyperplasia

    PubMed Central

    Araki, Tetsuro; Sholl, Lynette M.; Gerbaudo, Victor H.; Hatabu, Hiroto; Nishino, Mizuki

    2014-01-01

    OBJECTIVE The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia. MATERIALS AND METHODS Thirty-one patients (nine men and 22 women; age range, 20–68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n = 27), PET/CT (n = 5), or MRI (n = 6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared. RESULTS No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p > 0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p < 0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p = 0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66. CONCLUSION CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed

  2. Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia.

    PubMed

    Osgood, Michael J; Sexton, Kevin; Voskresensky, Igor; Hocking, Kyle; Song, Jun; Komalavilas, Padmini; Brophy, Colleen; Cheung-Flynn, Joyce

    2016-08-01

    Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV. Copyright © 2016. Published by Elsevier Inc.

  3. Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia

    PubMed Central

    Osgood, Michael J.; Sexton, Kevin; Voskresensky, Igor; Hocking, Kyle; Song, Jun; Komalavilas, Padmini; Brophy, Colleen; Cheung-Flynn, Joyce

    2017-01-01

    Background Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. Methods Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. Results FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. Conclusions Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV. PMID:27763268

  4. Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation.

    PubMed

    Ikutomi, Masayasu; Sahara, Makoto; Nakajima, Toshiaki; Minami, Yoshiyasu; Morita, Toshihiro; Hirata, Yasunobu; Komuro, Issei; Nakamura, Fumitaka; Sata, Masataka

    2015-09-01

    It is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries. BM mononuclear cells of Fisher-344 rats were cultured under endothelial cell-conditions. Early EPCs appeared on days 3-6. Late-outgrowth and very late-outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9-14 and 17-21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1×10(6) per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31(+) LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7±7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs. BM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH. Copyright © 2015. Published by Elsevier Ltd.

  5. Effect of methanolic extract of Piper sarmentosum leaves on neointimal foam cell infiltration in rabbits fed with high cholesterol diet

    PubMed Central

    Amran, Adel A.; Zakaria, Zaiton; Othman, Faizah; Das, Srijit; Al-Mekhlafi, Hesham M.; Raj, Santhana; Nordin, Nor-Anita MM

    2012-01-01

    Previous research has shown the beneficial effects of aqueous extract of Piper sarmentosum (P.s) on atherosclerosis. The first stage in atherosclerosis is the formation of foam cell. The aim of this study was to investigate the effect of the methanol extract of P.s on fatty streaks by calculating neointimal foam cell infiltration in rabbits fed with high cholesterol diet. Thirty six male New Zealand white rabbits were divided equally into six groups: (i) C: control group fed normal rabbit chow; (ii) CH: cholesterol diet (1 % cholesterol); (iii) PM1: 1 % cholesterol with methanol extract of P.s (62.5 mg/kg); (iv) PM2: 1 % cholesterol with methanol extract of P.s (125 mg/kg); (v) PM3: 1 % cholesterol with methanol extract of P.s (250 mg/kg); (vi) SMV group fed 1 % cholesterol supplemented with Simvistatin drug (1.2 mg/kg). All animals were treated for 10 weeks. At the end of the treatment, the rabbits were fasted and sacrificed and the aortic tissues were collected for histological studies to measure the area of the neointimal foam cell infiltration using software. The thickening of intima ratio of atherosclerosis and morphological changes by scanning electron microscope were measured. The results showed that the atherosclerotic group had significantly bigger area of fatty streak compared to the control group. The area of fatty streak in the abdominal aorta was significantly reduced in the treatment groups which were similar with the SMV group. Similarly, there was a reduction in the number of foam cell in the treatment groups compared to the atherosclerotic group as seen under scanning microscope. In conclusion, histological study demonstrated that the methanol extract of the P.s could reduce the neointimal foam cell infiltration in the lumen of the aorta and the atherosclerotic lesion. PMID:27366140

  6. Decreased Neointimal Extracellular Matrix Formation in RAGE-Knockout Mice After Microvascular Denudation

    SciTech Connect

    Groezinger, Gerd Schmehl, Joerg Bantleon, Ruediger Kehlbach, Rainer; Mehra, Tarun; Claussen, Claus Wiesinger, Benjamin

    2012-12-15

    Purpose: To evaluate in vivo the role of RAGE (receptor for advanced glycated end products) in the development of restenosis and neointimal proliferation in RAGE-deficient knockout (KO) mice compared with wild-type (WT) mice in an animal model. Materials and Methods: Sixteen WT and 15 RAGE-deficient mice underwent microvascular denudation of the common femoral artery under general anaesthesia. Contralateral arteries underwent a sham operation and served as controls. Four weeks after the intervention, all animals were killed, and paraformaldehyde-fixed specimens of the femoral artery were analysed with different stains (hematoxylin and eosin and Elastica van Gieson) and several different types of immunostaining (proliferating cell nuclear antigen, {alpha}-actin, collagen, von Willebrand factor, RAGE). Luminal area, area of the neointima, and area of the media were measured in all specimens. In addition, colony-formation assays were performed, and collagen production by WT smooth muscle cells (SMCs) and RAGE-KO SMCs was determined. For statistical analysis, P < 0.05 was considered statistically significant. Results: Four weeks after denudation, WT mice showed a 49.6% loss of luminal area compared with 14.9% loss of luminal area in RAGE-deficient mice (sham = 0% loss) (P < 0.001). The neointima was 18.2 (*1000 {mu}m{sup 2} [n = 15) in the WT group compared with only 8.4 (*1000 {mu}m{sup 2} [n = 16]) in the RAGE-KO group. RAGE-KO SMCs showed significantly decreased proliferation activity and production of extracellular matrix protein. Conclusion: RAGE may be shown to play a considerable role in the formation of neointima leading to restenosis after vascular injury.

  7. Impact of polymer formulations on neointimal proliferation after zotarolimus-eluting stent with different polymers: insights from the RESOLUTE trial.

    PubMed

    Waseda, Katsuhisa; Ako, Junya; Yamasaki, Masao; Koizumi, Tomomi; Sakurai, Ryota; Hongo, Yoichiro; Koo, Bon-Kwon; Ormiston, John; Worthley, Stephen G; Whitbourn, Robert J; Walters, Darren L; Meredith, Ian T; Fitzgerald, Peter J; Honda, Yasuhiro

    2011-06-01

    Polymer formulation may affect the efficacy of drug-eluting stents. Resolute, Endeavor, and ZoMaxx are zotarolimus-eluting stents with different stent platforms and different polymer coatings and have been tested in clinical trials. The aim of this analysis was to compare the efficacy of zotarolimus-eluting stents with different polymers. Data were obtained from the first-in man trial or first randomized trials of each stent, The Clinical RESpOnse EvaLUation of the MedTronic Endeavor CR ABT-578 Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (RESOLUTE), Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions (ENDEAVOR II), and ZoMaxx I trials. Follow-up intravascular ultrasound analyses (8 to 9 months of follow-up) were possible in 353 patients (Resolute: 88, Endeavor: 98, ZoMaxx: 82, Driver: 85). Volume index (volume/stent length) was obtained for vessel, stent, lumen, peristent plaque, and neointima. Cross-sectional narrowing was defined as neointimal area divided by stent area (%). Neointima-free frame ratio was calculated as the number of frames without intravascular ultrasound-detectable neointima divided by the total number of frames within the stent. At baseline, vessel, lumen, and peristent plaque volume index were not significantly different among the 4 stent groups. At follow-up, percent neointimal obstruction was significantly lower in Resolute compared with Endeavor, ZoMaxx, and Driver (Resolute: 3.7±4.0, Endeavor: 17.5±10.1, ZoMaxx: 14.6±8.1, Driver: 29.4±17.2%; P<0.001). Greater maximum cross-sectional narrowing and higher neointima-free frame ratio, suggesting less neointimal coverage, were observed in Resolute compared with other stent groups. Multiple regression analysis confirmed that the biodurable polymer used in Resolute independently correlated with neointimal suppression among 3 zotarolimus-eluting stents

  8. Automated detection of vessel lumen and stent struts in intravascular optical coherence tomography to evaluate stent apposition and neointimal coverage

    SciTech Connect

    Nam, Hyeong Soo; Kim, Chang-Soo; Yoo, Hongki E-mail: hyoo@hanyang.ac.kr; Lee, Jae Joong; Song, Joon Woo; Kim, Jin Won E-mail: hyoo@hanyang.ac.kr

    2016-04-15

    Purpose: Intravascular optical coherence tomography (IV-OCT) is a high-resolution imaging method used to visualize the microstructure of arterial walls in vivo. IV-OCT enables the clinician to clearly observe and accurately measure stent apposition and neointimal coverage of coronary stents, which are associated with side effects such as in-stent thrombosis. In this study, the authors present an algorithm for quantifying stent apposition and neointimal coverage by automatically detecting lumen contours and stent struts in IV-OCT images. Methods: The algorithm utilizes OCT intensity images and their first and second gradient images along the axial direction to detect lumen contours and stent strut candidates. These stent strut candidates are classified into true and false stent struts based on their features, using an artificial neural network with one hidden layer and ten nodes. After segmentation, either the protrusion distance (PD) or neointimal thickness (NT) for each strut is measured automatically. In randomly selected image sets covering a large variety of clinical scenarios, the results of the algorithm were compared to those of manual segmentation by IV-OCT readers. Results: Stent strut detection showed a 96.5% positive predictive value and a 92.9% true positive rate. In addition, case-by-case validation also showed comparable accuracy for most cases. High correlation coefficients (R > 0.99) were observed for PD and NT between the algorithmic and the manual results, showing little bias (0.20 and 0.46 μm, respectively) and a narrow range of limits of agreement (36 and 54 μm, respectively). In addition, the algorithm worked well in various clinical scenarios and even in cases with a low level of stent malapposition and neointimal coverage. Conclusions: The presented automatic algorithm enables robust and fast detection of lumen contours and stent struts and provides quantitative measurements of PD and NT. In addition, the algorithm was validated using

  9. Pseudoepitheliomatous hyperplasia after diode laser oral surgery. An experimental study

    PubMed Central

    Seoane, Juan; González-Mosquera, Antonio; García-Martín, José-Manuel; García-Caballero, Lucía; Varela-Centelles, Pablo

    2015-01-01

    Background To examine the process of epithelial reparation in a surgical wound caused by diode laser. Material and Methods An experimental study with 27 Sprage-Dawley rats was undertaken. The animals were randomly allocated to two experimental groups, whose individuals underwent glossectomy by means of a diode laser at different wattages, and a control group treated using a number 15 scalpel blade. The animals were slaughtered at the 2nd, 7th, and 14th day after glossectomy. The specimens were independently studied by two pathologists (blinded for the specimens’ group). Results At the 7th day, re-epithelisation was slightly faster for the control group (conventional scalpel) (p=0.011). At the 14th day, complete re-epithelization was observed for all groups. The experimental groups displayed a pseudoepitheliomatous hyperplasia. Conclusions It is concluded that, considering the limitations of this kind of experimental studies, early re-epithelisation occurs slightly faster when a conventional scalpel is used for incision, although re-epithelisation is completed in two weeks no matter the instrument used. In addition, pseudoepitheliomatous hyperplasia is a potential event after oral mucosa surgery with diode laser. Knowledge about this phenomenon (not previously described) may prevent diagnostic mistakes and inadequate treatment approaches, particularly when dealing with potentially malignant oral lesions. Key words:Diode laser, animal model, oral biopsy, oral cancer, oral precancer, pseudoepitheliomatous hyperplasia. PMID:26116841

  10. Prevention

    Treesearch

    Kerry Britton; Barbara Illman; Gary Man

    2010-01-01

    Prevention is considered the most cost-effective element of the Forest Service Invasive Species Strategy (USDA Forest Service 2004). What makes prevention difficult is the desire to maximize free trade and the resulting benefits to society while, at the same time, protecting natural resources. The role of science is to first identify which commodities pose an...

  11. [Phytotherapy of benign prostatic hyperplasia].

    PubMed

    Bracher, F

    1997-01-01

    Phytopharmaceutical agents have been used for a long time in the treatment of symptomatic benign prostatic hyperplasia (BPH). However, until recently, it has been questioned whether phytotherapy is superior to a placebo treatment. In this article, the most widely used phytopharmaceutical agents, such as saw palmetto berry extracts, Radix urticae extracts, pumpkin seeds, pollen extracts and different phytosterols, are described. In addition, both in vitro and in vivo studies are discussed in an attempt to explain a possible mechanism of action. There are several new clinical studies which demonstrate a significant benefit compared with placebo treatment. Based on these results, the use of phytopharmaceutical agents for the treatment of mild to moderate symptomatic BPH seems to be well justified. So far, no significant inhibition of further prostate growth has been demonstrated. For this, a careful follow-up of the patients is necessary so as not to miss a deterioration and perhaps the need for an operation.

  12. Lasers for median lobe hyperplasia.

    PubMed

    Muschter, R; Gilling, A P

    2001-08-01

    Laser treatment encompases a variety of techniques using different laser wavelengths, application systems, and surgical techniques to achieve contrasting tissue effects such as incision, resection, vaporization, or coagulation. Many studies have proven the clinical efficacy of the various laser techniques for the treatment of benign prostatiuc hyperplasia, including randomized studies versus transurethral prostatectomy (TURP). Recently, long-term follow-up of up to 5 years has demonstrated the durability of the results, although in some of the studies, retreatment rates were higher than after TURP. Median lobes were never seen as a contraindication for treatment in the laser based procedures. Technically, laser treatment techniques such as side-firing transurethral coagulation, contact- and free-beam laser vaporization, interstitial laser coagulation, and the holmium laser-based resection and enucleation are fully suitable for treatment of median lobes. Surprisingly, no studies focussing specifically on laser treatment of median lobes have been published.

  13. Focal epithelial hyperplasia - an update.

    PubMed

    Said, Ahmed K; Leao, Jair C; Fedele, Stefano; Porter, Stephen R

    2013-07-01

    Focal epithelial hyperplasia (FEH) is an asymptomatic benign mucosal disease, which is mostly observed in specific groups in certain geographical regions. FEH is usually a disease of childhood and adolescence and is generally associated with people who live in poverty and of low socioeconomic status. Clinically, FEH is typically characterized by multiple, painless, soft, sessile papules, plaques or nodules, which may coalesce to give rise to larger lesions. Human papillomavirus (HPV), especially genotypes 13 and 32, have been associated and detected in the majority of FEH lesions. The clinical examination and social history often allow diagnosis, but histopathological examination of lesional tissue is usually required to confirm the exact diagnosis. FEH sometimes resolves spontaneously however, treatment is often indicated as a consequence of aesthetic effects or any interference with occlusion. There remains no specific therapy for FEH, although surgical removal, laser excision or possibly topical antiviral agents may be of benefit. There remains no evidence that FEH is potentially malignant.

  14. Laser tonsillotomy in children with tonsillar hyperplasia.

    PubMed

    Baharudin, A; Shahid, H; Rhendra, M Z

    2006-08-01

    Tonsillectomy in children is performed on a regular basis in ENT. The indications are chronic tonsillitis, sleep apnea to deeper structures. The natural history of tonsillar hyperplasia is regression when a child is six years beyond. In children with bilateral tonsillar hyperplasia we studied the use of laser as an alternative procedure to reduce the bulk of the tonsillar mass. Children with symptoms of bilateral tonsillar hyperplasia underwent laser tonsillotomy. The tonsils were dissected using carbon dioxide (CO2) laser. The tonsillar bed was left untouched. Intraoperative and postoperative conditions were noted.

  15. Preventing in-stent restenosis using lipoprotein (a), lipid and cholesterol adsorbent materials.

    PubMed

    Kazemian, Mohammad Reza; Solouk, Atefeh; Tan, Aaron; Seifalian, Alexander M

    2015-12-01

    Atherosclerosis is one of the major cause of mortality in developed countries. The characteristic lesion of atherosclerosis is the atheroma or plaque that forms through thickening of the inner layer of the vessel wall (called the intima). The development of stent in 1980s revolutionised treatment of cardiovascular diseases, including atherosclerosis. However the advent of stenting was hindered by the new problem of in-stent restenosis. It was demonstrated that in-stent restenosis was the result of a new pathology in the form of neointimal hyperplasia, which was a maladaptive healing response to bare-metal stent implantation. Recent evidence suggests that although drug-eluting stent (DES) have reduced restenosis rates, important concerns have been raised regarding increased late stent thrombosis, myocardial infarction and death. With advances in nanotechnology and smart materials, covered stents has been proposed to overcome this problem. This is due to in-stent late restenosis and thromboses are mainly caused by smooth muscle cells (SMC) proliferation. Studies showed that there is a relation between high low-density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] level in blood stream and chance of in-stent restenosis, moreover studies show that Lp(a) could stimulate SMC proliferation. We hypothesis development of covered stent with novel design and use of smart materials which could adsorb cholesterol and prevent contact between Lp(a) and vessel wall to overcome problem indicated in DES. In addition cost of stents will significantly reduce by elimination of drugs as well as complex manufacturing of the drug incorporation.

  16. Kir2.1 regulates rat smooth muscle cell proliferation, migration, and post-injury carotid neointimal formation

    SciTech Connect

    Qiao, Yong; Tang, Chengchun Wang, Qingjie; Wang, Dong; Yan, Gaoliang; Zhu, Boqian

    2016-09-02

    Phenotype switching of vascular smooth muscle cells (VSMC) from the contractile type to the synthetic type is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. Inward rectifier K{sup +} channel 2.1 (Kir2.1) has been identified in VSMC. However, whether it plays a functional role in regulating cellular transformation remains obscure. In this study, we evaluated the role of Kir2.1 on VSMC proliferation, migration, phenotype switching, and post-injury carotid neointimal formation. Kir2.1 knockdown significantly suppressed platelet-derived growth factor BB-stimulated rat vascular smooth muscle cells (rat-VSMC) proliferation and migration. Deficiency in Kir2.1 contributed to the restoration of smooth muscle α-actin, smooth muscle 22α, and calponin and to a reduction in osteopontin expression in rat-VSMC. Moreover, the in vivo study showed that rat-VSMC switched to proliferative phenotypes and that knockdown of Kir2.1 significantly inhibited neointimal formation after rat carotid injury. Kir2.1 may be a potential therapeutic target in the treatment of cardiovascular diseases, such as atherosclerosis and restenosis following percutaneous coronary intervention.

  17. Nifedipine suppresses neointimal thickening by its inhibitory effect on vascular smooth muscle cell growth via a MEK-ERK pathway coupling with Pyk2

    PubMed Central

    Hirata, Akihiko; Igarashi, Masahiko; Yamaguchi, Hiroshi; Suwabe, Akira; Daimon, Makoto; Kato, Takeo; Tominaga, Makoto

    2000-01-01

    The aim of this study was to determine whether nifedipine could suppress an atherogenic process such as balloon-injured intimal thickening in vivo and the proliferation of vascular smooth muscle cells (VSMC) in vitro. First, we examined the in vivo effect of nifedipine to determine whether it could suppress intimal thickening induced by balloon catheterization. Sprague-Dawley (SD) rats were divided into three groups (L, nifedipine 0.3 mg kg−1 day−1; H, nifedipine 3 mg kg−1 day−1; C, no nifedipine), and Alzet® osmotic pumps were implanted in their backs for continuous administration. The neointimal layers were completely occupied by proliferated VSMC, and the area ratios of neointima/media treated with nifedipine significantly decreased dose-dependently compared to those of the control. Neither blood pressure nor lipid levels changed among the three groups. We next evaluated the in vitro effect of nifedipine on the proliferation of cultured rat VSMC. Nifedipine decreased the values of [3H]-thymidine incorporation and total cellular protein content as well as the levels of phosphorylated extracellular signal-regulated protein kinase (ERK) 1/2, mitogen-activated protein kinase kinase (MEK) 1/2, and even the phosphorylation of Pyk2, in dose-dependent fashions. In addition, nifedipine suppressed the levels of proliferative cell nuclear antigen (PCNA) dose-dependently in both VSMC and balloon-injured thoracic aortae. These results indicate that nifedipine has an inhibitory effect on intimal thickening by attenuating intimal VSMC proliferation, suggesting that nifedipine could be effective for preventing the progression of atherosclerotic plaque as in restenosis after angioplasty. PMID:11139427

  18. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Neuroendocrine Hyperplasia of Infancy.

    PubMed

    Carr, Laurie L; Kern, Jeffrey A; Deutsch, Gail H

    2016-09-01

    Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Altered dipeptidyl peptidase IV and prolyl endopeptidase activities in chronic tonsillitis, tonsillar hyperplasia and adenoid hyperplasia.

    PubMed

    Larrinaga, Gorka; Pérez, Itxaro; Sanz, Begoña; Zarrazquin, Idoia; Casis, Luis; Anta, Jose Antonio; Martínez, Agustin; Santaolalla, Francisco

    2011-03-01

    To analyse peptidase activities in the removed tonsils and adenoids from patients with chronic tonsillitis, tonsillar hyperplasia and adenoid hyperplasia. We have analyzed 48 tissue samples from patients undergoing tonsillectomy and adenoidectomy for chronic tonsillitis, tonsillar hyperplasia or adenoid hyperplasia. Tonsillectomy and adenoidectomy samples were collected and frozen for later enzyme analysis. The catalytic activity of a pool of peptidases (dipeptidyl peptidase IV, prolyl endopeptidase, aminopeptidase A, aminopeptidase N, aspartyl aminopeptidase, aminopeptidase B, neutral endopeptidase, pyroglutamyl peptidase I, puromycin-sensitive aminopeptidase and cystinyl aminopeptidase) was measured fluorometrically. The activity of prolyl endopeptidase was higher in tonsillar hyperplasia and adenoid hyperplasia than in chronic tonsillitis. On the contrary, dipeptidyl peptidase IV activity was higher in chronic tonsillitis than in hypertrophic tissues. When data were stratified by age and gender, dipeptidyl peptidase IV was also found to be more active in adult and male chronic tonsillitis tissues. Inversely, dipeptidyl peptidase IV activity was higher in tissues of females with tonsillar hyperplasia. These data indicate the involvement of dipeptidyl peptidase IV and prolyl endopeptidase in the mechanisms underlying chronic tonsillitis, tonsillar hyperplasia and adenoid hyperplasia. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Sebaceous hyperplasia: systemic treatment with isotretinoin*

    PubMed Central

    Tagliolatto, Sandra; Santos, Octavio de Oliveira; Alchorne, Maurício Mota de Avelar; Enokihara, Mauro Yoshiaki

    2015-01-01

    The study aimed to verify the therapeutic action of isotretinoin in the treatment of sebaceous hyperplasia. During two months, 20 patients with sebaceous hyperplasia took isotretinoin at a dosage of 1mg/kg per day. Their skin lesions were counted and photographed before and after treatment and re-evaluated two years later. The average number of sebaceous hyperplasia lesions before treatment was 24 per patient. At the end of two months of therapy, the number of lesions decreased to 2 per patient. The statistically analyzed data showed a reduction in the number of lesions following isotretinoin use (p < 0.05). Two years after the end of the treatment, the average number of sebaceous hyperplasia lesions was 4 per patient. There were no severe side effects. Thus, the data analysis suggests that isotretinoin is a safe and effective drug for treating the disease under study. PMID:25830991

  1. Diffuse villous hyperplasia of choroid plexus.

    PubMed

    Iplikcioglu, A C; Bek, S; Gökduman, C A; Bikmaz, K; Cosar, M

    2006-06-01

    Diffuse villous hyperplasia of choroid plexus (DVHCP) is a rare condition which is characterized by the presence of diffuse enlargement of the entire choroid plexus throughout the length of the choroidal fissure and overproduction of CSF. The diagnosis of diffuse villous hyperplasia of choroid plexus can be established by the MR demonstration of diffusely large, contrast enhanced choroid plexus in the cases of overproduction hydrocephalus. Although some authors recommend choroid plexus excision or coagulation, ventriculo-atrial shunt insertion is a simple and effective treatment modality in cases of diffuse villous hyperplasia of the choroid plexus. In this report we present a case of diffuse villous hyperplasia of the choroid plexus and a short review of the literature. To our knowledge, in the CT and MRI era only 5 cases of DVHCP cases have been reported.

  2. Oxidative stress in benign prostate hyperplasia.

    PubMed

    Zabaiou, N; Mabed, D; Lobaccaro, J M; Lahouel, M

    2016-02-01

    To assess the status of oxidative stress in benign prostate hyperplasia, a very common disease in older men which constitutes a public health problem in Jijel, prostate tissues were obtained by transvesical adenomectomy from 10 men with benign prostate hyperplasia. We measured the cytosolic levels of malondialdehyde (MDA) and glutathione (GSH) and cytosolic enzyme activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase. The development of benign prostate hyperplasia is accompanied by impaired oxidative status by increasing levels of MDA, depletion of GSH concentrations and a decrease in the activity of all the antioxidant enzymes studied. These results have allowed us to understand a part of the aetiology of benign prostate hyperplasia related to oxidative stress.

  3. Ancient history of congenital adrenal hyperplasia.

    PubMed

    New, Maria I

    2011-01-01

    Although there are many erudite reports on the history of endocrinology and endocrine disorders, the history of congenital adrenal hyperplasia has not been published. I have tried to review ancient as well as modern history of CAH.

  4. Sebaceous hyperplasia: systemic treatment with isotretinoin.

    PubMed

    Tagliolatto, Sandra; Santos Neto, Octavio de Oliveira; Alchorne, Maurício Mota de Avelar; Enokihara, Mauro Yoshiaki

    2015-01-01

    The study aimed to verify the therapeutic action of isotretinoin in the treatment of sebaceous hyperplasia. During two months, 20 patients with sebaceous hyperplasia took isotretinoin at a dosage of 1mg/kg per day. Their skin lesions were counted and photographed before and after treatment and re-evaluated two years later. The average number of sebaceous hyperplasia lesions before treatment was 24 per patient. At the end of two months of therapy, the number of lesions decreased to 2 per patient. The statistically analyzed data showed a reduction in the number of lesions following isotretinoin use (p < 0.05). Two years after the end of the treatment, the average number of sebaceous hyperplasia lesions was 4 per patient. There were no severe side effects. Thus, the data analysis suggests that isotretinoin is a safe and effective drug for treating the disease under study.

  5. An uncommon focal epithelial hyperplasia manifestation.

    PubMed

    dos Santos-Pinto, Lourdes; Giro, Elisa Maria Aparecida; Pansani, Cyneu Aguiar; Ferrari, Junia; Massucato, Elaine Maria Sgavioli; Spolidório, Luis Carlos

    2009-01-01

    Focal epithelial hyperplasia is a rare, contagious disease associated with infection of the oral mucosa by human papillomavirus types 13 or 32, characterized by multiple soft papules of the same color as the adjacent normal mucosa. It mainly affects the lower lip, buccal mucosa, and tongue. The purpose of this case report was to describe a rare verrucal lesion located in the upper gingiva that was clinically and histologically consistent with focal epithelial hyperplasia.

  6. Modulating vascular intimal hyperplasia using HSV-1 mutant requires activated MEK.

    PubMed

    Skelly, C L; He, Q; Spiguel, L; McCormick, S; Weichselbaum, R

    2013-02-01

    Outcomes of cardiovascular procedures, such as angioplasty and stent or bypass grafting are limited by failure, predominantly caused by pathological smooth muscle cell (SMC) proliferation, known as intimal hyperplasia. Local delivery of a genetically engineered herpes simplex virus (HSV) is known to block vascular SMC proliferation while allowing for re-endothelialization. However, the mechanism this mutant virus uses to prevent SMC hyperplasia is unknown. The Ras signaling cascade is activated in SMCs undergoing hyperplasia leading to phosphorylation of the mitogen-activated protein kinase (MAPK). In this study we tested the hypothesis that MAPK kinase (MEK) activity is the molecular basis by which SMCs are susceptible to mutant HSV. We show that genetically engineered herpes simplex-1 viruses (HSV-1) can target proliferating SMCs. We demonstrate that the molecular basis of this HSV-1 anti-proliferative effect is MEK activation in SMCs. We demonstrate efficacy and practicality of the MEK-dependent HSV-1 for the treatment of intimal hyperplasia in a clinically relevant in vivo model. Important to this strategy is the ability to modulate the effects by controlling viral dose. These results propel genetically engineered HSV-1 therapy towards clinical evaluation in treatment of intimal hyperplasia.

  7. Delay of Postnatal Maturation Sensitizes the Mouse Prostate to Testosterone-Induced Pronounced Hyperplasia

    PubMed Central

    Savolainen, Saija; Pakarainen, Tomi; Huhtaniemi, Ilpo; Poutanen, Matti; Mäkelä, Sari

    2007-01-01

    The role of estrogens in the etiology of prostate cancer is controversial. To demonstrate the specific effects of estrogens and androgens on the development of the prostatic epithelial hyperplasia, we used luteinizing hormone receptor knockout mice (LuRKO), which are resistant to pituitary regulation mediated by luteinizing hormone, lack postnatal androgen production, and have rudimentary accessory sex glands, the growth of which can be induced with exogenous androgen replacement. This model is thus ideal for the investigation of direct hormonal effects on the prostate. Testosterone, but not 5α-dihydrotestosterone, replacement from 21 days of life for 8 weeks induced pronounced hyperplasia and inflammation in the prostates of LuRKO mice. Interestingly, 5α-dihydrotestosterone combined with 17β-estradiol did not induce hyperplasia or inflammation, and treatments with inhibitors of estrogen action, aromatase inhibitor, and ICI 182780 further exacerbated testosterone-induced hyperplastic growth. However, the activation of estrogen receptor (ER)-β with a specific agonist, DPN [2,3-bis(4-hydroxyphenol)-propionitrile], prevented the development of prostatic hyperplasia and inflammation in testosterone-treated LuRKO mice. Thus, it seems that in the presence of sufficient androgenic stimulation, it is the balance between ER-α- and ER-β-mediated signaling that determines whether estrogens promote hyperplasia or protect the prostate against hyperplastic changes. PMID:17640960

  8. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice.

    PubMed

    Akagi, Daisuke; Chen, Mian; Toy, Robert; Chatterjee, Anuran; Conte, Michael S

    2015-06-01

    Vascular injury induces a potent inflammatory response that influences vessel remodeling and patency, limiting long-term benefits of cardiovascular interventions such as angioplasty. Specialized proresolving lipid mediators (SPMs) derived from ω-3 polyunsaturated fatty acids [eicosapentaenoic acid and docosahexaenoic acid (DHA)] orchestrate resolution in diverse settings of acute inflammation. We hypothesized that systemic administration of DHA-derived SPMs [resolvin D2 (RvD2) and maresin 1 (MaR1)] would influence vessel remodeling in a mouse model of arterial neointima formation (carotid ligation). In vitro, SPM treatment inhibited mouse aortic smooth muscle cell migration (IC₅₀ ≅ 1 nM) to a PDGF gradient and reduced TNF-α-stimulated p65 translocation, superoxide production, and proinflammatory gene expression (MCP-1). In vivo, adult FVB mice underwent unilateral carotid artery ligation with administration of RvD2, MaR1, or vehicle (100 ng by intraperitoneal injection at 0, 1, 3, 5, and 7 d after ligation). In ligated carotid arteries at 4 d, SPM treatment was associated with reduced cell proliferation and neutrophil and macrophage recruitment and increased polarization of M2 macrophages in the arterial wall. Neointimal hyperplasia (at 14 d) was notably attenuated in RvD2 (62%)- and MaR1 (67%)-treated mice, respectively. Modulation of resolution pathways may offer new opportunities to regulate the vascular injury response and promote vascular homeostasis.

  9. Mis-sizing of stent promotes intimal hyperplasia: impact of endothelial shear and intramural stress.

    PubMed

    Chen, Henry Y; Sinha, Anjan K; Choy, Jenny S; Zheng, Hai; Sturek, Michael; Bigelow, Brian; Bhatt, Deepak L; Kassab, Ghassan S

    2011-12-01

    Stent can cause flow disturbances on the endothelium and compliance mismatch and increased stress on the vessel wall. These effects can cause low wall shear stress (WSS), high wall shear stress gradient (WSSG), oscillatory shear index (OSI), and circumferential wall stress (CWS), which may promote neointimal hyperplasia (IH). The hypothesis is that stent-induced abnormal fluid and solid mechanics contribute to IH. To vary the range of WSS, WSSG, OSI, and CWS, we intentionally mismatched the size of stents to that of the vessel lumen. Stents were implanted in coronary arteries of 10 swine. Intravascular ultrasound (IVUS) was used to size the coronary arteries and stents. After 4 wk of stent implantation, IVUS was performed again to determine the extent of IH. In conjunction, computational models of actual stents, the artery, and non-Newtonian blood were created in a computer simulation to yield the distribution of WSS, WSSG, OSI, and CWS in the stented vessel wall. An inverse relation (R(2) = 0.59, P < 0.005) between WSS and IH was found based on a linear regression analysis. Linear relations between WSSG, OSI, and IH were observed (R(2) = 0.48 and 0.50, respectively, P < 0.005). A linear relation (R(2) = 0.58, P < 0.005) between CWS and IH was also found. More statistically significant linear relations between the ratio of CWS to WSS (CWS/WSS), the products CWS × WSSG and CWS × OSI, and IH were observed (R(2) = 0.67, 0.54, and 0.56, respectively, P < 0.005), suggesting that both fluid and solid mechanics influence the extent of IH. Stents create endothelial flow disturbances and intramural wall stress concentrations, which correlate with the extent of IH formation, and these effects were exaggerated with mismatch of stent/vessel size. These findings reveal the importance of reliable vessel and stent sizing to improve the mechanics on the vessel wall and minimize IH.

  10. [Expression of telomerase genes in mamary atypical ductal hyperplasia].

    PubMed

    Song, Min; Mi, Xiaoyi; Li, Bailin; Zhu, Jijiang; Gao, Yingxian; Cui, Shuang; Song, Jiye

    2002-02-01

    To investigate the relationship of telomerase genes and the malignant transformation of atypical mammary ductal hyperplasia. Telomerase genes hTR and hTRT in 50 cases of mammary hyperplasia (the cases included 6 benign hyperplasia, 9 mild atypical hyperplasia, 12 medium atypical hyperplasia, 23 severe atypical hyperplasia) and 26 cases of breast carcinoma were detected by in situ hybridization. The expression of hTR and hTRT mRNA were weak or negative in benign hyperplasia (1/6, 0), weaker in mild-moderate atypical hyperplasia (2/9, 1/9, 4/12, and 3/12), strong in severe atypical hyperplasia (14/23, 60.9% and 12/23, 52.1%), while very strong expression (23/26, 88.5% and 21/25, 80.8%) in carcinoma of the breast. The difference between mild-moderate atypical hyperplasia, invasive ductal carcinoma and severe atypical hyperplasia was significant (P < 0.05) and the difference between severe atypital hyperplasia and intraductal carcinoma was not significant (P > 0.05). Telmerase genes (hTR, hTRT) expression is closely related to the malignant transformation of atypical hyperplasia. The reactivated telomerase may play a crucial role in the development of breast cancer.

  11. Intrathyroidal parathyroid hyperplasia in tertiary hyperparathyroidism

    PubMed Central

    Kim, Byung Seup; Ryu, Han Suk; Kang, Kyung Ho; Park, Sung Jun

    2013-01-01

    We report herein a case of intrathyroidal parathyroid hyperplasia in a patient with tertiary hyperparathyroidism. The patient was recommended for parathyroidectomy due to sustained hypercalcemia after kidney transplantation. Preoperative radiologic evaluations showed a benign-looking thyroid mass and three enlarged parathyroid glands. Intraoperative intact parathyroid hormone (iPTH) level and frozen biopsy results indicated a missed parathyroid gland after immediate subtotal parathyroidectomy. Then, a secondary partial resection of thyroid including the thyroid nodule was performed. An excised intrathyroid nodule was diagnosed to be parathyroid hyperplasia by frozen biopsy, and intraoperative iPTH level abruptly decreased. A benign-looking thyroidal mass in patients with secondary or tertiary hyperparathyroidism should be carefully evaluated considering the possibility of an intrathyroidal parathyroid hyperplasia. PMID:24964443

  12. Pseudocarcinomatous hyperplasia of the urinary bladder.

    PubMed

    Wu, Angela

    2014-10-01

    We review the morphology and differential diagnoses of pseudocarcinomatous hyperplasia of the bladder, using a study case to illustrate the discussion. Pseudocarcinomatous hyperplasia is a rare, reactive response to an ischemic insult, classically to radiation therapy, and consists of proliferative, pseudoinfiltrative urothelial nests within the stroma. The presence of background radiation therapy-related changes, such as numerous dilated thrombosed vessels, reactive-appearing endothelial and stromal cells, edema, and hemorrhage, can provide clues to the diagnosis. The main differential diagnoses include invasive urothelial carcinoma and the nested variant of urothelial carcinoma; morphologic features, such as the presence or absence of background therapy-related changes and the architecture and the cytologic atypia of the nests, can help distinguish between pseudocarcinomatous hyperplasia and urothelial carcinoma.

  13. [Modern pharmacotherapy of benign prostatic hyperplasia].

    PubMed

    Krysiak, Robert; Okopień, Bogusław; Szkróbka, Witold; Herman, Zbigniew Stanisław

    2005-11-01

    Benign prostatic hyperplasia is the most common medical problem affecting elderly men throughout the world. With increasing awareness of health issues amongst males, the morbidity caused by this disease is not longer being accepted as just part of growing old. Until about 10 years ago, surgery was the only effective treatment for symptomatic benign prostatic hyperplasia. Now, many men suffering from this disorder may be effectively treated with a medical therapy. This article provides an overview of the efficacy and safety of 5alpha-reductase inhibitors, alpha1-adrenoceptor antagonists and herbal remedies, putting special emphasis on the current place of these agents in the modem therapy of benign prostatic hyperplasia. Wherever possible, our opinion is based on the detailed analysis of the results of available clinical trials.

  14. Outcome of congenital adrenal hyperplasia.

    PubMed

    Kuhnle, U; Bullinger, M

    1997-09-01

    In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, affected girls are born with ambiguous genitalia due to increased secretion of androgens in utero by the defective adrenal gland. Even though it is generally accepted that there are differences between male and female brain development, determining factors have been difficult to identify. Girls with CAH have frequently been studied to evaluate the impact of prenatal androgen exposure on psychological, psychosocial, and psychosexual development, and impairments in various areas have been identified. However, there is no comprehensive study available regarding the outcome of this chronic disorder in adult life. We studied the quality of life in women with CAH, with particular emphasis on how they cope with genital malformations, genital operations, and chronic disease as well as lifelong medication. The patients filled out questionnaires covering their physical state, psychological well-being, social relationships, and functional capacity, as well as questionnaires on psychosexual identification and psychosocial integration. The results were evaluated using a computerized statistical program for social studies. Out of a total of 94 patients above 18 years of age, 45 agreed to participate and were compared to 46 healthy, age-matched controls. Age at diagnosis was 2. 31 +/- 1.55 years and 38% suffered from the simple-virilizing, 45% from the salt-wasting, and 17.0% from the late-onset form of CAH. About one-third of patients had Prader stage 3 or 4 genital virilization. While the overall quality of life did not differ significantly, CAH patients were more often single (47.8% vs. 66.7%) and fewer of them had children (22.2% vs. 38.6%) compared to controls. Significant impairments were found in regard to body image and attitudes toward sexuality, but there was no increased homosexual preference. The women were successful in adjusting to illness and receiving social support. It is speculated that

  15. Pseudoepitheliomatous Hyperplasia in a Red Pigment Tattoo

    PubMed Central

    Kazlouskaya, Viktoryia

    2015-01-01

    Red pigment tattoos are known to cause pseudoepitheliomatous hyperplasia in the skin, frequently simulating squamous cell carcinoma or keratoacanthoma. Herein, the authors present two additional cases of red pigment tattoo pseudoepitheliomatous hyperplasia in which they noted a lichenoid tissue reaction. They reviewed the previously published cases and observed a lichenoid reaction in the histopathological images similar to hypertrophic lichen planus. The authors suggest that these reactions might best be referred to as “lichenoid reaction with pseudoepitheliomatous hyperplasia” or “hypertrophic lichen planus-like reaction.” Accordingly, recognition of an inflammatory component may allow additional treatment options. PMID:26705448

  16. Extensive Focal Epithelial Hyperplasia: A Case Report.

    PubMed

    Mansouri, Zahra; Bakhtiari, Sedigheh; Noormohamadi, Robab

    2015-01-01

    Focal epithelial hyperplasia (FEH) or Heck's disease is a rare viral infection of the oral mucosa caused by human papilloma virus especially subtypes 13 or 32. The frequency of this disease varies widely from one geographic region and ethnic groups to another. This paper reports an Iranian case of extensive focal epithelial hyperplasia. A 35-year-old man with FEH is described, in whom the lesions had persisted for more than 25 years. The lesion was diagnosed according to both clinical and histopathological features. Dental practitioner should be aware of these types of lesions and histopathological examination together and a careful clinical observation should be carried out for a definitive diagnosis.

  17. Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats.

    PubMed

    Zhang, Ying Qian; Tian, Feng; Zhou, Ying; Chen, Yun Dai; Li, Bo; Ma, Qiang; Zhang, Ying

    2016-04-08

    Diabetic patients suffer from undesired intimal hyperplasia after angioplasty. Nicorandil has a trend to reduce the rate of target lesion revascularization. However, whether nicorandil inhibits intimal hyperplasia and the possible mechanisms underlying it remain to be determined. We aimed at assessing the effect of nicorandil on intimal hyperplasia in diabetic rats. After intraperitoneal injection of streptozotocin (STZ, 50 mg/kg), balloon injury model was established in carotid arteries of diabetic rats. Rats were randomized to vehicle, nicorandil (15 mg/kg/day) or 5-hydroxydecanoate (5-HD, 10 mg/kg/day), a mitochondrial ATP-sensitive potassium channel (mitoKATP channel)-selective antagonist. Perivascular delivery of εPKC siRNA was conducted to determine the role of εPKC pathway in intimal hyperplasia. In hyperglycemia environment (25 mM glucose), primary culture of vascular smooth muscle cells (VSMCs) were treated with nicorandil or 5-HD. Cell proliferation and cell migration were analyzed. Intimal hyperplasia significantly increased 14 days after balloon injury in diabetic rats (p < 0.01). Nicorandil inhibited intima development, reduced inflammation and prevented cell proliferation in balloon-injured arteries (p < 0.01). The protective effects of nicorandil were reversed by 5-HD (p < 0.05). εPKC was activated in balloon-injured arteries (p < 0.01). Nicorandil inhibited εPKC activation by opening mitoKATP channel. Perivascular delivery of εPKC siRNA inhibited intimal hyperplasia, inflammation and cell proliferation (p < 0.01). High glucose-induced VSMCs proliferation and migration were inhibited by nicorandil. εPKC activation induced by high glucose was also inhibited by nicorandil and that is partially reversed by 5-HD. εPKC knockdown prevented VSMCs proliferation and migration (p < 0.01). Our study demonstrates that nicorandil inhibits intimal hyperplasia in balloon-injured arteries in diabetic rats. Nicorandil also prevents VSMCs proliferation and

  18. Effects of metal coverage rate of flow diversion device on neointimal growth at side branch ostium and stented artery: an animal experiment in rabbit abdominal aorta.

    PubMed

    Hong, Bo; Wang, Kuizhong; Huang, Qinghai; Xu, Yi; Fang, Xinggen; Li, Zhen; Liu, Jianmin

    2012-08-01

    To access the effect of actual metal coverage rate (MCR) on neointimal growth at covered side branch ostium and stented artery after implantation of a flow diversion device. Flow diverters (FDs) were implanted into abdominal aortas of 20 New Zealand rabbits. Four weeks and three months after FD implantation, the patency of side branches covered by the devices was assessed by angiography. The animals were sacrificed after angiography at 3 months postsurgery. The local actual MCR was measured under microscope and calculated. The extent of neointimal coverage at the ostia of branches and the neointima within the stent were examined by histology and scanning electron microscopy. No side branch occlusion was noted, either immediately after implantation or at follow-ups. At 3 months after implantation, the intimal coverage of branch ostia caused by a 30-40% MCR was not significantly different from that caused by an MCR ≤ 30% (p = 0.792), but it was significantly lower than that caused by an MCR ≥ 40% (p = 0.021). Neointimal thickness in the stented abdominal aorta was positively correlated to MCR (r = 0.523, p = 0.001). The neointima was composed predominantly of smooth muscle cells and collagen fibers. The actual MCR exhibited remarkable differences once FD was implanted in vivo. Significantly more intimal coverage at the side branch ostia could be induced when MCR was ≥40%. The neointimal thickness within the stent was positively correlated to device MCR.

  19. Pseudoepitheliomatous Hyperplasia in Oral Lesions: A Review

    PubMed Central

    Nayak, Vaidhehi Narayan; Uma, K; Girish, H C; Murgod, Sanjay; Shyamala, K; Naik, Ranajit B

    2015-01-01

    Pseudoepitheliomatous hyperplasia (PEH) is a histopathological reaction pattern to various stimuli, which includes trauma, infection, inflammation, neoplasia. It is seen as tongue like epithelial proliferation invading the connective tissue and should not be mistaken for squamous cell carcinoma (SCC). This review enlists oral lesions which exhibit PEH with a note on how to differentiate SCC from PEH. PMID:26435636

  20. Verrucous hyperplasia: A clinico-pathological study.

    PubMed

    Hazarey, Vinay K; Ganvir, Sindhu M; Bodhade, Ashish S

    2011-05-01

    Oral verrucous hyperplasia (OVH) is a premalignant lesion that may transform into an oral cancer. The present retrospective study was carried out to analyze the clinico-pathological features of verrucous hyperplasia (VH). Total 19 diagnosed cases of verrucous hyperplasia were retrospectively analyzed for demographic, clinical and histopathological features including dysplasia. Average age of occurrence of lesion was 4 (th) decade of life, with male predominance (2:1) and common site of occurrence being buccal mucosa. Clinically it present as verrucous exophytic growth with sharp or blunt projections on surface, which corresponds histologically. Tobacco lime quid placement in buccal vestibule was key etiologic factor. Histopathologicaly 68% cases showed dysplasia out of which moderate dysplasia predominates (42%). Moderately dysplastic cases were found to be associated with mixed habit pattern. Maximum cases were treated with excision. Biopsy specimen comprising of adjacent normal epithelium is key in distinguishing verrucous hyperplasia from verrucous carcinoma. Clinical behavior and recurrence potential needs to be assessed with long term follow up studies.

  1. Verrucous hyperplasia: A clinico-pathological study

    PubMed Central

    Hazarey, Vinay K; Ganvir, Sindhu M; Bodhade, Ashish S

    2011-01-01

    Context: Oral verrucous hyperplasia (OVH) is a premalignant lesion that may transform into an oral cancer. Aims: The present retrospective study was carried out to analyze the clinico-pathological features of verrucous hyperplasia (VH). Materials and Methods: Total 19 diagnosed cases of verrucous hyperplasia were retrospectively analyzed for demographic, clinical and histopathological features including dysplasia. Results: Average age of occurrence of lesion was 4 th decade of life, with male predominance (2:1) and common site of occurrence being buccal mucosa. Clinically it present as verrucous exophytic growth with sharp or blunt projections on surface, which corresponds histologically. Tobacco lime quid placement in buccal vestibule was key etiologic factor. Histopathologicaly 68% cases showed dysplasia out of which moderate dysplasia predominates (42%). Moderately dysplastic cases were found to be associated with mixed habit pattern. Maximum cases were treated with excision. Conclusion: Biopsy specimen comprising of adjacent normal epithelium is key in distinguishing verrucous hyperplasia from verrucous carcinoma. Clinical behavior and recurrence potential needs to be assessed with long term follow up studies. PMID:22529578

  2. Hereditary pituitary hyperplasia with infantile gigantism.

    PubMed

    Gläsker, Sven; Vortmeyer, Alexander O; Lafferty, Antony R A; Hofman, Paul L; Li, Jie; Weil, Robert J; Zhuang, Zhengping; Oldfield, Edward H

    2011-12-01

    We report hereditary pituitary hyperplasia. The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. The study is a retrospective analysis of three cases from one family. The study was conducted at the National Institutes of Health, a tertiary referral center. A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. The condition was treated by total hypophysectomy. We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development.

  3. Intravascular papillary endothelial hyperplasia of the foot.

    PubMed

    Cisco, R W; McCormac, R M

    1994-01-01

    Intravascular papillary endothelial hyperplasia is a rare benign reactive lesion usually found in thrombosed subcutaneous blood vessels. The lesion resembles malignant angiosarcoma clinically and histopathologically, and must be diagnosed correctly to avoid inappropriate treatment. The following is a case presentation involving the foot.

  4. Multifocal epithelial hyperplasia. Report of nine cases.

    PubMed

    Ledesma-Montes, Constantino; Vega-Memije, Elisa; Garcés-Ortíz, Maricela; Cardiel-Nieves, Maritza; Juárez-Luna, Claudia

    2005-01-01

    Multifocal epithelial hyperplasia (MEH) is also known as focal epithelial hyperplasia, Heck's disease or multifocal papillomavirus-induced epithelial hyperplasia. It is characterised by the presence of multiple lesions in the oral mucosa of children and it has been associated with the presence of the human papillomavirus. The aim of this study was to determine the clinico-pathological features of the cases diagnosed as MEH in the Service of Dermatology of the Hospital Manuel Gea González (SDHMGG). The files of the SDHMGG were reviewed and all cases diagnosed as MEH were retrieved. Nine MEH cases were found. Most of the patients were 20 year-old or younger (67%) and females were more commonly affected (78%). All patients presented multiple lesions and always, close relatives with similar lesions were found. Lesions were located most commonly in the buccal mucosa, lower lip and commissures. MEH is a soft tissue intraoral condition that needs treatment solely of the traumatised lesions or those with cosmetic problems. Remaining lesions will disappear with the age of the patients. It is suggested that this entity should be named multifocal epithelial hyperplasia since this name describes better the clinico-pathological and microscopic features of the disease.

  5. [Focal epithelial hyperplasia. An unusual clinical aspect].

    PubMed

    Bodokh, I; Lacour, J P; Rainero, C; Orth, G; Perrin, C; Hoffman, P; Santini, J; Ortonne, J P

    1993-01-01

    We report a case of focal epithelial hyperplasia in a child born in France of Algerian parents. The clinical appearance was unusual in that certain lesions were verrucous and pediculate. A virological study revealed the presence of papillomavirus 32, one of the two types of HPV specifically associated with this entity.

  6. Folic acid administration reduces neointimal thickening, augments neo-vasa vasorum formation and reduces oxidative stress in saphenous vein grafts from pigs used as a model of diabetes

    PubMed Central

    2013-01-01

    Aims/hypothesis There is evidence that plasma homocysteine augments vein graft failure and that it augments both micro- and macro-angiopathy in patients with diabetes mellitus. It is therefore suggested that homocysteine may augment vein graft thickening, a major cause of vein graft failure, in diabetic patients, as well as impairing adaptive growth of a new vasa vasorum, possibly through overproduction of superoxide. In order to test these proposals, the effect of folic acid administration, which lowers plasma homocysteine, on vein graft thickening and microvessel density was studied in pigs used as a model of diabetes. Methods Non-ketotic hyperglycaemia was induced in Landrace pigs by intravenous injection of streptozotocin, and folic acid was fed daily for 1 month. Vein grafts were excised and the thickness of the neointima and media and microvessel density were assessed by planimetry and superoxide formation. Results Plasma total homocysteine was significantly reduced by folic acid in both control and diabetic pigs, whereas glucose was unchanged. Compared with controls, diabetic pigs showed increased neointimal thickness and superoxide formation and decreased adventitial microvessel density. Folic acid reduced neointimal thickness and superoxide formation and augmented microvessel density in diabetic but not in control pigs. Conclusions Folic acid administration reduces neointimal thickening, augments vasa vasorum neoformation and reduces oxidative stress in saphenous vein grafts from diabetic pigs. Folic acid may therefore be particularly effective in reducing vein graft failure in diabetic patients. PMID:20182861

  7. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

    PubMed

    Louiset, Estelle; Duparc, Céline; Young, Jacques; Renouf, Sylvie; Tetsi Nomigni, Milène; Boutelet, Isabelle; Libé, Rossella; Bram, Zakariae; Groussin, Lionel; Caron, Philippe; Tabarin, Antoine; Grunenberger, Fabienne; Christin-Maitre, Sophie; Bertagna, Xavier; Kuhn, Jean-Marc; Anouar, Youssef; Bertherat, Jérôme; Lefebvre, Hervé

    2013-11-28

    Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of

  8. New developments in prenatal diagnosis of congenital adrenal hyperplasia.

    PubMed

    Kazmi, Diya; Bailey, Jack; Yau, Maggie; Abu-Amer, Wahid; Kumar, Ameet; Low, Merly; Yuen, Tony

    2017-01-01

    Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Females affected with classical CAH are at risk for genital ambiguity, but can be treated in utero with dexamethasone before 9 gestational weeks to prevent virilization. Early genetic diagnosis is unavailable through current invasive methods of chorionic villus sampling and amniocentesis. New developments in prenatal genetic testing utilize fetal DNA extracted from maternal blood through noninvasive methods, which allow the determination of fetal gender and the diagnosis of CAH at an early gestational age (<9 weeks). Noninvasive prenatal diagnosis allows for the establishment of early and effective management plans in fetuses at risk for CAH and avoids unnecessary prenatal dexamethasone treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Finasteride for benign prostatic hyperplasia.

    PubMed

    Tacklind, James; Fink, Howard A; Macdonald, Roderick; Rutks, Indy; Wilt, Timothy J

    2010-10-06

    Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH. To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS). We searched The Cochrane Library (which includes CDSR (Cochrane Database of Systematic Reviews), DARE (Database of Abstracts of Reviews of Effects), HTA (Heath Technology Assessments), and CENTRAL (Cochrane Central Register of Controlled Trials, and which includes EMBASE and MEDLINE), LILACS (Latin American and Caribbean Center on Health Sciences Information) and Google Scholar for randomized, controlled trials (RCTs). We also handsearched systematic reviews, references, and clinical-practice guidelines. Randomized trials in the English language with placebo and/or active arms with a duration of at least 6 months. JT extracted the data, which included patient characteristics, outcomes, and harms. Our primary outcome was change in a validated, urinary symptom-scale score, such as the AUA/IPSS. A clinically meaningful change was defined as 4 points. We also categorized outcomes by trial lengths of ≤ 1 year (short term) and > 1 year (long term). Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, ≥ 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more

  10. Proteomic signature of muscle fibre hyperplasia in response to faba bean intake in grass carp

    PubMed Central

    Yu, Er-Meng; Zhang, Hao-Fang; Li, Zhi-Fei; Wang, Guang-Jun; Wu, Hong-Kai; Xie, Jun; Yu, De-Guang; Xia, Yun; Zhang, Kai; Gong, Wang-Bo

    2017-01-01

    Fish muscle growth is important for the rapidly developing global aquaculture industry, particularly with respect to production and quality. Changes in muscle fibre size are accomplished by altering the balance between protein synthesis and proteolysis. However, our understanding regarding the effects of different protein sources on fish muscle proteins is still limited. Here we report on the proteomic profile of muscle fibre hyperplasia in grass carp fed only with whole faba bean. From the results, a total of 99 significantly changed proteins after muscle hyperplasia increase were identified (p < 0.05, ratio <0.5 or >2). Protein–protein interaction analysis demonstrated the presence of a network containing 56 differentially expressed proteins, and muscle fibre hyperplasia was closely related to a protein–protein network of 12 muscle component proteins. Muscle fibre hyperplasia was also accompanied by decreased abundance in the fatty acid degradation and calcium signalling pathways. In addition, metabolism via the pentose phosphate pathway decreased in grass carp after ingestion of faba bean, leading to haemolysis. These findings could provide a reference for the prevention and treatment of human glucose-6-phosphate dehydrogenase deficiency (“favism”). PMID:28367976

  11. Unilateral condylar hyperplasia: a treatment strategy.

    PubMed

    Ferreira, Sabrina; da Silva Fabris, André Luis; Ferreira, Gabriel Ramalho; Faverani, Leonardo Perez; Francisconi, Giovanna Barbosa; Souza, Francisley Avila; Garcia, Idelmo Rangel

    2014-05-01

    Condylar hyperplasia (CH) is a pathologic condition that causes overdevelopment of the condylar head and neck as well as the mandible. Slowly progressive unilateral enlargement of the head and the neck of the condyle causes crossbite malocclusion, facial asymmetry, and shifting of the midpoint of the chin to the unaffected side. The etiology and the pathogenesis of CH remain uncertain. The diagnosis is made by clinical and radiologic examinations and bone scintigraph. A difference in uptake of 10% or more between condyles is regarded as indicative of CH, and the affected condyles had a relative uptake of 55% or more. When the diagnosis of active CH is established, the treatment consists of removal of the growth center by a partial condylectomy. The authors present the case of a 46-year-old male patient with right active type II CH or hemimandibular hyperplasia who underwent a high condylectomy.

  12. Lymphoid papillary hyperplasia of the palatine tonsils.

    PubMed

    Carrillo-Farga, J; Abbud-Neme, F; Deutsch, E

    1983-09-01

    A rare case of papillary hyperplasia of the palatine tonsils is reported in a 9-year-old girl who presented with pharyngeal obstruction. The obstruction was due to the bilateral enlargement of the palatine tonsils with a papillary surface configuration so atypical that a diagnosis of malignant neoplasm was clinically considered. Histopathological study showed a peculiar form of lymphoid hyperplasia. No other members of the family were affected. As far as we know, this is the only case reported in recent years in an Occidental patient although a few similar cases have been reported from Japan. The importance of recognizing this peculiar abnormality rests in the fact that in spite of the clinical features simulating a cancer or multiple epithelial papillomas, the process is benign, probably non-neoplastic, and easily cured by bilateral tonsillectomy.

  13. Congenital adrenal hyperplasia with cholestatic jaundice.

    PubMed

    Ali, Nisreen Feroz; Zafar, Farhana; Bangash, Areeb Sohail; Malik, Abdul; Mohammedi, Karimunnisa

    2014-01-01

    Congenital Adrenal Hyperplasia describes a group of autosomal recessive disorders characterized by a decrease in Cortisol production. 11 beta hydroxylase deficiencies is the second most common form. However, its presentation with cholestatic jaundice is extremely rare. We present a case of a 29-day-old infant who came to us with unusual dark complexion, persistent jaundice, and electrolyte imbalance. On investigation he was diagnosed as a case of congenital adrenal hyperplasia. Treatment with hydrocortisone and fludrocortisone cleared his jaundice and complexion with subsequent improvement in electrolytes. The aim of this report is to illustrate an unusual presentation of CAH with Cholestatic jaundice. This is the first case to be reported from Pakistan. The case outlines the difficult workup that was encountered in the diagnosis and management of the patient.

  14. Extensive Focal Epithelial Hyperplasia: A Case Report

    PubMed Central

    Mansouri, Zahra; Bakhtiari, Sedigheh; Noormohamadi, Robab

    2015-01-01

    Focal epithelial hyperplasia (FEH) or Heck’s disease is a rare viral infection of the oral mucosa caused by human papilloma virus especially subtypes 13 or 32. The frequency of this disease varies widely from one geographic region and ethnic groups to another. This paper reports an Iranian case of extensive focal epithelial hyperplasia. A 35-year-old man with FEH is described, in whom the lesions had persisted for more than 25 years. The lesion was diagnosed according to both clinical and histopathological features. Dental practitioner should be aware of these types of lesions and histopathological examination together and a careful clinical observation should be carried out for a definitive diagnosis. PMID:26351501

  15. Myocardial hypertrophy induces carotid body hyperplasia.

    PubMed

    Sivridis, Efthimios; Pavlidis, Pavlos; Fiska, Aliki; Pitsiava, Dimitra; Giatromanolaki, Alexandra

    2011-01-01

    The carotid bodies tend to enlarge after long-standing cardiopulmonary disease. Our objective was to investigate whether cardiac hypertrophy is associated with carotid body hyperplasia. Fifteen autopsy cases with combined left and right ventricular hypertrophy were examined and compared with two control groups (16 cases). The study involved a meticulous dissection of carotid bifurcations, thin serial sections, and morphometric analysis of carotid body volume and cell types (progenitor, dark, light, and sustentacular). There was a significant increase in sustentacular cells in all individuals with cardiac hypertrophy, which was not drug-induced, and accompanied by a similar increase in carotid body volume. Dark or light cell accumulation was detected focally and only in three instances. It appears that the generalized sustentacular cell hyperplasia is the result of long-standing hypoxia, while a superimposed focal prominence of dark or light cells may be proliferative or metaplastic in nature and attributed to short-term hypoxia.

  16. Mandibular coronoid hyperplasia: a case report.

    PubMed

    Yura, Shinya; Ohga, Noritaka; Ooi, Kazuhiro; Izumiyama, Yuri

    2009-10-01

    A case of unilateral coronoid hyperplasia successfully treated by coronoidotomy with prolonged postoperative physiotherapy and reveal the postoperative radiographic changes between the sectioned part of the coronoid process and the mandibular ascending ramus is described. The patient was a 28-year-old man whose maximum mouth opening was 30 mm. A coronoidotomy of the left coronoid process was performed. Nine days after surgery, the patient started physiotherapy with a HU-OS(r) appliance. After coronoidotomy and physiotherapy, the maximum mouth opening had increased to 43 mm. Radiographic follow-up showed that the coronoid process apparently united with the mandibular ascending ramus, with moderate dislocation and inclination posteriorly. In the case presented, an intraoral coronoidotomy with postoperative physiotherapy for treatment of coronoid process hyperplasia allowed satisfactory and stable results in the correction of coronoid-malar interference.

  17. Hereditary Pituitary Hyperplasia with Infantile Gigantism

    PubMed Central

    Gläsker, Sven; Vortmeyer, Alexander O.; Lafferty, Antony R. A.; Hofman, Paul L.; Li, Jie; Weil, Robert J.; Zhuang, Zhengping

    2011-01-01

    Context: We report hereditary pituitary hyperplasia. Objective: The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. Design: The study is a retrospective analysis of three cases from one family. Setting: The study was conducted at the National Institutes of Health, a tertiary referral center. Patients: A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. Interventions: The condition was treated by total hypophysectomy. Main Outcome Measure(s): We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. Results: All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. Conclusions: This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development. PMID:21976722

  18. [Hepatocellular nodular hyperplasias, adenomas and carcinomas].

    PubMed

    Altmann, H W

    1995-01-01

    Nodular hyperplasias ("hyperplasiomas") are new formations whose development as a required and regulated response can be traced either to compensatory reactions to the loss of cells (regeneration in a narrow sense) and to decreased cellular performance, or to primary growth impulses. Included in this group are: the "macroregenerative nodules" after extensive cell losses; solitary nodules of uncertain etiology; and the minute foci of "micronodular transformation" whose origin can be traced to a particular disturbance of the hepatic blood supply. The so-called "adenomatous hyperplasias" of the cirrhotic liver that have a tendency towards carcinomatous change are not included in this group and are perhaps better considered as "hyperplasiogenic adenomas". The so-called "focal nodular hyperplasia" too, it must be stressed, should be separated from the simple hyperplasias, for it is more closely related to the adenomas, but represents a new formation of limited growth potential. Morphologically it is conspicuously subdivided by multiple connective tissue bands and scars, but it is above all characterized by metaplastically derived neoductuli, and hence it is appropriately designated as a "combined nodule". Among the true uninodular adenomas there are several variants differing in their morphology,--the so-called "atypical" or "intermediate" forms, that can give rise to carcinomas. The hepatocellular carcinoma, that may arise in a variety of ways, presents multiple cytological and histological variants, but only the so-called "fibrolamellar carcinoma" presents also a clinical peculiarity. "Hepatoblastomas" differ from the common hepatocellular carcinomas by their origin in early childhood from immature early precursor cells and, in the later phases of life, from redifferentiated cells that can even give rise to mesenchymal elements. There is no evidence of the existence of particular pluripotential stem cells.

  19. Focal epithelial hyperplasia in a Turkish family.

    PubMed

    Gökahmetoğlu, Selma; Ferahbaş, Ayten; Canöz, Özlem

    2014-12-01

    Focal epithelial hyperplasia (FEH) is a benign proliferative condition that is more frequently found in children of certain ethnic groups. Human papillomavirus (HPV) 13 and 32 genotypes has been consistently detected in these lesions. In this study a daughter, mother and father had FEH, and HPV 13 was shown by sequence analysis in the lesions of these patients. Cryotherapy was applied to the lesions and the lesions improved, but did not recover properly. In conclusion, HPV genotyping should be performed in FEH cases.

  20. Extensive focal epithelial hyperplasia: case report.

    PubMed

    Durso, Braz Campos; Pinto, José Marcelo Vargas; Jorge, Jacks; de Almeida, Oslei Paes

    2005-11-01

    Focal epithelial hyperplasia (FEH) is a rare benign lesion caused by human papillomavirus subtype 13 or 32. The condition occurs in numerous populations and ethnic groups. A higher incidence in close communities and among family members indicates infectious pathogenesis. A 21-year-old woman with FEH is described, in whom the lesions had persisted for 10 years. A literature review is also presented, with emphasis on manifestations in the oral mucosa and histopathological features.

  1. Metformin for endometrial hyperplasia: a Cochrane protocol

    PubMed Central

    Clement, Naomi S; Oliver, Thomas R W; Shiwani, Hunain; Saner, Juliane R F; Mulvaney, Caroline A; Atiomo, William

    2016-01-01

    Introduction Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. Methods and analysis We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. Ethics and dissemination

  2. High-dose metformin (420mg/kg daily p.o.) increases insulin sensitivity but does not affect neointimal thickness in the rat carotid balloon injury model of restenosis.

    PubMed

    Guo, June; Pereira, Troy J; Dalvi, Prasad; Yeung, Lucy Shu Nga; Swain, Nathan; Breen, Danna M; Lam, Loretta; Dolinsky, Vernon W; Giacca, Adria

    2017-03-01

    Our laboratory has shown that insulin's effect to decrease neointimal thickness after arterial injury is greatly diminished in insulin resistant conditions. Thus, in these conditions, a better alternative to insulin could be to use an insulin sensitizing agent. Metformin, the most commonly prescribed insulin sensitizer, has a cardiovascular protective role. Therefore, the objective of this study was to investigate the potential benefit of metformin on neointimal area after arterial injury in a rat model of restenosis. Rats fed with either normal or high fat diet and treated with or without oral metformin (420mg/kg daily) underwent carotid balloon injury. Effects of metformin on clamp-determined insulin sensitivity, vessel AMPK (AMP-activated protein kinase) phosphorylation (activation marker) and neointimal area were evaluated. Metformin increased insulin sensitivity, but did not affect neointimal thickness in either the normal fat or high fat diet-fed rats. Furthermore, metformin activated AMPK in uninjured but not in injured vessels. Similarly, 10mmol/L metformin inhibited proliferation and activated AMPK in smooth muscle cells of uninjured but not injured vessels, whereas 2mmol/L metformin did not have any effect. In rats, metformin does not decrease neointimal growth after arterial injury, despite increasing whole body insulin sensitivity. Copyright © 2016. Published by Elsevier Inc.

  3. Inflammatory papillary hyperplasia: A systematic review.

    PubMed

    Gual-Vaqués, P; Jané-Salas, E; Egido-Moreno, S; Ayuso-Montero, R; Marí-Roig, A; López-López, J

    2017-01-01

    Inflammatory papillary hyperplasia (IPH) is a benign lesion of the palatal mucosa. It is usually found in denture-wearers but also has been reported in patients without a history of use of a maxillary prosthesis use. The aim of this study is to review the literature to assess the prevalence of denture stomatitis and inflammatory papillary hyperplasia and the etiological factors associated. A search was carried out in PubMed (January 2005 to October 2015) with the key words "inflammatory papillary hyperplasia", "denture stomatitis", "granular stomatitis" and "Newton's type III" The inclusion criteria were studies including at least a sample of 50 apparently healthy patients, articles published from 2005 to 2015 written in English. The exclusion criteria were reviews and non-human studies. Out of the 190 studies obtained initially from the search 16 articles were selected to be included in our systematic review. The prevalence of denture stomatitis was 29.56% and 4.44% for IPH. We found 5 cases of denture stomatitis among non-denture-wearer individuals. All IPH cases were associated with the use of prosthesis. Smoking and continued use of ill-fitting dentures turned out to be the most frequent risk factors for developing IPH. IPH is a rare oral lesion and its pathogenesis still remains unclear. Its presentation among non-denture-wearers is extremely unusual.

  4. Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats.

    PubMed

    Sun, Qiang; Kawamura, Tomohiro; Masutani, Kosuke; Peng, Ximei; Sun, Qing; Stolz, Donna B; Pribis, John P; Billiar, Timothy R; Sun, Xuejun; Bermudez, Christian A; Toyoda, Yoshiya; Nakao, Atsunori

    2012-04-01

    Arterialized vein grafts often fail due to intimal hyperplasia. Hydrogen potently protects organs and cells from many insults via its anti-inflammatory and antioxidant properties. We investigated the efficacy of oral administration of hydrogen-rich water (HW) for prevention of intimal hyperplasia. The inferior vena cava was excised, stored in cold Ringer solution for 2 h, and placed as an interposition graft in the abdominal aorta of syngeneic Lewis rats. HW was generated by immersing a magnesium stick in tap water (Mg + 2H(2)O → Mg (OH)(2) + H(2)). Beginning on the day of graft implantation, recipients were given tap water [regular water (RW)], HW or HW that had been subsequently degassed water (DW). Six weeks after grafting, the grafts in the rats given RW or DW had developed intimal hyperplasia, accompanied by increased oxidative injury. HW significantly suppressed intimal hyperplasia. One week after grafting, the grafts in HW-treated rats exhibited improved endothelial integrity with less platelet and white blood cell aggregation. Up-regulation of the mRNAs for intracellular adhesion molecules was attenuated in the vein grafts of the rats receiving HW. Activation of p38 mitogen-activated protein kinase, matrix metalloproteinase (MMP)-2, and MMP-9 was also significantly inhibited in grafts receiving HW. In rat smooth muscle cell (A7r5) cultures, hydrogen treatment for 24 h reduced smooth muscle cell migration. Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel therapy for intimal hyperplasia and could easily be incorporated into daily life.

  5. Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats

    PubMed Central

    Sun, Qiang; Kawamura, Tomohiro; Masutani, Kosuke; Peng, Ximei; Sun, Qing; Stolz, Donna B.; Pribis, John P.; Billiar, Timothy R.; Sun, Xuejun; Bermudez, Christian A.; Toyoda, Yoshiya; Nakao, Atsunori

    2012-01-01

    Aims Arterialized vein grafts often fail due to intimal hyperplasia. Hydrogen potently protects organs and cells from many insults via its anti-inflammatory and antioxidant properties. We investigated the efficacy of oral administration of hydrogen-rich water (HW) for prevention of intimal hyperplasia. Methods and results The inferior vena cava was excised, stored in cold Ringer solution for 2 h, and placed as an interposition graft in the abdominal aorta of syngeneic Lewis rats. HW was generated by immersing a magnesium stick in tap water (Mg + 2H2O → Mg (OH)2 + H2). Beginning on the day of graft implantation, recipients were given tap water [regular water (RW)], HW or HW that had been subsequently degassed water (DW). Six weeks after grafting, the grafts in the rats given RW or DW had developed intimal hyperplasia, accompanied by increased oxidative injury. HW significantly suppressed intimal hyperplasia. One week after grafting, the grafts in HW-treated rats exhibited improved endothelial integrity with less platelet and white blood cell aggregation. Up-regulation of the mRNAs for intracellular adhesion molecules was attenuated in the vein grafts of the rats receiving HW. Activation of p38 mitogen-activated protein kinase, matrix metalloproteinase (MMP)-2, and MMP-9 was also significantly inhibited in grafts receiving HW. In rat smooth muscle cell (A7r5) cultures, hydrogen treatment for 24 h reduced smooth muscle cell migration. Conclusion Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel therapy for intimal hyperplasia and could easily be incorporated into daily life. PMID:22287575

  6. [Congenital unilateral muscular hyperplasia of the hand - a rare malformation].

    PubMed

    Pillukat, T; Lanz, U

    2004-01-01

    This is a report on eight cases of a rare congenital malformation in the upper extremity, consisting of a unilateral muscular hyperplasia. In addition to the hand, all segments of the upper extremity may be affected. The hyperplasia is always unilateral, preferably on the right hand side, in combination with accessory muscles. Hereditary dependence or association with other malformations has not been observed. Six of eight patients were male. Shoulder and arm function were normal in all cases. Ulnar drift of the fingers in the metacarpophalangeal joints (six of eight patients), flexion contractures of the metacarpophalangeal joints (six of eight patients) and extension contractures of the wrist (three of eight patients) to various degrees were seen. A prominence of the second and third metacarpal head with an enlarged space between them gave the affected hands a very typical appearance (six of eight patients). Deformities and functional limitations requiring surgical treatment were present in six patients. In all cases, accessory muscles were found intraoperatively and resected. The macroscopic and microscopic appearance of the muscle specimen did not differ from normal muscular tissue. In all cases, additional procedures were necessary to improve the overall function. Nevertheless, the reconstructive efforts did not lead to an entirely normal hand function or appearance. The malformation we describe can clearly be distinguished from other malformations such as arthrogryposis multiplex congenita, Freeman-Sheldon syndrome or macrodactyly. Up to now, only two other reports were found in the literature showing characteristics similar to those in our own cases. Four similar cases were observed by Benatar. From a pathomechanical point of view, a disturbance in the muscular balance seems to cause the deformities and functional limitations. This imbalance could be related to accessory muscles which are not opposed by defined antagonists or to an unbalanced hyperplasia of

  7. A Rapamycin-Releasing Perivascular Polymeric Sheath Produces Highly Effective Inhibition of Intimal Hyperplasia

    PubMed Central

    Yu, Xaohua; Takayama, Toshio; Goel, Shakti A.; Shi, Xudong; Zhou, Yifan; Kent, K. Craig; Murphy, William L.; Guo, Lian-Wang

    2014-01-01

    Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50 days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90 days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel’s anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery. PMID:24852098

  8. A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.

    PubMed

    Yu, Xiaohua; Takayama, Toshio; Goel, Shakti A; Shi, Xudong; Zhou, Yifan; Kent, K Craig; Murphy, William L; Guo, Lian-Wang

    2014-10-10

    Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel's anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.

  9. [Primary hyperaldosteronism due to unilateral adrenal hyperplasia with surgical resolution].

    PubMed

    Rubio-Puchol, O; Garzón-Pastor, S; Salom-Vendrell, C; Hernández-Mijares, A

    Unilateral adrenal hyperplasia is a rare cause of primary hyperaldosteronism (around a 3%) that has surgical treatment. A case of a patient with hypertension resistant to conventional therapy in treatment with 7 drugs who presented with primary hyperaldosteronism due to unilateral adrenal hyperplasia is presented. A left adrenalectomy was performed, and the patient had a good clinical response, with no need of any drug after 2 years of surgery. Unilateral adrenal hyperplasia is a different entity and it is not an asymmetric variant of the bilateral adrenal hyperplasia. In the study of patients with primary hyperaldosteronism and imaging tests with absence of adenoma is a diagnosis that must be considered before cataloguing patients with bilateral adrenal hyperplasia and start a medical treatment, because unilateral adrenal hyperplasia would have a surgical resolution.

  10. 18F-FDG-avid brunner gland hyperplasia.

    PubMed

    Park, Seol Hoon; Park, Kwang-Min; Kim, Jae Seung

    2014-08-01

    Brunner gland hyperplasia, a rare duodenal tumor, usually presents with benign features. A 68-year-old man with a history of anemia presented with a polypoid duodenal mass that was detected by CT and esophagogastroduodenoscopy. This mass showed high F-FDG avidity on PET/CT and was histopathologically confirmed as Brunner gland hyperplasia. We suggest that Brunner gland hyperplasia should be considered in the differential diagnosis of F-FDG-avid duodenal tumors.

  11. Unilateral condylar hyperplasia: A case report and review of literature.

    PubMed

    Bharathi, Saravana C; Senthilnathan, S; Kumar, Lokesh D; Mohan, Anand C S; Taranath, M

    2014-01-01

    Condylar hyperplasia is (CH) an uncommon malformation of the mandible involving change in size and morphology of the condylar neck and head. CH is an anomaly that usually occurs unilaterally and equally affects in both men and women. Hyperplasia of the condyle 'differentiated into hemimandibular hyperplasia, hemimandibular elongation and CH. Here, we are presenting a case of 17-year-old male patient with unilateral CH and its review of the literature.

  12. Denture hyperplasia with areas simulating oral inverted ductal papilloma.

    PubMed

    Vargas, Pablo Agustin; Perez, Danyel Elias da Cruz; Jorge, Jacks; Rangel, Ana Lúcia Carrinho Ayrosa; León, Jorge Esquiche; Almeida, Oslei Paes de

    2005-07-01

    Denture hyperplasia is a reactive lesion of the oral mucosa, usually associated to an ill-fitting denture. This lesion is easily diagnosed and in some cases distinct microscopic variations such as osseous, oncocytic and squamous metaplasia may be found. These metaplastic alterations probably are associated with the lymphocytic infiltrate usually present in denture hyperplasia. We present a case of denture hyperplasia containing salivary gland tissue with ductal alterations mimicking an oral inverted ductal papilloma.

  13. Potential of telmisartan in the treatment of benign prostatic hyperplasia.

    PubMed

    Ishola, Ismail Ogunbayode; Anunobi, Charles C; Tijani, Kehinde Habeeb; Afolayan, Olasunmbo; Udokwu, Victoria U

    2017-07-20

    Benign prostatic hyperplasia (BPH) is a common health problem in ageing men. This study was carried out to investigate the protective effect of telmisartan on testosterone-induced BPH in rats. Fifty-four male Wistar rats (200-250 g) were randomly divided into nine groups (n = 6) and orally treated for 28 consecutive days: group 1 - vehicle normal, olive oil (10 mL/kg); group 2 - BPH model control (10 mL/kg); groups 3-5 - telmisartan (5, 10 or 20 mg/kg, respectively); group 6 - pioglitazone (20 mg/kg); group 7 - celecoxib (20 mg/kg); group 8 - combination of telmisartan (5 mg/kg) and pioglitazone (20 mg/kg); group 9 - combination of telmisartan (5 mg/kg) and celecoxib (20 mg/kg). Animals in groups 2-9 were given testosterone propionate in olive oil (3 mg/kg) subcutaneously 15 min after pretreatments. On day 29, blood was collected for the estimation of serum testosterone and prostate-specific antigen (PSA). The prostates were excised, weighed and subjected to biochemical and histological studies. Testosterone injection induced significant increase in prostatic index, serum testosterone and PSA suggesting BPH as well as increased prostate oxidative stress which were ameliorated with the pretreatment of rats with telmisartan or co-administration of celecoxib and pioglitazone. Histological examination showed that testosterone disrupted the morphology of the prostate epithelial cells evidenced in the involution of the epithelial lining of the acini into the lumen indicating BPH which was reversed by telmisartan. Findings from this study showed that telmisartan alone or in combination with pioglitazone prevented the development of testosterone-induced prostatic hyperplasia. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  14. [Nodular regenerative hyperplasia associated with primary antiphospholipid syndrome].

    PubMed

    Cadranel, J F; Demontis, R; Guettier, C; Bouraya, D; Dautreaux, M; Ghazali, A; Poux, J M; Coutarel, P; Devergie, B; Fievet, P

    1996-01-01

    Nodular regenerative hyperplasia of the liver is characterized by diffuse nodularity of the hepatic parenchyma without fibrotic septa. It may be related to venous or arterial obstruction in the portal tract. We report a case of primary antiphospholipid syndrome associated with nodular regenerative hyperplasia in a 45-year old woman. The patient had an ischemic stroke, associated with an acute arterial ischemia of the left leg. She had high titers of serum anticardiolipin antibodies. Nodular regenerative hyperplasia of the liver was histologically confirmed and was associated with anicteric cholestasis. This case provides additional evidence that a thrombotic mechanism may play a role in the pathogenesis of nodular regenerative hyperplasia of the liver.

  15. Intimal hyperplasia in autogenous veins used for arterial replacement.

    PubMed

    Gunstensen, J; Smith, R C; El-Maraghi, N; Julian, J; Belbeck, L

    1982-03-01

    This study compares the effects on intimal hyperplasia of different methods of manipulating a vein graft before using it as an arterial substitute. Grafts that were denuded of endothelium showed the most intimal hyperplasia, while those that were washed with saline, dilated with saline or crushed did not differ appreciably from each other with respect to the degree of intimal hyperplasia. The hyperplasia was well developed and stabilized at 3 weeks, which coincided with restoration of the endothelial surface. The similarity between the last three methods of graft manipulation suggests that minor endothelial disruption produced at the time of harvesting the vein is equalized after insertion of the vein into the arterial circulation.

  16. Fabrication of an α-lipoic acid-eluting poly-(D,L-lactide-co-caprolactone) cuff for the inhibition of neointimal formation

    PubMed Central

    Lee, Hyo Jeong; Choi, Seung Hee; Nah, Mun Hee

    2009-01-01

    The purpose of this study was to develop a novel polymer cuff for the local delivery of α-lipoic acid (ALA) to inhibit neointimal formation in vivo. The polymer cuff was fabricated by incorporating the ALA into poly-(D,L-lactide-co-caprolactone) 40:60 (PLC), with or without methoxy polyethylene glycol (MethoxyPEG). The release kinetics of ALA and in vitro degradation by hydrolysis were analyzed by HPLC and field emission scanning electron microscopy (FE-SEM), respectively. In vivo evaluation of the effect of the ALA-containing polymer cuff was carried out using a rat femoral artery cuff injury model. At 24 h, 48% or 87% of the ALA was released from PCL cuffs with or without MethoxyPEG. FE-SEM results indicated that ALA was blended homogenously in the PLC with MethoxyPEG, whereas ALA was distributed on the surface of the PLC cuff without MethoxyPEG. The PLC cuff with MethoxyPEG showed prolonged and controlled release of ALA in PBS, in contrast to the PLC cuff without MethoxyPEG. Both ALA-containing polymer cuffs had a significant effect on the inhibition of neointimal formation in rat femoral artery. Novel ALA-containing polymer cuffs made of PLC were found to be biocompatible and effective in inhibiting neointimal formation in vivo. Polymer cuffs containing MethoxyPEG allowed the release of ALA for one additional week, and the rate of drug release from the PLC could be controlled by changing the composition of the polymer. These findings demonstrate that polymer cuffs may be an easy tool for the evaluation of anti-restenotic agents in animal models. PMID:19287197

  17. Stent coated with antibody against vascular endothelial-cadherin captures endothelial progenitor cells, accelerates re-endothelialization, and reduces neointimal formation.

    PubMed

    Lim, Woo-Hyun; Seo, Won-Woo; Choe, Wonseok; Kang, Chan-Koo; Park, Jonghanne; Cho, Hyun-Ju; Kyeong, San; Hur, Jin; Yang, Han-Mo; Cho, Hyun-Jai; Lee, Yoon-Sik; Kim, Hyo-Soo

    2011-12-01

    In contrast to CD34, vascular endothelial-cadherin (VE-cadherin) is exclusively expressed on the late endothelial progenitor cells (EPC) whereas not on the early or myeloid EPC. Thus, VE-cadherin could be an ideal target surface molecule to capture circulating late EPC. In the present study, we evaluated whether anti-VE-cadherin antibody-coated stents (VE-cad stents) might accelerate endothelial recovery and reduce neointimal formation through the ability of capturing EPC. The stainless steel stents were coated with rabbit polyclonal anti-human VE-cadherin antibodies and exposed to EPC for 30 minutes in vitro. The number of EPC that adhered to the surface of VE-cad stents was significantly higher than bare metal stents (BMS) in vitro, which was obliterated by pretreatment of VE-cad stent with soluble VE-cadherin proteins. We deployed VE-cad stents and BMS in the rabbit right and left iliac arteries, respectively. At 48 hours after stent deployment in vivo, CD-31-positive endothelial cells adhered to VE-cad stent significantly more than to BMS. At 3 days, scanning electron microscopy showed that over 90% surface of VE-cad stents was covered with endothelial cells, which was significantly different from BMS. At 42 days, neointimal area that was filled with smooth muscle cells positive for actin or calponin was significantly smaller in VE-cad stents than in BMS by histological analysis (0.95±0.22 versus 1.34±0.43 mm(2), respectively, P=0.02). Immuno-histochemical analysis revealed that infiltration of inflammatory cells was not significantly different between 2 stents. VE-cad stents captured EPC successfully in vitro, accelerated endothelial recovery on stent, and eventually reduced neointimal formation in vivo.

  18. The effect of Echinacea purpurea (L.) Moench extract on experimental prostate hyperplasia.

    PubMed

    Skaudickas, D; Kondrotas, A J; Kevelaitis, E; Venskutonis, P R

    2009-10-01

    The aim of this study was to examine the effect of purple coneflower (Echinacea purpurea L. Moench) on the prostate gland of rats using an experimental model of benign prostate hyperplasia (BPH). The animals were administered 50 mg/kg of extract preparation for 4 and 8 weeks and the prostate mass and structural degenerative changes were evaluated in the course of the experiment. The administration of E. purpurea extract to rats with hyperplasia for 4 and 8 weeks gradually and significantly reduced the prostate mass and reversed the degenerative changes in the structure of the prostate gland. The present investigation suggests extract of purple coneflower prevents the development of BPH. (c) 2009 John Wiley & Sons, Ltd.

  19. Inflammatory papillary hyperplasia: A systematic review

    PubMed Central

    Gual-Vaqués, Patricia; Jané-Salas, Enric; Egido-Moreno, Sonia; Ayuso-Montero, Raúl; Marí-Roig, Antoni

    2017-01-01

    Introduction Inflammatory papillary hyperplasia (IPH) is a benign lesion of the palatal mucosa. It is usually found in denture-wearers but also has been reported in patients without a history of use of a maxillary prosthesis use. Objetives The aim of this study is to review the literature to assess the prevalence of denture stomatitis and inflammatory papillary hyperplasia and the etiological factors associated. Material and Methods A search was carried out in PubMed (January 2005 to October 2015) with the key words “inflammatory papillary hyperplasia”, “denture stomatitis”, “granular stomatitis” and “Newton’s type III” The inclusion criteria were studies including at least a sample of 50 apparently healthy patients, articles published from 2005 to 2015 written in English. The exclusion criteria were reviews and non-human studies. Results Out of the 190 studies obtained initially from the search 16 articles were selected to be included in our systematic review. The prevalence of denture stomatitis was 29.56% and 4.44% for IPH. We found 5 cases of denture stomatitis among non-denture-wearer individuals. All IPH cases were associated with the use of prosthesis. Smoking and continued use of ill-fitting dentures turned out to be the most frequent risk factors for developing IPH. Conclusions IPH is a rare oral lesion and its pathogenesis still remains unclear. Its presentation among non-denture-wearers is extremely unusual. Key words:Inflammatory papillary hyperplasia, denture stomatitis, prevalence, granular stomatitis, Newton’s type III stomatitis. PMID:27918740

  20. Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice.

    PubMed

    Gonzales, G F; Gasco, M; Malheiros-Pereira, A; Gonzales-Castañeda, C

    2008-06-01

    The plants from the Lepidium gender have demonstrated to have effect on the size of the prostate. Lepidium meyenii (Maca) is a Peruvian plant that grows exclusively over 4000 m above sea level. The present study was designed to determine the effect of red maca (RM) in the prostate hyperplasia induced with testosterone enanthate (TE) in adult mice. Prostate hyperplasia was induced by administering TE, and then these animals (n = 6, each group) were treated with RM or Finasteride (positive control) for 21 days. There was an additional group without prostate hyperplasia (vehicle). Mice were killed on days 7, 14 and 21 after treatment with RM. Testosterone and oestradiol levels were measured on the last day of treatment. Prostatic stroma, epithelium and acini were measured histologically. RM reduced prostate weight at 21 days of treatment. Weights of seminal vesicles, testis and epididymis were not affected by RM treatment. The reduction in prostate size by RM was 1.59 times. Histological analysis showed that TE increased 2-fold the acinar area, effect prevented in the groups receiving TE + RM for 14 (P < 0.05) and 21 (P < 0.05) days and the group receiving TE + Finasteride for 21 days (P < 0.05). TE increased prostatic stroma area and this effect was prevented by treatment with RM since 7 days of treatment or Finasteride. The reduction in prostatic stroma area by RM was 1.42 times. RM has an anti-hyperplastic effect on the prostate of adult mice when hyperplasia was induced with TE acting first at prostatic stromal level.

  1. Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia

    PubMed Central

    Turcu, Adina F.; Auchus, Richard J.

    2015-01-01

    Synopsis Adrenal steroidogenesis is a dynamic process, reliant on de novo synthesis from cholesterol, under the stimulation of ACTH and other regulators. The syntheses of mineralocorticoids, glucocorticoids and adrenal androgens occur in separate adrenal cortical zones, each expressing specific enzymes. Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive enzymatic defects in cortisol biosynthesis. 21-hydroxylase (21OHD) deficiency accounts for over 90% of CAH cases and when milder or nonclassic forms are included, 21OHD is one of the most common genetic diseases. This review discusses in detail the epidemiology, genetics, diagnostic, clinical aspects and management of 21OHD. PMID:26038201

  2. Angiofollicular lymph node hyperplasia with amyloidosis.

    PubMed Central

    West, K. P.; Morgan, D. R.; Lauder, I.

    1989-01-01

    Two cases of angiofollicular lymph node hyperplasia are described, one of the solitary plasma cell type the other of the multicentric hyaline vascular type. Both cases illustrate the wide ranging clinical and pathological findings associated with this condition but both also have unusual features. The solitary plasma cell lesion had an exceptional 32 year clinical history and was associated with systemic amyloidosis of AL type. The multicentric hyaline vascular case was associated with coexistent multiple myeloma and amyloid deposition also of AL type. These cases are presented with a review of the relevant literature. Images Figure 1 Figure 2 PMID:2780459

  3. Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia.

    PubMed

    Nimkarn, Saroj; Lin-Su, Karen; New, Maria I

    2011-10-01

    Steroid 21 hydroxylase deficiency is the most common form of congenital adrenal hyperplasia (CAH). The severity of this disorder depends on the extent of impaired enzymatic activity, which is caused by various mutations of the 21 hydroxylase gene. This article reviews adrenal steroidogenesis and the pathophysiology of 21 hydroxylase deficiency. The three forms of CAH are then discussed in terms of clinical presentation, diagnosis and treatment, and genetic basis. Prenatal diagnosis and treatment are also reviewed. The goal of therapy is to correct the deficiency in cortisol secretion and suppress androgen overproduction. Glucocorticoid replacement has been the mainstay of treatment for CAH, but new treatment strategies continue to be developed and studied.

  4. Multifocal epithelial hyperplasia: report of 3 cases.

    PubMed

    Tehranchinia, Zohreh; Mozafari, Nikoo; Barikbin, Behrooz; Nadji, Seyed Alireza

    2014-08-17

    Multifocal epithelial hyperplasia (MEH) is a rare disorder characterized by multiple painless discrete and soft flattened papules on the oral mucosa. It is caused by human papilloma virus 13 and 32. The frequency of this disease varies widely from one geographic region to another. Generally it is very rare in Asia. Herein we report 3 Iranian cases with oral lesions, which showed clinical and histopathological characteristics of MEH disease. Two of them were siblings and HPV13 was detected in one of the patients.

  5. Finasteride Reduces the Risk of Incident Clinical Benign Prostatic Hyperplasia

    PubMed Central

    Parsons, J. Kellogg; Schenk, Jeannette M.; Arnold, Kathryn B.; Messer, Karen; Till, Cathee; Thompson, Ian M.; Kristal, Alan R.

    2014-01-01

    Background Despite the high prevalence of clinical benign prostatic hyperplasia (BPH) among older men, there remains a notable absence of studies focused on BPH prevention. Objective To determine if finasteride prevents incident clinical BPH in healthy older men. Design, setting, and participants Data for this study are from the Prostate Cancer Prevention Trial. After excluding those with a history of BPH diagnosis or treatment, or an International Prostate Symptom Score (IPSS) ≥8 at study entry, 9253 men were available for analysis. Outcome measurements and statistical analysis The primary outcome was incident clinical BPH, defined as the initiation of medical treatment, surgery, or sustained, clinically significant urinary symptoms (IPSS >14). Finasteride efficacy was estimated using Cox proportional regression models to generate hazards ratios (HRs). Results and limitations Mean length of follow-up was 5.3 yr. The rate of clinical BPH was 19 per 1000 person-years in the placebo arm and 11 per 1000 person-years in the finasteride arm (p < 0.001). In a covariate-adjusted model, finasteride reduced the risk of incident clinical BPH by 40% (HR: 0.60; 95% confidence interval, 0.51–0.69; p < 0.001). The effect of finasteride on incident clinical BPH was attenuated in men with a body mass index ≥30 kg/m2 (pinteraction = 0.04) but otherwise did not differ significantly by physical activity, age, race, current diabetes, or current smoking. The post hoc nature of the analysis is a potential study limitation. Conclusions Finasteride substantially reduces the risk of incident clinical BPH in healthy older men. These results should be considered in formulating recommendations for the use of finasteride to prevent prostate diseases in asymptomatic older men. PMID:22459892

  6. Giant lymph node hyperplasia of the mediastinum and refractory anaemia.

    PubMed Central

    Geary, C G; Fox, H

    1978-01-01

    An example is described of the syndrome of refractory anaemia in association with the plasma cell variant of giant lymph node hyperplasia of the mediastinum; the anaemia responded to removal of the lymphoid mass. The entity of giant lymph node hyperplasia is discussed and its relationship to the haematological syndrome is considered. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:690239

  7. Focal epithelial hyperplasia caused by human papillomavirus 13.

    PubMed

    Saunders, Natasha R; Scolnik, Dennis; Rebbapragada, Anuradha; Koelink, Eric; Craw, Lindsey; Roth, Sherryn; Aronson, Leya; Perusini, Stephen; Silverman, Michael S

    2010-06-01

    Focal epithelial hyperplasia is a benign, papulo-nodular disease of the oral cavity. It is rare, affecting primarily Native American populations during childhood. It is closely associated with human papillomavirus 13 and 32. This report describes the diagnosis of 2 cases of focal epithelial hyperplasia in children from southern Guyana. The diagnosis was made using clinical criteria, polymerase chain reaction, and DNA sequencing.

  8. Pseudocarcinomatous hyperplasia involving the ear from gout: a diagnostic pitfall.

    PubMed

    Morrissey, Kelly A; Garcia-Albea, Victoria; Goldberg, Lynne J

    2014-01-01

    The ear is a characteristic location for deposition of uric acid in patients with gout. Pseudocarcinomatous hyperplasia has not been described in this location. We report three patients with tophaceous gout on the ear whose biopsies exhibited epidermal hyperplasia mimicking squamous cell carcinoma, in order to call attention to this potential diagnostic pitfall.

  9. Genetics of primary macronodular adrenal hyperplasia.

    PubMed

    Fragoso, Maria Candida Barisson Villares; Alencar, Guilherme Asmar; Lerario, Antonio Marcondes; Bourdeau, Isabelle; Almeida, Madson Queiroz; Mendonca, Berenice Bilharinho; Lacroix, André

    2015-01-01

    ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression. © 2015 Society for Endocrinology.

  10. Leydig Cell Hyperplasia Revealed by Gynecomastia

    PubMed Central

    Tazi, Mohamed Fadl; Mellas, Soufiane; El Fassi, Mohamed Jamal; Farih, Moulay Hassan

    2008-01-01

    Leydig cell tumors are rare and represent 1% to 3% of all tumors of the testis. Leydig cell tumors affect males at any age, but there are 2 peak periods of incidence: between 5 and 10 years and between 25 and 35 years. Their main clinical presentation is a testicular mass associated with endocrinal manifestations that are variable according to age and appearance of the tumor. Our patient, a 17-year-old adolescent, presented with an isolated and painless hypertrophy of the right mammary gland. Clinical examination found gynecomastia and no testicular mass. Hormonal levels and tumor markers were normal. Testicular sonography showed an ovular and homogeneous right intratesticular mass 6 mm in diameter. We treated the patient with an inguinal right orchidectomy. The anatomopathological study found a nodule of Leydig cell hyperplasia. The patient recovered without recurrence at 8-month follow-up. The patient opted for mammoplasty 2 months after his orchidectomy rather than wait for the spontaneous gradual regression of his gynecomastia, which requires at least 1 year. Leydig cell hyperplasia manifests in the adult by signs of hypogonadism, most frequently gynecomastia. Although many teams prefer total orchidectomy because of the diagnostic difficulty associated with malignant forms, simple subcapsular orchidectomy should become the first-line treatment, provided it be subsequently followed by close surveillance, as it preserves maximum fertility, and these tumors usually resolve favorably. PMID:18660859

  11. Leydig cell hyperplasia revealed by gynecomastia.

    PubMed

    Tazi, Mohamed Fadl; Mellas, Soufiane; El Fassi, Mohamed Jamal; Farih, Moulay Hassan

    2008-01-01

    Leydig cell tumors are rare and represent 1% to 3% of all tumors of the testis. Leydig cell tumors affect males at any age, but there are 2 peak periods of incidence: between 5 and 10 years and between 25 and 35 years. Their main clinical presentation is a testicular mass associated with endocrinal manifestations that are variable according to age and appearance of the tumor. Our patient, a 17-year-old adolescent, presented with an isolated and painless hypertrophy of the right mammary gland. Clinical examination found gynecomastia and no testicular mass. Hormonal levels and tumor markers were normal. Testicular sonography showed an ovular and homogeneous right intratesticular mass 6 mm in diameter. We treated the patient with an inguinal right orchidectomy. The anatomopathological study found a nodule of Leydig cell hyperplasia. The patient recovered without recurrence at 8-month follow-up. The patient opted for mammoplasty 2 months after his orchidectomy rather than wait for the spontaneous gradual regression of his gynecomastia, which requires at least 1 year. Leydig cell hyperplasia manifests in the adult by signs of hypogonadism, most frequently gynecomastia. Although many teams prefer total orchidectomy because of the diagnostic difficulty associated with malignant forms, simple subcapsular orchidectomy should become the first-line treatment, provided it be subsequently followed by close surveillance, as it preserves maximum fertility, and these tumors usually resolve favorably.

  12. Torus hyperplasia of the pyloric antrum.

    PubMed

    Kim, Chi-Hun; Han, Hye Seung; Lee, Sun-Young; Kim, Byung Kook; Sung, In-Kyung; Seong, Moo Kyung; Lee, Kyung Yung

    2010-01-01

    Primary or idiopathic hypertrophy of the pyloric muscle in adult, so called torus hyperplasia, is an infrequent but an established entity. It is caused by a circular muscle hypertrophy affecting the lesser curvature near the pylorus. Since most of the lesions are difficult to differentiate from tumor, distal gastrectomy is usually preformed to rule out most causes of pyloric lesions including neoplastic ones through a pathological study. A 56-yr-old man with a family history of gastric cancer presented with abdominal discomfort of 1 month duration. Upper gastrointestinal endoscopy showed a 1.0 cm sized irregular submucosal lesion proximal to the pylorus to the distal antrum on the lesser curvature. On colonoscopy examination, a 1.5 cm sized protruding mass was noticed on the appendiceal orifice. Gastrectomy and cecectomy were done, and histological section revealed marked hypertrophy of the distal circular pyloric musculature and an appendiceal mucocele. To the best of our knowledge, this is the first case of torus hyperplasia with appendiceal mucocele which is found incidentally.

  13. Diagnosis and management of benign prostatic hyperplasia.

    PubMed

    Edwards, Jonathan L

    2008-05-15

    Benign prostatic hyperplasia is a common condition affecting older men. Typical presenting symptoms include urinary hesitancy, weak stream, nocturia, incontinence, and recurrent urinary tract infections. Acute urinary retention, which requires urgent bladder catheterization, is relatively uncommon. Irreversible renal damage is rare. The initial evaluation should assess the frequency and severity of symptoms and the impact of symptoms on the patient's quality of life. The American Urological Association Symptom Index is a validated instrument for the objective assessment of symptom severity. The initial evaluation should also include a digital rectal examination and urinalysis. Men with hematuria should be evaluated for bladder cancer. A palpable nodule or induration of the prostate requires referral for assessment to rule out prostate cancer. For men with mild symptoms, watchful waiting with annual reassessment is appropriate. Over the past decade, numerous medical and surgical interventions have been shown to be effective in relieving symptoms of benign prostatic hyperplasia. Alpha blockers improve symptoms relatively quickly. Although 5-alpha reductase inhibitors have a slower onset of action, they may decrease prostate size and alter the disease course. Limited evidence shows that the herbal agents saw palmetto extract, rye grass pollen extract, and pygeum relieve symptoms. Transurethral resection of the prostate often provides permanent relief. Newer laser-based surgical techniques have comparable effectiveness to transurethral resection up to two years after surgery with lower perioperative morbidity. Various outpatient surgical techniques are associated with reduced morbidity, but symptom relief may be less durable.

  14. Progestin Therapy of Complex Endometrial Hyperplasia With and Without Atypia

    PubMed Central

    Reed, SD; Voigt, LF; Newton, KM; Garcia, R; Allison, HK; Epplein, M; Jordan, D; Swisher, E; Weiss, NS

    2009-01-01

    Precis Complex hyperplasia regression is common with and without progestin therapy, and the likelihood of atypical hyperplasia regression is greater with progestin therapy than without. Objective To assess likelihood of histologic persistence/progression of complex hyperplasia and atypical hyperplasia among women treated with progestin compared to those not treated, with attention to type, dose and duration. Methods This was a cohort study of women at an integrated health plan, ages 18-85 years, with complex or atypical hyperplasia on independent pathology review with a second endometrial specimen in the 2-6 months following the index diagnosis. Progestin therapy between index diagnosis and follow-up biopsy was determined from the pharmacy database. Medical record abstraction was performed. Relative risks (RR), adjusted for age and body mass index, were calculated. Results Among 185 women, average age 55.9 years, follow-up 16.1 weeks, 115 women had complex and 70 had atypical hyperplasia. Among women with complex hyperplasia 28.4% of women treated with progestin and 30.0% of those not treated had persistence/progression (RR 1.20, 95% confidence interval (CI) 0.53-2.72). Among women with atypical hyperplasia, 26.9% of those treated with progestin and 66.7% of those not treated had persistence/progression (RR 0.39, 95% CI 0.21-0.70); there was a suggestion that use of at least a medium dose, or a duration of at least 3 months, was associated with a particularly low probability of persistence/progression. Conclusion While progestin treatment of women with atypical hyperplasia was associated with a substantial increase in the likelihood of regression of the lesion during the ensuing 2-6 months, persistence/progression was nonetheless present in more than one-quarter of treated women. Regression of complex hyperplasia without atypia was common whether progestin had or had not been used. PMID:19300331

  15. Saratin (an inhibitor of platelet-collagen interaction) decreases platelet aggregation and homocysteine-mediated postcarotid endarterectomy intimal hyperplasia in a dose-dependent manner.

    PubMed

    Davis, Joseph A; Brown, Aliza T; Alshafie, Tarek; Poirier, Lionel A; Cruz, Carlos P; Wang, Yunfang; Eidt, John F; Moursi, Mohammed M

    2004-12-01

    This study investigated Saratin's (Merck KGaA, Darmstadt, Germany) prevention of platelet adhesion and intimal hyperplasia at different doses and in the hyperhomocystinemia rat carotid endarterectomy (CEA) model. Rats were divided into two groups: (1) platelet adhesion or (2) luminal stenosis because of intimal hyperplasia. At CEA, rats received 0, 0.5, 5.0, 10.0, or 20.0 microg Saratin on the artery. Post-CEA platelet aggregation was evaluated by standard error of the mean. Intimal hyperplasia group received either (1) control or (2) 4.5 g/kg DL-homocystine diets for two weeks followed by CEA and treated with diluent or 5.0 microg Saratin. Endpoints included platelet adhesion, intimal hyperplasia, plasma homocysteine (HCys), and its metabolic enzymes cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR). Platelet adhesion: post-CEA, platelet adhesion was reduced by 63%, 67%, and 67% in Saratin doses > or =5.0 microg. Intimal hyperplasia: 5.0 microg Saratin in the HCys group decreased intimal hyperplasia by 45% compared with the non-Saratin-treated HCys group. Plasma HCys levels were not altered with Saratin treatment in the HCys groups nor were CBS or MTHFR. Saratin significantly inhibited platelet adhesion at > or =5.0 microg, and Saratin at 5.0 microg attenuated luminal stenosis in a hyperhomocysteinemic rat CEA model.

  16. Therapeutic effect of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats.

    PubMed

    Bisson, Jean-François; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

    2007-12-01

    Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that results in obstructive lower urinary tract symptoms. Plant extracts are frequently used to treat BPH rather than therapeutics that can cause severe side effects. ACTICOA() (Ba0rry Callebaut France, Louviers, France) powder (AP) is a cocoa polyphenolic extract, and we have shown in a previous study that oral treatment with AP prevented prostate hyperplasia. This study investigated whether AP could improve established prostate hyperplasia using the same testosterone propionate (TP)-induced prostate hyperplasia model in rats. Male Wistar-Unilever rats were randomly divided in four groups of 12 rats: one group injected with corn oil and orally treated with the vehicle (negative control) and three groups injected subcutaneously with TP and orally treated with the vehicle (positive control) or AP at 24 (AP24) and 48 (AP48) mg/kg/day. Treatments started 1 week after the start of the induction of prostate hyperplasia and lasted for 2 weeks. The influence of TP and AP on body weights, food and water consumptions, plasma polyphenolic concentration, and serum dihydrotestoterone (DHT) level of rats was examined. At completion of the study, rats were sacrificed, and the prostates were removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. TP significantly influenced the body weight gain of the rats and their food and water consumptions, while AP reduced significantly these differences in a dose-dependent manner. AP significantly reduced serum DHT level and prostate size ratio in comparison with positive controls also dose-dependently. In conclusion, AP orally administered was effective for reducing established prostate hyperplasia, especially at the dose of 48 mg/kg/day.

  17. Sequence-independent inhibition of in vitro vascular smooth muscle cell proliferation, migration, and in vivo neointimal formation by phosphorothioate oligodeoxynucleotides.

    PubMed Central

    Wang, W; Chen, H J; Schwartz, A; Cannon, P J; Stein, C A; Rabbani, L E

    1996-01-01

    Phosphorothioate oligodeoxynucleotides (PS oligos) are antisense (sequence-specific) inhibitors of vascular smooth muscle cell (SMC) proliferation when targeted against different genes. Recently an aptameric G-quartet inhibitory effect of PS oligos has been demonstrated. To determine whether PS oligos manifest non-G-quartet, non-sequence-specific effects on human aortic SMC, we examined the effects of S-dC28, a 28-mer phosphorothioate cytidine homopolymer, on SMC proliferation induced by several SMC mitogens. S-dC28 significantly inhibited SMC proliferation induced by 10% FBS as well as the mitogens PDGF, bFGF, and EGF without cytotoxicity. Moreover, S-dC28 abrogated PDGF-induced in vitro migration in a modified micro-Boyden chamber. Furthermore, S-dC28 manifested in vivo antiproliferative effects in the rat carotid balloon injury model. S-dC28 suppressed neointimal cross-sectional area by 73% and the intima/media area ratio by 59%. Therefore, PS oligos exert potent non-G-quartet, non-sequence-specific effects on in vitro SMC proliferation and migration as well as in vivo neointimal formation. PMID:8755655

  18. Effect of dutasteride on clinical progression of benign prostatic hyperplasia in asymptomatic men with enlarged prostate: a post hoc analysis of the REDUCE study.

    PubMed

    Toren, Paul; Margel, David; Kulkarni, Girish; Finelli, Antonio; Zlotta, Alexandre; Fleshner, Neil

    2013-04-15

    To assess the role of dutasteride in preventing clinical progression of benign prostatic hyperplasia in asymptomatic men with larger prostates. Post hoc analysis of four year, double blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study 1617 men randomised to dutasteride or placebo with a prostate size >40 mL and baseline International Prostate Symptom Score (IPSS) <8. Subjects who took medications for benign prostatic hyperplasia were excluded at study entry. Placebo or dutasteride 0.5 mg daily. Comparison of risk of clinical progression of benign prostatic hyperplasia at four years (defined as a ≥ 4 point worsening on IPSS, acute urinary retention, urinary tract infection, or surgery related to benign prostatic hyperplasia). 825 participants took placebo, 792 took dutasteride. A total of 464 (29%) experienced clinical progression benign prostatic hyperplasia, 297(36%) taking placebo, 167 (21%) taking dutasteride (P<0.001). The relative risk reduction was 41% and the absolute risk reduction 15%, with a number needed to treat (NNT) of 7. Among men who had acute urinary retention and surgery related to benign prostatic hyperplasia, the absolute risk reduction for dutasteride was 6.0% and 3.8%, respectively. On multivariable regression analysis adjusting for covariates, dutasteride significantly reduced clinical progression of benign prostatic hyperplasia with an odds ratio of 0.47 (95% CI 0.37 to 0.59, P<0.001). Analysis of time to first event yielded a hazard ratio of 0.673 (P<0.001) for those taking dutasteride. Sexual adverse events were most common and similar to prior reports. Further prospective studies may be warranted to demonstrate generalisability of these results. This study is the first to explore the benefit of treating asymptomatic or mildly symptomatic men with an enlarged prostate. Dutasteride significantly decreased the incidence of benign prostatic hyperplasia clinical progression.

  19. Effect of dutasteride on clinical progression of benign prostatic hyperplasia in asymptomatic men with enlarged prostate: a post hoc analysis of the REDUCE study

    PubMed Central

    Toren, Paul; Margel, David; Kulkarni, Girish; Finelli, Antonio; Zlotta, Alexandre

    2013-01-01

    Objective To assess the role of dutasteride in preventing clinical progression of benign prostatic hyperplasia in asymptomatic men with larger prostates. Design Post hoc analysis of four year, double blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study Participants 1617 men randomised to dutasteride or placebo with a prostate size >40 mL and baseline International Prostate Symptom Score (IPSS) <8. Subjects who took medications for benign prostatic hyperplasia were excluded at study entry. Interventions Placebo or dutasteride 0.5 mg daily. Main outcome measures Comparison of risk of clinical progression of benign prostatic hyperplasia at four years (defined as a ≥4 point worsening on IPSS, acute urinary retention, urinary tract infection, or surgery related to benign prostatic hyperplasia). Results 825 participants took placebo, 792 took dutasteride. A total of 464 (29%) experienced clinical progression benign prostatic hyperplasia, 297(36%) taking placebo, 167 (21%) taking dutasteride (P<0.001). The relative risk reduction was 41% and the absolute risk reduction 15%, with a number needed to treat (NNT) of 7. Among men who had acute urinary retention and surgery related to benign prostatic hyperplasia, the absolute risk reduction for dutasteride was 6.0% and 3.8%, respectively. On multivariable regression analysis adjusting for covariates, dutasteride significantly reduced clinical progression of benign prostatic hyperplasia with an odds ratio of 0.47 (95% CI 0.37 to 0.59, P<0.001). Analysis of time to first event yielded a hazard ratio of 0.673 (P<0.001) for those taking dutasteride. Sexual adverse events were most common and similar to prior reports. Limitations Further prospective studies may be warranted to demonstrate generalisability of these results. Conclusions This study is the first to explore the benefit of treating asymptomatic or mildly symptomatic men with an enlarged prostate. Dutasteride significantly decreased the incidence of

  20. Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH

    PubMed Central

    Saito, Motoaki; Tsounapi, Panagiota; Oikawa, Ryo; Shimizu, Shogo; Honda, Masashi; Sejima, Takehiro; Kinoshita, Yukako; Tomita, Shuhei

    2014-01-01

    In the light of increasing evidence that benign prostatic hyperplasia is associated with cardiovascular disease, we have investigated the relationship between prostatic blood flow and prostatic hyperplasia in the spontaneously-hypertensive-rat (SHR). Twelve-week-old male SHRs were treated with nicorandil for six weeks. Wistar-Kyoto rats were used as controls. Six weeks after nicorandil treatment, blood pressure and the prostatic blood flow were estimated, and tissue levels of malondialdehyde, HIF-1α, TGF-β1, bFGF, dihydrotestosterone, and α-SMA were measured. SHRs showed significant increases in blood pressure, tissue levels of malondialdehyde, HIF-1α, TGF-β1, bFGF, α-SMA and a significant decrease in the prostatic blood flow. Although treatment with nicorandil failed to alter the blood-pressure and α-SMA, it significantly ameliorated the increased levels of malondialdehyde, HIF-1α, TGF-β1, and bFGF. There were no significant differences in tissue levels of dihydrotestosterone among any groups. These data indicate that development of prostatic hyperplasia may be associated with prostatic hypoxia, which nicorandil prevents via its effect to increase the blood flow. PMID:24448152

  1. Giant fibroadenomatoid hyperplasia of the breast: a case report.

    PubMed

    Zhang, Hao; Wang, Xin-Lu; Ren, Wei-Dong; Shi, Tie-Mei

    2014-01-01

    Fibroadenomatoid hyperplasia of the breast (FAHB) is a rare benign breast lesion and its clinical features are similar to fibroadenoma and fibrocystic changes. FAHB has been previously termed sclerosing lobular hyperplasia, fibroadenomatosis, fibroadenomatoid change, or fibroadenomatoid mastopathy. Typically, FAHB is derived from stroma and epithelia. The pathologic characteristics of FAHB are microfocal lobulocentric proliferation of stroma accompanied by epithelial and myoepithelial components resembling similar histological changes, as found in fibroadenoma, apocrine hyperplasia, intraductal hyperplasia, and lobular hyperplasia. FAHB could be present as a localized or diffused pattern in pathology. Most cases show no well-circumscribed mass lesions and no apparent capsules; it is usually identified as an incidental finding in other benign lesions or in random sampling in cancerous breast tissues. FAHB is categorized as a benign proliferative breast disease and it has previously been reported; however, the authors believe this study may be the first case with two giant masses reported. Fiber adenoma hyperplasia is a rare cystic hyperplasia of breast pathology and its ultrasonographic manifestations are easily confused with breast cancer. Comparative MRI ultrasound analysis will help make the differential diagnosis. © 2014 S. Karger AG, Basel.

  2. C-cell hyperplasia and medullary thyroid microcarcinoma.

    PubMed

    Albores-Saavedra, J A; Krueger, J E

    2001-01-01

    Since the discovery of the thyroid C-cell, considerable progress has been made regarding its origin, function, and pathology. In this article an attempt is made to summarize and update our knowledge about physiologic or reactive C-cell hyperplasia, neoplastic C-cell hyperplasia (medullary carcinoma in situ), and medullary microcarcinoma. Seldom recognized preoperatively, physiologic C-cell hyperplasia is associated with inflammatory, metabolic, and neoplastic thyroid disorders as well as with hypercalcemia. However, the pathogenesis is still unclear. Although physiologic C-cell hyperplasia may progress to medullary carcinoma, the full malignant potential is unknown. Problems related to the definition of physiologic C-cell hyperplasia are discussed. Immunohistochemistry and quantitative analysis are required for the diagnosis. By contrast, C-cell hyperplasia associated with MEN II syndromes or familial medullary carcinoma can be diagnosed preoperatively in asymptomatic children or adolescents by the detection of germline mutations of the RET protooncogene. Morphologic and genetic abnormalities support the idea that C-cells in the familial form of C-cell hyperplasia are neoplastic and can be recognized with conventional stains. Therefore, the number of C-cells is irrelevant for the diagnosis. Medullary microcarcinoma is a neoplasm that measures < 1 cm. The sporadic variant is usually an incidental microscopic finding, whereas the familial form can be diagnosed by genetic testing. Its morphologic features and biologic behavior differ from those of larger medullary carcinomas. The frequency of medullary microcarcinoma will probably increase with the use of genetic testing.

  3. Anti-hyperplasia effects of Rosa rugosa polyphenols in rats with hyperplasia of mammary gland.

    PubMed

    Chen, Tao; Li, Jingjing; Chen, Jinglou; Song, Hongping; Yang, Chuhao

    2015-03-01

    Rosa rugosa (Thunb.) is used in Chinese traditional medicine with the functions of promoting blood circulation, relieving the depressed liver and attenuating breast disorders. This study was to investigate the anti-hyperplasia effects of the polyphenols-rich fraction from R. rugosa (FRR) in rat. Rat model of hyperplasia of mammary gland (HMG) was induced by intramuscularly injected with estrogen (0.5mg/kg/d) for 25 days, and followed with progestogen (5mg/kg/d) for another 5 days. Meanwhile, FRR was orally given for 30 days. Then, the levels of estradiol and oxidative stress were assessed. The mammary expressions of AKT and JNK were evaluated by Western blot analysis. The expressions of NFκB-p65, COX-2 and VEGF were measured by immunohistochemical analysis. The whole results indicated that FRR could exert anti-hyperplasia effects in rat via modulating the mammary expression of JNK and AKT, as well as alleviating the NFκB related oxidative stress and inflammatory responses. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Risk stratification for benign prostatic hyperplasia.

    PubMed

    Zattoni, Fabio; Ficarra, Vincenzo; Novara, Giacomo

    2017-03-18

    Benign prostatic hyperplasia (BPH) represents an important public health problem in ageing men due to frequently associated lower urinary tract symptoms (LUTS), which may impair quality of life. BPH is also a progressive disease, mainly characterized by a worsening of LUTS over time, and in some patients by the occurrence of serious outcomes such as acute urinary retention and need for BPH-related surgery. The management of BPH and LUTS in men should move forward its focus on symptom control only. Indeed, the goals of therapy for BPH are not only to improve bothersome LUTS but also to identify those patients at risk of unfavourable outcomes in order to optimize their management and reduce complications. Risk stratification and tailored treatment should improve the reductions in both symptoms and the long-term consequences of BPH and BPH treatments. To do this, clinicians need to know possible factors that may support the develop of PBH and possible risks due to the BPH itself.

  5. Benign prostatic hyperplasia: clinical manifestations and evaluation.

    PubMed

    Santos Dias, José

    2012-12-01

    Benign prostatic hyperplasia (BPH) is a very common condition, related to aging and causing symptoms, called lower urinary tract symptoms. On account of its huge prevalence, it is important for clinicians who are involved in the management of patients with BPH to be aware of the very strict recommendations for BPH evaluation. In this article, we describe the different steps and procedures doctors should follow to evaluate these patients; symptoms and signs of BPH are reviewed, as well as the clinical evaluation steps and examinations available. The basic evaluation of the patients with BPH should include, according to the recommendations of the most relevant international guidelines, lower urinary tract symptoms evaluation with appropriate symptom scores, digital rectal examination, voiding charts, prostate-specific antigen and creatinine measurement, urinalysis, and imaging of the urinary tract.

  6. Microwave Treatment of Prostate Cancer and Hyperplasia

    NASA Technical Reports Server (NTRS)

    Arndt, G. Dickey; Ngo, Phong; Carl, J. R.; Raffoul, George

    2005-01-01

    Microwave ablation in the form of microwave energy applied to a heart muscle by a coaxial catheter inserted in a vein in the groin area can be used to heat and kill diseased heart cells. A microwave catheter has been developed to provide deep myocardial ablation to treat ventricular tachycardia by restoring appropriate electrical activity within the heart and eliminating irregular heartbeats. The resulting microwave catheter design, which is now being developed for commercial use in treating ventricular tachycardia, can be modified to treat prostate cancer and benign prostatic hyperplasia (BPH). Inasmuch as the occurrence of BPH is increasing currently 350,000 operations per year are performed in the United States alone to treat this condition this microwave catheter has significant commercial potential.

  7. Saw palmetto and benign prostatic hyperplasia.

    PubMed

    Gong, Edward M; Gerber, Glenn S

    2004-01-01

    Benign prostatic hyperplasia (BPH) is a common health issue that affects 8% of all men at the age of 40, 60% of men in their 70s, and 90% of those greater than 80 years of age. One-fourth of these men will develop moderate to severe lower urinary tract symptoms that greatly affect their quality of life. Recent evidence suggests that the use of saw palmetto leads to improvements in urinary function for those suffering from BPH. The favorable comparison of saw palmetto with tamsulosin, a well-known first line agent in the treatment of urinary tract symptoms, demonstrates promise towards a beneficial effect of this herbal agent, with very few, if any, adverse effects. However, what degree of this beneficial activity is due to placebo effects is yet to be determined. In addition, the precise mechanism of action of saw palmetto in men with BPH remains unclear.

  8. Verrucous Hyperplasia: Case report and differential diagnosis.

    PubMed

    Grover, Sonal; Jha, Mihir; Sharma, Bhushan; Kapoor, Shekhar; Mittal, Kumud; Parakkat, Nithin K; Shivappa, Anil B; Kaur, Ravleen

    2017-02-01

    Verrucous hyperplasia (VH) is a rare exophytic oral mucosal lesion which can transform into verrucous carcinoma (VC), its malignant but clinically similar counterpart. These entities can be distinguished by the lack of invasive growth in VH cases; as such, it is essential to include a margin with adequate depth when performing a biopsy of the epithelium of the lesion. We report an 80-year-old male patient who presented to the Bapuji Dental College & Hospital, Davangere, Karanataka, India, in 2011 with a warty whitish-pink growth on the inside of his cheek. The patient was treated with wide surgical excision of the lesion and a diagnosis of VH was made based on histopathological features. There was no evidence of recurrence at a five-year follow-up. This report highlights the histological variations, pathogenesis and differential diagnosis of VH.

  9. Pseudoepitheliomatous Hyperplasia: Relevance in Oral Pathology

    PubMed Central

    Sarangarajan, R; Vedam, V K Vaishnavi; Sivadas, G; Krishnaraj, R; Sarangarajan, Anuradha; Shanmugam, K T

    2015-01-01

    Pseudoepitheliomatous hyperplasia (PEH), a neglected entity by oral pathologist possesses utmost importance in the field of research. Of all the investigative challenges, PEH, a reactive epithelial proliferation is seen secondary to lesions with infectious, inflammatory, reactive, and degenerative origin. Small sized samples, incomplete excision, improper orientation, and dense inflammatory changes render diagnostic confront to the oral pathologist in exclusion of frankly invasive malignant lesions like squamous cell carcinoma from lesions exhibiting PEH. The diagnosis can occasionally be difficult as they mimic other lesions also, on clinic-pathological assessment. Thus, this article gives an insight regarding the various concepts of etiopathogenesis, histopathology, differential diagnosis, and malignant potential of PEH. A combined effort of a clinician and pathologist benefits every patient to rule out malignancy and render appropriate treatment as the only local conservative approach is essential to remove PEH associated lesions. PMID:26229388

  10. Congenital adrenal hyperplasia: Treatment and outcomes.

    PubMed

    Kamoun, Mahdi; Feki, Mouna Mnif; Sfar, Mohamed Habib; Abid, Mohamed

    2013-10-01

    Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders where there is impairment of cortisol biosynthesis. CAH due to 21-hydroxylase deficiency accounts for 95% of cases and shows a wide range of clinical severity. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment of CAH. The optimal treatment for adults with CAH continues to be a challenge. Important long-term health issues for adults with CAH affect both men and women. These issues may either be due to the disease or to steroid treatment and may affect final height, fertility, cardiometabolic risk, bone metabolism, neuro-cognitive development and the quality-of-life. Patients with CAH should be regularly followed-up from childhood to adulthood by multidisciplinary teams who have knowledge of CAH. Optimal replacement therapy, close clinical and laboratory monitoring, early life-style interventions, early and regular fertility assessment and continuous psychological management are needed to improve outcome.

  11. Transurethral microwave hyperthermia in benign prostatic hyperplasia

    NASA Astrophysics Data System (ADS)

    Petrovich, Zbigniew; Ameye, Filip; Baert, Luc

    1992-09-01

    Benign prostatic hyperplasia (BPH) is a common disease affecting past middle-aged males. Surgical treatment has been successfully used since the early 1900s. Currently, nonsurgical treatment modalities are under intensive study in BPH patients who have relative contraindications to surgery. Transurethral microwave hyperthermia (TUHT) is one of these modalities under study. TUHT has been applied in five to ten treatment sessions. The treatments were well tolerated with no major toxicity being reported. In BPH patients with predominance of median lobe or median bar enlargement the treatment efficacy was reduced to 30%. The effectiveness of TUHT was of particular importance in patients who had urinary retention. In the group 72% had normal voiding for 12 months or longer. A strong correlation between applied temperature and response to treatment was demonstrated. Current efforts are directed toward optimization of technique and treatment schedule. A phase III prospective randomized trial is required to define the role of TUHT in the management of BPH patients.

  12. Papillary endothelial hyperplasia (Masson's tumor) in children.

    PubMed

    Liné, A; Sanchez, J; Jayyosi, L; Birembaut, P; Ohl, X; Poli-Mérol, M-L; François, C

    2016-06-23

    The intravascular papillary endothelial hyperplasia (IPEH/Masson's tumor) is a rare benign tumor of the skin and subcutaneous vessels. We report, in four pediatric cases, clinical presentation, care (diagnostic and surgical) of Masson's tumor in children. Two boys (two years) and two girls (four and six years) showed a pain subcutaneous tumor (one to five centimeters). They were in the transverse abdominal muscle, between two metatarsals, at the front of thigh and in the axilla. Imaging performed (MRI, Doppler ultrasound) evoked either a hematoma, a lymphangioma or hemangioma. The indication for removal was selected from pain and/or parental concern. The diagnosis was histologically. A lesion persisted in residual form (incomplete initial resection), and is currently not scalable for eleven years.

  13. Pseudoangiomatous stromal hyperplasia causing massive breast enlargement.

    PubMed

    Bourke, Anita Geraldine; Tiang, Stephen; Harvey, Nathan; McClure, Robert

    2015-10-16

    Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign mesenchymal proliferative process, initially described by Vuitch et al. We report an unusual case of a 46-year-old woman who presented with a 6-week history of bilateral massive, asymmetrical, painful enlargement of her breasts, without a history of trauma. On clinical examination, both breasts were markedly enlarged and oedematous, but there were no discrete palpable masses. Preoperative image-guided core biopsies and surgery showed PASH. PASH is increasingly recognised as an incidental finding on image-guided core biopsy performed for screen detected lesions. There are a few reported cases of PASH presenting as rapid breast enlargement. In our case, the patient presented with painful, asymmetrical, massive breast enlargement. Awareness needs to be raised of this entity as a differential diagnosis in massive, painful breast enlargement.

  14. Neonatal screening for congenital adrenal hyperplasia.

    PubMed Central

    Cacciari, E; Balsamo, A; Cassio, A; Piazzi, S; Bernardi, F; Salardi, S; Cicognani, A; Pirazzoli, P; Zappulla, F; Capelli, M

    1983-01-01

    Capillary blood samples from 42930 infants born in the Italian region of Emilia-Romagna were collected for 17-hydroxyprogesterone radioimmunoassays on days 2, 3, 4, 5, 6, and 7, or between days 7 and 15 of life. A microfilter paper method modified from that of Pang et al.1 was used for this assay. Pathologic values of 17-hydroxyprogesterone were found in 5 infants giving an incidence in this homogeneous Caucasian population of 1:8586. We also investigated 17-hydroxyprogesterone values in relation to the day of sampling and the possible correlation between 17-hydroxyprogesterone values and birthweight and gestational age. We concluded that neonatal screening for congenital adrenal hyperplasia caused by 21-hydroxylase deficiency was possible by this method and that the infants' maturity and the particular day of collection of the samples affect the values but not the validity of the screening. PMID:6639129

  15. Optimizing the management of benign prostatic hyperplasia

    PubMed Central

    Elterman, Dean S.; Kaplan, Steven A.

    2012-01-01

    One of the challenges facing primary care physicians and specialists as the population ages is the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). While as many as 18% of men in their 40s report bother from an enlarged prostate, that figure rises dramatically, whereby 50% of men in their 50s and 90% of men in their 90s will complain of bothersome symptoms related to an enlarged prostate. Studies have shown that BPH is a progressive disease, which if left untreated can result in worsening of symptoms, acute urinary retention and renal failure. Until about 20 years ago the only management option available to urologists was surgery. In the early 1990s medical therapy emerged as the predominant treatment for BPH. Therapy may be tailored to target symptoms and progression of disease. PMID:22496710

  16. Therapy monitoring in congenital adrenal hyperplasia by dried blood samples.

    PubMed

    Wieacker, Isabelle; Peter, Michael; Borucki, Katrin; Empting, Susann; Roehl, Friedrich-Wilhelm; Mohnike, Klaus

    2015-07-01

    Careful monitoring of the therapy is crucial for patients with congenital adrenal hyperplasia (CAH) in order to prevent the effects of increased androgen production as well as life-threatening salt-wasting crisis. The key metabolite, 17α-hydroxyprogesterone (17-OHP) can be detected in serum, saliva or dried blood. In clinical practice there are challenges due to discomfort of venous blood sampling and complicated retrieval of saliva during infancy. Furthermore, the immunoassay method is limited in its specificity due to cross-reactions. In this observational study we prospectively examined over a period of 5 years, 20 patients with CAH due to 21-hydroxylase deficiency using standard immunoassays for serum samples (radioimmunoassay and enzyme immunoassay) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in dried blood spots. Bland-Altman plots show goodness of agreement between both the methods for the desirable therapeutic concentration range of 17-OHP. LC-MS/MS is characterized by a high accuracy in the therapeutic concentration range of 17-OHP <100 nmol/L (r=0.91). Dried blood samples are convenient and reliable specimen for 17-OHP measured by LC-MS/MS. This method could be used for home monitoring of hydrocortisone replacement therapy both in salt-waster and simple virilizer CAH.

  17. Fibroadenoma with "immature-like" type of usual ductal hyperplasia.

    PubMed

    Bezić, Joško; Karaman, Ivana; Kunac, Nenad

    2016-01-01

    We herein report a case of the breast fibroadenoma with foci of so-called immature variant of the conventional ductal hyperplasia. This type of usual ductal hyperplasia is histologically characterised by encircling intraductal proliferation of large cells with pale to amphophilic cytoplasm and large nuclei which vary in shape and in staining quality of the chromatin. We showed here, using the cytokeratin immunohistochemistry, that the proliferating cells were not of immature but rather mature immunohistochemical phenotype. Because of the presented discordance between immature histology and mature immunohistological profile we suggest that this rare type of usual ductal hyperplasia should be called "immature-like".

  18. Rare Posterior Pharyngeal Mass: Atypical Marginal Zone Hyperplasia.

    PubMed

    Eliçora, Sultan Şevik; Güven, Mehmet; Varli, Ali F; Yilmaz, Mahmut S; Alponat, Selin

    2016-03-01

    Cases of posterior pharyngeal masses are quite rare, and are typically derived from schwannoma or encephalocele, or are of vascular or infectious origin. They are clinically significant due to their tendency to cause airway obstruction. The aim of this study was to present a rare atypical marginal hyperplasia case of a posterior pharyngeal wall mass. A 10-year-old male was admitted to our clinic with dyspnea. A plane-surfaced 4 × 3 × 3 cm mass was observed on the posterior pharyngeal wall upon physical examination. The patient underwent magnetic resonance imaging and surgical treatment. Following excision of material from the patient's mass, a pathologic diagnosis of atypical marginal zone hyperplasia was made. Atypical marginal zone hyperplasia of the posterior pharyngeal wall has not yet been reported in the literature. Marginal zone hyperplasia associated with a lymphoproliferative disease should be considered when making differential diagnoses of posterior pharyngeal wall masses.

  19. Ortho-surgical management of condylar hyperplasia: Rare case reports.

    PubMed

    Singh, Virendra; Verma, Ajay; Attresh, Gyanander; Batra, Jitender

    2014-01-01

    Condylar hyperplasia of the mandible is a clinical condition of over-development and growth because of excessive cellular growth of one condylar part of the mandible leading to facial asymmetry, mandibular deviation and enlargement of condyle. The elongation of the condylar neck in turn leads to malocclusion and articular dysfunction. In the past the interceptive and corrective procedures of growth and deformity in condylar hyperplasia were either condylectomy or high condylotomy. However, the deformity ceases after growth is completed. Therefore, other surgical procedures have to be undertaken to correct the manifested deformity of condylar hyperplasia. Further it has to be stressed that no single procedure can completely correct the deformity. So in addition to condylectomy, other orthognathic surgical procedures both on body and ramus and also on maxilla can be undertaken to correct the canting of occlusion. Two rare cases of unilateral hyperplasia encountered in our hospital are presented which required different lines of treatment.

  20. Axon and muscle spindle hyperplasia in the myostatin null mouse

    PubMed Central

    Elashry, Mohamed I; Otto, Anthony; Matsakas, Antonios; El-Morsy, Salah E; Jones, Lisa; Anderson, Bethan; Patel, Ketan

    2011-01-01

    Germline deletion of the myostatin gene results in hyperplasia and hypertrophy of the tension-generating (extrafusal) fibres in skeletal muscle. As this gene is expressed predominantly in myogenic tissues it offers an excellent model with which to investigate the quantitative relationship between muscle and axonal development. Here we show that skeletal muscle hyperplasia in myostatin null mouse is accompanied by an increase in nerve fibres in major nerves of both the fore- and hindlimbs. We show that axons within these nerves undergo hypertrophy. Furthermore, we provide evidence that the age-related neural atrophic process is delayed in the absence of myostatin. Finally, we show that skeletal muscle hyperplasia in the myostatin null mouse is accompanied by an increase in the number of muscle spindles (also called stretch receptors or proprioceptors). However, our work demonstrates that the mechanisms regulating intrafusal fibre hyperplasia and hypertrophy differ from those that control the aetiology of extrafusal fibres. PMID:21208206

  1. Axon and muscle spindle hyperplasia in the myostatin null mouse.

    PubMed

    Elashry, Mohamed I; Otto, Anthony; Matsakas, Antonios; El-Morsy, Salah E; Jones, Lisa; Anderson, Bethan; Patel, Ketan

    2011-02-01

    Germline deletion of the myostatin gene results in hyperplasia and hypertrophy of the tension-generating (extrafusal) fibres in skeletal muscle. As this gene is expressed predominantly in myogenic tissues it offers an excellent model with which to investigate the quantitative relationship between muscle and axonal development. Here we show that skeletal muscle hyperplasia in myostatin null mouse is accompanied by an increase in nerve fibres in major nerves of both the fore- and hindlimbs. We show that axons within these nerves undergo hypertrophy. Furthermore, we provide evidence that the age-related neural atrophic process is delayed in the absence of myostatin. Finally, we show that skeletal muscle hyperplasia in the myostatin null mouse is accompanied by an increase in the number of muscle spindles (also called stretch receptors or proprioceptors). However, our work demonstrates that the mechanisms regulating intrafusal fibre hyperplasia and hypertrophy differ from those that control the aetiology of extrafusal fibres.

  2. A giant prostatic hyperplasia treated by open surgery

    PubMed Central

    Ogawa, Soichiro; Manome, Masahiko; Yabe, Michihiro; Kuma, Yoshinobu; Yamaoka, Masaaki; Sato, Yuichi; Akaihata, Hidenori; Oguro, Toshiki; Kataoka, Masao; Kumagai, Shin; Kojima, Yoshiyuki

    2012-01-01

    We report a rare case of giant prostatic hyperplasia treated by open surgery. A 70-year-old man was suffering from macrohematuria. Computed tomography revealed a markedly enlarged prostate measuring 580 mL. The serum prostate-specific antigen level was 9.430 ng/mL. Prostatic biopsy showed benign prostatic hyperplasia. We perfomed retropubic open prostatectomy, since macrohematuria continued and he was also suffering from lower urinary tract symptoms. The adenoma was completely enucleated in one piece. The removed specimen was 13 × 11 × 6 cm in size and weighed 475 g. Histological examination also demonstrated prostatic fibromuscular hyperplasia. This is the 15th-heaviest adenoma ever reported in English-language journals. Transurethral surgical techniques or other minimally invasive approaches are performed for patients with small to medium-sized prostates. However, open surgery is recommended for markedly enlarged prostatic hyperplasia. PMID:23271919

  3. A patient with congenital hypertrichosis, gum hyperplasia and macromastia.

    PubMed

    Sood, A; Garg, R K; Saily, R; Dash, R J

    2000-05-01

    A syndrome of congenital hypertrichosis, hirsutism, gum hyperplasia and macromastia is described. The patient was demonstrated to have mild hyperinsulinemia with normal oral glucose tolerance test. This is the second such patient reported in the literature.

  4. Focal epithelial hyperplasia. A rare disease in our area.

    PubMed

    Segura-Saint-Gerons, Rafael; Toro-Rojas, Mariano; Ceballos-Salobreña, Alejandro; Aparicio-Soria, Jose Luis; Fuentes-Vaamonde, Helena

    2005-01-01

    Focal epithelial hyperplasia is a benign, asymptomatic disease, occurring with very low frequency within our population. It appears as papules, principally on the lower lip, although it can also be found on the retro-commissural mucosa and tongue, and less frequently on the upper lip, gingiva and palate. We present the clinical case of a 9-year-old Saharan girl with lesions that clinically and histologically corresponded to a focal epithelial hyperplasia.

  5. Cell adhesion and apoptosis in ovarian stromal hyperplasia and hyperthecosis.

    PubMed

    Sharabidze, N; Burkadze, G; Sabakhtarashvili, M

    2006-02-01

    The aim of our study was to investigate cell adhesion and apoptosis in ovarian stromal hyperplasia and hyperthecosis in reproductive women with and without polycystic ovarian disease. We have studied 104 patients with a histological diagnosis of ovarian stromal hyperthecosis and stromal hyperplasia. Paraffin sections were stained by hematoxylin-eosin, von Gieson and immunohistochemistry for Bcl-2 (anti-apoptotic protein) and E-cadherin (cell adhesion marker). We assessed the number of Bcl-2-positive and E-cadherin-positive cells. The patients were divided into 4 groups: group 1-33 patients with polycystic ovarian disease and coexistent stromal hyperthecosis, group 2-28 patients with polycystic ovarian disease and coexistent stromal hyperplasia, group 3-24 patients with ovarian stromal hyperthecosis, group 4-19 patients with ovarian stromal hyperplasia. Our results suggest that in ovarian stromal hyperthecosis and stromal hyperplasia coexistent with polycystic ovarian disease, E-cadherin-positivity in internal and external theca cells, and granulosa cells is associated with Bcl-2 expression. Therefore, ovarian cells expressing Bcl-2 and maintaining E-cadherin-positivity may be the viable cells that escape the apoptotic process. In ovarian stromal hyperthecosis without polycystic ovarian disease, luteinized stromal cells are potentially resistant to apoptosis as they are positive for Bcl-2. In ovarian stromal hyperplasia without polycystic ovarian disease, hyperplastic stromal cells are potentially susceptible to apoptosis as they are negative for Bcl-2. E-cadherin is negative both in stromal hyperthecosis and hyperplasia suggesting that E-cadherin expression in ovary is limited to granulosa and theca cells only. Described characteristics of cell adhesion and apoptosis may play a role in pathogenesis of ovarian stromal hyperthecosis and stromal hyperplasia with and without polycystic ovarian disease.

  6. Effects of genistein in combination with conjugated estrogens on endometrial hyperplasia and metabolic dysfunction in ovariectomized mice.

    PubMed

    Kim, Jun Ho; Kim, Young Jun

    2015-01-01

    Tissue-selective estrogen complex (TSEC), which combines a selective estrogen receptor modulator (SERM) with one or more estrogens, is a novel approach to menopausal therapy. It has been demonstrated that the phytoestrogen genistein (GEN) exhibits mixed estrogen receptor agonist and antagonist activity, suggesting that GEN may have potential for use as a natural SERM. We evaluated, for the first time, the effects of GEN, conjugated estrogens (CE), and their pairing effects as a TSEC treatment on estrogen-induced endometrial hyperplasia and metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet. CE replacement prevented fat accumulation in the adipose tissue and liver, improved glucose homeostasis, and induced endometrial hyperplasia in OVX mice. GEN at 100 mg/kg showed CE mimetic effects in preventing ovariectomy-induced metabolic dysfunctions without endometrial stimulation. Combination treatments with CE and GEN prevented metabolic dysfunctions more strongly than CE alone, but at both low and high doses, GEN did not reverse CE-induced endometrial hyperplasia. In addition, we found that in a TSEC regimen, a typical SERM raloxifene maintains the metabolic benefits of CE while simultaneously protecting the endometrium in OVX mice. These findings indicate that GEN acts as an estrogen agonist in metabolic regulation, but has no SERM function in the uteri of OVX mice.

  7. Pygeum africanum for benign prostatic hyperplasia.

    PubMed

    Wilt, T; Ishani, A; Mac Donald, R; Rutks, I; Stark, G

    2002-01-01

    Benign prostatic hyperplasia (BPH), nonmalignant enlargement of the prostate, can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH has been growing steadily. The extract of the African prune tree, Pygeum africanum, is one of the several phytotherapeutic agents available for the treatment of BPH. To investigate the evidence whether extracts of Pygeum africanum (1) are more effective than placebo in the treatment of Benign Prostatic Hyperplasia (BPH), (2) are as effective as standard pharmacologic BPH treatments, and (3) have less side effects compared to standard BPH drugs. Trials were searched in computerized general and specialized databases (MEDLINE (1966-2000), EMBASE, Cochrane Library, Phytodok), by checking bibliographies, and by contacting relevant manufacturers and researchers. Trials were eligible if they (1) were randomized (2) included men with BPH (3) compared preparations of Pygeum africanum (alone or in combination) with placebo or other BPH medications (4) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements. Eligibility was assessed by at least two independent observers. Information on patients, interventions, and outcomes were extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of Pygeum africanum with placebo and standard BPH medications was the change in urologic symptoms scale scores. Secondary outcomes included change in urologic symptoms including nocturia and urodynamic measures (peak and mean urine flow, prostate size). The main outcome measure for adverse effects was the number of men reporting adverse effects. A total of 18 randomized controlled trials involving 1562 men met inclusion criteria and were analyzed. Only one of the studies reported a method of treatment allocation concealment, though 17

  8. Chronic Prostate Inflammation is Associated with Severity and Progression of Benign Prostatic Hyperplasia, Lower Urinary Tract Symptoms and Risk of Acute Urinary Retention.

    PubMed

    Nickel, J Curtis; Roehrborn, Claus G; Castro-Santamaria, Ramiro; Freedland, Stephen J; Moreira, Daniel M

    2016-11-01

    We evaluated associations between histological prostate inflammation, and the development and progression of benign prostatic hyperplasia/lower urinary tract symptoms in men randomized to placebo in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study in a 4-year period. The association of acute and chronic inflammation detected on baseline biopsies and benign prostatic hyperplasia related parameters, including I-PSS (International Prostate Symptom Score) and prostate volume, at multiple time points during 4 years in men randomized to placebo enrolled in the REDUCE prostate cancer prevention study was analyzed with the Student t-test. The association of inflammation with newly developed benign prostatic hyperplasia/lower urinary tract symptoms and benign prostatic hyperplasia progression in patients with existing benign prostatic hyperplasia/lower urinary tract symptoms was analyzed with univariable and multivariable Cox models. Acute and chronic inflammation was seen in baseline negative biopsies of 641 (15.6%) and 3,216 (78.3%) of the 4,109 men in the study. Chronic but not acute inflammation was associated with slightly higher baseline I-PSS (0.6 difference, p = 0.001) and larger prostate volume (3.2 cc difference, p <0.001), a difference noted throughout the study interval. The presence of acute and chronic inflammation was not associated with the incidence of benign prostatic hyperplasia/lower urinary tract symptoms in men without those conditions at baseline or the progression of symptomatic benign prostatic hyperplasia in men with benign prostatic hyperplasia/lower urinary tract symptoms at baseline. However, an association was observed with more severe inflammation. Chronic inflammation at baseline was associated with an increased risk of acute urinary retention (HR 1.6-1.8, p = 0.001). Our longitudinal evaluation of REDUCE patients randomized to placebo for 4 years confirmed that chronic inflammation is associated with severity and the

  9. Association of Cervical Microglandular Hyperplasia With Exogenous Progestin Exposure.

    PubMed

    Heller, Debra S; Nguyen, Lena; Goldsmith, Laura T

    2016-04-01

    Although microglandular hyperplasia is a benign endocervical lesion, it may raise concern of malignancy in an inexperienced pathologist, because clinicians may not be familiar with it on a report. It has been reported to occur in association with progestational stimulation, but this has not been well studied. The aim of the study was to evaluate this potential association. This was an observational case control study of patients seen from January 01, 1991 to November 01, 2014 at the University Hospital, Newark, New Jersey. Cases of microglandular hyperplasia and controls were identified from the files of the Department of Pathology. Controls were cases of endocervical curettages for whom no microglandular hyperplasia was detected. Medical records were reviewed for evidence of exogenous progestin exposure within the previous 6 months. Eighty-nine cases of microglandular hyperplasia and 97 controls were identified. Of the cases of microglandular hyperplasia, 26 (29.2%) of 89 cases had exposure to progestational medication, significantly greater than that of controls (10/97, 10.3%; p = .0014). Our data show that a significantly higher percentage of women with microglandular hyperplasia had progestin exposure than women who do not exhibit this benign lesion. Clinicians and pathologists should be aware of this association, as well as the benign nature of the lesion.

  10. Noninvasive inductive stent heating: alternative approach to prevent instent restenosis?

    PubMed

    Floren, Michael G; Günther, Rolf W; Schmitz-Rode, Thomas

    2004-05-01

    To test noninvasive inductive heating of implanted vascular stents as an alternative approach for reduction or prevention of neointimal hyperplasia. Calorimetric pretests were performed to get an orientation on the different parameters of influence for inductive heating of stents. The field strength was set to a maximum of 90 kA/m within a frequency range from 80 kHz to 320 kHz. The electromagnetic field was emitted by a custom-made water-cooled copper winding antenna. A flow model for stent heating was set up to assess the increase in temperature of an expanded 316L stainless steel stent with typical coronary stent dimensions of 3.5 mm diameter and 14.5 mm in length, and in a second setup with 4.5 mm diameter and 13 mm in length, respectively. The stent was located in a bioartificial artery, simulated by a fibrinogen matrix with a defined number of vital cells. The system was exposed to a pulsating perfusion and to an electromagnetic field of 200 kHz over a period of 20 minutes and in a second setup to an electromagnetic field of 300 kHz and increasing intensity up to maximum power-output. Afterward, the artificial vessel was sliced and examined by fluorescence microscopy to evaluate the number and location of damaged cells. The calorimetric tests show an exponential correlation of energy uptake in the stent with an increase in frequency and a constant generator output. At a frequency of 80 kHz, the power uptake accounts for 0.1 W (250 kHz 1.0 W; 320 kHz 1.9 W, respectively). The flow tests confirmed feasibility to elevate the stent temperature from 37 degrees C body temperature to 44 degrees C at 200 kHz within 55 seconds. The temperature increase of the fluid passing the heated vessel region was only marginal (maximum of 0.5 degrees C). Cell necrosis after 20 minutes of treatment was not observed. In a second set-up with 4.5 mm stent diameter, a frequency of 300 kHz and with maximum power output, the stent temperature was increased to 80 degrees C and there was

  11. Relation of Internal Elastic Lamellar Layer Disruption to Neointimal Cellular Proliferation and Type III Collagen Deposition in Human Peripheral Artery Restenosis.

    PubMed

    Krishnan, Prakash; Purushothaman, K-Raman; Purushothaman, Meerarani; Baber, Usman; Tarricone, Arthur; Vasquez, Miguel; Wiley, Jose; Kini, Annapoorna; Sharma, Samin K; O'Connor, William N; Moreno, Pedro R

    2016-04-01

    Smooth muscle cell proliferation and extracellular matrix formation are responsible for disease progression in de novo and restenotic atherosclerosis. Internal elastic lamella (IEL) layer maintains the structural integrity of intima, and disruption of IEL may be associated with alterations in neointima, type III collagen deposition, and lesion progression in restenosis. Nineteen restenotic plaques (12 patients) procured during peripheral interventions were compared with 13 control plaques (12 patients) without restenosis. Hematoxylin & Eosin and elastic trichrome stains were used to measure length and percentage of IEL disruption, cellularity, and inflammation score. Type I and III collagens, smooth muscle cell (smc), fibroblast density, and nuclear proliferation (Ki67) percentage were evaluated by immunohistochemistry. IEL disruption percentage (28 ± 3.6 vs 6.1 ± 2.4; p = 0.0006), type III collagen content (0.33 ± 0.06 vs 0.17 ± 0.07; p = 0.0001), smc density (2014 ± 120 vs 923 ± 150; p = 0.0001), fibroblast density (2,282 ± 297 vs 906 ± 138; p = 0.0001), and Ki67 percentage (21.6 ± 2 vs 8.2 ± 0.65; p = 0.0001) were significantly increased in restenotic plaques compared to de novo plaques. Logistic regression analysis identified significant correlation between IEL disruption and neointimal smc density (r = 0.45; p = 0.01) and with type III collagen deposition (r = 0.61; p = 0.02) in restenosis. Increased IEL disruption may trigger cellular proliferation, altering collagen production, and enhancing restenotic neointima. In conclusion, understanding the pathologic and molecular basis of restenosis and meticulous-guided interventions oriented to minimize IEL damage may aid to reduce neointimal proliferation and the occurrence of restenosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Fabrication of drug-eluting covered stents with micropores and differential coating of heparin and FK506.

    PubMed

    Nakayama, Yasuhide; Nishi, Shogo; Ishibashi-Ueda, Hatsue

    2003-01-01

    To reduce in-stent restenosis rates, we developed a novel drug-eluting covered stent with a microporous elastometric covered film, in which its luminal surface was flat and immobilized with heparin for anticoagulation and its outer surface immobilized with FK506 to prevent neointimal hyperplasia. One month after implantation into the bilateral common carotid arteries, all stented arteries were patent and the luminal surfaces were fully covered with a confluent of endothelial cells irrespective of the drug immobilization. In the control group, which consisted of covered stents without drug immobilization, intensive inflammatory cells adjacent to the stents and neointimal hyperplasia, indicating vascular injury, were observed. In contrast, in the developed drug-eluting stents, only a few inflammatory cells around the stent strut and covered film were observed, and there was no significant neointimal thickening.

  13. Magnetic resonance imaging of benign prostatic hyperplasia.

    PubMed

    Guneyli, Serkan; Ward, Emily; Thomas, Stephen; Yousuf, Ambereen Nehal; Trilisky, Igor; Peng, Yahui; Antic, Tatjana; Oto, Aytekin

    2016-01-01

    Benign prostatic hyperplasia (BPH) is a common condition in middle-aged and older men and negatively affects the quality of life. An ultrasound classification for BPH based on a previous pathologic classification was reported, and the types of BPH were classified according to different enlargement locations in the prostate. Afterwards, this classification was demonstrated using magnetic resonance imaging (MRI). The classification of BPH is important, as patients with different types of BPH can have different symptoms and treatment options. BPH types on MRI are as follows: type 0, an equal to or less than 25 cm3 prostate showing little or no zonal enlargements; type 1, bilateral transition zone (TZ) enlargement; type 2, retrourethral enlargement; type 3, bilateral TZ and retrourethral enlargement; type 4, pedunculated enlargement; type 5, pedunculated with bilateral TZ and/or retrourethral enlargement; type 6, subtrigonal or ectopic enlargement; type 7, other combinations of enlargements. We retrospectively evaluated MRI images of BPH patients who were histologically diagnosed and presented the different types of BPH on MRI. MRI, with its advantage of multiplanar imaging and superior soft tissue contrast resolution, can be used in BPH patients for differentiation of BPH from prostate cancer, estimation of zonal and entire prostatic volumes, determination of the stromal/glandular ratio, detection of the enlargement locations, and classification of BPH types which may be potentially helpful in choosing the optimal treatment.

  14. Magnetic resonance imaging of benign prostatic hyperplasia

    PubMed Central

    Guneyli, Serkan; Ward, Emily; Thomas, Stephen; Yousuf, Ambereen Nehal; Trilisky, Igor; Peng, Yahui; Antic, Tatjana; Oto, Aytekin

    2016-01-01

    Benign prostatic hyperplasia (BPH) is a common condition in middle-aged and older men and negatively affects the quality of life. An ultrasound classification for BPH based on a previous pathologic classification was reported, and the types of BPH were classified according to different enlargement locations in the prostate. Afterwards, this classification was demonstrated using magnetic resonance imaging (MRI). The classification of BPH is important, as patients with different types of BPH can have different symptoms and treatment options. BPH types on MRI are as follows: type 0, an equal to or less than 25 cm3 prostate showing little or no zonal enlargements; type 1, bilateral transition zone (TZ) enlargement; type 2, retrourethral enlargement; type 3, bilateral TZ and retrourethral enlargement; type 4, pedunculated enlargement; type 5, pedunculated with bilateral TZ and/or retrourethral enlargement; type 6, subtrigonal or ectopic enlargement; type 7, other combinations of enlargements. We retrospectively evaluated MRI images of BPH patients who were histologically diagnosed and presented the different types of BPH on MRI. MRI, with its advantage of multiplanar imaging and superior soft tissue contrast resolution, can be used in BPH patients for differentiation of BPH from prostate cancer, estimation of zonal and entire prostatic volumes, determination of the stromal/glandular ratio, detection of the enlargement locations, and classification of BPH types which may be potentially helpful in choosing the optimal treatment. PMID:27015442

  15. Nonclassical Congenital Adrenal Hyperplasia and Pregnancy

    PubMed Central

    Cuhaci, Neslihan; Aydın, Cevdet; Yesilyurt, Ahmet; Pınarlı, Ferda Alpaslan; Ersoy, Reyhan; Cakir, Bekir

    2015-01-01

    Objective. The most common form of congenital adrenal hyperplasia (CAH) is 21-hydroxylase (21-OH) deficiency due to mutation of the CYP21A2 gene. Patients with nonclassical CAH (NC-CAH) are usually asymptomatic at birth and typically present in late childhood, adolescence, or adulthood with symptoms of excessive androgen secretion. Subfertility is relative in NC-CAH, but the incidence of spontaneous miscarriage is higher. Here, we report a previously undiagnosed female who gave birth to a normal male child and is planning to become pregnant again. Case Report. A 32-year-old female was referred to our clinic for obesity. Her medical history revealed that she had had three pregnancies. She was planning to become pregnant again. Her laboratory results revealed that she had NC-CAH. Since her husband is the son of her aunt and she had miscarriages and intrauterin exitus in her history, their genetic analyses were performed. Conclusion. Since most patients with NC-CAH have a severe mutation, these patients may give birth to a child with the classical CAH (C-CAH) if their partner is also carrying a severe mutation. Females with NC-CAH who desire pregnancy must be aware of the risk of having an infant with C-CAH. PMID:26558116

  16. Benign Prostatic Hyperplasia: from Bench to Clinic

    PubMed Central

    Cho, Hee Ju

    2012-01-01

    Benign prostatic hyperplasia (BPH) is a prevalent disease, especially in old men, and often results in lower urinary tract symptoms (LUTS). This chronic disease has important care implications and financial risks to the health care system. LUTS are caused not only by mechanical prostatic obstruction but also by the dynamic component of obstruction. The exact etiology of BPH and its consequences, benign prostatic enlargement and benign prostatic obstruction, are not identified. Various theories concerning the causes of benign prostate enlargement and LUTS, such as metabolic syndrome, inflammation, growth factors, androgen receptor, epithelial-stromal interaction, and lifestyle, are discussed. Incomplete overlap of prostatic enlargement with symptoms and obstruction encourages focus on symptoms rather than prostate enlargement and the shifting from surgery to medicine as the treatment of BPH. Several alpha antagonists, including alfuzosin, doxazosin, tamsulosin, and terazosin, have shown excellent efficacy without severe adverse effects. In addition, new alpha antagonists, silodosin and naftopidil, and phosphodiesterase 5 inhibitors are emerging as BPH treatments. In surgical treatment, laser surgery such as photoselective vaporization of the prostate and holmium laser prostatectomy have been introduced to reduce complications and are used as alternatives to transurethral resection of the prostate (TURP) and open prostatectomy. The status of TURP as the gold standard treatment of BPH is still evolving. We review several preclinical and clinical studies about the etiology of BPH and treatment options. PMID:22468207

  17. Emerging drug therapies for benign prostatic hyperplasia.

    PubMed

    Bullock, Travis L; Andriole, Gerald L

    2006-03-01

    Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland caused by increases in number of both epithelial and stromal cells. Clinically, BPH leads to voiding dysfunction, which is most often referred to as lower urinary tract symptoms (LUTS). Historically, the only treatments for LUTS due to BPH were watchful waiting or surgery (transurethral or open prostatectomy). However, over the last 20 years medical therapy has taken a prominent role in the management of BPH. Current medical treatments for BPH include alpha-adrenergic receptor antagonists, inhibitors of the 5-alpha reductase enzyme and various phytotherapies. These agents are generally effective and safe; however, many patients are unable to tolerate the side effects or are refractory to medical management and require surgery. In light of this, many potential new therapies for the treatment of BPH are under development. Some represent a variation of current treatments, whereas others target novel molecular pathways within the prostate. The aim of this review is to examine current pharmacotherapies as well as to highlight emerging drugs that may improve our treatment of patients with LUTS secondary to BPH.

  18. Dutasteride/tamsulosin: in benign prostatic hyperplasia.

    PubMed

    Keating, Gillian M

    2012-05-01

    The 5α-reductase inhibitor dutasteride and the α(1)-adrenergic receptor antagonist tamsulosin are available as a fixed-dose combination for use in men with symptomatic benign prostatic hyperplasia (BPH) and an enlarged prostate. Dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day improved lower urinary tract symptoms (LUTS) to a significantly greater extent than dutasteride or tamsulosin alone in men with BPH, moderate to severe LUTS and an increased risk of disease progression, according to the results of the randomized, double-blind, multinational CombAT trial. The mean change from baseline in the total International Prostate Symptom Score was significantly greater with dutasteride plus tamsulosin than with dutasteride or tamsulosin alone after 2 years (primary endpoint) and 4 years of therapy. After 4 years' therapy in the CombAT trial, the time to first acute urinary retention or BPH-related surgery (primary endpoint) significantly favoured men with symptomatic BPH who were receiving dutasteride plus tamsulosin versus those receiving tamsulosin alone, with no significant difference between recipients of dutasteride plus tamsulosin and recipients of dutasteride alone. In the CombAT trial, health-related quality of life and treatment satisfaction were improved to a significantly greater extent with dutasteride plus tamsulosin than with dutasteride or tamsulosin alone. Combination therapy with oral dutasteride plus tamsulosin was generally well tolerated in patients with symptomatic BPH in the CombAT trial.

  19. Delay of postnatal maturation sensitizes the mouse prostate to testosterone-induced pronounced hyperplasia: protective role of estrogen receptor-beta.

    PubMed

    Savolainen, Saija; Pakarainen, Tomi; Huhtaniemi, Ilpo; Poutanen, Matti; Mäkelä, Sari

    2007-09-01

    The role of estrogens in the etiology of prostate cancer is controversial. To demonstrate the specific effects of estrogens and androgens on the development of the prostatic epithelial hyperplasia, we used luteinizing hormone receptor knockout mice (LuRKO), which are resistant to pituitary regulation mediated by luteinizing hormone, lack postnatal androgen production, and have rudimentary accessory sex glands, the growth of which can be induced with exogenous androgen replacement. This model is thus ideal for the investigation of direct hormonal effects on the prostate. Testosterone, but not 5alpha-dihydrotestosterone, replacement from 21 days of life for 8 weeks induced pronounced hyperplasia and inflammation in the prostates of LuRKO mice. Interestingly, 5alpha-dihydrotestosterone combined with 17beta-estradiol did not induce hyperplasia or inflammation, and treatments with inhibitors of estrogen action, aromatase inhibitor, and ICI 182780 further exacerbated testosterone-induced hyperplastic growth. However, the activation of estrogen receptor (ER)-beta with a specific agonist, DPN [2,3-bis(4-hydroxyphenol)-propionitrile], prevented the development of prostatic hyperplasia and inflammation in testosterone-treated LuRKO mice. Thus, it seems that in the presence of sufficient androgenic stimulation, it is the balance between ER-alpha- and ER-beta-mediated signaling that determines whether estrogens promote hyperplasia or protect the prostate against hyperplastic changes.

  20. Association between benign prostatic hyperplasia, body mass index, and metabolic syndrome in Chinese men

    PubMed Central

    Yin, Zhuo; Yang, Jin-Rui; Rao, Jian-Ming; Song, Wei; Zhou, Ke-Qin

    2015-01-01

    Previous studies have showed that men suffering from diabetes mellitus, metabolic syndrome (MetS) and obesity have a higher risk of benign prostatic hyperplasia (BPH). The present study aimed to examine the association between BPH, obesity, and features of MetS among men of the Hunan area of China. For this cross-sectional study, 904 males (aged 50–59 years) were included. MetS parameters, International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) levels, total prostate volume (TPV), postvoid residual volume (PVR) and maximum urine flow rate (Qmax) were measured. Results showed that MetS was associated with TPV (P = 0.048), PVR (P = 0.004) and IPSS (P = 0.011), but not with other indicators of BPH progression such as PSA levels or Qmax. MetS was associated with the voiding symptoms score (P < 0.05), but not with the storage symptom score. In addition, body mass index and fasting blood glucose positively correlated with TPV (r = 0.416, P < 0.001; and r = 0.310, P= 0.011, respectively). In conclusion, results suggest that MetS is associated with higher prostatic volume, prostate symptom score and voiding symptoms, but not with other features of prostatic hyperplasia such as PSA levels or Qmax. Changes in lifestyle factors, including physical activity and prevention of MetS, might be useful to prevent BPH and its progression, but further studies are needed. PMID:25677137

  1. Proliferation and apoptosis in ovarian stromal hyperplasia and hyperthecosis.

    PubMed

    Sharabidze, N; Sabakhtarashvili, M; Burkadze, G

    2005-12-01

    The aim of our study was to investigate proliferation and apoptosis in ovarian stromal hyperplasia and hyperthecosis in reproductive women with and without polycystic ovarian disease. We have studied 104 patients with a histological diagnosis of ovarian stromal hyperthecosis and stromal hyperplasia. Paraffin sections were stained by hematoxylin-eosin, von Gieson and immunohistochemistry for Bcl-2 (anti-apoptotic protein) and Ki-67 antigen (proliferation marker). We assessed the number of Bcl-2-positive and Ki-67-positive cells. The patients were divided into 4 groups: group 1 -- 33 patients with polycystic ovarian disease and coexistent stromal hyperthecosis, group 2 -- 28 patients with polycystic ovarian disease and coexistent stromal hyperplasia, group 3 -- 24 patients with ovarian stromal hyperthecosis, group 4-19 patients with ovarian stromal hyperplasia. The results suggest that in ovarian stromal hyperthecosis coexistent with polycystic ovarian disease luteinized stromal cells show high proliferation activity and resistance to apoptosis, and internal and external theca cells show resistance to apoptosis. In ovarian stromal hyperplasia coexistent with polycystic ovarian disease, hyperplastic stromal cells show high proliferation activity and resistance to apoptosis. Proliferation activity is also increased in vascular endothelial and smooth muscle cells. Internal and external theca cells show resistance to apoptosis. In ovarian stromal hyperthecosis without polycystic ovarian disease, luteinized stromal cells show high proliferation activity and resistance to apoptosis. In ovarian stromal hyperplasia without polycystic ovarian disease, hyperplastic stromal cells show high proliferation activity and potential susceptibility to apoptosis. Proliferation activity is also increased in vascular endothelial and smooth muscle cells. These characteristics of proliferation and apoptosis have meaning in pathogenesis of ovarian stromal hyperthecosis and stromal

  2. Testicular Adrenal Rest Tumors in Patients with Congenital Adrenal Hyperplasia

    PubMed Central

    Şentürk Mutlu, Fatma; Eren, Erdal; Paşa, Aliye Özlem; Sağlam, Halil; Tarım, Ömer

    2012-01-01

    Objective: Early diagnosis and treatment of testicular adrenal rest tumors (TART) is important for gonadal functions and fertility protection in boys with congenital adrenal hyperplasia (CAH). In this descriptive study, we investigated the prevalence of TART in boys with 21-hydroxylase deficient (21OHD) CAH followed in our pediatric endocrine clinic. Methods: The study group consisted of 14 male patients with a mean age of 9.6±5.1 (range: 0.8-18.3) years. Six (42.9%) of the 14 patients were diagnosed as having salt-wasting type (SW) and eight (57.1%) patients - as having the simple virilizing (SV) form of 21OHD. Mean age at diagnosis was 2.9±2.7 (range: 0.03-6.3) years. Two different radiologists performed scrotal ultrasonography. Chronological age, bone age, and anthropometric measurements were evaluated. Serum adrenocorticotropic hormone (ACTH), 17-alpha-hydroxyprogesterone (17OHP) and androstenedione levels were also evaluated in all patients during the follow-up period. Results: Scrotal ultrasonography revealed bilateral TART in two patients (14.3%) and testicular microlithiasis (TM) in four patients (28.6%). One patient had both TART and TM bilaterally. During the follow-up period, the mean serum adrenocorticotropic hormone, 17OHP and androstenedione levels in the total group of patients were 130.0±179.1 pg/mL (21.7-726.5), 5.8±3.3 ng/mL (0.8-11.4) and 4.3±4.1 (0.2-11.0) ng/mL, respectively. Conclusions: Microlithiasis or TART may be frequently encountered during the follow-up of patients with CAH. In order to prevent late complications including infertility, we suggest that ultrasonographic evaluations be performed yearly in all male CAH patients. Conflict of interest:None declared. PMID:22672867

  3. Rebound Thymic Hyperplasia after Chemotherapy in Children with Lymphoma.

    PubMed

    Chen, Chih-Ho; Hsiao, Chih-Chen; Chen, Yu-Chieh; Ko, Sheung-Fat; Huang, Shu-Hua; Huang, Shun-Chen; Hsieh, Kai-Sheng; Sheen, Jiunn-Ming

    2017-04-01

    Development of mediastinal masses after completion of chemotherapy in pediatric patients with malignant lymphoma is worrisome and challenging to clinicians. We performed a retrospective review of 67 patients with lymphoma treated at our hospital from January 1, 2001 to June 1, 2013. Patients who received at least two chest computed tomography (CT) examinations after complete remission (CR) was achieved were further analyzed. Gallium-67 scans and positron emission tomography (PET) were recorded and compared between these patients. Sixty-two of 67 patients reached CR, of whom 31 (22 male, 9 female) were patients that received at least two chest CT examinations after CR. Rebound thymic hyperplasia (RTH) was diagnosed in 21/31 patients (67.7%), including 14/23 (60.9%) and seven out of eight (87.5%) with non-Hodgkin's lymphoma and Hodgkin's lymphoma, respectively. Ages ranged from 3 years to 18 years (median 10 years). Increased radioactivity uptake of the anterior mediastinum in gallium scans was found in nine out of 20 patients (45%) with thymic rebound. PET was performed in six out of 21 patients. Increased fluorodeoxyglucose (FDG)-avid uptake in the anterior mediastinum was observed in four of six patients (66.7%) by PET. One patient received thymectomy. No patients with RTH had lymphoma relapse within the median follow-up period (5 years). Relapse was statistically significantly different (p = 0.001) between patients with and without RTH. RTH developed in 67.7% of pediatric patients with lymphoma in CR after chemotherapy. The association of RTH development and lowered relapse rates has yet to be determined. Awareness of this phenomenon is important in the prevention of unnecessary surgical intervention or chemotherapy. Copyright © 2016. Published by Elsevier B.V.

  4. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.

    PubMed Central

    Law, R E; Meehan, W P; Xi, X P; Graf, K; Wuthrich, D A; Coats, W; Faxon, D; Hsueh, W A

    1996-01-01

    Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis. PMID:8878442

  5. Oxidative Stress Promotes Benign Prostatic Hyperplasia

    PubMed Central

    Vital, Paz; Castro, Patricia; Ittmann, Michael

    2017-01-01

    BACKGROUND Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH. METHODS Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter. RESULTS Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls. CONCLUSIONS Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH. PMID:26417670

  6. Oxidative stress promotes benign prostatic hyperplasia.

    PubMed

    Vital, Paz; Castro, Patricia; Ittmann, Michael

    2016-01-01

    Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH. Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter. Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls. Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH. © 2015 Wiley Periodicals, Inc.

  7. Exophytic oral verrucous hyperplasia: a new entity.

    PubMed

    Patil, Shankargouda; Warnakulasuriya, Saman; Raj, Thirumal; Sanketh, D S; Rao, Roopa S

    2016-11-01

    Exophytic oral verrucous hyperplasia (OVH) is a new entity described by an expert working group from South Asia. First reported in Taiwan, there are no reports so far from an Indian population. The aim was to use the microscopic features described by the expert group to differentiate OVH from other oral verruco-papillary lesions in an Indian archive. In a retrospective multicentre study, using pathology archives, 188 verruco-papillary lesions were retrieved from pathology archives. A proforma listing histopathological criteria for OVH based on published guidelines (Annals of Dentistry, University of Malaya, 2013) was used. Patients' demographic and clinical data were transcribed from patient charts. The Pearson chi-square test was used to determine associations between clinical and histopathological features. Of 188 oral verruco-papillary lesions that were evaluated, based on microscopic features the cases were reclassified as OVH (57), verrucous carcinoma (VC) (84), oral squamous cell carcinoma (16), and other verruco-papillary lesions (31). Both OVH (70%) and VC (60%) showed male predominance and commonly affected buccal mucosa (OVH 74% and VC 57%). Absence of downward growth of the hyperplastic epithelium into lamina propria when compared with the level of the basement membrane of the adjacent normal epithelium was a distinct feature in OVH. Keratin plugging, epithelial dysplasia and subepithelial lymphocytic infiltration were found to be significantly different (P < 0.05) in OVH versus VC. The sample size of other verruco-papillary lesions was insufficient for statistical comparison. Apart from the absence of an endophytic growth pattern in OVH, we noted the presence of dysplasia in OVH. This significant observation does institute a debate as to whether this enigmatic lesion could possibly be a precedent of oral squamous or verrucous carcinoma. We propose OVH is a distinct entity in our Indian population and should be considered in the classification of oral

  8. Current Laser Treatments for Benign Prostatic Hyperplasia

    PubMed Central

    Son, Hwancheol; Song, Sang Hoon

    2010-01-01

    The latest technical improvements in the surgical armamentarium are remarkable. In particular, advancements in the urologic field are so exceptional that we could observe the flare-up of robot-assisted laparoscopic radical prostatectomy for prostate cancer and laser prostatectomy for benign prostatic hyperplasia (BPH). Photoselective vaporization of the prostate (PVP) and holmium laser prostatectomy are the most generalized options for laser surgery of BPH, and both modalities have shown good postoperative results. In comparison to transurethral prostatectomy (TURP), they showed similar efficacy and a much lower complication rate in randomized prospective clinical trials. Even in cases of large prostates, laser prostatectomy showed comparable efficacy and safety profiles compared to open prostatectomy. From a technical point of view, PVP is considered to be an easier technique for the urologist to master. Furthermore, patients can be safely followed up in an outpatient clinic. Holmium laser enucleation of the prostate (HoLEP) mimics open prostatectomy because the adenomatous tissue is peeled off the surgical capsule in both procedures. Therefore, HoLEP shows notable volume reduction of the prostate similar to open prostatectomy with fewer blood transfusions, shorter hospital stay, and cost reduction regardless of prostate size. Outcomes of laser prostatectomy for BPH are encouraging but sometimes are unbalanced because safety and feasibility studies were reported mainly for PVP, whereas long-term data are mostly available for HoLEP. We need longer-term randomized clinical data to identify the reoperation rate of PVP and to determine which procedure is the ideal alternative to TURP and open prostatectomy for each patient. PMID:21165192

  9. Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis.

    PubMed

    Li, Yonghong; Cai, Shanglang; Wang, Qixin; Zhou, Jingwei; Hou, Bo; Yu, Haichu; Ge, Zhiming; Guan, Renyan; Liu, Xu

    2016-05-15

    The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P < 0.05 or < 0.01). Additionally, the p-ERK protein expression was increased (P < 0.01). Treatment with valsartan significantly increased the angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression but decreased the angiotensin II level, ACE and AT1 receptor mRNA/protein expression, as well as the p-ERK protein expression, compared to the injured group (all P < 0.05 or < 0.01). These results suggest that valsartan attenuates neointimal hyperplasiain balloon-injured rat aortic arteries through activation of the ACE2-angiotensin-(1-7)-Mas axis as well as inhibition of the ACE-angiotensin II-AT1 and p-ERK pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 1, Pathological Background and Clinical Implications

    SciTech Connect

    Sun, Fei Crisóstomo, Verónica Báez-Díaz, Claudia Sánchez, Francisco M.

    2016-01-15

    Pathological features of benign prostatic hyperplasia (BPH) dictate various responses to prostatic artery embolization (PAE). Typically, BPH originates in the transition zone and periurethral region, where should be considered the primary target area in PAE procedures. Given that histological heterogeneity of components in hyperplasia nodules, epithelial or stromal, identifying the more responsive nodules to PAE will have clinical implications. Since some lower urinary tract symptoms (LUTS) in patients with BPH are usually related to bladder outlet obstruction-induced changes in bladder function rather than to outflow obstruction directly, proper selection of candidate patients prior to PAE is of great clinical importance. BPH is a typical chronic progressive condition, suggesting PAE could aim not only to relieve LUTS but also to delay or prevent the clinical progression. Awareness of the pathological background of BPH is essential for interventional radiologists to improve clinical outcomes and develop new treatment strategies in clinical practice of PAE.

  11. Lymphoid Hyperplasia of the Appendix: A Potential Pitfall in the Sonographic Diagnosis of Appendicitis.

    PubMed

    Xu, Yingding; Jeffrey, R Brooke; DiMaio, Michael A; Olcott, Eric W

    2016-01-01

    The objective of this study was to test the hypothesis that thickening of the lamina propria, a finding produced by lymphoid hyperplasia, is significantly associated with false-positive sonographic diagnoses of appendicitis in 6- to 8-mm noncompressible appendixes. Sonograms of 119 consecutive patients with suspected appendicitis and 6- to 8-mm noncompressible appendixes were retrospectively blindly evaluated for thickening of the lamina propria (short axis thickness ≥ 1 mm). The reference standard for appendicitis was pathologic analysis of resected specimens. Results were compared with the two-tailed Fisher exact test. Thirty-one patients (26.1%) had a thickened lamina propria and 88 (73.9%) did not. Of the 27 pediatric patients with a thickened lamina propria, five (18.5%) had true-positive and 22 (81.5%) had false-positive sonograms for appendicitis; among the 55 pediatric patients without a thickened lamina propria, 27 (49.1%) had true-positive and 28 (50.9%) had false-positive sonograms for appendicitis (p = 0.009). Similar differences in adult patients were not statistically significant. All five pediatric patients with appendicitis and thickened lamina propria also showed two or more findings of periappendiceal fluid, hyperechoic periappendiceal fat, or mural hyperemia on color Doppler examination, compared with two of 22 similar pediatric patients without appendicitis (p < 0.001). Lymphoid hyperplasia may result in a noncompressible appendix 6-8 mm in diameter and may be misdiagnosed as appendicitis in pediatric patients. True-positive diagnoses of appendicitis can be accurately identified by the presence of at least two additional findings from the group of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia. Identifying the characteristic sonographic appearance of lymphoid hyperplasia may help prevent false-positive misdiagnoses of appendicitis.

  12. The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer

    PubMed Central

    Elkahwaji, Johny E

    2013-01-01

    Benign prostatic hyperplasia and prostate cancer remain the most prevalent urologic health concerns affecting elderly men in their lifetime. Only 20% of benign prostatic hyperplasia and prostate cancer cases coexist in the same zone of the prostate and require a long time for initiation and progression. While the pathogenesis of both diseases is not fully understood, benign prostatic hyperplasia and prostate cancer are thought to have a multifactorial etiology, their incidence and prevalence are indeed affected by age and hormones, and they are associated with chronic prostatic inflammation. At least 20% of all human malignancies arise in a tissue microenvironment dominated by chronic or recurrent inflammation. In prostate malignancy, chronic inflammation is an extremely common histopathologic finding; its origin remains a subject of debate and may in fact be multifactorial. Emerging insights suggest that prostate epithelium damage potentially inflicted by multiple environmental factors such as infectious agents, dietary carcinogens, and hormones triggers procarcinogenic inflammatory processes and promotes cell transformation and disease development. Also, the coincidence of chronic inflammation and tumorigenesis in the peripheral zone has recently been linked by studies identifying so-called proliferative inflammatory atrophy as a possible precursor of prostatic intraepithelial neoplasia and prostate cancer. This paper will discuss the available evidence suggesting that chronic inflammation may be involved in the development and progression of chronic prostatic disease, although a direct causal role for chronic inflammation or infection in prostatic carcinogenesis has yet to be established in humans. Further basic and clinical research in the area, trying to understand the etiology of prostatic inflammation and its signaling pathway may help to identify new therapeutic targets and novel preventive strategies for reducing the risk of developing benign and malignant

  13. EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

    PubMed Central

    Arcidiacono, Maria Vittoria; Sato, Tetsuhiko; Alvarez-Hernandez, Daniel; Yang, Jing; Tokumoto, Masanori; Gonzalez-Suarez, Ignacio; Lu, Yan; Tominaga, Yoshihiro; Cannata-Andia, Jorge; Slatopolsky, Eduardo; Dusso, Adriana S.

    2008-01-01

    Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-α is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-α, the progression of growth, and the reduction of VDR. Increased TGF-α/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-β, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-β transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-α activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol. PMID:18216322

  14. A novel androgen receptor mutation resulting in complete androgen insensitivity syndrome and bilateral Leydig cell hyperplasia.

    PubMed

    Singh, Rajender; Shastry, Prabhakar K; Rasalkar, Avinash A; Singh, Lalji; Thangaraj, K

    2006-01-01

    Androgens drive male secondary sexual differentiation and maturation. Mutations in the androgen receptor (AR) gene cause a broad spectrum of abnormal phenotypes in humans, ranging from mild through partial to complete androgen insensitivity. We have analyzed the AR gene by using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing and have studied gonads histologically in a familial case of complete androgen insensitivity syndrome. Sequence analysis of the AR gene showed a novel C2578T missense mutation, resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand-binding domain of the receptor. The residue L859, located in helix 10 of the androgen receptor, plays a significant role in overall architecture of ligand-binding pocket. The mutation was absent from the father, normal brother of the patients, and 100 normal males recruited in this study as controls. The inheritance of the mutation in the family clearly shows that C2578T is the underlying mutation for the eventual phenotype in the patients. Histology of patient's gonads showed Leydig cell hyperplasia, with a few or no spermatogonium. It is thought that AR gene mutations result in hormonal imbalance, resulting in the high levels of luteinizing hormone (LH) and ultimately Leydig cell hyperplasia or tumor formation. In the present study, we have reported a rare familial case of Leydig cell hyperplasia despite consistently normal LH levels. The finding will help in giving counseling to this family and prevent the transmission of the mutated X chromosome to the coming generations.

  15. Pigment Epithelium-Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia.

    PubMed

    Goldberg, Keren; Bar-Joseph, Hadas; Grossman, Hadas; Hasky, Noa; Uri-Belapolsky, Shiri; Stemmer, Salomon M; Chuderland, Dana; Shalgi, Ruth; Ben-Aharon, Irit

    2015-12-01

    Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro- and anti-angiogenic factors. VEGF is a pro-angiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-α and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

  16. Congenital Hemifacial Hyperplasia: Clinical Presentation and Literature Review

    PubMed Central

    Shanmugasundaram, Karpagavalli; Ganapathy, Sivadas; Sathish, Sivan; Satti, Parvathi

    2016-01-01

    Hemifacial hyperplasia is a rare congenital malformation characterized by noticeable unilateral excess development of hard and soft tissues of the face. Asymmetry in Congenital Hemifacial Hyperplasia (CHH) is usually evident at birth and accentuated at the age of puberty. The affected side grows exponentially as compared to the unaffected side. Multiple tissue involvement has resulted due to etiological heterogeneity like heredity, chromosomal abnormalities, altered intrauterine environment, and endocrine dysfunctions. As this lesion is rarely seen in our routine clinical practice, we present a case of hemifacial hyperplasia with reported orofacial features that supplement existing clinical knowledge. This paper also adds knowledge to the readers regarding detailed investigation procedures which has complemented our diagnosis. Further emphasis has been placed on periodic approach to its diagnosis and multidisciplinary management following correct diagnosis. PMID:27843653

  17. Congenital Hemifacial Hyperplasia: Clinical Presentation and Literature Review.

    PubMed

    Shanmugasundaram, Karpagavalli; Vedam, V K Vaishnavi; Ganapathy, Sivadas; Sathish, Sivan; Satti, Parvathi

    2016-01-01

    Hemifacial hyperplasia is a rare congenital malformation characterized by noticeable unilateral excess development of hard and soft tissues of the face. Asymmetry in Congenital Hemifacial Hyperplasia (CHH) is usually evident at birth and accentuated at the age of puberty. The affected side grows exponentially as compared to the unaffected side. Multiple tissue involvement has resulted due to etiological heterogeneity like heredity, chromosomal abnormalities, altered intrauterine environment, and endocrine dysfunctions. As this lesion is rarely seen in our routine clinical practice, we present a case of hemifacial hyperplasia with reported orofacial features that supplement existing clinical knowledge. This paper also adds knowledge to the readers regarding detailed investigation procedures which has complemented our diagnosis. Further emphasis has been placed on periodic approach to its diagnosis and multidisciplinary management following correct diagnosis.

  18. Pathophysiology and management of endometrial hyperplasia and carcinoma.

    PubMed Central

    Fu, Y. S.; Gambone, J. C.; Berek, J. S.

    1990-01-01

    Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade. Images PMID:2202159

  19. [Current possibilities of examination and preservative treatment in endometrial hyperplasia].

    PubMed

    Kołodziejczak, Małgorzata; Knapp, Paweł; Kuźmicki, Mariusz; Knapp, Piotr

    2011-07-01

    Endometrial hyperplasia is one of the most frequent reasons of pre- and menopausal bleeding. In recent years, knowledge of biology of hyperplastic endometrium has changed some medical guidelines in a group of patients diagnosed with endometrial lesions. In many cases radical procedures have been replaced with preservative treatment, especially for those women who wished to spare their uterus. Also, in many high-risk surgical procedures there are a number of algorithms which allow to perform non-radical treatment in those cases. Enforcement of those strategy should be linked to precise examination of endometrium morphology Summarizing, a preservative treatment in case of endometrial hyperplasia needs sensitive and specific tests which determine safety limits of the procedure. This paper has presented current possibilities of examination and non-radical treatment of endometrial hyperplasia.

  20. Nonsurgical Management of Phenytoin-induced Gingival Hyperplasia.

    PubMed

    AlJehani, Yousef A

    2015-04-01

    The aim of this report is to present a severe case of phenytoin (PHT)-induced gingival hyperplasia in a Saudi patient. A 12-year-old male epileptic patient, undergoing PHT therapy, was diagnosed clinically with severe gingival hyperplasia. His treatment consisted meticulous oral care and weekly professional prophylaxis. The patient was advised oral folic acid supplementation (0.5 mg/day) and was also recommended 0.2% chlorhexidine gluconate mouthwash twice daily. There was significant reduction in the hyperplastic tissue within 4 weeks of treatment. It is possible to treat PHT-induced gingival hyperplasia non-surgically with intensive dental care, correct oral hygiene and oral folic acid supplements.

  1. MMPI drug-eluting IVC filter decreases adhesion between caval wall and filter.

    PubMed

    Xiao, Liang; Wang, Man

    2013-03-01

    The implantation of inferior vena cava (IVC) filter was a safe and effective therapy for preventing fatal pulmonary embolism. However, there are risks associated with long-term implantation of filters. Retrievable filters are designed to be removed, but may also remain permanently. Retrieval can reduce risk of long-term complications. The difficulty or impossibility of retrieval is still an issue of retrieval filter. The major causes of filters retrieval failure were intimal overgrowth and severely tilted filter with apex embedded into the caval wall. Matrix metalloproteinases (MMPs) play a key role in neointimal hyperplasia. It is documented that neointimal hyperplasia can be reduced by inhibiting MMP activity and hence smooth muscle cell migration. MMP inhibitors (MMPI) can potently inhibit the activity of MMPs. We hypothesize that a drug-eluting filter which contains MMPI may inhibit IVC neointimal hyperplasia and decrease the adhesion between vascular wall and filter struts. After implantation of drug-eluting retrieval filter, MMPI is released slowly at the sites where the filter struts are in contact with the caval wall; the activity of MMPs of caval wall will be inhibited, injury in basement membrane is decreased, migration of SMC maybe reduced, and the release of extracellular matrix maybe lessened. Finally, neointimal hyperplasia maybe inhibited, the adhesion between vascular wall and filter maybe weakened, the success rate maybe increased, and the vascular injury during retrieval maybe reduced. The hypothesis might improve the long-term prognosis of venous thromboembolism patients.

  2. Management of atypical lobular hyperplasia, atypical ductal hyperplasia, and lobular carcinoma in situ.

    PubMed

    Clauser, Paola; Marino, Maria A; Baltzer, Pascal A T; Bazzocchi, Massimo; Zuiani, Chiara

    2016-01-01

    Atypical hyperplasia and lobular carcinoma in situ are rare proliferative breast lesions, growing inside ducts and terminal ducto-lobular units. They represent a marker of increased risk for breast cancer and a non-obligate precursor of malignancy. Evidence available on diagnosis and management is scarce. They are frequently found incidentally associated with other lesions, but can be visible through mammography, ultrasound or magnetic resonance. Due to the risk of underestimation, surgical excision is often performed. The analysis of imaging and histopathological characteristics could help identifying low-risk cases, for which surgery is not necessary. Chemopreventive agents can be used for risk reduction. Careful imaging follow up is mandatory; the role of breast MRI as screening modality is under discussion.

  3. Reactive fibrous hyperplasia associated with a natal tooth.

    PubMed

    Singh, S; Subba Reddy, V V; Dhananjaya, G; Patil, R

    2004-01-01

    A natal tooth is that which is present in the oral cavity at the time of birth. Fibrous hyperplasia is a non-specific reactive lesion of soft tissues of unknown etiology usually associated with trauma or local irritation. Natal teeth can occur as an isolated dental finding, but many times they are associated wilh syndromes and developmental disturbances. This is a rare case, where in a natal tooth has led to the formation of a reactive fibrous hyperplasia in a four and half month old infant, a relationship not reported previously.

  4. Oral focal epithelial hyperplasia: report of five cases.

    PubMed

    Borborema-Santos, Cristina Maria; Castro, Maria Marta de; Santos, Paulo José Benevides dos; Talhari, Sinésio; Astolfi-Filho, Spartaco

    2006-01-01

    Focal epithelial hyperplasia or Heck's disease is a rare contagious disease caused by human papillomavirus types 13 or 32, initially described among Native American populations. This condition is characterized by the occurrence of multiple small papules or nodules in oral cavity, especially on labial and buccal mucosa and tongue. This report describes the diagnosis of focal epithelial hyperplasia in five Central Amazonian Indians who sought treatment at the Amazonas State Foundation of Tropical Medicine (FMT-AM), using clinical criteria, polymerase chain reaction (PCR) and DNA sequencing.

  5. An Extensive Denture-Induced Hyperplasia of Maxilla

    PubMed Central

    Veena, KM; Jagadishchandra, H; Sequria, J; Hameed, SK; Chatra, L; Shenai, P

    2013-01-01

    Denture-induced hyperplasia is a reactive lesion arising from excessive and chronic mechanical pressure on the vestibular oral mucosa. It has a female predilection and it is mostly seen in the maxilla. The size of the lesion may be as small as a few millimeters to massive lesion involving the entire vestibule. It is usually asymptomatic but sometimes severe inflammation and ulceration can occur. Elimination of the inflammation and excision of the lesion is the treatment of choice. Denture induced hyperplasia in right maxillary buccal vestibule in a middle age old female patient was presented. Surgical excision was done and new denture was fabricated. PMID:24349860

  6. Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia.

    PubMed

    Luo, Li; Luo, Bing; Zheng, Ying; Zhang, Heng; Li, Jing; Sidell, Neil

    2013-06-05

    Endometrial carcinoma is the most common gynaecologic malignancy in the world and develops through preliminary stages of endometrial hyperplasia. Typical endometrial hyperplasia suggests a significant pre-malignant state with frank progression to endometrial carcinoma. Because atypical endometrial hyperplasia tends to occur at a young age, it has become increasingly important and necessary to find a safe and effective fertility-sparing treatment with better tolerability and fewer side effects than the options for treatment that are currently available. The levonorgestrel-releasing intrauterine system has already been used to provide endometrial protection in women with breast cancer who are on adjuvant tamoxifen. The antiproliferative function of levonorgestrel is thought to reduce the risk of endometrial hyperplasia. To determine the efficacy and safety of the levonorgestrel-releasing intrauterine system in reversing atypical endometrial hyperplasia. In November 2012 we searched the Cochrane Menstrual Disorders and Subfertility Review Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library; MEDLINE; EMBASE; and the China National Knowledge Infrastructure for relevant trials. Attempts were made to identify trials from references in published studies. We also searched for ongoing trials in five major clinical trials registries. Randomised controlled trials (RCTs) of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus progestin therapy in women with a confirmed histological diagnosis of simple or complex endometrial hyperplasia with atypia. No eligible study was found. We did not identify any studies which met our full inclusion criteria. There is no evidence available from randomised controlled trials regarding the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) for atypical endometrial hyperplasia. RCTS are

  7. Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

    PubMed

    Hata, Jonathan A; Petrofski, Jason A; Schroder, Jacob N; Williams, Matthew L; Timberlake, Sarah H; Pippen, Anne; Corwin, Michael T; Solan, Amy K; Jakoi, Andre; Gehrig, Thomas R; Kontos, Christopher D; Milano, Carmelo A

    2005-06-01

    -derived growth factor-induced phosphorylation of Akt, a downstream effector of phosphatidylinositol 3-kinase. PTEN-treated vascular smooth muscle cells demonstrated decreased basal, platelet-derived growth factor-stimulated, and serum-stimulated proliferation. This study demonstrates that PTEN overexpression in aortocoronary saphenous vein grafts reduces intimal hyperplasia. The mechanism of this antiproliferative effect in vascular smooth muscle cells is likely due to inhibition of phosphatidylinositol 3-kinase signaling through Akt, with resultant decreases in vascular smooth muscle cell growth and survival. Therefore modulation of the phosphatidylinositol 3-kinase pathway through PTEN overexpression might represent a novel therapy to prevent saphenous vein graft intimal hyperplasia after coronary artery bypass grafting.

  8. Temporal evaluation of cardiac myocyte hypertrophy and hyperplasia in male rats secondary to chronic volume overload.

    PubMed

    Du, Yan; Plante, Eric; Janicki, Joseph S; Brower, Gregory L

    2010-09-01

    The temporal myocardial remodeling induced by chronic ventricular volume overload in male rats was examined. Specifically, left ventricular (LV) cardiomyocyte length and width, sarcomere length, and number of nuclei were measured in male rats (n = 8 to 17) at 1, 3, 5, 7, 21, 35, and 56 days after creation of an infrarenal aortocaval fistula. In contrast to previously published reports of progressive increases in cardiomyocyte length and cross-sectional area at 5 days post-fistula and beyond in female hearts, cardiomyocyte length and width did not increase significantly in males during the first 35 days of volume overload. Furthermore, a significant decrease in cardiomyocyte length relative to age-matched controls, together with a reduced number of sarcomeres per cell, was noted in male hearts at 5 days post-fistula. There was a concurrent increase in the percentage of mononucleated cardiomyocytes from 11.6% to 18% at 5 days post-fistula. These initial differences could not be attributed to cardiomyocyte proliferation, and treatment with a microtubule stabilizing agent prevented them from occurring. The subsequent significant increase in LV weight without corresponding increases in cardiomyocyte dimensions is indicative of hyperplasia. Thus, these findings indicate hyperplasia resulting from cytokinesis of cardiomyocytes is a key mechanism, independent of hypertrophy, that contributes to the significant increase in LV mass in male hearts subjected to chronic volume overload.

  9. The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats.

    PubMed

    Wang, Chao; Luo, Fei; Zhou, Ying; Du, Xiaoling; Shi, Jiandang; Zhao, Xiaoling; Xu, Yong; Zhu, Yan; Hong, Wei; Zhang, Ju

    2016-07-15

    Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression.

  10. The histological and histometrical effects of Urtica dioica extract on rat's prostate hyperplasia.

    PubMed

    Moradi, Hamid Reza; Erfani Majd, Naeem; Esmaeilzadeh, Saleh; Fatemi Tabatabaei, Sayed Reza

    2015-01-01

    Benign prostatic hyperplasia (BPH) is a common disease in human that gradual overgrowth of the prostate gland leads to impinge on the urethra with impairment in urinary function. Numerous plants improve uncontrolled growth of the prostate gland and improve urinary tract symptoms associated with BPH. In this study, 25 healthy adult male Wistar rats were divided randomly in five groups: G1 (Control group) received ordinary feed without any treatment, G2 received 10 mg kg(-1) testosterone subcutaneously, G3 received 50 mg kg(-1) nettle root extract orally, G4 received 50 mg kg(-1) nettle root extract orally and 10 mg kg(-1) testosterone, G5 received 10 mg kg(-1) almond oil (Almond oil was used as testosterone solvent) subcutaneously. After six weeks, volume and weight of each lobe were measured and samples were taken. The 5 to 6 µm thickness sections were made using paraffin embedding method and stained by hematoxylin and eosin and periodic acid-Schiff. The results showed that prostate volume and ratio of prostate to body weight were increased significantly in the testosterone. Histological and histometrical results showed that dorsal and lateral type 1 and 2 lobes were not changed significantly but the ventral and anterior lobes have changed significantly. Over all, the nettle root could prevent from some of prostatic hyperplasia effects, so that percentage of folded alveoli in ventral lobe reduced insignificantly.

  11. The histological and histometrical effects of Urtica dioica extract on rat’s prostate hyperplasia

    PubMed Central

    Moradi, Hamid Reza; Erfani Majd, Naeem; Esmaeilzadeh, Saleh; Fatemi Tabatabaei, Sayed Reza

    2015-01-01

    Benign prostatic hyperplasia (BPH) is a common disease in human that gradual overgrowth of the prostate gland leads to impinge on the urethra with impairment in urinary function. Numerous plants improve uncontrolled growth of the prostate gland and improve urinary tract symptoms associated with BPH. In this study, 25 healthy adult male Wistar rats were divided randomly in five groups: G1 (Control group) received ordinary feed without any treatment, G2 received 10 mg kg-1 testosterone subcutaneously, G3 received 50 mg kg-1 nettle root extract orally, G4 received 50 mg kg-1 nettle root extract orally and 10 mg kg-1 testosterone, G5 received 10 mg kg-1 almond oil (Almond oil was used as testosterone solvent) subcutaneously. After six weeks, volume and weight of each lobe were measured and samples were taken. The 5 to 6 µm thickness sections were made using paraffin embedding method and stained by hematoxylin and eosin and periodic acid-Schiff. The results showed that prostate volume and ratio of prostate to body weight were increased significantly in the testosterone. Histological and histometrical results showed that dorsal and lateral type 1 and 2 lobes were not changed significantly but the ventral and anterior lobes have changed significantly. Over all, the nettle root could prevent from some of prostatic hyperplasia effects, so that percentage of folded alveoli in ventral lobe reduced insignificantly. PMID:25992248

  12. Atypical Marginal Zone Hyperplasia Is a Mimic for Lymphoma in Pediatric Transplant Recipients: Report of Two Patients.

    PubMed

    Caltharp, Shelley A; Qayed, Muna; Park, Sunita I

    2015-01-01

    Atypical marginal zone hyperplasia (AMZH) of mucosa-associated lymphoid tissue (MALT) closely resembles lymphoma in that it shows expansion of the marginal zones with prominent intraepithelial B lymphocytes, is immunoglobulin light-chain restricted, and may show aberrant CD43 expression. However, unlike lymphoma, it does not show rearrangement of the immunoglobulin heavy chain gene (immunoglobulin H [IgH]) by polymerase chain reaction (PCR), and it behaves in a benign fashion. We identified AMZH in 2 pediatric solid organ transplant recipients who presented with adenotonsillar hypertrophy. To date, the patients have experienced a self-limited course in the absence of treatment or reduction of immunosuppression. Atypical marginal zone hyperplasia is a pitfall for posttransplant lymphoproliferative disorder and MALT lymphoma in the pediatric solid organ transplant population. In transplant patients with a lambda-restricted B-cell clone and marginal zone hyperplasia in native MALT sites, PCR for IgH and IgK gene rearrangement is essential to prevent misdiagnosis.

  13. Muscle-derived stem cells promote angiogenesis and attenuate intimal hyperplasia in different murine vascular disease models.

    PubMed

    Park, Hyung Sub; Hahn, Soli; Choi, Geum Hee; Yoo, Young Sun; Lee, Ji Youl; Lee, Taeseung

    2013-03-15

    Muscle-derived stem cells (MDSCs) are known to promote angiogenesis, but have never been studied in vascular diseases. We differentiated MDSCs into endothelial lineage cells in vitro by stimulation with shear stress and vascular endothelial growth factor. Such differentiated MDSCs (diff-MDSC) showed strong angiogenic potential in vitro. When tested in ischemic hindlimbs of mice, diff-MDSCs increased perfusion and decreased necrosis of the ischemic limbs, by promoting new vessel formation and by upregulating genes involved in endothelial expression. Such effects were not observed with native MDSCs (without endothelial stimulation in vitro). Diff-MDSCs were also injected into carotid arteries of rats after balloon denudation of the intima layer to induce intimal hyperplasia. The cell-treated group had significantly reduced intima-to-media thickness ratio compared to control, thus attenuating intimal hyperplasia by early re-endothelialization of the intima layer. Our findings suggest that MDSCs are a potential source of stem cell therapy for treatment of various vascular diseases, by inducing angiogenesis to improve perfusion in sites of ischemia, and by preventing intimal hyperplasia in sites of vessel injury.

  14. Microwave thermotherapy for benign prostatic hyperplasia.

    PubMed

    Hoffman, Richard M; Monga, Manoj; Elliott, Sean P; Macdonald, Roderick; Langsjoen, Jens; Tacklind, James; Wilt, Timothy J

    2012-09-12

    Transurethral resection of the prostate (TURP) has been the gold-standard treatment for alleviating urinary symptoms and improving urinary flow in men with symptomatic benign prostatic hyperplasia (BPH). However, the morbidity of TURP approaches 20%, and less invasive techniques have been developed for treating BPH. Preliminary data suggest that microwave thermotherapy, which delivers microwave energy to produce coagulation necrosis in prostatic tissue, is a safe, effective treatment for BPH. To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. Randomized controlled trials were identified from The Cochrane Library, MEDLINE, EMBASE, bibliographies of retrieved articles, reviews, technical reports, and by contacting relevant expert trialists and microwave manufacturers. All randomized controlled trials evaluating transurethral microwave thermotherapy (TUMT) for men with symptomatic BPH were eligible for this review. Comparison groups could include transurethral resection of the prostate, minimally invasive prostatectomy techniques, sham thermotherapy procedures, and medications. Outcome measures included urinary symptoms, urinary function, prostate volume, mortality, morbidity, and retreatment. Two review authors independently identified potentially relevant abstracts and then assessed the full papers for inclusion. Two review authors independently abstracted study design, baseline characteristics, and outcomes data and assessed methodological quality using a standard form. We attempted to obtain missing data from authors or sponsors, or both. In this update, we identified no new randomized comparisons of TUMT that provided evaluable effectiveness data. Fifteen studies involving 1585 patients met the inclusion criteria, including six comparisons of microwave thermotherapy with TURP, eight comparisons with sham thermotherapy procedures, and one comparison with an alpha

  15. Biomarkers of progestin therapy resistance and endometrial hyperplasia progression

    PubMed Central

    Upson, Kristen; Allison, Kimberly H.; Reed, Susan D.; Jordan, Carolyn D.; Newton, Katherine M.; Swisher, Elizabeth M.; Doherty, Jennifer A.; Garcia, Rochelle L.

    2012-01-01

    Objective To identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia. Study Design We performed a nested case-control study among women with complex (n=73) and atypical (n=41) hyperplasia treated with oral progestin, followed 2–6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptors A (PRA) and B (PRB), PTEN, Pax-2 and Bcl-2. Odds ratios and 95% confidence intervals were estimated. Results Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI: 0.01–0.8). High expression of PRA and PRB suggested decreased risk of persistence/ progression (OR=0.1, 95% CI: 0.02–1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression. Conclusions PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions. PMID:22727345

  16. MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

    EPA Science Inventory

    MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

    Epidemiological studies have shown a positive association between chronic exposure to chlorinated drinking water and human cancer, particularly of the urinary bladder. MX (3- chloro-4-(dichloromethyl)-5-hydrox...

  17. Congenital adrenal hyperplasia with localized aggressive periodontitis and amelogenesis imperfecta.

    PubMed

    Ajlan, Sumaiah Abdulbaqi

    2015-11-01

    Congenital adrenal hyperplasia (CAH) is an inherited medical condition that implies defects in steroid biosynthesis. The dental findings of a female patient with CAH are reported. The patient suffered from severe periodontal tissue destruction, obvious enamel defects, as well as some occlusal problems. The management approach is presented and the possibility of interrelation of her dental findings with her medical condition is discussed.

  18. Diffuse Neuroendocrine Cell Hyperplasia: Report of Two Cases

    PubMed Central

    Cansız Ersöz, Cevriye; Cangır, Ayten Kayı; Dizbay Sak, Serpil

    2016-01-01

    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder characterised by a proliferation of neuroendocrine cells within the lung. It is believed that a minority of the patients with DIPNECH can develop carcinoid tumors. Here, we report two new cases of DIPNECH with coexisting carcinoid tumors. PMID:27293939

  19. Mistaken gender identity in non-classical congenital adrenal hyperplasia.

    PubMed

    Kukreti, Prerna; Kandpal, Manish; Jiloha, R C

    2014-04-01

    Gender identity is the sense of belonging that one feels for a particular sex psychologically and socially, independent of one's biological sex. There is much less systematic data on gender identity in females with congenital adrenal hyperplasia (CAH). We report a case of non-classical CAH presenting as a case of gender identity disorder.

  20. [Bilateral hyperplasia of the coronoid apophyses. A clinical case].

    PubMed

    Parascandolo, S; Rusciano, A; Tamai, M; Morlino, M

    1993-03-01

    The authors report on the case of a young patient affected with bilateral hyperplasia of the coronoid apophyses, who presented a serious reduction of the mandibular excursion. Normal mouth opening was re-established by a bilateral osteotomy with endoral removal of the coronoid apophyses.

  1. Norethindrone acetate and estradiol-induced endometrial hyperplasia.

    PubMed

    Kurman, R J; Félix, J C; Archer, D F; Nanavati, N; Arce, J; Moyer, D L

    2000-09-01

    To identify the lowest effective continuous dose of norethindrone acetate that significantly reduces 12-month incidence of endometrial hyperplasia associated with unopposed 17beta-estradiol (E2), 1 mg. In a double-masked, randomized, multicenter study, 1176 healthy postmenopausal women 45 years of age or older without evidence of endometrial abnormalities were given 12 months of treatment with unopposed E2, 1 mg, or continuous-combined regimens of E2, 1 mg, and norethindrone acetate, 0.1 mg, 0.25 mg, or 0.5 mg. Endometrial histology was evaluated at the end of the treatment period. Continuous-combined E2-norethindrone acetate regimens significantly reduced 12-month incidence of endometrial hyperplasia compared with unopposed E2 1 mg (P <.001). Endometrial hyperplasia occurred in 14.6% of women treated with unopposed E2 1 mg, whereas in all continuous-combined groups, the rate decreased to less than 1%. Among patients who received E2-norethindrone acetate 0.1 mg, incidence was 0.8%; among those who received 0.25 mg and 0.5 mg, it was 0.4%. Continuous norethindrone acetate at doses as low as 0.1 mg combined with E2 1 mg effectively negated risk for endometrial hyperplasia associated with unopposed E2 1 mg, at least for the first year of therapy.

  2. Holmium laser treatment of benign prostatic hyperplasia: an update.

    PubMed

    Matlaga, Brian R; Miller, Nicole L; Lingeman, James E

    2007-01-01

    The surgical treatment of benign prostatic hyperplasia is a dynamic, evolving field. Holmium laser enucleation of the prostate has been one of the most rigorously analyzed interventions for benign prostatic hyperplasia. In the 12 months since July 2005, a number of important studies have been published concerning this technique. In the 12-month period of this review, there have been a number of articles published on holmium laser enucleation of the prostate. Among these are five randomized controlled trials. These studies emphasize the unique advantages of holmium laser enucleation of the prostate over other surgical treatments for benign prostatic hyperplasia. Holmium laser enucleation of the prostate is a more efficient procedure than competitor techniques, when grams of tissue removed per unit time are quantified. Additionally, holmium laser enucleation of the prostate is associated with a reduced length of catheterization and hospitalization when compared with other surgical therapies for men with benign prostatic hyperplasia. Outcome measures for men undergoing holmium laser enucleation of the prostate are in many cases superior to those of other modalities. It is likely that the completeness of adenoma removal with holmium laser enucleation of the prostate confers many of these advantages.

  3. Paediatric cyclical Cushing's disease due to corticotroph cell hyperplasia.

    PubMed

    Noctor, E; Gupta, S; Brown, T; Farrell, M; Javadpour, M; Costigan, C; Agha, A

    2015-06-12

    Cushing's disease is very rare in the paediatric population. Although uncommon, corticotroph hyperplasia causing Cushing's syndrome has been described in the adult population, but appears to be extremely rare in children. Likewise, cyclical cortisol hypersecretion, while accounting for 15 % of adult cases of Cushing's disease, has only rarely been described in the paediatric population. Here, we describe a very rare case of a 13-year old boy with cyclical cortisol hypersecretion secondary to corticotroph cell hyperplasia. The case is that of a 13-year old boy, presenting with a long history of symptoms and signs suggestive of hypercortisolism, who was found to have cyclical ACTH-dependent hypercortisolism following dynamic pituitary testing and serial late-night salivary cortisol measurements. The patient underwent endoscopic transsphenoidal resection of the pituitary. Early surgical remission was confirmed by undetectable post-operative morning plasma cortisol levels. Histology and immunocytochemistry of the resected pituitary tissue showed extensive corticotroph cell hyperplasia. This report describes a rare case of cyclical Cushing's disease secondary to corticotroph hyperplasia in a paediatric patient. This highlights the challenging and varied nature of Cushing's disease and its diagnosis, and the need to keep a differential diagnosis in mind during the diagnostic process.

  4. MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

    EPA Science Inventory

    MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

    Epidemiological studies have shown a positive association between chronic exposure to chlorinated drinking water and human cancer, particularly of the urinary bladder. MX (3- chloro-4-(dichloromethyl)-5-hydrox...

  5. [Focal epithelial hyperplasia (Heck's disease) in a Turkish family].

    PubMed

    Weidner, F

    1996-12-01

    A 31-year-old Turkish patient and some family members suffered from multiple hyperplastic oral mucosal papules. Intralesional papilloma virus was not found but the patient had elevated levels of CD8 lymphocytes in his peripheral blood. We diagnosed focal epithelial hyperplasia of Heck.

  6. Focal epithelial hyperplasia (Heck disease) associated with AIDS.

    PubMed

    Viraben, R; Aquilina, C; Brousset, P; Bazex, J

    1996-01-01

    Focal epithelial hyperplasia (FEH) of the oral mucosa occurring in a HIV-infected man is described. Molecular biology disclosed an HPV-32 type in oral lesions. The association of FEH and AIDS is uncommon although many HPV subtypes may manifest during HIV infection.

  7. Hyperplasia and Hypertrophy of Pacinian Corpuscles: A Case Report.

    PubMed

    García, Fernando Cano; Acosta, Dalia Rodríguez; Diaz González, José Manuel; Lima, Marcela Saeb

    2015-08-01

    The proliferation of Pacinian corpuscles is a rare benign lesion that occurs frequently in the fingers of hands, with the only clinical sign of pain when a drastic temperature change happens. A case of an extremely rare lesion in which we observed hypertrophy and hyperplasia of Pacinian corpuscles has been reported.

  8. Mistaken gender identity in non-classical congenital adrenal hyperplasia

    PubMed Central

    Kukreti, Prerna; Kandpal, Manish; Jiloha, R. C.

    2014-01-01

    Gender identity is the sense of belonging that one feels for a particular sex psychologically and socially, independent of one's biological sex. There is much less systematic data on gender identity in females with congenital adrenal hyperplasia (CAH). We report a case of non-classical CAH presenting as a case of gender identity disorder. PMID:24891708

  9. Thymic remodeling associated with hyperplasia in myasthenia gravis.

    PubMed

    Le Panse, Rozen; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Weiss, Julia Miriam; Cufi, Perrine; Dartevelle, Philippe; De Rosbo, Nicole Kerlero; Berrih-Aknin, Sonia

    2010-08-01

    Acquired myasthenia gravis (MG), a neurological autoimmune disease, is caused by autoantibodies against components of the neuromuscular junction that lead to disabling muscle fatigability. The thymus is clearly involved in the pathogenesis of early-onset MG with anti-acetylcholine receptor antibodies, and thymic hyperplasia of lympho-proliferative origin is a hallmark of the disease. In this review, we describe the structural and cellular changes associated with thymic hyperplasia, its main characteristics being the development of ectopic germinal centers (GCs) associated with active neoangiogenic processes, such as development of high endothelial venules and lymphangiogenesis. What triggers such thymic abnormalities in MG is not yet clear. A thymic transcriptome analysis has demonstrated a strong inflammatory signature in MG that could orchestrate the development of thymic hyperplasia. In this context, thymic epithelial cells (TECs) seem to play a central role, either by contributing or responding to the inflammatory environment and up-regulating the autoimmune response. In particular, MG TECs clearly overexpress various cytokines, among which chemokines play a crucial role in the recruitment of peripheral lymphocytes to the thymus via the newly expanded vessel network, thereby leading to the development of ectopic GCs. Clearly, a better understanding of major events that lead to thymic hyperplasia will help optimize strategies toward more specific therapy for MG.

  10. Early Hormonal Influences on Cognitive Functioning in Congenital Adrenal Hyperplasia.

    ERIC Educational Resources Information Center

    Resnick, Susan M.; And Others

    1986-01-01

    Reports the results of cognitive test performance and early childhood activities in individuals with congenital adrenal hyperplasia, an autosomal recessive disorder associated with elevated prenatal adrenal androgen levels, demonstrating the effects of early exposure to excess androgenizing hormones on sexually dimorphic cognitive functioning.…

  11. Sevelamer hydrochloride (Renagel), a non-calcaemic phosphate binder, arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency.

    PubMed

    Nagano, N; Miyata, S; Obana, S; Ozai, M; Kobayashi, N; Fukushima, N; Burke, S K; Wada, M

    2001-09-01

    It has been demonstrated that dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)(2)D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a non-calcaemic phosphate binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI. Male Sprague-Dawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)(2)D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser. Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)(2)D3 levels did not show any correlation with serum PTH levels and maximal PTG area. Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.

  12. The effects of knee immobilization on marrow adipocyte hyperplasia and hypertrophy at the proximal rat tibia epiphysis.

    PubMed

    Trudel, Guy; Uhthoff, Hans K; Solanki, Sanjay; Laneuville, Odette

    2017-09-01

    Marrow adipose deposition is observed during aging and in association with extended periods of immobility. The objective of this study was to determine the contribution of adipocyte hypertrophy and hyperplasia to bone marrow fat deposition induced by immobilization of the rat knee joint for 2, 4, 16 or 32 weeks. Histomorphometric analyses compared immobilized to sham-operated proximal tibia from age and gender matched rats to assess the contribution of aging and duration of immobilization on the number and size of marrow adipocytes. Results indicated that marrow adipose tissue increased with the duration of immobilization and was significant larger at 16 weeks compared to the sham-operated group (0.09956±0.13276mm(2) vs 0.01990±0.01100mm(2), p=0.047). The marrow adipose tissue was characterized by hyperplasia of adipocytes with a smaller average size after 2 and 4 weeks of immobilization (at 2 weeks hyperplasia: 68.86±33.62 vs 43.57±24.47 adipocytes/mm(2), p=0.048; at 4 weeks hypotrophy: 0.00036±0.00019 vs 0.00046±0.00023mm(2), p=0.027), and by adipocyte hypertrophy after 16 weeks of immobilization (0.00083±0.00049 vs 0.00046±0.00028mm(2), p=0.027) compared to sham-operated. Both immobilized and sham-operated groups showed marrow adipose conversion with age; immobilized (p=0.008; sham: p=0.003). Overall, fat deposition in the bone marrow of the proximal rat tibia epiphysis and induced by knee joint immobilization was characterized by hyperplasia of small adipocytes in the early phase and by adipocyte hypertrophy in the later phase. Mediators of marrow fat deposition after immobilization and preventive countermeasures need to be investigated. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. Role of Hyperplasia of Gingival Lymphatics in Periodontal Inflammation.

    PubMed

    Papadakou, P; Bletsa, A; Yassin, M A; Karlsen, T V; Wiig, H; Berggreen, E

    2017-04-01

    Lymphatic vessels are important for maintenance of tissue fluid homeostasis and afferent antigen transport. In chronic inflammation, lymphangiogenesis takes place and is characterized by lymphatic endothelial cell proliferation and lymphatic hyperplasia. Vascular endothelial growth factor C (VEGFC) is the main known lymphangiogenic growth factor, and its expression is increased in periodontitis, a common chronic infectious disease that results in tissue destruction and alveolar bone loss. The role of lymphangiogenesis during development of periodontitis is unknown. Here, we test if transgenic overexpression of epithelial VEGFC in a murine model is followed by hyperplasia of lymphatic vessels in oral mucosa and if the lymphatic drainage capacity is altered. We also test if lymphatic hyperplasia protects against periodontal disease development. Transgenic keratin 14 (K14)-VEGFC mice had significant hyperplasia of lymphatics in oral mucosa, including gingiva, without changes in blood vessel vasculature. The basal lymph flow was normal but slightly lower than in wild-type mice when oral mucosa was challenged with lipopolysaccharide from Porphyromonas gingivalis. Under normal conditions, K14-VEGFC mice exhibited an increased number of neutrophils in gingiva, demonstrated enhanced phagocyte recruitment in the cervical lymph nodes, and had more alveolar bone when compared with their wild-type littermates. After induction of periodontitis, no strain differences were observed in the periodontal tissues with respect to granulocyte recruitment, bone resorption, angiogenesis, cytokines, and bone-related protein expressions or in draining lymph node immune cell proportions and vascularization. We conclude that overexpression of VEGFC results in hyperplastic lymphatics, which do not enhance lymphatic drainage capacity but facilitate phagocyte transport to draining lymph nodes. Hyperplasia of lymphatics does not protect against development of ligature-induced periodontitis.

  14. SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition.

    PubMed

    Abdesselem, Houari; Madani, Aisha; Hani, Ahmad; Al-Noubi, Muna; Goswami, Neha; Ben Hamidane, Hisham; Billing, Anja M; Pasquier, Jennifer; Bonkowski, Michael S; Halabi, Najeeb; Dalloul, Rajaa; Sheriff, Mohamed Z; Mesaeli, Nasrin; ElRayess, Mohamed; Sinclair, David A; Graumann, Johannes; Mazloum, Nayef A

    2016-01-29

    The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition*

    PubMed Central

    Abdesselem, Houari; Madani, Aisha; Hani, Ahmad; Al-Noubi, Muna; Goswami, Neha; Ben Hamidane, Hisham; Billing, Anja M.; Pasquier, Jennifer; Bonkowski, Michael S.; Halabi, Najeeb; Dalloul, Rajaa; Sheriff, Mohamed Z.; Mesaeli, Nasrin; ElRayess, Mohamed; Sinclair, David A.; Graumann, Johannes; Mazloum, Nayef A.

    2016-01-01

    The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity. PMID:26655722

  16. A prospective, single-blind, multicenter, dose escalation study of intracoronary iNOS lipoplex (CAR-MP583) gene therapy for the prevention of restenosis in patients with de novo or restenotic coronary artery lesion (REGENT I extension).

    PubMed

    von der Leyen, Heiko E; Mügge, Andreas; Hanefeld, Christoph; Hamm, Christian W; Rau, Mathias; Rupprecht, Hans J; Zeiher, Andreas M; Fichtlscherer, Stephan

    2011-08-01

    Neointimal hyperplasia causing recurrent stenosis is a limitation of the clinical utility of percutaneous transluminal coronary interventions (PCI). Nitric oxide (NO) inhibits smooth muscle cell proliferation, platelet activation, and inflammatory responses, all of which have been implicated in the pathogenesis of restenosis. In animals, neointimal proliferation after balloon injury has been shown to be effectively reduced by gene transfer of the inducible NO synthase (iNOS). The primary objective of this first multicenter, prospective, single-blind, dose escalation study was to obtain safety and tolerability information of the iNOS lipoplex (CAR-MP583) gene therapy for reducing restenosis following PCI. Local coronary intramural CAR-MP583 delivery was achieved using the Infiltrator balloon catheter. A total of 30 patients were treated in the study (six patients, 0.5 μg; six patients, 2.0 μg; six patients, 5.0 μg; and 12 patients, 10 μg). There were no complications related to local application of CAR-MP583. In one patient, PCI procedure-related transient vessel occlusion occurred with consecutive troponin elevation. There were no signs of inflammatory responses or hepatic or renal toxicity. No dose relationship was seen with regard to adverse events across the dose groups. Thus, coronary intramural lipoplex-enhanced iNOS gene therapy during PCI is feasible and appears to be safe. These initial clinical results are encouraging to support further clinical research, in particular in conjunction with new local drug delivery technologies.

  17. Effects of adrenal steroids on the bone metabolism of children with congenital adrenal hyperplasia.

    PubMed

    Lin-Su, Karen; New, Maria I

    2007-11-01

    The primary treatment for patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is glucocorticoid replacement therapy, which at supraphysiologic levels can result in diminished bone accrual and lead to osteopenia and osteoporosis. Unlike other diseases treated with chronic glucocorticoid therapy, previous studies of patients with 21OHD have not demonstrated a detrimental effect of glucocorticoid treatment on bone mineral density (BMD). It has been postulated that the elevated androgens typically found in these patients have a protective effect on bone integrity, but the precise mechanism remains unknown. We propose that the inhibitory effect of corticosteroid therapy on bone formation is counteracted by estrogen's effect on bone resorption through the RANK-L/osteoprotegerin (OPG) system. A better understanding of the mechanism by which patients with 21OHD are protected against bone loss may lead to novel therapeutic measures to prevent or treat osteopenia and osteoporosis in other conditions, including postmenopausal women.

  18. ANTEMORTEM DIAGNOSIS OF CYSTIC ENDOMETRIAL HYPERPLASIA AND SUCCESSFUL OVARIOHYSTERECTOMY IN AN AFRICAN WARTHOG (PHACOCHOERUS AFRICANUS).

    PubMed

    Thompson, Kimberly A; Niehaus, Andrew; Shellabarger, Wynona; Depenbrock, Sarah; Agnew, Dalen

    2015-12-01

    During a routine geriatric examination on a 9-yr-old, nulliparous female African warthog (Phacochoerus africanus), a severely enlarged, mixed echogenicity uterus was discovered during transabdominal ultrasound. Ovariohysterectomy (OVH) was elected and performed due to concern for a potential neoplastic condition. Postoperatively, the warthog was treated prophylactically with metoclopramide and ranitidine to promote gastrointestinal motility and prevent postoperative ileus. The gross appearance and histopathology confirmed the presence of extensive widely disseminated cystic changes consistent with cystic endometrial hyperplasia (CEH) and multiple para-ovarian cysts. Uterine pathology, including CEH, is a common condition in domestic potbellied pigs (Sus scrofa), and as a result, it is recommended to perform an OVH at an early age. The advanced uterine changes may have accounted for this animal's history of infertility. This case provides evidence that nulliparity may be associated with the development of uterine pathology in warthogs. Increased knowledge of reproductive pathology will aid in improved management strategies for breeding nondomestic suids.

  19. Health problems in congenital adrenal hyperplasia due to 21-hy