WorldWideScience

Sample records for vascular targeting relevance

  1. Novel therapies targeting vascular endothelium.

    Science.gov (United States)

    Tousoulis, Dimitris; Antoniades, Charalambos; Koumallos, Nikolaos; Marinou, Kyriakoula; Stefanadi, Elli; Latsios, George; Stefanadis, Christodoulos

    2006-01-01

    Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature may improve the long-term outcome in healthy individuals, high-risk subjects, or patients with advanced atherosclerosis. Several therapeutic strategies are now available, targeting both the synthesis and oxidative inactivation of nitric oxide (NO) in human vasculature. Statins seem to be currently the most powerful category of these agents, improving endothelial function and decreasing cardiovascular risk after long-term administration. Other cardiovascular agents improving endothelial function in humans are angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, which increase NO bioavailability by modifying the rennin-angiotensin-aldosterone system. Newer therapeutic approaches targeting endothelial dysfunction in specific disease states include insulin sensitizers, L-arginine (the substrate for endothelial NO synthase [eNOS]) as well as substances that target eNOS "coupling," such as folates or tetrahydrobiopterin. Although there are a variety of strategies to improve NO bioavailability in human endothelium, it is still unclear whether they have any direct benefit at a clinical level.

  2. Angiogenesis and vascular targeting: Relevance for hyperthermia

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2008-01-01

    in influencing the response to hyperthermia. Generally, the poorer the blood supply the better the heat effect, thus combining VTAs with heat would appear to be a logical approach. Numerous pre-clinical studies have now demonstrated the benefits of combining AIAs or VDAs with heat to improve tumour response...

  3. Vascular-targeted therapies for Duchenne muscular dystrophy

    Science.gov (United States)

    2013-01-01

    Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy

  4. Rho kinase as a target for cerebral vascular disorders

    Science.gov (United States)

    Bond, Lisa M; Sellers, James R; McKerracher, Lisa

    2015-01-01

    The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations. PMID:26062400

  5. Structural and functional imaging for vascular targeted photodynamic therapy

    Science.gov (United States)

    Li, Buhong; Gu, Ying; Wilson, Brian C.

    2017-02-01

    Vascular targeted photodynamic therapy (V-PDT) has been widely used for the prevention or treatment of vascular-related diseases, such as localized prostate cancer, wet age-related macular degeneration, port wine stains, esophageal varices and bleeding gastrointestinal mucosal lesions. In this study, the fundamental mechanisms of vascular responses during and after V-PDT will be introduced. Based on the V-PDT treatment of blood vessels in dorsal skinfold window chamber model, the structural and functional imaging, which including white light microscopy, laser speckle imaging, singlet oxygen luminescence imaging, and fluorescence imaging for evaluating vascular damage will be presented, respectively. The results indicate that vessel constriction and blood flow dynamics could be considered as the crucial biomarkers for quantitative evaluation of vascular damage. In addition, future perspectives of non-invasive optical imaging for evaluating vascular damage of V-PDT will be discussed.

  6. Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance.

    Science.gov (United States)

    Makarović, Sandra; Makarović, Zorin; Steiner, Robert; Mihaljević, Ivan; Milas-Ahić, Jasminka

    2015-06-01

    Osteoprotegerin (OPG) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG -/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental studies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored.

  7. Vascular targeting of nanoparticles for molecular imaging of diseased endothelium.

    Science.gov (United States)

    Atukorale, Prabhani U; Covarrubias, Gil; Bauer, Lisa; Karathanasis, Efstathios

    2017-04-01

    This review seeks to highlight the enormous potential of targeted nanoparticles for molecular imaging applications. Being the closest point-of-contact, circulating nanoparticles can gain direct access to targetable molecular markers of disease that appear on the endothelium. Further, nanoparticles are ideally suitable to vascular targeting due to geometrically enhanced multivalent attachment on the vascular target. This natural synergy between nanoparticles, vascular targeting and molecular imaging can provide new avenues for diagnosis and prognosis of disease with quantitative precision. In addition to the obvious applications of targeting molecular signatures of vascular diseases (e.g., atherosclerosis), deep-tissue diseases often manifest themselves by continuously altering and remodeling their neighboring blood vessels (e.g., cancer). Thus, the remodeled endothelium provides a wide range of targets for nanoparticles and molecular imaging. To demonstrate the potential of molecular imaging, we present a variety of nanoparticles designed for molecular imaging of cancer or atherosclerosis using different imaging modalities. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Identification of novel vascular targets in lung cancer

    Science.gov (United States)

    Zhuang, X; Herbert, J M J; Lodhia, P; Bradford, J; Turner, A M; Newby, P M; Thickett, D; Naidu, U; Blakey, D; Barry, S; Cross, D A E; Bicknell, R

    2015-01-01

    Background: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. Methods: Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology. Results: Bioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation. Conclusions: The identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development. PMID:25535734

  9. Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.

    Science.gov (United States)

    Ringvold, H C; Khalil, R A

    2017-01-01

    Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ɛ, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation, and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps, and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation, and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin-myosin interaction, and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia-reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems and could reduce PKC hyperactivity in vascular disorders. First-generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease. © 2017 Elsevier Inc. All rights reserved.

  10. Uterine fibroid vascularization and clinical relevance to uterine fibroid embolization.

    Science.gov (United States)

    Pelage, Jean-Pierre; Cazejust, Julien; Pluot, Etienne; Le Dref, Olivier; Laurent, Alexandre; Spies, James B; Chagnon, Sophie; Lacombe, Pascal

    2005-10-01

    Embolization has become a first-line treatment for symptomatic uterine fibroid tumors. Selective catheterization and embolization of both uterine arteries, which are the predominant source of blood flow to fibroid tumors in most cases, is the cornerstone of treatment. Although embolization for treatment of uterine fibroid tumors is widely accepted, great familiarity with the normal and variant pelvic arterial anatomy is needed to ensure the safety and success of the procedure. The uterine artery classically arises as a first or second branch of the anterior division of the internal iliac artery and is usually dilated in the presence of a uterine fibroid tumor. Angiography is used for comprehensive pretreatment assessment of the pelvic arterial anatomy; for noninvasive evaluation, Doppler ultrasonography, contrast material-enhanced magnetic resonance (MR) imaging, and MR angiography also may be used. After the uterine artery is identified, selective catheterization should be performed distal to its cervicovaginal branch. For targeted embolization of the perifibroid arterial plexus, injection of particles with diameters larger than 500 mum is generally recommended. Excessive embolization may injure normal myometrium, ovaries, or fallopian tubes and lead to uterine necrosis or infection or to ovarian failure. Incomplete treatment or additional blood supply to the tumor (eg, via an ovarian artery) may result in clinical failure. The common postembolization angiographic end point is occlusion of the uterine arterial branches to the fibroid tumor while antegrade flow is maintained in the main uterine artery. Copyright RSNA, 2005.

  11. Vascular targets for cannabinoids: animal and human studies

    Science.gov (United States)

    Stanley, Christopher; O'Sullivan, Saoirse E

    2014-01-01

    Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1, CBe, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6 PMID:24329566

  12. Vascular risk factors as treatment target to prevent cognitive decline.

    Science.gov (United States)

    Richard, Edo; Moll van Charante, Eric P; van Gool, Willem A

    2012-01-01

    Epidemiological studies have consistently shown that vascular risk factors including hypertension, diabetes, obesity, hypercholesterolemia, smoking, and lack of physical exercise are associated with an increased risk of cognitive decline and dementia. Neuroradiological and neuropathological studies have confirmed the importance of cerebrovascular lesions in the etiology of late onset dementia. We have reviewed the literature and conclude that up until now randomized controlled clinical trials targeting individual risk factors and assessing cognitive decline or dementia as an outcome have not convincingly shown that treatment of vascular risk factors can actually prevent or postpone cognitive decline and dementia. New studies targeting several vascular risk factors at the same time and using cognitive decline or dementia as primary outcome might answer the question whether cognitive decline can really be postponed or even prevented. The design of such studies is not straightforward and long follow-up is required. In this review we discuss several pertinent methodological issues that need to be addressed to achieve an optimal design of new randomized controlled trials.

  13. Targeting local vascular and systemic consequences of inflammation on vascular and cardiac valve calcification.

    Science.gov (United States)

    Hénaut, Lucie; Sanchez-Nino, Maria Dolores; Aldamiz-Echevarría Castillo, Gonzalo; Sanz, Ana B; Ortiz, Alberto

    2016-01-01

    Cardiac valve calcification and vascular calcification (VC) are associated with cardiovascular mortality in the general population and in patients with chronic kidney disease (CKD). CKD, diabetes mellitus, and atherosclerosis are among the causes of systemic inflammation that are associated with VC. This review collates clinical and experimental evidence that inflammation accelerates VC progression. Specifically, we review the actions of key pro-inflammatory cytokines and inflammation-related transcription factors on VC, and the role played by senescence. Inflammatory cytokines, such as the TNF superfamily and IL-6 superfamily, and inflammation-related transcription factor NF-κB promote calcification in cultured vascular smooth muscle cells, valvular interstitial cells, or experimental animal models through direct effects, but also indirectly by decreasing circulating Fetuin A or Klotho levels. Experimental evidence suggests a causal link between inflammation and VC that would change the clinical approach to prevention and treatment of VC. However, the molecular basis remains unclear and little is known about VC in humans treated with drugs targeting inflammatory cytokines. The effect of biologicals targeting TNF-α, RANKL, IL-6, and other inflammatory mediators on VC, in addition to the impact of dietary phosphate in patients with chronic systemic inflammation, requires study.

  14. [Relevance of Vascular Trauma in Trauma Care - Impact on Clinical Course and Mortality].

    Science.gov (United States)

    Lech, L; Jerkku, T; Kanz, K-G; Wierer, M; Mutschler, W; Koeppel, T A; Lefering, R; Banafsche, R

    2016-10-01

    There is a lack of evidence as to the relevance of vascular trauma (VT) in patients with severe injuries. Therefore, we reviewed registry data in the present study in order to systematically objectify the effect of VT in these patients. This study aimed to provide an adequate picture of the relevance of vascular trauma and to identify adverse prognostic factors. In a retrospective analysis of records from the TraumaRegister DGU® (TR-DGU) in two subgroups with moderate and severe VT, we examined the records for differences in terms of morbidity, mortality, follow-up and prognostic parameters compared to patients without VT with the same ISS. From a total of 42,326 patients, 2,961 (7 %) had a VT, and in 2,437 cases a severe VT (AIS ≥ 3) was diagnosed (5.8 %). In addition to a higher incidence of shock and a 2 to 3-fold increase in fluid replacement and erythrocyte transfusion, patients with severe VT had a 60 % higher rate of multiple organ failure, and in-hospital mortality was twice as high (33.8 %). The massively increased early mortality (8.0 vs. 25.2 %) clearly illustrates how severely injured patients are placed at risk by the presence of a relevant VT with a comparable ISS. In our opinion, due to an unexpected poor prognosis in the TR-DGU data for vascular injuries, increased attention is required in the care of severely injured patients. Based on our comprehensive analysis of negative prognostic factors, a further adjustment to the standards of vascular medicine could be advisable. The influence of the level of care provided by the admitting hospital and the relevance of a further hospital transfer to prognosis and clinical outcome is currently being analysed. Georg Thieme Verlag KG Stuttgart · New York.

  15. Real time laser speckle imaging monitoring vascular targeted photodynamic therapy

    Science.gov (United States)

    Goldschmidt, Ruth; Vyacheslav, Kalchenko; Scherz, Avigdor

    2017-02-01

    Laser speckle imaging is a technique that has been developed to non-invasively monitor in vivo blood flow dynamics and vascular structure, at high spatial and temporal resolution. It can record the full-field spatio-temporal characteristics of microcirculation and has therefore, often been used to study the blood flow in tumors after photodynamic therapy (PDT). Yet, there is a paucity of reports on real-time laser speckle imaging (RTLSI) during PDT. Vascular-targeted photodynamic therapy (VTP) with WST11, a water-soluble bacteriochlorophyll derivative, achieves tumor ablation through rapid occlusion of the tumor vasculature followed by a cascade of events that actively kill the tumor cells. WST11-VTP has been already approved for treatment of early/intermediate prostate cancer at a certain drug dose, time and intensity of illumination. Application to other cancers may require different light dosage. However, incomplete vascular occlusion at lower light dose may result in cancer cell survival and tumor relapse while excessive light dose may lead to toxicity of nearby healthy tissues. Here we provide evidence for the feasibility of concomitant RTLSI of the blood flow dynamics in the tumor and surrounding normal tissues during and after WST11-VTP. Fast decrease in the blood flow is followed by partial mild reperfusion and a complete flow arrest within the tumor by the end of illumination. While the primary occlusion of the tumor feeding arteries and draining veins agrees with previous data published by our group, the late effects underscore the significance of light dose control to minimize normal tissue impairment. In conclusion- RTSLI application should allow to optimize VTP efficacy vs toxicity in both the preclinical and clinical arenas.

  16. Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

    Science.gov (United States)

    Touré, Fatouma; Chitayat, Seth; Pei, Renjun; Song, Fei; Li, Qing; Zhang, Jinghua; Rosario, Rosa; Ramasamy, Ravichandran; Chazin, Walter J.

    2012-01-01

    The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA. PMID:23209312

  17. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    Science.gov (United States)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  18. MR molecular imaging of tumor vasculature and vascular targets.

    Science.gov (United States)

    Pathak, Arvind P; Penet, Marie-France; Bhujwalla, Zaver M

    2010-01-01

    Tumor angiogenesis and the ability of cancer cells to induce neovasculature continue to be a fascinating area of research. As the delivery network that provides substrates and nutrients, as well as chemotherapeutic agents to cancer cells, but allows cancer cells to disseminate, the tumor vasculature is richly primed with targets and mechanisms that can be exploited for cancer cure or control. The spatial and temporal heterogeneity of tumor vasculature, and the heterogeneity of response to targeting, make noninvasive imaging essential for understanding the mechanisms of tumor angiogenesis, tracking vascular targeting, and detecting the efficacy of antiangiogenic therapies. With its noninvasive characteristics, exquisite spatial resolution and range of applications, magnetic resonance imaging (MRI) techniques have provided a wealth of functional and molecular information on tumor vasculature in applications spanning from "bench to bedside". The integration of molecular biology and chemistry to design novel imaging probes ensures the continued evolution of the molecular capabilities of MRI. In this review, we have focused on developments in the characterization of tumor vasculature with functional and molecular MRI. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  19. Vascular structural and functional changes: their association with causality in hypertension: models, remodeling and relevance.

    Science.gov (United States)

    Lee, Robert Mkw; Dickhout, Jeffrey G; Sandow, Shaun L

    2017-04-01

    Essential hypertension is a complex multifactorial disease process that involves the interaction of multiple genes at various loci throughout the genome, and the influence of environmental factors such as diet and lifestyle, to ultimately determine long-term arterial pressure. These factors converge with physiological signaling pathways to regulate the set-point of long-term blood pressure. In hypertension, structural changes in arteries occur and show differences within and between vascular beds, between species, models and sexes. Such changes can also reflect the development of hypertension, and the levels of circulating humoral and vasoactive compounds. The role of perivascular adipose tissue in the modulation of vascular structure under various disease states such as hypertension, obesity and metabolic syndrome is an emerging area of research, and is likely to contribute to the heterogeneity described in this review. Diversity in structure and related function is the norm, with morphological changes being causative in some beds and states, and in others, a consequence of hypertension. Specific animal models of hypertension have advantages and limitations, each with factors influencing the relevance of the model to the human hypertensive state/s. However, understanding the fundamental properties of artery function and how these relate to signalling mechanisms in real (intact) tissues is key for translating isolated cell and model data to have an impact and relevance in human disease etiology. Indeed, the ultimate aim of developing new treatments to correct vascular dysfunction requires understanding and recognition of the limitations of the methodologies used.

  20. Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants.

    Science.gov (United States)

    Roubicek, Deborah A; Souza-Pinto, Nadja C de

    2017-11-01

    The mitochondrial DNA (mtDNA) is a closed circular molecule that encodes, in humans, 13 polypeptides components of the oxidative phosphorylation complexes. Integrity of the mitochondrial genome is essential for mitochondrial function and cellular homeostasis, and mutations and deletions in the mtDNA lead to oxidative stress, mitochondrial dysfunction and cell death. In vitro and in situ studies suggest that when exposed to certain genotoxins, mtDNA accumulates more damage than nuclear DNA, likely owing to its organization and localization in the mitochondrial matrix, which tends to accumulate lipophilic, positively charged molecules. In that regard, several relevant environmental and occupational contaminants have physical-chemical characteristics that indicate that they might accumulate in mitochondria and target mtDNA. Nonetheless, very little is known so far about mtDNA damage and mitochondrial dysfunction due to environmental exposure, either in model organisms or in humans. In this article, we discuss some of the characteristics of mtDNA which render it a potentially relevant target for damage by environmental contaminants, as well as possible functional consequences of damage/mutation accumulation. In addition, we review the data available in the literature focusing on mitochondrial effects of the most common classes of environmental pollutants. From that, we conclude that several lines of experimental evidence support the idea that mitochondria and mtDNA are susceptible and biologically relevant targets for pollutants, and more studies, including mechanistic ones, are needed to shed more light into the contribution of mitochondrial dysfunction to the environmental and human health effects of chemical exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Enzyme Tunnels and Gates As Relevant Targets in Drug Design.

    Science.gov (United States)

    Marques, Sergio M; Daniel, Lukas; Buryska, Tomas; Prokop, Zbynek; Brezovsky, Jan; Damborsky, Jiri

    2017-09-01

    Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules-into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs. © 2016 Wiley Periodicals, Inc.

  2. Vascular AMPK as an attractive target in the treatment of vascular complications of obesity.

    Science.gov (United States)

    García-Prieto, C F; Gil-Ortega, M; Aránguez, I; Ortiz-Besoain, M; Somoza, B; Fernández-Alfonso, M S

    2015-01-01

    The key for the survival of all organisms is the regulation and control of energy metabolism. Thus, several strategies have evolved in each tissue in order to balance nutrient supply with energy demand. Adenosine monophosphate-activated protein kinase (AMPK) is now recognized as a key participant in energy metabolism. It ensures an appropriate energetic supply by promoting energy conserving pathways in detriment of anabolic processes not essential for cell survival. Vascular AMPK plays a critical role in the regulation of blood flow and vascular tone through several mechanisms, including vasodilation by stimulating nitric oxide release in endothelial cells. Since obesity leads to endothelial damage and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. In the present review we focus on the role of vascular AMPK in both endothelial and smooth muscle cells, paying special attention to its dysregulation in obesity- and high-fat diet-related complications, as well as to the mechanisms and benefits of vascular AMPK activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Fluoroscopic Targeting of Wallstents and Amplatzer Vascular Plugs in Sharp Recanalization of Chronic Venous Occlusions.

    Science.gov (United States)

    Khaja, Minhaj S; Chick, Jeffrey Forris Beecham; Schuman, Ari D; Cooper, Kyle J; Majdalany, Bill S; Saad, Wael E; Williams, David M

    2017-11-01

    Sharp recanalization of chronic venous occlusions is usually performed with targeting of wire-capture devices like loop snares or balloons. We describe sharp recanalization of chronic venous occlusions using self-expanding stents and vascular plugs. We retrospectively reviewed all sharp venous recanalization procedures performed over an 11-month period and found Wallstent and Amplatzer vascular plug (AVP) targeting was performed in 16 patients. Patient demographics, occlusion site, targeting device, technical success of the targeting, and overall procedural success were recorded. Technical success was achieved in twelve (86%) Wallstent and two (67%) AVP deployments. Procedural success was achieved in 15 (94%). Three minor complications occurred. Wallstent and AVP targeting may be a useful technique when performing sharp recanalization for chronic venous occlusions. These devices expand the target space and present the same cross section viewed from any angle and can directly capture and extract the wire, features helpful in regions with crowded vascular anatomy.

  4. Suppressing iron oxide nanoparticle toxicity by vascular targeted antioxidant polymer nanoparticles.

    Science.gov (United States)

    Cochran, David B; Wattamwar, Paritosh P; Wydra, Robert; Hilt, J Zach; Anderson, Kimberly W; Eitel, Richard E; Dziubla, Thomas D

    2013-12-01

    The biomedical use of superparamagnetic iron oxide nanoparticles has been of continued interest in the literature and clinic. Their ability to be used as contrast agents for imaging and/or responsive agents for remote actuation makes them exciting materials for a wide range of clinical applications. Recently, however, concern has arisen regarding the potential health effects of these particles. Iron oxide toxicity has been demonstrated in in vivo and in vitro models, with oxidative stress being implicated as playing a key role in this pathology. One of the key cell types implicated in this injury is the vascular endothelial cells. Here, we report on the development of a targeted polymeric antioxidant, poly(trolox ester), nanoparticle that can suppress oxidative damage. As the polymer undergoes enzymatic hydrolysis, active trolox is locally released, providing a long term protection against pro-oxidant agents. In this work, poly(trolox) nanoparticles are targeted to platelet endothelial cell adhesion molecules (PECAM-1), which are able to bind to and internalize in endothelial cells and provide localized protection against the cytotoxicity caused by iron oxide nanoparticles. These results indicate the potential of using poly(trolox ester) as a means of mitigating iron oxide toxicity, potentially expanding the clinical use and relevance of these exciting systems. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Tackling the vascular heterogeneity issue in tumors : identification of novel targets for tumor therapy

    NARCIS (Netherlands)

    Roodink, I.

    2009-01-01

    This thesis focuses on the identification of novel vascular targeting agents directed against tumor endothelium and the expression patterns of their targets in (clinical) tumor samples. Tumors obtain their blood supply by the formation of new vessels and/or by the incorporation, and possibly

  6. Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium.

    Science.gov (United States)

    D'Arrigo, Joseph S

    2018-01-01

    Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted "lipid-coated microbubble" [LCM]/"nanoparticle-derived" [ND] (or LCM/ND) nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly class B type I), or SR-BI, making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Signaling pathways relevant to cognition-enhancing drug targets.

    Science.gov (United States)

    Ménard, Caroline; Gaudreau, Pierrette; Quirion, Rémi

    2015-01-01

    Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.

  8. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity

    Directory of Open Access Journals (Sweden)

    Mostafa Wanees Ahmed El husseny

    2017-01-01

    Full Text Available Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM, insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity.

  9. MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension

    DEFF Research Database (Denmark)

    Carr, Georgina; Barrese, Vincenzo; Stott, Jennifer B

    2016-01-01

    of concept of Kv7.4 regulation by miR153. CONCLUSION: This study is the first to define a role for aberrant miR153 contributing to the hypertensive state through targeting of KCNQ4 in an animal model of hypertension, raising the possibility of the use of miR153-related therapies in vascular disease....

  10. Vascular Targeting of Nanocarriers: Perplexing Aspects of the Seemingly Straightforward Paradigm

    Science.gov (United States)

    2015-01-01

    Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers. PMID:24787360

  11. Photoacoustic tomography assessment of vascular targeted therapy to determine vessel regrowth following treatment

    Science.gov (United States)

    Johnson, S. P.; Ogunlade, O.; Zhang, E.; Laufer, J.; Rajkumar, V.; Walker-Samuel, S.; Lythgoe, M. F.; Pedley, R. B.; Beard P., P.

    2013-06-01

    Photoacoustic tomography (PAT) is ideally suited to image tissue vasculature and is therefore able to provide functional response data for the pharmacodynamic time course of vascular targeted therapies. We show in a preclinical model of colorectal carcinoma that 40mg/kg of the vascular disrupting agent OXi4503 causes central tumour blood vessel destruction that can be assessed by PAT at 48 hours. This is confirmed with histological haematoxylin and eosin staining. Outward growth of solid tumours is then static until 16 days post-dose whilst vessel regrowth occurs inwardly to repopulate the necrotic core.

  12. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies

    DEFF Research Database (Denmark)

    Horsman, Michael Robert; Siemann, D.W.

    2006-01-01

    of vascular-targeting agent (VTA) have now emerged: those that prevent the angiogenic development of the neovasculature of the tumor and those that specifically damage the already established tumor vascular supply. When used alone neither approach readily leads to tumor control, and so, for VTAs to be most...... successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences...... on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy....

  13. Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia.

    Science.gov (United States)

    Reslan, Ossama M; Khalil, Raouf A

    2010-10-01

    remodeling and further vasoconstriction in the uterine and systemic circulation. Some of these biologically active factors and vascular mediators have been proposed as biomarkers for early prediction or diagnosis of PE, and as potential targets for prevention or treatment of the disease.

  14. Antarctic strict anaerobic microbiota from Deschampsia antarctica vascular plants rhizosphere reveals high ecology and biotechnology relevance.

    Science.gov (United States)

    Peixoto, Rafael José Marques; Miranda, Karla Rodrigues; Lobo, Leandro Araujo; Granato, Alessandra; de Carvalho Maalouf, Pedro; de Jesus, Hugo Emiliano; Rachid, Caio T C C; Moraes, Saulo Roni; Dos Santos, Henrique Fragoso; Peixoto, Raquel Silva; Rosado, Alexandre Soares; Domingues, Regina Maria Cavalcanti Pilotto

    2016-11-01

    The Antarctic soil microbial community has a crucial role in the growth and stabilization of higher organisms, such as vascular plants. Analysis of the soil microbiota composition in that extreme environmental condition is crucial to understand the ecological importance and biotechnological potential. We evaluated the efficiency of isolation and abundance of strict anaerobes in the vascular plant Deschampsia antarctica rhizosphere collected in the Antarctic's Admiralty Bay and associated biodiversity to metabolic perspective and enzymatic activity. Using anaerobic cultivation methods, we identified and isolated a range of microbial taxa whose abundance was associated with Plant Growth-Promoting Bacteria (PGPB) and presences were exclusively endemic to the Antarctic continent. Firmicutes was the most abundant phylum (73 %), with the genus Clostridium found as the most isolated taxa. Here, we describe two soil treatments (oxygen gradient and heat shock) and 27 physicochemical culture conditions were able to increase the diversity of anaerobic bacteria isolates. Heat shock treatment allowed to isolate a high percentage of new species (63.63 %), as well as isolation of species with high enzymatic activity (80.77 %), which would have potential industry application. Our findings contribute to the understanding of the role of anaerobic microbes regarding ecology, evolutionary, and biotechnological features essential to the Antarctic ecosystem.

  15. New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes.

    Science.gov (United States)

    Lee, Timmy; Misra, Sanjay

    2016-08-08

    Vascular access dysfunction remains a major cause of morbidity and mortality in hemodialysis patients. At present there are few effective therapies for this clinical problem. The poor understanding of the pathobiology that leads to arteriovenous fistula (AVF) and graft (AVG) dysfunction remains a critical barrier to development of novel and effective therapies. However, in recent years we have made substantial progress in our understanding of the mechanisms of vascular access dysfunction. This article presents recent advances and new insights into the pathobiology of AVF and AVG dysfunction and highlights potential therapeutic targets to improve vascular access outcomes. Copyright © 2016 by the American Society of Nephrology.

  16. Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses.

    Science.gov (United States)

    Work, Lorraine M; Büning, Hildegard; Hunt, Ela; Nicklin, Stuart A; Denby, Laura; Britton, Nicola; Leike, Kristen; Odenthal, Margarete; Drebber, Uta; Hallek, Michael; Baker, Andrew H

    2006-04-01

    Virus-mediated gene delivery is restricted by the infectivity profile of the chosen vector. Targeting the vascular endothelium via systemic delivery has been attempted using peptides isolated in vitro (using either phage or vector display) and implicit reliance on target receptor expression in vivo. This has limited application since endothelial cells in vitro and in vivo differ vastly in receptor profiles and because of the existence of complex endothelial "zip codes" in vivo. We therefore tested whether in vivo phage display combined with adeno-associated virus (AAV) capsid modifications would allow in vivo homing to the endothelium residing in defined organs. Extensive in vivo biopanning in rats identified four consensus peptides homing to the lung or brain. Each was incorporated into the VP3 region of the AAV-2 capsid to display the peptide at the virion surface. Peptides that conferred heparan independence were shown to retarget virus to the expected vascular bed in vivo in a preferential manner, determined 28 days post-systemic injection by both virion DNA and transgene expression profiling. Our findings significantly impact the design of viral vectors for targeting individual vascular beds in vivo.

  17. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

    Science.gov (United States)

    Little, Peter J; Ballinger, Mandy L; Osman, Narin

    2007-01-01

    Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors—hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis. PMID:17583182

  18. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  19. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis.

    Science.gov (United States)

    Little, Peter J; Ballinger, Mandy L; Osman, Narin

    2007-01-01

    Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors--hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.

  20. TREATMENT EFFECTS OF WST11 VASCULAR TARGETED PHOTODYNAMIC THERAPY IN UROTHELIAL CELL CARCINOMA AND FEASIBILITY, SAFETY, AND LONG TERM OUTCOMES IN THE UPPER URINARY TRACT OF SWINE

    Science.gov (United States)

    Murray, Katie S; Winter, Ashley G; Corradi, Renato Beluco; LaRosa, Stephen; Jebiwott, Sylvia; Somma, Alexander; Takaki, Haruyuki; Srimathveeravalli, Govindarajan; Lepherd, Michelle; Monette, Sebastien; Kim, Kwanghee; Scherz, Avigdor; Coleman, Jonathan A

    2016-01-01

    Purpose Surgical management of upper tract urothelial carcinoma requires removal of kidney and ureter, compromising renal function. Non-surgical alternatives have potentially prohibitive safety concerns. We examine the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular-targeted photodynamic therapy in a porcine model and report efficacy of WST11 vascular-targeted photodynamic therapy in a murine model. Materials and Methods Following approval, we performed 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4mg/kg) followed by laser illumination (10 minutes) was performed via percutaneous access or retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology was evaluated at several post-ablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours, 50 mW/cm laser fluence produced superficial necrosis of the ureter and deeper necrosis (penetrating the muscularis propria or adventitia) was produced by treatment with 200 mW/cm in the ureter and renal pelvis. At 4 weeks, superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis, or abnormality of lab testing was noted up to 4 weeks. In mice, 80% had no evidence of tumor at 19 days after WST11 vascular-targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular-targeted photodynamic therapy. Depth of WST11 vascular-targeted photodynamic therapy treatment effects can be modulated in a dose-dependent manner by titration of light intensity. Moreover, this treatment modality, applied to the porcine upper urinary tract, is feasible via antegrade and retrograde access. PMID:26860792

  1. Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment.

    Science.gov (United States)

    Schinzari, Francesca; Tesauro, Manfredi; Cardillo, Carmine

    2017-06-01

    The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

  2. Earlier saccades to task-relevant targets irrespective of relative gain between peripheral and foveal information.

    Science.gov (United States)

    Wolf, Christian; Schütz, Alexander C

    2017-06-01

    Saccades bring objects of interest onto the fovea for high-acuity processing. Saccades to rewarded targets show shorter latencies that correlate negatively with expected motivational value. Shorter latencies are also observed when the saccade target is relevant for a perceptual discrimination task. Here we tested whether saccade preparation is equally influenced by informational value as it is by motivational value. We defined informational value as the probability that information is task-relevant times the ratio between postsaccadic foveal and presaccadic peripheral discriminability. Using a gaze-contingent display, we independently manipulated peripheral and foveal discriminability of the saccade target. Latencies of saccades with perceptual task were reduced by 36 ms in general, but they were not modulated by the information saccades provide (Experiments 1 and 2). However, latencies showed a clear negative linear correlation with the probability that the target is task-relevant (Experiment 3). We replicated that the facilitation by a perceptual task is spatially specific and not due to generally heightened arousal (Experiment 4). Finally, the facilitation only emerged when the perceptual task is in the visual but not in the auditory modality (Experiment 5). Taken together, these results suggest that saccade latencies are not equally modulated by informational value as by motivational value. The facilitation by a perceptual task only arises when task-relevant visual information is foveated, irrespective of whether the foveation is useful or not.

  3. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

    Directory of Open Access Journals (Sweden)

    Peter J Little

    2007-03-01

    Full Text Available Peter J Little1, 2, 3, Mandy L. Ballinger1, Narin Osman1,31Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia; Monash University, Departments of 2Medicine and 3Immunology, Central and Eastern Clinical School, Alfred Hospital, Melbourne, AustraliaAbstract: Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors —hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL binding are the length and sulfation pattern on the glycosaminoglycan (GAG chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.Keywords: proteoglycans, signaling, lipoproteins, atherosclerosis

  4. MicroRNA-147b regulates vascular endothelial barrier function by targeting ADAM15 expression.

    Directory of Open Access Journals (Sweden)

    Victor Chatterjee

    Full Text Available A disintegrin and metalloproteinase15 (ADAM15 has been shown to be upregulated and mediate endothelial hyperpermeability during inflammation and sepsis. This molecule contains multiple functional domains with the ability to modulate diverse cellular processes including cell adhesion, extracellular matrix degradation, and ectodomain shedding of transmembrane proteins. These characteristics make ADAM15 an attractive therapeutic target in various diseases. The lack of pharmacological inhibitors specific to ADAM15 prompted our efforts to identify biological or molecular tools to alter its expression for further studying its function and therapeutic implications. The goal of this study was to determine if ADAM15-targeting microRNAs altered ADAM15-induced endothelial barrier dysfunction during septic challenge by bacterial lipopolysaccharide (LPS. An in silico analysis followed by luciferase reporter assay in human vascular endothelial cells identified miR-147b with the ability to target the 3' UTR of ADAM15. Transfection with a miR-147b mimic led to decreased total, as well as cell surface expression of ADAM15 in endothelial cells, while miR-147b antagomir produced an opposite effect. Functionally, LPS-induced endothelial barrier dysfunction, evidenced by a reduction in transendothelial electric resistance and increase in albumin flux across endothelial monolayers, was attenuated in cells treated with miR-147b mimics. In contrast, miR-147b antagomir exerted a permeability-increasing effect in vascular endothelial cells similar to that caused by LPS. Taken together, these data suggest the potential role of miR147b in regulating endothelial barrier function by targeting ADAM15 expression.

  5. Mosaic vectors comprised of modified AAV1 capsid proteins for efficient vector purification and targeting to vascular endothelial cells.

    Science.gov (United States)

    Stachler, M D; Bartlett, J S

    2006-06-01

    Vascular-targeted gene therapies have the potential to treat many of the leading causes of mortality in the western world. Unfortunately, these therapies have been ineffective due to poor vascular gene transfer. The use of alternative virus serotypes and the incorporation of vascular targeting ligands into vectors has resulted in only modest increases in vascular gene transfer. Adeno-associated virus (AAV) 1 has shown the most promise among the AAV vectors for the transduction of vascular endothelial cells. However, no straightforward small-scale purification strategy exists for AAV1 as it does for AAV2 making it difficult to quickly produce AAV1 vector for analysis. Here we have combined two AAV1 capsid protein modifications to enhance vascular gene transfer and allow easy purification of vector particles. Mosaic vector particles have been produced comprised of capsid proteins containing the well-characterized RGD4C modification to target integrins present on the vasculature, and capsid proteins containing a modification that permits metabolic biotinylation and efficient purification of mosaic particles by avidin affinity chromatography. We show that the RGD modification results in a 50-100-fold enhancement in endothelial cell gene transfer that is maintained in biotinylated mosaic AAV1 particles. These results suggest that mosaic virions hold significant promise for targeted gene delivery to the vasculature.

  6. Rac-1 as a new therapeutic target in cerebro- and cardio-vascular diseases.

    Science.gov (United States)

    Carrizzo, Albino; Forte, Maurizio; Lembo, Maria; Formisano, Luigi; Puca, Annibale A; Vecchione, Carmine

    2014-01-01

    Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in the development of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress in the vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases are a family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidase contains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, and the cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essential for the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvement of Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocyte hypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increased activation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction and heart failure. The Rac1/NADPH pathway has also been found involved in different pathologies of the cerebral district, such as ischemic stroke, cognitive impairment, subaracnoid hemorrhage and neuronal oxidative damage typical of several neurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovascular diseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodia formation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a new pharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficial pleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concern for the

  7. Replicated, replicable and relevant-target engagement and pharmacological experimentation in the 21st century.

    Science.gov (United States)

    Kenakin, Terry; Bylund, David B; Toews, Myron L; Mullane, Kevin; Winquist, Raymond J; Williams, Michael

    2014-01-01

    A pharmacological experiment is typically conducted to: i) test or expand a hypothesis regarding the potential role of a target in the mechanism(s) underlying a disease state using an existing drug or tool compound in normal and/or diseased tissue or animals; or ii) characterize and optimize a new chemical entity (NCE) targeted to modulate a specific disease-associated target to restore homeostasis as a potential drug candidate. Hypothesis testing necessitates an intellectually rigorous, null hypothesis approach that is distinct from a high throughput fishing expedition in search of a hypothesis. In conducting an experiment, the protocol should be transparently defined along with its powering, design, appropriate statistical analysis and consideration of the anticipated outcome (s) before it is initiated. Compound-target interactions often involve the direct study of phenotype(s) unique to the target at the cell, tissue or animal/human level. However, in vivo studies are often compromised by a lack of sufficient information on the compound pharmacokinetics necessary to ensure target engagement and also by the context-free analysis of ubiquitous cellular signaling pathways downstream from the target. The use of single tool compounds/drugs at one concentration in engineered cell lines frequently results in reductionistic data that have no physiologically relevance. This overview, focused on trends in the peer-reviewed literature, discusses the execution and reporting of experiments and the criteria recommended for the physiologically-relevant assessment of target engagement to identify viable new drug targets and facilitate the advancement of translational studies. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Multi-ligand nanoparticles for targeted drug delivery to the injured vascular wall

    Science.gov (United States)

    Kona, Soujanya

    Pathological conditions like coronary artery disease, acute myocardial infarction, stroke, and peripheral artery diseases as well as cardiovascular interventions used in the treatment of coronary artery diseases such as angioplasty and stenting damage/injure the blood vessel wall, leading to inflamed or activated endothelial cells that have been implicated in events leading to thrombosis, inflammation, and restenosis. Oral administration of anti-coagulant and anti-inflammatory drugs causes systemic toxicity, bleeding, patient incompliance, and inadequate amounts of drugs at the injured area. Though drug-eluting stents have shown therapeutic benefits, complications such as in-stent restenosis and late thrombosis still remain and are a cause for concern. Rapid growth in the field of nanotechnology and nanoscience in recent years has paved the way for new targeted and controlled drug delivery strategies. In this perspective, the development of biodegradable nanoparticles for targeted intracellular drug delivery to the inflamed endothelial cells may offer an improved avenue for treatment of cardiovascular diseases. The major objective of this research was to develop "novel multi-ligand nanoparticles," as drug carriers that can efficiently target and deliver therapeutic agents to the injured/inflamed vascular cells under dynamic flow conditions. Our approach mimics the natural binding ability of platelets to injured/activated endothelial cells through glycoprotein Ib (GPIb) bound to P-selectin expressed on inflamed endothelial cells and to the subendothelium through GPIb binding to von Willebrand factor (vWF) deposited onto the injured vascular wall. Our design also exploits the natural cell membrane translocation ability of the internalizing cell peptide - trans-activating transcriptor (TAT) to enhance the nanoparticle uptake by the targeted cells. Our hypothesis is that these multi-ligand nanoparticles would show an increased accumulation at the injury site since GPIb

  9. Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes.

    Science.gov (United States)

    Yamagishi, Sho-Ichi; Nakamura, Nobutaka; Suematsu, Mika; Kaseda, Kuniyoshi; Matsui, Takanori

    2015-10-27

    A nonenzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and subsequently alters their structural integrity and function. This process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent and senescent macroprotein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence indicating that interaction of AGEs with their receptor (RAGE) elicits oxidative stress generation and as a result evokes proliferative, inflammatory, thrombotic and fibrotic reactions in a variety of cells. This evidence supports AGEs' involvement in diabetes- and aging-associated disorders such as diabetic vascular complications, cancer, Alzheimer's disease and osteoporosis. Therefore, inhibition of AGE formation could be a novel molecular target for organ protection in diabetes. This report summarizes the pathophysiological role of AGEs in vascular complications in diabetes and discusses the potential clinical utility of measurement of serum levels of AGEs for evaluating organ damage in diabetes.

  10. Type I interferon is a therapeutic target for virus-induced lethal vascular damage.

    Science.gov (United States)

    Baccala, Roberto; Welch, Megan J; Gonzalez-Quintial, Rosana; Walsh, Kevin B; Teijaro, John R; Nguyen, Anthony; Ng, Cherie T; Sullivan, Brian M; Zarpellon, Alessandro; Ruggeri, Zaverio M; de la Torre, Juan Carlos; Theofilopoulos, Argyrios N; Oldstone, Michael B A

    2014-06-17

    The outcome of a viral infection reflects the balance between virus virulence and host susceptibility. The clone 13 (Cl13) variant of lymphocytic choriomeningitis virus--a prototype of Old World arenaviruses closely related to Lassa fever virus--elicits in C57BL/6 and BALB/c mice abundant negative immunoregulatory molecules, associated with T-cell exhaustion, negligible T-cell-mediated injury, and high virus titers that persist. Conversely, here we report that in NZB mice, despite the efficient induction of immunoregulatory molecules and high viremia, Cl13 generated a robust cytotoxic T-cell response, resulting in thrombocytopenia, pulmonary endothelial cell loss, vascular leakage, and death within 6-8 d. These pathogenic events required type I IFN (IFN-I) signaling on nonhematopoietic cells and were completely abrogated by IFN-I receptor blockade. Thus, IFN-I may play a prominent role in hemorrhagic fevers and other acute virus infections associated with severe vascular pathology, and targeting IFN-I or downstream effector molecules may be an effective therapeutic approach.

  11. Identification of relevant non-target organisms exposed to weevil-resistant Bt sweetpotato in Uganda.

    Science.gov (United States)

    Rukarwa, R J; Mukasa, S B; Odongo, B; Ssemakula, G; Ghislain, M

    2014-06-01

    Assessment of the impact of transgenic crops on non-target organisms (NTO) is a prerequisite to their release into the target environment for commercial use. Transgenic sweetpotato varieties expressing Cry proteins (Bt sweetpotato) are under development to provide effective protection against sweetpotato weevils (Coleoptera) which cause severe economic losses in sub-Saharan Africa. Like any other pest control technologies, genetically engineered crops expressing insecticidal proteins need to be evaluated to assess potential negative effects on non-target organisms that provide important services to the ecosystem. Beneficial arthropods in sweetpotato production systems can include pollinators, decomposers, and predators and parasitoids of the target insect pest(s). Non-target arthropod species commonly found in sweetpotato fields that are related taxonomically to the target pests were identified through expert consultation and literature review in Uganda where Bt sweetpotato is expected to be initially evaluated. Results indicate the presence of few relevant non-target Coleopterans that could be affected by Coleopteran Bt sweetpotato varieties: ground, rove and ladybird beetles. These insects are important predators in sweetpotato fields. Additionally, honeybee (hymenoptera) is the main pollinator of sweetpotato and used for honey production. Numerous studies have shown that honeybees are unaffected by the Cry proteins currently deployed which are homologous to those of the weevil-resistant Bt sweetpotato. However, because of their feeding behaviour, Bt sweetpotato represents an extremely low hazard due to negligible exposure. Hence, we conclude that there is good evidence from literature and expert opinion that relevant NTOs in sweetpotato fields are unlikely to be affected by the introduction of Bt sweetpotato in Uganda.

  12. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.

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    Sarah Garrido-Urbani

    Full Text Available Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

  13. Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors

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    Niederman, Thomas M. J.; Ghogawala, Zoher; Carter, Bob S.; Tompkins, Hillary S.; Russell, Margaret M.; Mulligan, Richard C.

    2002-05-01

    The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the chain of the T cell receptor. After transduction of primary murine CD8 lymphocytes by such vectors, the transduced cells were shown to possess an efficient killing specificity for cells expressing the VEGF receptor, Flk-1, as measured by in vitro cytotoxicity assays. After adoptive transfer into tumor-bearing mice, the genetically modified cytotoxic T lymphocytes strongly inhibited the growth of a variety of syngeneic murine tumors and human tumor xenografts. An increased effect on in vivo tumor growth inhibition was seen when this therapy was combined with the systemic administration of TNP-470, a conventional angiogenesis inhibitor. The utilization of the immune system to target angiogenic markers expressed on tumor vasculature may prove to be a powerful means for controlling tumor growth.

  14. Systemic coagulation parameters in mice after treatment with vascular targeting agents

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    Gottstein Claudia

    2005-12-01

    Full Text Available Abstract Background Vascular targeting of malignant tumors has become a clinically validated new treatment approach with clear patient benefit. However clinical studies have also revealed that some types of vascular targeting agents (VTAs are prone to coagulation system side effects. It is therefore essential to predetermine coagulation parameters in preclinical studies. As of to date, this has rarely been done, predominantly due to technical issues. The goal of this study was to establish and apply a standardized process, whereby systemic coagulation activation can be routinely measured in mice. Results We have evaluated a number of sampling techniques and coagulation tests regarding their suitability for this purpose. We were able to adapt two assays measuring soluble fibrin, a marker for a prethrombotic status. Thus, soluble fibrin could be measured for the first time in mice. All assays were validated in a positive control model for systemic coagulation activation, i.e. lipopolysaccharide-induced endotoxemia. Based on our results, we selected a panel of coagulation tests, which are both feasable and informative for preclinical testing of VTAs: soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell counts and platelet counts. The effect of tumor transplants on coagulation parameters was evaluated using this panel. We then applied this set of assays in treatment studies with a VTA developed in our laboratory to investigate a potential systemic coagulation activation. Conclusion We have established a standardized panel of assays that can be used to test murine blood samples for coagulation activation in preclinical studies. All tests are feasible to perform in any research laboratory without specialized equipment. In addition, this is the first report to measure soluble fibrin, an early marker of systemic coagulation activation, in mice. The panel was applied on tumor bearing mice and mice treated with a VTA

  15. Vascular endothelium as a target of beraprost sodium and fenofibrate for antiatherosclerotic therapy in type 2 diabetes mellitus

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    Michio Otsuki

    2005-10-01

    Full Text Available Michio Otsuki, Kayoko Goya, Soji KasayamaDepartment of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, JapanAbstract: Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor α activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule-1 (VCAM-1 concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.Keywords: vascular cell adhesion molecule-1, endothelial nitric oxide synthase, peroxisome proliferators-activated receptor α, berparost sodium, fenofibrate

  16. CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND ARTERIAL HYPERTENSION: VASCULAR WALL AS THE TARGET ORGAN IN COMORBID PATIENTS

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    N. A. Karoli

    2017-01-01

    Full Text Available Studies of endothelial dysfunction in patients with respiratory diseases have become relevant in recent years. Perhaps endothelial dysfunction and high arterial stiffness bind bronchopulmonary and cardiovascular diseases.Aim. To reveal features of disturbances of arterial wall vasoregulatory function in patients with chronic obstructive pulmonary disease (COPD in the presence and absence of arterial hypertension (HT.Material and methods. The study included 50 patients with COPD with normal blood pressure (BP and 85 patients with COPD and HT. Control group was presented by 20 practically healthy men comparable in age with COPD patients. Tests with reactive hyperemia (endothelium-dependent dilation and nitroglycerin (endothelium-independent dilation were performed in order to evaluate endothelium function. The number of desquamated endotheliocytes in the blood was determined.Results. In patients with COPD and HT in comparison with COPD patients without HT and healthy individuals more pronounced damages of the vascular wall, endothelium vasoregulatory function disturbances and a tendency to the reduction in endothelium-dependent vasodilation were determined both during COPD exacerbation and remission. These differences were most pronounced during the COPD exacerbation. In patients with COPD and HT in comparison with COPD patients without HT the damage of the vascular wall was more pronounced during the remission and endothelium-dependent dilatation disorder – during the exacerbation. The revealed disorders in patients with COPD and HT were associated with smoking status (r=0.61, p<0.01, severity of bronchial obstruction (r=-0.49, p<0.05, and hypoxemia (r=-0.76, p<0.01. We noted relationships between the parameters of 24-hour BP monitoring and remodeling of the brachial artery (r=0.34, p<0.05, endothelium lesion (r=0.25, p<0.05, and impairment of its vasoregulating function (r=-0.58, p<0.05. At that, the following parameters were important: the

  17. Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes.

    Science.gov (United States)

    Colussi, G; Catena, C; Novello, M; Bertin, N; Sechi, L A

    2017-03-01

    To overview the effects of omega-3 polyunsaturated fatty acids (PUFA) on blood vessels and blood pressure (BP) and their relevance for cardiovascular prevention. The importance of omega-3 PUFA for the cardiovascular system has come under the spotlight during the last decades. These fatty acids are present in variable amounts in cell membranes of mammal species, and their content affects a variety of cellular functions. Evidence obtained in animal and human studies suggests that omega-3 PUFA affect many steps of the atherosclerotic process. In blood vessels, omega-3 PUFA improve endothelial function; promote vasodilatation through relaxation of smooth muscle cells; exert antioxidant, anti-inflammatory, and antithrombotic actions; delay development of plaques and increase their stability; and decrease wall stiffening. Omega-3 PUFA might affect BP, and studies conducted with ambulatory monitoring suggest that supplementation with these fatty acids decreases the average 24-h BP levels. This effect on BP is related to the pretreatment membrane content of omega-3 PUFA, and this might explain some inconsistencies among intervention trials. Meta-analyses indicate that omega-3 PUFA have a mild but significant BP lowering effect. While encouraging results were initially obtained with the use of omega-3 PUFA supplements in secondary prevention trials, meta-analyses have not confirmed the ability of these fatty acids to decrease the risk of coronary heart and cerebrovascular disease. Omega-3 PUFA are associated with significant improvement in vascular function and lowering of BP. However, the evidence currently supporting the role of these fatty acids in cardiovascular prevention is weak and needs further investigation. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All

  18. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases.

    Science.gov (United States)

    Siller-Matula, Jolanta M; Krumphuber, Julia; Jilma, Bernd

    2010-02-01

    Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current 'gold standard' antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.

  19. Vascular CXCR4 expression - a novel antiangiogenic target in gastric cancer?

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    Barbara Ingold

    Full Text Available BACKGROUND: G-protein-coupled receptors (GPCRs are prime candidates for novel cancer prevention and treatment strategies. We searched for differentially expressed GPCRs in node positive gastric carcinomas. METHODOLOGY/PRINCIPAL FINDINGS: Differential expression of GPCRs in three node positive vs. three node negative intestinal type gastric carcinomas was analyzed by gene array technology. The candidate genes CXCL12 and its receptor CXCR4 were validated by real-time reverse-transcription polymerase chain reaction in an independent set of 37 gastric carcinomas. Translation was studied by immunohistochemistry in 347 gastric carcinomas using tissue microarrays as well as in 61 matching lymph node metastases. Protein expression was correlated with clinicopathological patient characteristics and survival. 52 GPCRs and GPCR-related genes were up- or down-regulated in node positive gastric cancer, including CXCL12. Differential expression of CXCL12 was confirmed by RT-PCR and correlated with local tumour growth. CXCL12 immunopositivity was negatively associated with distant metastases and tumour grade. Only 17% of gastric carcinomas showed CXCR4 immunopositive tumour cells, which was associated with higher local tumour extent. 29% of gastric carcinomas showed CXCR4 positive tumour microvessels. Vascular CXCR4 expression was significantly associated with higher local tumour extent as well as higher UICC-stages. When expressing both, CXCL12 in tumour cells and CXCR4 in tumour microvessels, these tumours also were highly significantly associated with higher T- and UICC-stages. Three lymph node metastases revealed vascular CXCR4 expression while tumour cells completely lacked CXCR4 in all cases. The expression of CXCL12 and CXCR4 had no impact on patient survival. CONCLUSIONS/SIGNIFICANCE: Our results substantiate the significance of GPCRs on the biology of gastric carcinomas and provide evidence that the CXCL12-CXCR4 pathway might be a novel promising

  20. A tyrosine kinase inhibitor-based high-affinity PET radiopharmaceutical targets vascular endothelial growth factor receptor.

    Science.gov (United States)

    Li, Feng; Jiang, Sheng; Zu, Youli; Lee, Daniel Y; Li, Zheng

    2014-09-01

    Tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR) have gained significant attention as pharmacologic targets. However, clinical evaluation of small-molecule drugs or biologics that target these pathways has so far yielded mixed results in a variety of solid tumors. The reasons for response variability remain unknown, including the temporal and spatial patterns of receptor tyrosine kinase expression. Methods to detect and quantify the presence of such cellular receptors would greatly facilitate drug development and therapy response assessment. We aimed to generate specific imaging agents as potential companion diagnostics that could also be used for targeted radionuclide therapy. Here, we report on the synthesis and initial preclinical performance of (64)Cu-labeled probes that were based on the kinase inhibitor already in clinical use, vandetanib (ZD6474), as a VEGFR-selective theranostic radiopharmaceutical. A monomeric (ZD-G1) and a dimeric (ZD-G2) derivative of ZD6474 were synthesized and conjugated with DOTA for chelation with (64)Cu to produce the probes (64)Cu-DOTA-ZD-G1 and (64)Cu-DOTA-ZD-G2. The binding affinity and specificity to VEGFR were measured using U-87 MG cells known to overexpress VEGFR. Small-animal PET and biodistribution studies were performed with (64)Cu-labeled probes (3-4 MBq) intravenously administered in U-87 MG tumor-bearing mice with or without coinjection of unlabeled ZD-G2 for up to 24 h after injection. Receptor-binding assays yielded a mean equilibrium dissociation constant of 44.7 and 0.45 nM for monomeric and dimeric forms, respectively, indicating a synergistic effect in VEGFR affinity by multivalency. Small-animal PET/CT imaging showed rapid tumor accumulation of (64)Cu-DOTA-ZD-G2, with excellent tumor-to-normal tissue contrast by 24 h. Coinjection of the (64)Cu-DOTA-ZD-G2 with 50 nmol (60 μg) of nonradioactive ZD-G2 effectively blocked tumor uptake. A (64)Cu-labeled probe derived from an

  1. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2.

    Science.gov (United States)

    Spratlin, Jennifer L; Cohen, Roger B; Eadens, Matthew; Gore, Lia; Camidge, D Ross; Diab, Sami; Leong, Stephen; O'Bryant, Cindy; Chow, Laura Q M; Serkova, Natalie J; Meropol, Neal J; Lewis, Nancy L; Chiorean, E Gabriela; Fox, Floyd; Youssoufian, Hagop; Rowinsky, Eric K; Eckhardt, S Gail

    2010-02-10

    PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

  2. ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells.

    Science.gov (United States)

    Singh, Neha; Joshi, Shrinidh; Guo, Lirong; Baker, Matthew B; Li, Yan; Castellano, Ronald K; Raizada, Mohan K; Jarajapu, Yagna P R

    2015-11-15

    CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings

  3. The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis

    Science.gov (United States)

    Ding, Yihong

    Targeting cytotoxic agents to tumor angiogenesis, instead of the tumor itself, is an attractive new approach in Radiation Oncology. Unlike tumor cells, endothelial cells are less likely to develop radio-resistance. Investigations have shown that radiation can cause a definite increase in cell permeability. Permeability changes in the tumor capillary endothelium can contribute to circulatory failure and serve as a site for clot formation. Therefore, radiation could initiate platelet aggregation and blood coagulation locally within the tumor vasculature, leading to tumor cell killing through depletion of oxygen and nutrients. In order to analyze the efficacy of a potential 90Y-labeled compound for vascular targeting radiotherapy and to evaluate the factors that may affect targets' absorbed dose, a tumor vasculature model including its angiogenesis process as a function of time and tumor growth are adopted and improved from the Liotta model. Its output is used to estimate targets' absorbed doses by Monte Carlo simulation. The results show that the effectiveness of vascular targeting therapy depends on the existence of available tumor endothelial cells and target expression. The alphavbeta3 antagonist model compound is less effective in the early stage tumors, which have very few vessels. Although a high administered dose, such as injecting of 2.1 mCi/kg to saturate all available binding sites, can destroy tumor endothelium network, the toxicity to bone marrow makes it impossible to inject such a dose. To a vascularized tumor, after giving one maximum allowable administered activity, 0.83 mCi/kg for the 90Y-labeled model compound, an average of 9.8%, 27.3%, 34.7% and 37.8% of endothelial cells would be killed when treatment starts at day 4, 7, 9 and 12 after tumor development, respectively. Therefore, recurrent treatment by vascular targeting therapy to well-vascularized tumor has the potential to slow down tumor growth or may even cause tumor regression at the primary

  4. Epigenetic targets of some toxicologically relevant metals: a review of the literature.

    Science.gov (United States)

    Cheng, Tsu-Fan; Choudhuri, Supratim; Muldoon-Jacobs, Kristi

    2012-09-01

    The term epigenetics was coined in the context of developmental studies, but the meaning of the term has evolved over time. Epigenetic modulators of gene expression are now known to include DNA methylation, chromatin modifications and noncoding RNAs. The observation that epigenetic changes can be transmitted transgenerationally makes the science of epigenetics very relevant to the field of environmental and molecular toxicology. Heavy metals constitute an important class of environmental contaminants that have been known to influence gene expression directly by binding various metal response elements in the target gene promoters. Recent research suggests that metals can also influence gene expression through epigenetic mechanisms; this adds a new twist to the complexity of metal-mediated gene expression. Here, we review recent studies that investigate the epigenetic, gene expression, and biological effects of various inorganic and organic forms of heavy metals, such as cadmium, arsenic, nickel, chromium, methylmercury, lead, copper and organotin compounds. Copyright © 2012 John Wiley & Sons, Ltd.

  5. Evaluation of Novel Antimouse VEGFR2 Antibodies as Potential Antiangiogenic or Vascular Targeting Agents for Tumor Therapy

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    Sophia Ran

    2003-07-01

    Full Text Available We generated a panel of eight rat IgG2a monoclonal antibodies with high affinity for mouse VEGFR2 (KDR/Flk-1, the main receptor that mediates the angiogenic effect of VEGF-A. The antibodies (termed RAFL, Rat Anti Flk bound to dividing endothelial cells more strongly than they did to nondividing cells. Most of the RAFL antibodies blocked [125I]VEGF165 binding to VEGFR2. Three of eight antibodies localized to VEGFR2-positive tumor endothelium after intravenous injection into mice bearing orthotopic MDA-MB-231 breast carcinomas, as judged by indirect immunohistochemistry. An average of 60% of vessels in the tumors was stained. The majority (50–80% of vessels were also stained in a variety of other human and murine tumors growing in mice. The antibodies did not bind detectably to the vascular endothelium in normal heart, lung, liver, and brain cortex, whereas the vascular endothelium in kidney glomerulus and pancreatic islets was stained. Treatment of mice bearing orthotopic MDA-MB-231 tumors with RAFL-1 antibody inhibited tumor growth by an average of 48% and reduced vascular density by 65%, compared to tumors in mice treated with control IgG. Vascular damage was not observed in normal organs, including kidneys and pancreas. These studies demonstrate that anti-VEGFR2 antibodies have potential for vascular targeting and imaging of tumors in vivo.

  6. Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function.

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    Jennifer M Kleinhenz

    Full Text Available Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE. Our results demonstrate that smPPARγOE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARγOE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis.

  7. Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

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    Sung Won Youn

    2015-05-01

    Full Text Available Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis.

  8. Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

    OpenAIRE

    Vorkapić, Emina

    2016-01-01

    Abdominal aortic aneurysm (AAA) is a degenerative weakening of the aortic wall, mainly affecting elderly men with a prevalence of 4.4-7.7 %. AAA is characterized by medial and adventitial inflammatory cell infiltration associated with vascular remodeling of the extracellular matrix proteins such as collagen and elastin and with phenotypic modulation and loss of vascular smooth muscle cells (VSMCs). Although much research has been performed, the precise cellular and molecular pathways behind t...

  9. Multifunctional polyurethane-urea nanoparticles to target and arrest inflamed vascular environment: a potential tool for cancer therapy and diagnosis.

    Science.gov (United States)

    Morral-Ruíz, G; Melgar-Lesmes, P; Solans, C; García-Celma, M J

    2013-10-28

    Activation of inflammatory pathways in endothelial cells contributes to tumour growth and progression in multiple human cancers. Cellular adhesion molecules are involved in leukocyte recruitment to the vascular inflammatory environment where it plays a critical role in angiogenesis, suppression of apoptosis, proliferation, invasion and metastasis. We describe here the development of streptavidin-coated polyurethane-urea nanoparticles as multifunctional nanocarriers for fluorescence imaging or targeting of the tumour environment to identify and arrest the vascular network irrigating the tumour tissue. The design of these multifunctional nanoparticles involves incorporating streptavidin to the nanoparticle polymeric matrix. The obtained nanoparticles are spherical and exhibit an average diameter of 70-74 nm. Streptavidin-coated nanoparticles spontaneously bind biotinylated antibodies against VCAM-1 and ICAM-1 which in vitro and in vivo specifically attached to inflamed endothelial cells. Indeed the incorporation of CBO-P11 (a specific inhibitor of the vascular endothelial growth factor proangiogenic and proinflammatory pathway) to these nanoparticles allows a targeted pharmacological effect thereby decreasing the proliferation only in inflamed endothelial cells. The multiple functionalisation strategy described here could be exploited for tumour diagnostics or targeted drug delivery to tumour vasculature with a good safety profile and an attractive array of possibilities for biomedical applications. © 2013.

  10. Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    El Kaffas, Ahmed; Sadeghi-Naini, Ali; Falou, Omar; Tran, William Tyler; Czarnota, Gregory J., E-mail: gregory.czarnota@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7 (Canada); Zhou, Stephanie; Fernandes, Jason; Giles, Anoja [Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Hashim, Amr [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada)

    2015-08-15

    Purpose: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Methods: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results: Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R{sup 2} of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Conclusions: Results from QUS

  11. Evaluation of hepatic vascular endothelial injury during liver storage by molecular detection and targeted contrast-enhanced ultrasound imaging.

    Science.gov (United States)

    Xie, Fang; Zhang, Shu-Hua; Cheng, Jia; Wang, Hong-Wei; Fei, Xiang; Jiao, Zi-Yu; Tang, Jie; Luo, Yu-Kun

    2016-01-01

    We hypothesized that lack of the high-energy phosphates during liver storage may potentially cause persistent injury to the vascular endothelium. Biopsies were obtained from livers obtained from beating heart human donors, stored either in the standard storage solution, that is, University of Wisconsin solution (UWS) or Celsior, and examined for various markers related to progressive endothelial injury. The expression of P2Y1 receptor, the major signal transduction machinery for adenosine triphosphate/adenosine diphosphate, decreased in hepatic vascular endothelial cells over time. Despite unaltered endothelial nitric oxide synthase (eNOS) levels, serine1177-phosphorylated eNOS, the active form of eNOS, progressively decreased with time. The production of nitric oxide enzyme decreased with time when liver tissues were examined in vitro. This also coincided with decreased interaction of eNOS with actin nucleating proteins like myristoylated alanine-rich C kinase substrate and Rac1, which plays a role in modulating the cytoskeleton and helps position eNOS in a favorable cytosolic position for active enzymatic activity. Conversely, the interaction of eNOS with caveolin1 was significantly increased 6 H after ex vivo storage. Finally, we demonstrated by targeted contrast-enhanced ultrasound that membrane-bound vascular cell adhesion molecule-1 in the hepatic vascular endothelial cell increased after 6 H of ex vivo storage. Overall, the results of this study provide evidence of a progressive hepatic vascular endothelial injury during the ex vivo storage. This may be a causative factor for ischemic cholangiopathy and delayed graft function post liver transplantation. © 2015 IUBMB Life, 68(1):51-57, 2015. © 2015 International Union of Biochemistry and Molecular Biology.

  12. An intensive nurse-led, multi-interventional clinic is more successful in achieving vascular risk reduction targets than standard diabetes care.

    LENUS (Irish Health Repository)

    MacMahon Tone, J

    2009-06-01

    The aim of this research was to determine whether an intensive, nurse-led clinic could achieve recommended vascular risk reduction targets in patients with type 2 diabetes as compared to standard diabetes management.

  13. Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

    Directory of Open Access Journals (Sweden)

    Keri S. Stewart

    2011-01-01

    Full Text Available Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM cell participation in vascular development have identified VEGF, SDF-1α, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway.

  14. Vascular Endothelial-Targeted Therapy Combined with Cytotoxic Chemotherapy Induces Inflammatory Intratumoral Infiltrates and Inhibits Tumor Relapses after Surgery

    Directory of Open Access Journals (Sweden)

    Brendan F. Judy

    2012-04-01

    Full Text Available Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS, cisplatin (cis, or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02. Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.

  15. Smart mechanosensing machineries enable migration of vascular smooth muscle cells in atherosclerosis-relevant 3D matrices.

    Science.gov (United States)

    Chi, Qingjia; Shan, Jieling; Ding, Xiaorong; Yin, Tieying; Wang, Yazhou; Jia, Dongyu; Wang, Guixue

    2017-06-01

    At the early stage of atherosclerosis, neointima is formed due to the migration of vascular smooth muscle cells (VSMCs) from the media to the intima. VSMCs are surrounded by highly adhesive 3D matrices. They take specific strategies to cross various 3D matrices in the media, including heterogeneous collagen and mechanically strong basement membrane. Migration of VSMCs is potentially caused by biomechanical mechanism. Most in vitro studies focus on cell migration on 2D substrates in response to biochemical factors. How the cells move through 3D matrices under the action of mechanosensing machineries remains unexplored. In this review, we propose that several interesting tension-dependent machineries act as "tractor"-posterior myosin II accumulation, and "wrecker"-anterior podosome maintaining, to power VSMCs ahead. VSMCs embedded in 3D matrices may accumulate a minor myosin II isoform, myosin IIB, at the cell rear. Anisotropic myosin IIB distribution creates cell rear, polarizes cell body, pushes the nucleus and reshapes the cell body, and cooperates with a uniformly distributed myosin IIA to propel the cell forward. On the other hand, matrix digestion by podosome further promote the migration when the matrix becomes denser. Actomyosin tension activates Src to induce podosome in soft 3D matrices and retain the podosome integrity to steadily digest the matrix. © 2017 International Federation for Cell Biology.

  16. Computational modeling of joint U.S.-Russian experiments relevant to magnetic compression/magnetized target fusion (MAGO/MTF)

    Energy Technology Data Exchange (ETDEWEB)

    Sheehey, P.T.; Faehl, R.J.; Kirkpatrick, R.C.; Lindemuth, I.R. [Los Alamos National Lab., NM (United States)

    1997-12-31

    Magnetized Target Fusion (MTF) experiments, in which a preheated and magnetized target plasma is hydrodynamically compressed to fusion conditions, present some challenging computational modeling problems. Recently, joint experiments relevant to MTF (Russian acronym MAGO, for Magnitnoye Obzhatiye, or magnetic compression) have been performed by Los Alamos National Laboratory and the All-Russian Scientific Research Institute of Experimental Physics (VNIIEF). Modeling of target plasmas must accurately predict plasma densities, temperatures, fields, and lifetime; dense plasma interactions with wall materials must be characterized. Modeling of magnetically driven imploding solid liners, for compression of target plasmas, must address issues such as Rayleigh-Taylor instability growth in the presence of material strength, and glide plane-liner interactions. Proposed experiments involving liner-on-plasma compressions to fusion conditions will require integrated target plasma and liner calculations. Detailed comparison of the modeling results with experiment will be presented.

  17. Change detection in urban and rural driving scenes: Effects of target type and safety relevance on change blindness.

    Science.gov (United States)

    Beanland, Vanessa; Filtness, Ashleigh J; Jeans, Rhiannon

    2017-03-01

    The ability to detect changes is crucial for safe driving. Previous research has demonstrated that drivers often experience change blindness, which refers to failed or delayed change detection. The current study explored how susceptibility to change blindness varies as a function of the driving environment, type of object changed, and safety relevance of the change. Twenty-six fully-licenced drivers completed a driving-related change detection task. Changes occurred to seven target objects (road signs, cars, motorcycles, traffic lights, pedestrians, animals, or roadside trees) across two environments (urban or rural). The contextual safety relevance of the change was systematically manipulated within each object category, ranging from high safety relevance (i.e., requiring a response by the driver) to low safety relevance (i.e., requiring no response). When viewing rural scenes, compared with urban scenes, participants were significantly faster and more accurate at detecting changes, and were less susceptible to "looked-but-failed-to-see" errors. Interestingly, safety relevance of the change differentially affected performance in urban and rural environments. In urban scenes, participants were more efficient at detecting changes with higher safety relevance, whereas in rural scenes the effect of safety relevance has marginal to no effect on change detection. Finally, even after accounting for safety relevance, change blindness varied significantly between target types. Overall the results suggest that drivers are less susceptible to change blindness for objects that are likely to change or move (e.g., traffic lights vs. road signs), and for moving objects that pose greater danger (e.g., wild animals vs. pedestrians). Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Sphingosine kinase 1 is a relevant molecular target in gastric cancer

    DEFF Research Database (Denmark)

    Fuereder, Thorsten; Hoeflmayer, Doris; Jaeger-Lansky, Agnes

    2011-01-01

    as a novel molecular target for gastric cancer by using an antisense oligonucleotide approach in vitro and in vivo. Gastric cancer cell lines (MKN28 and N87) were treated with Sphk1 with locked nucleic acid-antisense oligonucleotides (LNA-ASO). Sphk1 target regulation, cell growth, and apoptosis were...

  19. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    Science.gov (United States)

    2014-05-01

    in May 2013, the difference between nude mice (which lack T- cells , but still have a partially functional adaptive and innate immune system) and NSG...Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human...Targeting of Cerebral Breast Cancer Metastases Using a T- Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel

  20. Placental Nano-vesicles Target to Specific Organs and Modulate Vascular Tone In Vivo.

    Science.gov (United States)

    Tong, Mancy; Stanley, Joanna L; Chen, Q; James, Joanna L; Stone, Peter R; Chamley, Larry W

    2017-11-01

    How do nano-vesicles extruded from normal first trimester human placentae affect maternal vascular function? Placental nano-vesicles affect the ability of systemic mesenteric arteries to undergo endothelium- and nitric oxide- (NO-) dependent vasodilation in vivo in pregnant mice. Dramatic cardiovascular adaptations occur during human pregnancy, including a substantial decrease in total peripheral resistance in the first trimester. The human placenta constantly extrudes extracellular vesicles that can enter the maternal circulation and these vesicles may play an important role in feto-maternal communication. Human placental nano-vesicles were administered into CD1 mice via a tail vein and their localization and vascular effects at 30 min and 24 h post-injection were investigated. Nano-vesicles from normal first trimester human placentae were collected and administered into pregnant (D12.5) or non-pregnant female mice. After either 30 min or 24 h of exposure, all major organs were dissected for imaging (n = 7 at each time point) while uterine and mesenteric arteries were dissected for wire myography (n = 6 at each time point). Additional in vitro studies using HMEC-1 endothelial cells were also conducted to investigate the kinetics of interaction between placental nano-vesicles and endothelial cells. Nano-vesicles from first trimester human placentae localized to the lungs, liver and kidneys 24 h after injection into pregnant mice (n = 7). Exposure of pregnant mice to placental nano-vesicles for 30 min in vivo increased the vasodilatory response of mesenteric arteries to acetylcholine, while exposure for 24 h had the opposite effect (P nano-vesicles did not affect the function of uterine arteries or mesenteric arteries from non-pregnant mice. Placental nano-vesicles rapidly interacted with endothelial cells via a combination of phagocytosis, endocytosis and cell surface binding in vitro. N/A. As it is not ethical to administer labelled placental nano-vesicles to

  1. Relevance-Based Template Matching for Tracking Targets in FLIR Imagery

    Directory of Open Access Journals (Sweden)

    Gianluca Paravati

    2014-08-01

    Full Text Available One of the main challenges in automatic target tracking applications is represented by the need to maintain a low computational footprint, especially when dealing with real-time scenarios and the limited resources of embedded environments. In this context, significant results can be obtained by using forward-looking infrared sensors capable of providing distinctive features for targets of interest. In fact, due to their nature, forward-looking infrared (FLIR images lend themselves to being used with extremely small footprint techniques based on the extraction of target intensity profiles. This work proposes a method for increasing the computational efficiency of template-based target tracking algorithms. In particular, the speed of the algorithm is improved by using a dynamic threshold that narrows the number of computations, thus reducing both execution time and resources usage. The proposed approach has been tested on several datasets, and it has been compared to several target tracking techniques. Gathered results, both in terms of theoretical analysis and experimental data, showed that the proposed approach is able to achieve the same robustness of reference algorithms by reducing the number of operations needed and the processing time.

  2. Capture reactions at astrophysically relevant energies: extended gas target experiments and GEANT simulations

    CERN Document Server

    Kölle, V; Braitmayer, S E; Mohr, P J; Wilmes, S; Staudt, G; Hammer, J W; Jäger, M; Knee, H; Kunz, R; Mayer, A

    1999-01-01

    Several resonances of the capture reaction sup 2 sup 0 Ne(alpha, gamma) sup 2 sup 4 Mg were measured using an extended windowless gas target system. Detailed GEANT simulations were performed to derive the strength and the total width of the resonances from the measured yield curve. The crucial experimental parameters, which are mainly the density profile in the gas target and the efficiency of the gamma-ray detector, were analyzed by a comparison between the measured data and the corresponding simulation calculations. The excellent agreement between the experimental data and the simulations gives detailed insight into these parameters. (author)

  3. Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo.

    Science.gov (United States)

    Geoghegan, James C; Keiser, Nicholas W; Okulist, Anna; Martins, Inês; Wilson, Matthew S; Davidson, Beverly L

    2014-10-14

    Recently, we described a peptide-modified AAV2 vector (AAV-GMN) containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium.

  4. Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo

    Directory of Open Access Journals (Sweden)

    James C Geoghegan

    2014-01-01

    Full Text Available Recently, we described a peptide-modified AAV2 vector (AAV-GMN containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium.

  5. Effect of variation in hemorheology between human and animal blood on the binding efficacy of vascular-targeted carriers.

    Science.gov (United States)

    Namdee, K; Carrasco-Teja, M; Fish, M B; Charoenphol, P; Eniola-Adefeso, O

    2015-06-26

    Animal models are extensively used to evaluate the in vivo functionality of novel drug delivery systems (DDS). However, many variations likely exist in vivo between the animals and human physiological environment that significantly alter results obtained with animal models relative to human system. To date, it is not clear if the variation in hemorheology and hemodynamics between common animal and human models affect the functionality of DDS. This study investigates the role of hemorheology of humans and various animal models in dictating the binding efficiency of model vascular-targeted carriers (VTCs) to the wall in physiological blood flows. Specifically, the adhesion of sLe(A)-coated nano- and micro-spheres to inflamed endothelial cells monolayers were conducted via a parallel plate flow chamber assay with steady and disturbed red blood cells (RBCs)-in-buffer and whole blood flows of common animal models. Our results suggest that the ratio of carrier size to RBC size dictate particle binding in blood flow. Additionally, the presence of white blood cells affects the trend of particle adhesion depending on the animal species. Overall, this work sheds light on some deviation in VTC vascular wall interaction results obtained with in vivo animal experimentation from expected outcome and efficiency in vivo in human.

  6. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.

    Science.gov (United States)

    Schwabl, Philipp; Hambruch, Eva; Seeland, Berit A; Hayden, Hubert; Wagner, Michael; Garnys, Lukas; Strobel, Bastian; Schubert, Tim-Lukas; Riedl, Florian; Mitteregger, Dieter; Burnet, Michael; Starlinger, Patrick; Oberhuber, Georg; Deuschle, Ulrich; Rohr-Udilova, Nataliya; Podesser, Bruno K; Peck-Radosavljevic, Markus; Reiberger, Thomas; Kremoser, Claus; Trauner, Michael

    2017-04-01

    Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; pportal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. Copyright © 2016

  7. Risk factors for the development of clinical leprosy among contacts, and their relevance for targeted interventions

    NARCIS (Netherlands)

    Moet, F. J.; Meima, A.; Oskam, L.; Richardus, J. H.

    2004-01-01

    Existing knowledge on risk factors for the development of clinical leprosy among contacts of known leprosy patients is reviewed with the aim to identify factors associated with leprosy among contacts that have potential for developing effective targeted interventions in leprosy control. Different

  8. ICAM-1 targeted catalase encapsulated PLGA-b-PEG nanoparticles against vascular oxidative stress.

    Science.gov (United States)

    Sari, Ece; Tunc-Sarisozen, Yeliz; Mutlu, Hulya; Shahbazi, Reza; Ucar, Gulberk; Ulubayram, Kezban

    2015-01-01

    Targeted delivery of therapeutics is the favourable idea, whereas it is possible to distribute the therapeutically active drug molecule only to the site of action. For this purpose, in this study, catalase encapsulated poly(D,L-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles were developed and an endothelial target molecule (anti-ICAM-1) was conjugated to this carrier system in order to decrease the oxidative stress level in the target site. According to the enzymatic activity results, initial catalase activity of nanoparticles was increased from 27.39 U/mg to up to 45.66 U/mg by adding 5 mg/mL bovine serum albumin (BSA). After 4 h, initial catalase activity was preserved up to 46.98% while free catalase retained less than 4% of its activity in proteolytic environment. Furthermore, FITC labelled anti-ICAM-1 targeted catalase encapsulated nanoparticles (anti-ICAM-1/CatNPs) were rapidly taken up by cultured endothelial cells and concomitantly endothelial cells were resistant to H2O2 induced oxidative impairment.

  9. The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow.

    Science.gov (United States)

    Zhang, Yun-Peng; Huang, Yi-Tao; Huang, Tse-Shun; Pang, Wei; Zhu, Juan-Juan; Liu, Yue-Feng; Tang, Run-Ze; Zhao, Chuan-Rong; Yao, Wei-Juan; Li, Yi-Shuan; Chien, Shu; Zhou, Jing

    2017-11-08

    The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up-regulation both in vitro and in vivo. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease.

  10. Permanent occlusion of feeding arteries and draining veins in solid mouse tumors by vascular targeted photodynamic therapy (VTP with Tookad.

    Directory of Open Access Journals (Sweden)

    Noa Madar-Balakirski

    Full Text Available BACKGROUND: Antiangiogenic and anti-vascular therapies present intriguing alternatives to cancer therapy. However, despite promising preclinical results and significant delays in tumor progression, none have demonstrated long-term curative features to date. Here, we show that a single treatment session of Tookad-based vascular targeted photodynamic therapy (VTP promotes permanent arrest of tumor blood supply by rapid occlusion of the tumor feeding arteries (FA and draining veins (DV, leading to tumor necrosis and eradication within 24-48 h. METHODOLOGY/PRINCIPAL FINDINGS: A mouse earlobe MADB106 tumor model was subjected to Tookad-VTP and monitored by three complementary, non-invasive online imaging techniques: Fluorescent intravital microscopy, Dynamic Light Scattering Imaging and photosensitized MRI. Tookad-VTP led to prompt tumor FA vasodilatation (a mean volume increase of 70% with a transient increase (60% in blood-flow rate. Rapid vasoconstriction, simultaneous blood clotting, vessel permeabilization and a sharp decline in the flow rates then followed, culminating in FA occlusion at 63.2 sec+/-1.5SEM. This blockage was deemed irreversible after 10 minutes of VTP treatment. A decrease in DV blood flow was demonstrated, with a slight lag from FA response, accompanied by frequent changes in flow direction before reaching a complete standstill. In contrast, neighboring, healthy tissue vessels of similar sizes remained intact and functional after Tookad-VTP. CONCLUSION/SIGNIFICANCE: Tookad-VTP selectively targets the tumor feeding and draining vessels. To the best of our knowledge, this is the first mono-therapeutic modality that primarily aims at the larger tumor vessels and leads to high cure rates, both in the preclinical and clinical arenas.

  11. Targeted testing with diethylthiourea often reveals clinically relevant allergic contact dermatitis caused by neoprene rubber

    DEFF Research Database (Denmark)

    Dall, Anne B-H; Andersen, Klaus Ejner; Mortz, Charlotte G

    2012-01-01

    Background. Diethylthiourea is widely used in the rubber industry, particularly in neoprene rubber, and may cause allergic contact dermatitis. However, as thiourea allergens are not part of the European baseline series, the diagnosis of allergic contact dermatitis caused by thiourea compounds......, and positive reactions were found in 15% (13/88). Thus, 15% (37/239) had positive patch test reactions to diethylthiourea, all with current clinical relevance and all strong. Conclusion. Clinical suspicion of neoprene rubber allergy and subsequent aimed patch testing with diethylthiourea give a high yield...

  12. Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects.

    Science.gov (United States)

    Stimac, Monika; Dolinsek, Tanja; Lampreht, Ursa; Cemazar, Maja; Sersa, Gregor

    2015-01-01

    Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β) co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET) (TS plasmid), in comparison to the plasmid with constitutive promoter (CON plasmid), in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET) of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined.

  13. Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects.

    Directory of Open Access Journals (Sweden)

    Monika Stimac

    Full Text Available Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET (TS plasmid, in comparison to the plasmid with constitutive promoter (CON plasmid, in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined.

  14. Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity.

    Directory of Open Access Journals (Sweden)

    Irit Ben Aharon

    Full Text Available Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets' activity and interaction with endothelial cells (EC and to examine potential protectants to reduce DXR acute effect on the blood flow.The effect of DXR on platelet adhesion and aggregation were studied in vitro. For in vivo studies, mice were injected with either low molecular weight heparin (LMWH; Enoxaparin or with eptifibatide (Integrilin(© prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound.Platelet treatment with DXR did not affect platelet adhesion to a thrombogenic surface but significantly decreased ADP-induced platelet aggregation by up to 40% (p<0.001. However, there was a significant increase in GPIIbIIIa-mediated platelet adhesion to DXR-exposed endothelial cells (EC; 5.7-fold; p<0.001 reflecting the toxic effect of DXR on EC. The testicular arterial blood flow was preserved in mice pre-treated with LMWH or eptifibatide prior to DXR (P<0.01.DXR-induced acute vascular toxicity may involve increased platelet-EC adhesion leading to EC-bound microthrombi formation resulting in compromised blood flow. Anti-platelet/anti-coagulant agents are effective in reducing the detrimental effect of DXR on the vasculature and thus may serve as potential protectants to lessen this critical toxicity.

  15. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

    OpenAIRE

    Little, Peter J.; Mandy L Ballinger; Narin Osman

    2007-01-01

    Peter J Little1, 2, 3, Mandy L. Ballinger1, Narin Osman1,31Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia; Monash University, Departments of 2Medicine and 3Immunology, Central and Eastern Clinical School, Alfred Hospital, Melbourne, AustraliaAbstract: Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertens...

  16. Final Technical Report: Targeting DOE-Relevant Ions with Supramolecular Strategies, DE-SC0010555

    Energy Technology Data Exchange (ETDEWEB)

    Bowman-James, Kristin [Univ. of Kansas, Lawrence, KS (United States). Dept. of Chemistry

    2017-04-13

    The effectiveness of three popular supramolecular strategies to selectively target negatively charged ions (anions) was evaluated. Ions of interest included oxo anions, particularly sulfate, that hamper nuclear waste remediation. Three objectives were pursued using a simple building block strategies and by strategically placing anion-binding sites at appropriate positions on organic host molecules. The goal of the first objective was to assess the influence of secondary, tertiary and quaternized amines on binding tetrahedral anions using mixed amide/amine macrocyclic and urea/amine hosts containing aromatic or heteroaromatic spacers. Objective 2 focused on the design of ion pair hosts, using mixed macrocyclic anion hosts joined through polyether linkages. Objective 3 was to explore the synthesis of new metal-linked extended macrocyclic frameworks to leverage anion binding. Key findings were that smaller 24-membered macrocycles provided the most complementary binding for sulfate ion and mixed urea/amine chelates showed enhanced binding over amide corollaries in addition to being highly selective for SO42- in the presence of small quantities of water. In addition to obtaining prototype metal-linked macrocyclic anion hosts, a new dipincer ligand was designed that can be used to link macrocyclic or other supramolecular hosts in extended frameworks. When the tetraamide-based pincers are bound to two metal ions, an interesting phenomenon occurs. Upon deprotonation of the amides, two new protons appear between adjacent carbonyl pairs on the ligand, which may modify the chemistry, and metal-metal interactions in the complexes. Gel formation occurred for some of these extended hosts, and the physical properties are currently under investigation. The new tetracarboxamide-based pincers can also provide basic frameworks for double macrocycles capable of binding ion pairs as well as for binding metal ions and exploring intermetallic interactions through

  17. Cathepsin K-targeted sub-micron particles for regenerative repair of vascular elastic matrix.

    Science.gov (United States)

    Jennewine, Brenton; Fox, Jonathan; Ramamurthi, Anand

    2017-04-01

    Abdominal Aortic Aneurysms (AAA) involve slow dilation and weakening of the aortic wall due to breakdown of structural matrix components, such as elastic fibers by chronically overexpressed matrix metalloproteinases (MMPs), primarily, MMPs-2 and -9. Auto-regenerative repair of disrupted elastic fibers by smooth muscle cells (SMCs) at the AAA site is intrinsically poor and together with chronic proteolysis prevents restoration of elastin homeostasis, necessary to enable AAA growth arrest or regression to a healthy state. Oral doxycycline (DOX) therapy can inhibit MMPs to slow AAA growth, but has systemwide side-effects and inhibits new elastin deposition within AAA tissue, diminishing prospects for restoring elastin homeostasis preventing the arrest/regression of AAA growth. We have thus developed cationic amphiphile (DMAB)-modified submicron particles (SMPs) that uniquely exhibit pro-elastogenic and anti-proteolytic properties, separate from similar effects of the encapsulated drug. These SMPs can enable sustained, low dose DOX delivery within AAA tissue to augment elastin regenerative repair. To provide greater specificity of SMP targeting, we have conjugated the DOX-SMP surface with an antibody against cathepsin K, a lysosomal protease that is highly overexpressed within AAA tissue. We have determined conditions for efficient cathepsin K Ab conjugation onto the SMPs, improved SMP binding to aneurysmal SMCs in culture and to injured vessel walls ex vivo, conjugation did not affect DOX release from the SMPs, and improved pro-elastogenic and anti-proteolytic effects due to the SMPs likely due to their increased proximity to cells via binding. Our study results suggest that cathepsin K Ab conjugation is a useful targeting modality for our pro-regenerative SMPs. Future studies will investigate SMP retention and biodistribution following targeting to induced AAAs in rat models through intravenous or catheter-based aortal infusion and thereafter their efficacy for

  18. Development and Characterization of a Camelid Single Domain Antibody–Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2

    Directory of Open Access Journals (Sweden)

    Baomin Tian

    2017-08-01

    Full Text Available Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs. In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21 and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody–urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3 pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido-diethyleneglycol] ester (SM(PEG2, which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis

  19. ICAM-1-Targeted Liposomes Loaded with Liver X Receptor Agonists Suppress PDGF-Induced Proliferation of Vascular Smooth Muscle Cells

    Science.gov (United States)

    Huang, Xu; Xu, Meng-Qi; Zhang, Wei; Ma, Sai; Guo, Weisheng; Wang, Yabin; Zhang, Yan; Gou, Tiantian; Chen, Yundai; Liang, Xing-Jie; Cao, Feng

    2017-05-01

    The proliferation of vascular smooth muscle cells (VSMCs) is one of the key events during the progress of atherosclerosis. The activated liver X receptor (LXR) signalling pathway is demonstrated to inhibit platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation. Notably, following PDGF-BB stimulation, the expression of intercellular adhesion molecule-1 (ICAM-1) by VSMCs increases significantly. In this study, anti-ICAM-1 antibody-conjugated liposomes were fabricated for targeted delivery of a water-insoluble LXR agonist (T0901317) to inhibit VSMC proliferation. The liposomes were prepared by filming-rehydration method with uniform size distribution and considerable drug entrapment efficiency. The targeting effect of the anti-ICAM-T0901317 liposomes was evaluated by confocal laser scanning microscope (CLSM) and flow cytometry. Anti-ICAM-T0901317 liposomes showed significantly higher inhibition effect of VSMC proliferation than free T0901317 by CCk8 proliferation assays and BrdU staining. Western blot assay further confirmed that anti-ICAM-T0901317 liposomes inhibited retinoblastoma (Rb) phosphorylation and MCM6 expression. In conclusion, this study identified anti-ICAM-T0901317 liposomes as a promising nanotherapeutic approach to overcome VSMC proliferation during atherosclerosis progression.

  20. New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways.

    Science.gov (United States)

    Burris, Howard; Rocha-Lima, Caio

    2008-03-01

    In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti-HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.

  1. European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy.

    Science.gov (United States)

    Powles, Thomas; Staehler, Michael; Ljungberg, Börje; Bensalah, Karim; Canfield, Steven E; Dabestani, Saeed; Giles, Rachel H; Hofmann, Fabian; Hora, Milan; Kuczyk, Markus A; Lam, Thomas; Marconi, Lorenzo; Merseburger, Axel S; Volpe, Alessandro; Bex, Axel

    2016-11-01

    The European Association of Urology renal cancer guidelines panel recommends nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of vascular endothelial growth factor-targeted therapy. New data have recently become available showing a survival benefit for cabozantinib. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  2. European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy

    NARCIS (Netherlands)

    Powles, Thomas; Staehler, Michael; Ljungberg, Börje; Bensalah, Karim; Canfield, Steven E; Dabestani, Saeed; Giles, Rachel H; Hofmann, Fabian; Hora, Milan; Kuczyk, Markus A; Lam, Thomas; Marconi, Lorenzo; Merseburger, Axel S; Volpe, Alessandro; Bex, Axel

    2016-01-01

    The European Association of Urology renal cancer guidelines panel recommends nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of vascular endothelial growth factor-targeted therapy. New data have recently become available showing a survival

  3. European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy

    NARCIS (Netherlands)

    Powles, Thomas; Staehler, Michael; Ljungberg, Börje; Bensalah, Karim; Canfield, Steven E; Dabestani, Saeed; Giles, Rachel H; Hofmann, Fabian; Hora, Milan; Kuczyk, Markus A; Lam, Thomas; Marconi, Lorenzo; Merseburger, Axel S; Volpe, Alessandro; Bex, Axel

    The European Association of Urology renal cancer guidelines panel recommends nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of vascular endothelial growth factor-targeted therapy. New data have recently become available showing a survival

  4. Relevance of Target-Organ Lesions as Predictors of Mortality in Patients with Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Henrique Tria Bianco

    2014-10-01

    Full Text Available Background: Patients with diabetes are in extract higher risk for fatal cardiovascular events. Objective: To evaluate major predictors of mortality in subjects with type 2 diabetes. Methods: A cohort of 323 individuals with type 2 diabetes from several regions of Brazil was followed for a long period. Baseline electrocardiograms, clinical and laboratory data obtained were used to determine hazard ratios (HR and confidence interval (CI related to cardiovascular and total mortality. Results: After 9.2 years of follow-up (median, 33 subjects died (17 from cardiovascular causes. Cardiovascular mortality was associated with male gender; smoking; prior myocardial infarction; long QTc interval; left ventricular hypertrophy; and eGFR <60 mL/min. These factors, in addition to obesity, were predictors of total mortality. Cardiovascular mortality was adjusted for age and gender, but remained associated with: smoking (HR = 3.8; 95% CI 1.3-11.8; p = 0.019; prior myocardial infarction (HR = 8.5; 95% CI 1.8-39.9; p = 0.007; eGFR < 60 mL/min (HR = 9.5; 95% CI 2.7-33.7; p = 0.001; long QTc interval (HR = 5.1; 95% CI 1.7-15.2; p = 0.004; and left ventricular hypertrophy (HR = 3.5; 95% CI 1.3-9.7; p = 0.002. Total mortality was associated with obesity (HR = 2.3; 95% CI 1.1-5.1; p = 0.030; smoking (HR = 2.5; 95% CI 1.0-6.1; p = 0.046; prior myocardial infarction (HR = 3.1; 95% CI 1.4-6.1; p = 0.005, and long QTc interval (HR = 3.1; 95% CI 1.4-6.1; p = 0.017. Conclusions: Biomarkers of simple measurement, particularly those related to target-organ lesions, were predictors of mortality in subjects with type 2 diabetes.

  5. Relevance of Target-Organ Lesions as Predictors of Mortality in Patients with Diabetes Mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Bianco, Henrique Tria, E-mail: henriquetria@uol.com.br; Izar, Maria Cristina; Fonseca, Henrique Andrade; Póvoa, Rui Manuel [Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil); Saraiva, José Francisco [Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, SP (Brazil); Forti, Adriana [Centro de Diabetes e Hipertensão de Fortaleza, Fortaleza, CE (Brazil); Jardim, Paulo Cesar B. V. [Universidade Federal de Goiânia, Goiânia, GO (Brazil); Introcaso, Luis [Centro de Investigação Clínica de Brasília, Brasília, DF (Brazil); Yugar-Toledo, Juan [Escola de Medicina de São José do Rio Preto, São José do Rio Preto, SP (Brazil); Xavier, Hermes Tóros [Centro de Investigação Clínica de Santos, Santos, SP (Brazil); Universidade de São Paulo (USP), São Paulo, SP (Brazil); Faludi, André Arpad [Instituto Dante Pazzanese de Cardiologia, São Paulo, SP (Brazil); Fonseca, Francisco A. H. [Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil)

    2014-10-15

    Patients with diabetes are in extract higher risk for fatal cardiovascular events. To evaluate major predictors of mortality in subjects with type 2 diabetes. A cohort of 323 individuals with type 2 diabetes from several regions of Brazil was followed for a long period. Baseline electrocardiograms, clinical and laboratory data obtained were used to determine hazard ratios (HR) and confidence interval (CI) related to cardiovascular and total mortality. After 9.2 years of follow-up (median), 33 subjects died (17 from cardiovascular causes). Cardiovascular mortality was associated with male gender; smoking; prior myocardial infarction; long QTc interval; left ventricular hypertrophy; and eGFR <60 mL/min. These factors, in addition to obesity, were predictors of total mortality. Cardiovascular mortality was adjusted for age and gender, but remained associated with: smoking (HR = 3.8; 95% CI 1.3-11.8; p = 0.019); prior myocardial infarction (HR = 8.5; 95% CI 1.8-39.9; p = 0.007); eGFR < 60 mL/min (HR = 9.5; 95% CI 2.7-33.7; p = 0.001); long QTc interval (HR = 5.1; 95% CI 1.7-15.2; p = 0.004); and left ventricular hypertrophy (HR = 3.5; 95% CI 1.3-9.7; p = 0.002). Total mortality was associated with obesity (HR = 2.3; 95% CI 1.1-5.1; p = 0.030); smoking (HR = 2.5; 95% CI 1.0-6.1; p = 0.046); prior myocardial infarction (HR = 3.1; 95% CI 1.4-6.1; p = 0.005), and long QTc interval (HR = 3.1; 95% CI 1.4-6.1; p = 0.017). Biomarkers of simple measurement, particularly those related to target-organ lesions, were predictors of mortality in subjects with type 2 diabetes.

  6. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

    Directory of Open Access Journals (Sweden)

    M J Pont

    Full Text Available Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage-restricted expression as potential targets for immunotherapy of hematological cancers.

  7. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Directory of Open Access Journals (Sweden)

    Kalpna Gupta

    2013-02-01

    Full Text Available Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm3 grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve

  8. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Energy Technology Data Exchange (ETDEWEB)

    Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

    2013-02-18

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  9. Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain

    Science.gov (United States)

    Aryal, Muna

    The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8+/-0.5 microg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 microl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly

  10. Activity ranking of synthetic analogs targeting vascular endothelial growth factor receptor 2 by an integrated cell membrane chromatography system.

    Science.gov (United States)

    Wang, Dongyao; Lv, Diya; Chen, Xiaofei; Liu, Yue; Ding, Xuan; Jia, Dan; Chen, Langdong; Zhu, Zhenyu; Cao, Yan; Chai, Yifeng

    2015-12-01

    Evaluating the biological activities of small molecules represents an important part of the drug discovery process. Cell membrane chromatography (CMC) is a well-developed biological chromatographic technique. In this study, we have developed combined SMMC-7721/CMC and HepG2/CMC with high-performance liquid chromatography and time-of-flight mass spectrometry to establish an integrated screening platform. These systems was subsequently validated and used for evaluating the activity of quinazoline compounds, which were designed and synthesized to target vascular endothelial growth factor receptor 2. The inhibitory activities of these compounds towards this receptor were also tested using a classical caliper mobility shift assay. The results revealed a significant correlation between these two methods (R(2) = 0.9565 or 0.9420) for evaluating the activities of these compounds. Compared with traditional methods of evaluating the activities analogous compounds, this integrated cell membrane chromatography screening system took less time and was more cost effective, indicating that it could be used as a practical method in drug discovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. An effective technique for calibrating the intrinsic parameters of a vascular C-arm from a planar target

    Science.gov (United States)

    Gorges, Sébastien; Kerrien, Erwan; Berger, Marie-Odile; Trousset, Yves; Pescatore, Jérémie; Anxionnat, René; Picard, Luc

    2006-03-01

    The real time recovery of the projection geometry is a fundamental issue in interventional navigation applications (e.g. guide wire reconstruction, medical augmented reality). In most works, the intrinsic parameters are supposed to be constant and the extrinsic parameters (C-arm motion) are deduced either from the orientation sensors of the C-arm or from other additional sensors (eg. optical and/or electro-magnetic sensors). However, due to the weight of the X-ray tube and the C-arm, the system is undergoing deformations which induce variations of the intrinsic parameters as a function of the C-arm orientation. In our approach, we propose to measure the effects of the mechanical deformations onto the intrinsic parameters in a calibration procedure. Robust calibration methods exist (the gold standard is the multi-image calibration) but they are time consuming and too tedious to set up in a clinical context. For these reasons, we developed an original and easy to use method, based on a planar calibration target, which aims at measuring with a high level of accuracy the variation of the intrinsic parameters on a vascular C-arm. The precision of the planar-based method was evaluated by the mean of error propagation using techniques described in. 8 It appeared that the precision of the intrinsic parameters are comparable to the one obtained from the multi-image calibration method. The planar-based method was also successfully used to assess to behavior of the C-arm with respect to the C-arm orientations. Results showed a clear variation of the principal point when the LAO/RAO orientation was changed. In contrast, the intrinsic parameters do not change during a cranio-caudal C-arm motion.

  12. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Song, Sang Heon [Department of Internal Medicine, Pusan National University Hospital, Busan (Korea, Republic of); Shin, Hwa Kyoung [Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan (Korea, Republic of); Bae, Sun Sik, E-mail: sunsik@pusan.ac.kr [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of)

    2015-08-14

    Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs.

  13. RNAi targeting embryonic myosin heavy chain isoform inhibited bound thrombin-induced migration of vascular smooth muscle cells

    National Research Council Canada - National Science Library

    Sunagawa, Masanori; Shimada, Seiji; Nakamura, Mariko; Kosugi, Tadayoshi

    2009-01-01

    To investigate the effect of bound thrombin, a complex of alpha-thrombin with fibrin fragments derived from clots, on proliferation and migration of cultured rabbit vascular smooth muscle cells, cell...

  14. Vascular dementia.

    Science.gov (United States)

    O'Brien, John T; Thomas, Alan

    2015-10-24

    Vascular dementia is one of the most common causes of dementia after Alzheimer's disease, causing around 15% of cases. However, unlike Alzheimer's disease, there are no licensed treatments for vascular dementia. Progress in the specialty has been difficult because of uncertainties over disease classification and diagnostic criteria, controversy over the exact nature of the relation between cerebrovascular pathology and cognitive impairment, and the paucity of identifiable tractable treatment targets. Although there is an established relation between vascular and degenerative Alzheimer's pathology, the mechanistic link between the two has not yet been identified. This Series paper critiques some of the key areas and controversies, summarises treatment trials so far, and makes suggestions for what progress is needed to advance our understanding of pathogenesis and thus maximise opportunities for the search for new and effective management approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System.

    Science.gov (United States)

    Moreo, Antonella; Vallerio, Paola; Ricotta, Riccardo; Stucchi, Miriam; Pozzi, Mattia; Musca, Francesco; Meani, Paolo; Maloberti, Alessandro; Facchetti, Rita; Di Bella, Sara; Giganti, Maria Olga; Sartore-Bianchi, Andrea; Siena, Salvatore; Mancia, Giuseppe; Giannattasio, Cristina

    2016-02-01

    In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs. Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment. Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped. All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

    Directory of Open Access Journals (Sweden)

    Mitesh J Borad

    2014-02-01

    Full Text Available Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM. In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

  17. Causes of failure to achieve the low density lipoprotein cholesterol therapeutic target in patients with high and very high vascular risk controlled in Lipid and Vascular Risk Units. EROMOT study.

    Science.gov (United States)

    Morales, Clotilde; Plana, Núria; Arnau, Anna; Matas, Laia; Mauri, Marta; Vila, Àlex; Vila, Lluís; Soler, Cristina; Montesinos, Jesús; Masana, Lluís; Pedro-Botet, Juan

    2017-09-12

    Determination of the level of achievement of the low density lipoprotein cholesterol (LDL-C) therapeutic target in patients with high and very high vascular risk treated in Lipid Units, as well as the causes of non-achievement. Multicentre retrospective observational study that included patients over 18 years with high and very high vascular risk, according to the criteria of the 2012 European Guidelines on Cardiovascular Disease Prevention, referred consecutively to Lipid Units between January and June 2012 and with follow-up two years after the first visit. The study included a total of 243 patients from 16 lipid units. The mean age was 52.2 years (SD 13.7), of whom 62.6% were males, and 40.3% of them were very high risk. At the first visit, 86.8% (25.1% in combination) and 95.0% (47.3% in combination) in the second visit (P<.001) were treated with lipid-lowering treatment. The therapeutic target was achieved by 28% (95 CI: 22.4-34.1). As regards the causes of non-achievement, 24.6% were related to the medication (10.3% maximum tolerated dose and 10.9% due to the appearance of adverse effects), 43.4% due to the physician (19.4% by inertia, 13.7% considering that target already reached), and 46.9% due to the patient, highlighting the therapeutic non-compliance (31,4%). LDL-C targets were achieved in about one-third of patients. The low adherence of the patient, followed by medical inertia are the most frequent causes that can explain these results. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Vascular targeting to the SST2 receptor improves the therapeutic response to near-IR two-photon activated PDT for deep-tissue cancer treatment.

    Science.gov (United States)

    Starkey, Jean R; Pascucci, Elizabeth M; Drobizhev, Mikhail A; Elliott, Aleisha; Rebane, Aleksander K

    2013-10-01

    Broader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo-activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment. Human tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting. Tumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~120fs to ~3ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors. The use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. PLS-based and regularization-based methods for the selection of relevant variables in non-targeted metabolomics data

    Directory of Open Access Journals (Sweden)

    Renata Bujak

    2016-07-01

    Full Text Available Non-targeted metabolomics constitutes a part of systems biology and aims to determine many metabolites in complex biological samples. Datasets obtained in non-targeted metabolomics studies are multivariate and high-dimensional due to the sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA without and with multiple testing correction as well as least absolute shrinkage and selection operator (LASSO were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction, selected 46 and 218 variables based on VIP criteria using Pareto and UV scaling, respectively. In the case of the PH study, 217 and 320 variables were selected based on VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built with multiple testing correction, selected 4 and 19 variables as statistically significant in terms of Pareto and UV scaling, respectively. For PH study, 14 and 18 variables were selected based on VIP criteria in terms of Pareto and UV scaling, respectively. Additionally, the concept and fundaments of the least absolute shrinkage and selection operator (LASSO with bootstrap procedure evaluating reproducibility of results, was demonstrated. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3% and 100%. However, apart from the popularity of PLS-DA and OPLS-DA methods in metabolomics, it should be highlighted that they do not control type I or type II error, but only arbitrarily establish a cut-off value for PLS-DA loadings

  20. VASCULAR DEMENTIA

    Directory of Open Access Journals (Sweden)

    Maria Alekseyevna Cherdak

    2010-01-01

    vascular cognitive disorders and vascular dementia (VD. The heterogeneity of vascular cognitive disorders, concurrence of vascular and neurodegenerative diseases are discussed. Data from studies of specific therapy for VD are given.

  1. Trimer hydroxylated quinone (IIIHyQ) derived from apocynin targets cysteine residues of p47phox preventing the activation of human vascular NADPH oxidase

    OpenAIRE

    Mora-Pale, Mauricio; Joon-Kwon, Seok; Linhardt, Robert J.; Dordick, Jonathan S.

    2011-01-01

    Enzymatic derived oligophenols from apocynin can be effective inhibitors of human vascular NADPH oxidase. An isolated IIIHyQ has been shown to inhibit endothelial NADPH oxidase with an IC50 ~30 nM. In vitro studies demonstrated that IIIHyQ is capable on disrupting the interaction between p47phox and p22phox, thereby blocking the activation of the Nox2 isoform. Herein, we report the role of key cysteine residues in p47phox as targets for the IIIHyQ. Incubation of p47phox with IIIHyQ results in...

  2. Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

    Directory of Open Access Journals (Sweden)

    Craig B Bennett

    Full Text Available BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1 to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34 and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1. Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII carboxy terminal domain (P-CTD, phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1

  3. MicroRNA-199b Modulates Vascular Cell Fate During iPS Cell Differentiation by Targeting the Notch Ligand Jagged1 and Enhancing VEGF Signaling.

    Science.gov (United States)

    Chen, Ting; Margariti, Andriana; Kelaini, Sophia; Cochrane, Amy; Guha, Shaunta T; Hu, Yanhua; Stitt, Alan W; Zhang, Li; Xu, Qingbo

    2015-05-01

    Recent ability to derive endothelial cells (ECs) from induced pluripotent stem (iPS) cells holds a great therapeutic potential for personalized medicine and stem cell therapy. We aimed that better understanding of the complex molecular signals that are evoked during iPS cell differentiation toward ECs may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration. In this study, we have generated mouse iPS cells from fibroblasts using established protocol. When iPS cells were cultivated on type IV mouse collagen-coated dishes in differentiation medium, cell differentiation toward vascular lineages were observed. To study the molecular mechanisms of iPS cell differentiation, we found that miR-199b is involved in EC differentiation. A step-wise increase in expression of miR-199 was detected during EC differentiation. Notably, miR-199b targeted the Notch ligand JAG1, resulting in vascular endothelial growth factor (VEGF) transcriptional activation and secretion through the transcription factor STAT3. Upon shRNA-mediated knockdown of the Notch ligand JAG1, the regulatory effect of miR-199b was ablated and there was robust induction of STAT3 and VEGF during EC differentiation. Knockdown of JAG1 also inhibited miR-199b-mediated inhibition of iPS cell differentiation toward smooth muscle markers. Using the in vitro tube formation assay and implanted Matrigel plugs, in vivo, miR-199b also regulated VEGF expression and angiogenesis. This study indicates a novel role for miR-199b as a regulator of the phenotypic switch during vascular cell differentiation derived from iPS cells by regulating critical signaling angiogenic responses. Stem Cells 2015;33:1405-1418. © 2015 AlphaMed Press.

  4. A PEGylated platelet free plasma hydrogel based composite scaffold enables stable vascularization and targeted cell delivery for volumetric muscle loss.

    Science.gov (United States)

    Aurora, Amit; Wrice, Nicole; Walters, Thomas J; Christy, Robert J; Natesan, Shanmugasundaram

    2018-01-01

    Extracellular matrix (ECM) scaffolds are being used for the clinical repair of soft tissue injuries. Although improved functional outcomes have been reported, ECM scaffolds show limited tissue specific remodeling response with concomitant deposition of fibrotic tissue. One plausible explanation is the regression of blood vessels which may be limiting the diffusion of oxygen and nutrients across the scaffold. Herein we develop a composite scaffold as a vasculo-inductive platform by integrating PEGylated platelet free plasma (PFP) hydrogel with a muscle derived ECM scaffold (m-ECM). In vitro, adipose derived stem cells (ASCs) seeded onto the composite scaffold differentiated into two distinct morphologies, a tubular network in the hydrogel, and elongated structures along the m-ECM scaffold. The composite scaffold showed a high expression of ITGA5, ITGB1, and FN and a synergistic up-regulation of ang1 and tie-2 transcripts. The in vitro ability of the composite scaffold to provide extracellular milieu for cell adhesion and molecular cues to support vessel formation was investigated in a rodent volumetric muscle loss (VML) model. The composite scaffold delivered with ASCs supported robust and stable vascularization. Additionally, the composite scaffold supported increased localization of ASCs in the defect demonstrating its ability for localized cell delivery. Interestingly, ASCs were observed homing in the injured muscle and around the perivascular space possibly to stabilize the host vasculature. In conclusion, the composite scaffold delivered with ASCs presents a promising approach for scaffold vascularization. The versatile nature of the composite scaffold also makes it easily adaptable for the repair of soft tissue injuries. Decellularized extracellular matrix (ECM) scaffolds when used for soft tissue repair is often accompanied by deposition of fibrotic tissue possibly due to limited scaffold vascularization, which limits the diffusion of oxygen and nutrients

  5. Therapeutic Vascular Targeting and Irradiation: Correlation of MRI Tissue Changes at Cellular and Molecular Levels to Optimizing Outcome

    Science.gov (United States)

    2008-06-01

    cylindrical copper tube about 2 cm deep and acting as a single-turn solenoid ), is placed around the tumor-bearing pedicle. Shimming is performed on the...number of perfused vessels was evident at 2 h (21 6/mm2 vs. 145 23/mm2 pre-CA4P, p 0.01), followed by recovered per- fusion at 24 h (114 19/mm2...Horsman MR, et al. Acute effects of vascular modifying agents in solid tumors assessed by nonin- vasive laser Doppler flowmetry and near infrared

  6. Receptor-Mediated Melanoma Targeting with Radiolabeled α-Melanocyte-Stimulating Hormone: Relevance of the Net Charge of the Ligand

    Directory of Open Access Journals (Sweden)

    Alex N. Eberle

    2017-04-01

    of peptides with an overall net charge between +2 and −2, we now demonstrate that a net charge of −1, with the extra negative charges preferably placed in the N-terminal region, has led to the lowest kidney uptake and retention. Charges of +2 or −2 markedly increased kidney uptake and retention. In conclusion, the novel DOTA-Phospho-MSH2-9 may represent a new lead compound for negatively charged linear MC1R ligands that can be further developed into a clinically relevant melanoma targeting radiopeptide.

  7. Bioprinting for vascular and vascularized tissue biofabrication.

    Science.gov (United States)

    Datta, Pallab; Ayan, Bugra; Ozbolat, Ibrahim T

    2017-03-15

    Bioprinting is a promising technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision. Bioprinting enables the deposition of various biologics including growth factors, cells, genes, neo-tissues and extra-cellular matrix-like hydrogels. Benefits of bioprinting have started to make a mark in the fields of tissue engineering, regenerative medicine and pharmaceutics. Specifically, in the field of tissue engineering, the creation of vascularized tissue constructs has remained a principal challenge till date. However, given the myriad advantages over other biofabrication methods, it becomes organic to expect that bioprinting can provide a viable solution for the vascularization problem, and facilitate the clinical translation of tissue engineered constructs. This article provides a comprehensive account of bioprinting of vascular and vascularized tissue constructs. The review is structured as introducing the scope of bioprinting in tissue engineering applications, key vascular anatomical features and then a thorough coverage of 3D bioprinting using extrusion-, droplet- and laser-based bioprinting for fabrication of vascular tissue constructs. The review then provides the reader with the use of bioprinting for obtaining thick vascularized tissues using sacrificial bioink materials. Current challenges are discussed, a comparative evaluation of different bioprinting modalities is presented and future prospects are provided to the reader. Biofabrication of living tissues and organs at the clinically-relevant volumes vitally depends on the integration of vascular network. Despite the great progress in traditional biofabrication approaches, building perfusable hierarchical vascular network is a major challenge. Bioprinting is an emerging technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision

  8. Uncertainties in target volume delineation in radiotherapy – are they relevant and what can we do about them?

    Directory of Open Access Journals (Sweden)

    Segedin Barbara

    2016-09-01

    Full Text Available Modern radiotherapy techniques enable delivery of high doses to the target volume without escalating dose to organs at risk, offering the possibility of better local control while preserving good quality of life. Uncertainties in target volume delineation have been demonstrated for most tumour sites, and various studies indicate that inconsistencies in target volume delineation may be larger than errors in all other steps of the treatment planning and delivery process. The aim of this paper is to summarize the degree of delineation uncertainties for different tumour sites reported in the literature and review the effect of strategies to minimize them.

  9. Cardio-ankle vascular index is associated with cardiovascular target organ damage and vascular structure and function in patients with diabetes or metabolic syndrome, LOD-DIABETES study: a case series report.

    Science.gov (United States)

    Gómez-Marcos, Manuel Ángel; Recio-Rodríguez, José Ignacio; Patino-Alonso, María Carmen; Agudo-Conde, Cristina; Gómez-Sánchez, Leticia; Gomez-Sanchez, Marta; Rodríguez-Sanchez, Emiliano; Maderuelo-Fernandez, Jose Angel; García-Ortiz, Luís

    2015-01-16

    The cardio ankle vascular index (CAVI) is a new index of the overall stiffness of the artery from the origin of the aorta to the ankle. This index can estimate the risk of atherosclerosis. We aimed to find the relationship between CAVI and target organ damage (TOD), vascular structure and function, and cardiovascular risk factors in Caucasian patients with type 2 diabetes mellitus or metabolic syndrome. We included 110 subjects from the LOD-Diabetes study, whose mean age was 61 ± 11 years, and 37.3% were women. Measurements of CAVI, brachial ankle pulse wave velocity (ba-PWV), and ankle brachial index (ABI) were taken using the VaSera device. Cardiovascular risk factors, renal function by creatinine, glomerular filtration rate, and albumin creatinine index were also obtained, as well as cardiac TOD with ECG and vascular TOD and carotid intima media thickness (IMT), carotid femoral PWV (cf-PWV), and the central and peripheral augmentation index (CAIx and PAIx). The Framingham-D'Agostino scale was used to measure cardiovascular risk. Mean CAVI was 8.7 ± 1.3. More than half (54%) of the participants showed one or more TOD (10% cardiac, 13% renal; 48% vascular), and 13% had ba-PWV ≥ 17.5 m/s. Patients with any TOD had the highest CAVI values: 1.15 (CI 95% 0.70 to 1.61, p < 0.001) and 1.14 (CI 95% 0.68 to 1.60, p < 0.001) when vascular TOD was presented, and 1.30 (CI 95% 0.51 to 2.10, p = 0.002) for the cardiac TOD. The CAVI values had a positive correlation with HbA1c and systolic and diastolic blood pressure, and a negative correlation with waist circumference and body mass index. The positive correlations of CAVI with IMT (β = 0.29; p < 0.01), cf-PWV (β = 0.83; p < 0.01), ba-PWV (β = 2.12; p < 0.01), CAIx (β = 3.42; p < 0.01), and PAIx (β = 5.05; p = 0.04) remained after adjustment for cardiovascular risk, body mass index, and antihypertensive, lipid-lowering, and antidiabetic drugs. The

  10. Pulse pressure and nocturnal fall in blood pressure are predictors of vascular, cardiac and renal target organ damage in hypertensive patients (LOD-RISK study).

    Science.gov (United States)

    García-Ortiz, Luis; Gómez-Marcos, Manuel A; Martín-Moreiras, Javier; González-Elena, Luis J; Recio-Rodriguez, Jose I; Castaño-Sánchez, Yolanda; Grandes, Gonzalo; Martínez-Salgado, Carlos

    2009-08-01

    To analyse the relationship between various parameters derived from ambulatory blood pressure monitoring (ABPM) and vascular, cardiac and renal target organ damage. A cross-sectional, descriptive study. It included 353 patients with short-term or recently diagnosed hypertension. ABPM, carotid intima-media thickness (IMT), Cornell voltage-duration product (Cornell VDP), glomerular filtration rate and albumin/creatinine ratio to assess vascular, cardiac and renal damage. Two hundred and twenty-three patients (63.2%) were males, aged 56.12+/-11.21 years. The nocturnal fall in blood pressure was 11.33+/-8.41, with a dipper pattern in 49.0% (173), nondipper in 30.3% (107), extreme dipper in 12.7% (45) and riser in 7.9% (28). The IMT was lower in the extreme dipper (0.716+/-0.096 mm) and better in the riser pattern (0.794+/-0.122 mm) (P<0.05). The Cornell VDP and albumin/creatinine ratio were higher in the riser pattern (1818.94+/-1798.63 mm/ms and 140.78+/-366.38 mg/g, respectively) than in the other patterns. In the multivariate analysis after adjusting for age, sex and antihypertensive treatment, with IMT as dependent variable the 24-h pulse pressure (beta = 0.003), with Cornell VDP the rest pulse pressure (beta = 12.04), and with the albumin/creatinine ratio the percentage of nocturnal fall in systolic blood pressure (beta = -3.59), the rest heart rate (beta = 1.83) and the standard deviation of 24-h systolic blood pressure (beta = 5.30) remain within the equation. The estimated pulse pressure with ABPM is a predictor of vascular and cardiac organ damage. The nocturnal fall and the standard deviation in 24-h systolic blood pressure measured with the ABPM is a predictor of renal damage.

  11. Anti-Cancer Activity of an Osthole Derivative, NBM-T-BMX-OS01: Targeting Vascular Endothelial Growth Factor Receptor Signaling and Angiogenesis

    Science.gov (United States)

    Chiu, Pei-Ting; Ho, Shiau-Jing; Wang, Chi-Han; Chi, Chih-Chin; Huang, Yu-Han; Lee, Cheng-Feng; Li, Ying-Shiuan; Ou, George; Hsu, Ming-Jen

    2013-01-01

    Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID:24312323

  12. Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Hung-Yu Yang

    Full Text Available Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX, derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L. Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs. BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

  13. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1).

    Science.gov (United States)

    Schwartz, Jonathan D; Rowinsky, Eric K; Youssoufian, Hagop; Pytowski, Bronislaw; Wu, Yan

    2010-02-15

    The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG(1) antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. (c) 2010 American Cancer Society.

  14. Relevance of compartmentalization of T-cell subsets for clinical improvement in psoriasis: effect of immune-targeted antipsoriatic therapies.

    NARCIS (Netherlands)

    Lingen, R.G. van; Korver, J.E.M.; Kerkhof, P.C.M. van de; Berends, M.A.M.; Rens, D.W.A. van; Langewouters, A.M.G.; Boezeman, J.B.M.; Seyger, M.M.B.; Jong, E.M.G.J. de

    2008-01-01

    BACKGROUND: Therapies targeting the T cell-mediated pathology of psoriasis have been found to achieve remarkable clinical improvement and have confirmed the crucial role of the immune system either in peripheral blood (PB) or in skin. No analyses of T-cell counts in both compartments have been

  15. METACASPASE9 modulates autophagy to confine cell death to the target cells during Arabidopsis vascular xylem differentiation

    Directory of Open Access Journals (Sweden)

    Sacha Escamez

    2016-02-01

    Full Text Available We uncovered that the level of autophagy in plant cells undergoing programmed cell death determines the fate of the surrounding cells. Our approach consisted of using Arabidopsis thaliana cell cultures capable of differentiating into two different cell types: vascular tracheary elements (TEs that undergo programmed cell death (PCD and protoplast autolysis, and parenchymatic non-TEs that remain alive. The TE cell type displayed higher levels of autophagy when expression of the TE-specific METACASPASE9 (MC9 was reduced using RNAi (MC9-RNAi. Misregulation of autophagy in the MC9-RNAi TEs coincided with ectopic death of the non-TEs, implying the existence of an autophagy-dependent intercellular signalling from within the TEs towards the non-TEs. Viability of the non-TEs was restored when AUTOPHAGY2 (ATG2 was downregulated specifically in MC9-RNAi TEs, demonstrating the importance of autophagy in the spatial confinement of cell death. Our results suggest that other eukaryotic cells undergoing PCD might also need to tightly regulate their level of autophagy to avoid detrimental consequences for the surrounding cells.

  16. MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jie, E-mail: wj2170@qq.com [Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Yan, Cheng-Hui, E-mail: yanch1029@163.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Li, Yang, E-mail: liyang19830925@126.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Xu, Kai, E-mail: xukai2001@gmail.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Tian, Xiao-Xiang, E-mail: tian_xx@163.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Peng, Cheng-Fei, E-mail: pengchengfei2000@126.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Tao, Jie, E-mail: taojie1976@163.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Sun, Ming-Yu, E-mail: sunmingyu1976@126.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China); Han, Ya-Ling, E-mail: yalinghan@gmail.com [Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China)

    2013-05-01

    Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. The cellular repressor of E1A-stimulated genes (CREG) has been shown to play an important role in phenotypic modulation of VSMCs. However, the mechanism regulating CREG upstream signaling remains unclear. MicroRNAs (miRNAs) have recently been found to play a critical role in cell differentiation via target-gene regulation. This study aimed to identify a miRNA that binds directly to CREG, and may thus be involved in CREG-mediated VSMC phenotypic modulation. Computational analysis indicated that miR-31 bound to the CREG mRNA 3′ untranslated region (3′-UTR). miR-31 was upregulated in quiescent differentiated VSMCs and downregulated in proliferative cells stimulated by platelet-derived growth factor and serum starvation, demonstrating a negative relationship with the VSMC differentiation marker genes, smooth muscle α-actin, calponin and CREG. Using gain-of-function and loss-of-function approaches, CREG and VSMC differentiation marker gene expression levels were shown to be suppressed by a miR-31 mimic, but increased by a miR-31 inhibitor at both protein and mRNA levels. Notably, miR-31 overexpression or inhibition affected luciferase expression driven by the CREG 3′-UTR containing the miR-31 binding site. Furthermore, miR-31-mediated VSMC phenotypic modulation was inhibited in CREG-knockdown human VSMCs. We also determined miR-31 levels in the serum of patients with coronary artery disease (CAD), with or without in stent restenosis and in healthy controls. miR-31 levels were higher in the serum of CAD patients with restenosis compared to CAD patients without restenosis and in healthy controls. In summary, these data demonstrate that miR-31 not only directly binds to its target gene CREG and modulates the VSMC phenotype through this interaction, but also can be an important biomarker in diseases involving VSMC

  17. System-wide Analysis of SUMOylation Dynamics in Response to Replication Stress Reveals Novel Small Ubiquitin-like Modified Target Proteins and Acceptor Lysines Relevant for Genome Stability

    DEFF Research Database (Denmark)

    Xiao, Zhenyu; Chang, Jer-Gung; Hendriks, Ivo A

    2015-01-01

    Genotoxic agents can cause replication fork stalling in dividing cells due to DNA lesions, eventually leading to replication fork collapse when the damage is not repaired. Small Ubiquitin-like Modifiers (SUMOs) are known to counteract replication stress, nevertheless, only a small number...... of relevant SUMO target proteins are known. To address this, we have purified and identified SUMO-2 target proteins regulated by replication stress in human cells. The developed methodology enabled single step purification of His10-SUMO-2 conjugates under denaturing conditions with high yield and high purity....... Following statistical analysis on five biological replicates, a total of 566 SUMO-2 targets were identified. After 2 hours of Hydroxyurea treatment, 10 proteins were up-regulated for SUMOylation and 2 proteins were down-regulated for SUMOylation, whereas after 24 hours, 35 proteins were up...

  18. Targeting Rapamycin to Podocytes Using a Vascular Cell Adhesion Molecule-1 (VCAM-1-Harnessed SAINT-Based Lipid Carrier System.

    Directory of Open Access Journals (Sweden)

    Ganesh Ram R Visweswaran

    Full Text Available Together with mesangial cells, glomerular endothelial cells and the basement membrane, podocytes constitute the glomerular filtration barrier (GFB of the kidney. Podocytes play a pivotal role in the progression of various kidney-related diseases such as glomerular sclerosis and glomerulonephritis that finally lead to chronic end-stage renal disease. During podocytopathies, the slit-diaphragm connecting the adjacent podocytes are detached leading to severe loss of proteins in the urine. The pathophysiology of podocytopathies makes podocytes a potential and challenging target for nanomedicine development, though there is a lack of known molecular targets for cell selective drug delivery. To identify VCAM-1 as a cell-surface receptor that is suitable for binding and internalization of nanomedicine carrier systems by podocytes, we investigated its expression in the immortalized podocyte cell lines AB8/13 and MPC-5, and in primary podocytes. Gene and protein expression analyses revealed that VCAM-1 expression is increased by podocytes upon TNFα-activation for up to 24 h. This was paralleled by anti-VCAM-1 antibody binding to the TNFα-activated cells, which can be employed as a ligand to facilitate the uptake of nanocarriers under inflammatory conditions. Hence, we next explored the possibilities of using VCAM-1 as a cell-surface receptor to deliver the potent immunosuppressant rapamycin to TNFα-activated podocytes using the lipid-based nanocarrier system Saint-O-Somes. Anti-VCAM-1-rapamycin-SAINT-O-Somes more effectively inhibited the cell migration of AB8/13 cells than free rapamycin and non-targeted rapamycin-SAINT-O-Somes indicating the potential of VCAM-1 targeted drug delivery to podocytes.

  19. Cell-Surface and Nuclear Receptors in the Colon as Targets for Bacterial Metabolites and Its Relevance to Colon Health

    Science.gov (United States)

    Sivaprakasam, Sathish; Bhutia, Yangzom D.; Ramachandran, Sabarish; Ganapathy, Vadivel

    2017-01-01

    The symbiotic co-habitation of bacteria in the host colon is mutually beneficial to both partners. While the host provides the place and food for the bacteria to colonize and live, the bacteria in turn help the host in energy and nutritional homeostasis, development and maturation of the mucosal immune system, and protection against inflammation and carcinogenesis. In this review, we highlight the molecular mediators of the effective communication between the bacteria and the host, focusing on selective metabolites from the bacteria that serve as messengers to the host by acting through selective receptors in the host colon. These bacterial metabolites include the short-chain fatty acids acetate, propionate, and butyrate, the tryptophan degradation products indole-3-aldehyde, indole-3-acetic, acid and indole-3-propionic acid, and derivatives of endogenous bile acids. The targets for these bacterial products in the host include the cell-surface G-protein-coupled receptors GPR41, GPR43, and GPR109A and the nuclear receptors aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and farnesoid X receptor (FXR). The chemical communication between these bacterial metabolite messengers and the host targets collectively has the ability to impact metabolism, gene expression, and epigenetics in colonic epithelial cells as well as in mucosal immune cells. The end result, for the most part, is the maintenance of optimal colonic health. PMID:28796169

  20. Immunotherapy targeting α-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders.

    Science.gov (United States)

    Lindström, Veronica; Ihse, Elisabet; Fagerqvist, Therese; Bergström, Joakim; Nordström, Eva; Möller, Christer; Lannfelt, Lars; Ingelsson, Martin

    2014-01-01

    Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

  1. Recent advances in targeting DNA repair pathways for the treatment of ovarian cancer and their clinical relevance.

    Science.gov (United States)

    Oda, Katsutoshi; Tanikawa, Michihiro; Sone, Kenbun; Mori-Uchino, Mayuyo; Osuga, Yutaka; Fujii, Tomoyuki

    2017-08-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency.

  2. Recent experimental results on ICF target implosions by Z-pinch radiation sources and their relevance to ICF ignition studies.

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, James E.; Chandler, Gordon Andrew; Vesey, Roger Alan; Hanson, David Lester; Olson, Craig Lee; Nash, Thomas J.; Matzen, Maurice Keith; Ruiz, Carlos L.; Porter, John Larry, Jr.; Cuneo, Michael Edward; Varnum, William S.; Bennett, Guy R. (K-tech Corporation, Albuquerque, NM); Cooper, Gary Wayne; Schroen, Diana Grace (Schafer Gorp., Livermore, CA); Slutz, Stephen A.; MacFarlane, Joseph John (Prism Computational Sciences, Madison, WI); Leeper, Ramon Joe; Golovkin, I. E. (Prism Computational Sciences, Madison, WI); Mehlhorn, Thomas Alan; Mancini, Roberto Claudio (University of Nevada, Reno, NV)

    2003-07-01

    Inertial confinement fusion capsule implosions absorbing up to 35 kJ of x-rays from a {approx}220 eV dynamic hohlraum on the Z accelerator at Sandia National Laboratories have produced thermonuclear D-D neutron yields of (2.6 {+-} 1.3) x 10{sup 10}. Argon spectra confirm a hot fuel with Te {approx} 1 keV and n{sub e} {approx} (1-2) x 10{sup 23} cm{sup -3}. Higher performance implosions will require radiation symmetry control improvements. Capsule implosions in a {approx}70 eV double-Z-pinch-driven secondary hohlraum have been radiographed by 6.7 keV x-rays produced by the Z-beamlet laser (ZBL), demonstrating a drive symmetry of about 3% and control of P{sub 2} radiation asymmetries to {+-}2%. Hemispherical capsule implosions have also been radiographed in Z in preparation for future experiments in fast ignition physics. Z-pinch-driven inertial fusion energy concepts are being developed. The refurbished Z machine (ZR) will begin providing scaling information on capsule and Z-pinch in 2006. The addition of a short pulse capability to ZBL will enable research into fast ignition physics in the combination of ZR and ZBL-petawatt. ZR could provide a test bed to study NIF-relevant double-shell ignition concepts using dynamic hohlraums and advanced symmetry control techniques in the double-pinch hohlraum backlit by ZBL.

  3. A DNA enzyme targeting Egr-1 inhibits rat vascular smooth muscle cell proliferation by down-regulation of cyclin D1 and TGF-β1

    Directory of Open Access Journals (Sweden)

    Y. Wu

    2010-01-01

    Full Text Available We have demonstrated that a synthetic DNA enzyme targeting early growth response factor-1 (Egr-1 can inhibit neointimal hyperplasia following vascular injury. However, the detailed mechanism of this inhibition is not known. Thus, the objective of the present study was to further investigate potential inhibitory mechanisms. Catalytic DNA (ED5 and scrambled control DNA enzyme (ED5SCR were synthesized and transfected into primary cultures of rat vascular smooth muscle cells (VSMCs. VSMC proliferation and DNA synthesis were analyzed by the MTT method and BrdU staining, respectively. Egr-1, TGF-β1, p53, p21, Bax, and cyclin D1 expression was detected by RT-PCR and Western blot. Apoptosis and cell cycle assays were performed by FACS. Green fluorescence could be seen localized in the cytoplasm of 70.6 ± 1.52 and 72 ± 2.73% VSMCs 24 h after transfection of FITC-labeled ED5 and ED5SCR, respectively. We found that transfection with ED5 significantly inhibited cultured VSMC proliferation in vitro after 24, 48, and 72 h of serum stimulation, and also effectively decreased the uptake of BrdU by VSMC. ED5 specifically reduced serum-induced Egr-1 expression in VSMCs, further down-regulated the expression of cyclin D1 and TGF-β1, and arrested the cells at G0/G1, inhibiting entry into the S phase. FACS analysis indicated that there was no significant difference in the rate of apoptosis between ED5- and ED5SCR-transfected cells. Thus, ED5 can specifically inhibit Egr-1 expression, and probably inhibits VSMC proliferation by down-regulating the expressions of cyclin D1 and TGF-β1. However, ED5 has no effect on VSMC apoptosis.

  4. Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1.

    Science.gov (United States)

    Schreier, Barbara; Döhler, Maria; Rabe, Sindy; Schneider, Bettina; Schwerdt, Gerald; Ruhs, Stefanie; Sibilia, Maria; Gotthardt, Michael; Gekle, Michael; Grossmann, Claudia

    2011-07-01

    Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC). We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (EGFR(Δ/Δ VSMC)→VSMC(EGFR-/-) and EGFR(Δ/+ VSMC)→VSMC(EGFR+/-)) and the respective littermate controls (EGFR(+/+ VSMC)→VSMC(EGFR+/+)) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca(2+) homeostasis. In VSMC(EGFR-/-), epidermal growth factor-induced signaling was abolished; VSMC(EGFR+/-) showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC(EGFR-/-) endothelin-1- or α(1)-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca(2+) responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca(2+) signal. Oxidative stress (H(2)O(2)) induced ERK1/2 activation in VSMC(EGFR+/+) and VSMC(EGFR+/-) but not in VSMC(EGFR-/-). The Ca(2+) signal was enhanced in VSMC(EGFR-/-), similar to purinergic stimulation by ATP. In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein-coupled receptors or radical stress. Ca(2+) signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.

  5. Assessing environmental impacts of genetically modified plants on non-target organisms: The relevance of in planta studies.

    Science.gov (United States)

    Arpaia, Salvatore; Birch, A Nicholas E; Kiss, Jozsef; van Loon, Joop J A; Messéan, Antoine; Nuti, Marco; Perry, Joe N; Sweet, Jeremy B; Tebbe, Christoph C

    2017-04-01

    In legal frameworks worldwide, genetically modified plants (GMPs) are subjected to pre-market environmental risk assessment (ERA) with the aim of identifying potential effects on the environment. In the European Union, the EFSA Guidance Document introduces the rationale that GMPs, as well as their newly produced metabolites, represent the potential stressor to be evaluated during ERA. As a consequence, during several phases of ERA for cultivation purposes, it is considered necessary to use whole plants or plant parts in experimental protocols. The importance of in planta studies as a strategy to address impacts of GMPs on non-target organisms is demonstrated, to evaluate both effects due to the intended modification in plant phenotype (e.g. expression of Cry proteins) and effects due to unintended modifications in plant phenotype resulting from the transformation process (e.g. due to somaclonal variations or pleiotropic effects). In planta tests are also necessary for GMPs in which newly expressed metabolites cannot easily be studied in vitro. This paper reviews the scientific literature supporting the choice of in planta studies as a fundamental tool in ERA of GMPs in cultivation dossiers; the evidence indicates they can realistically mimic the ecological relationships occurring in their receiving environments and provide important insights into the biology and sustainable management of GMPs. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases.

    Science.gov (United States)

    Suen, Colin M; Mei, Shirley H J; Kugathasan, Lakshmi; Stewart, Duncan J

    2013-10-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that, despite significant advances in medical therapies over the last several decades, continues to have an extremely poor prognosis. Gene therapy is a method to deliver therapeutic genes to replace defective or mutant genes or supplement existing cellular processes to modify disease. Over the last few decades, several viral and nonviral methods of gene therapy have been developed for preclinical PAH studies with varying degrees of efficacy. However, these gene delivery methods face challenges of immunogenicity, low transduction rates, and nonspecific targeting which have limited their translation to clinical studies. More recently, the emergence of regenerative approaches using stem and progenitor cells such as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) have offered a new approach to gene therapy. Cell-based gene therapy is an approach that augments the therapeutic potential of EPCs and MSCs and may deliver on the promise of reversal of established PAH. These new regenerative approaches have shown tremendous potential in preclinical studies; however, large, rigorously designed clinical studies will be necessary to evaluate clinical efficacy and safety. © 2013 American Physiological Society. Compr Physiol 3:1749-1779, 2013.

  7. Vascular Cures

    Science.gov (United States)

    ... is the first national program to bring the power of the patient to vascular research and care. ... Our recent national Vascular Research Summit brought together leaders from 31 institutions to generate collaborative projects for ...

  8. Enhanced guide-RNA Design and Targeting Analysis for Precise CRISPR Genome Editing of Single and Consortia of Industrially Relevant and Non-Model Organisms.

    Science.gov (United States)

    Mendoza, Brian J; Trinh, Cong T

    2017-09-08

    Genetic diversity of non-model organisms offers a repertoire of unique phenotypic features for exploration and cultivation for synthetic biology and metabolic engineering applications. To realize this enormous potential, it is critical to have an efficient genome editing tool for rapid strain engineering of these organisms to perform novel programmed functions. To accommodate the use of CRISPR/Cas systems for genome editing across organisms, we have developed a novel method, named CASPER (CRISPR Associated Software for Pathway Engineering and Research), for identifying on- and off-targets with enhanced predictability coupled with an analysis of non-unique (repeated) targets to assist in editing any organism with various endonucleases. Utilizing CASPER, we demonstrated a modest 2.4% and significant 30.2% improvement (F-test, p<0.05) over the conventional methods for predicting on- and off-target activities, respectively. Further we used CASPER to develop novel applications in genome editing: multitargeting analysis (i.e. simultaneous multiple-site modification on a target genome with a sole guide-RNA (gRNA) requirement) and multispecies population analysis (i.e. gRNA design for genome editing across a consortium of organisms). Our analysis on a selection of industrially relevant organisms revealed a number of non-unique target sites associated with genes and transposable elements that can be used as potential sites for multitargeting. The analysis also identified shared and unshared targets that enable genome editing of single or multiple genomes in a consortium of interest. We envision CASPER as a useful platform to enhance the precise CRISPR genome editing for metabolic engineering and synthetic biology applications. https://github.com/TrinhLab/CASPER. Supplementary data are available at Bioinformatics online.

  9. Controversies in renal cell carcinoma: treatment choice after progression on vascular endothelial growth factor-targeted therapy.

    Science.gov (United States)

    Calvo, Emiliano; Grünwald, Viktor; Bellmunt, Joaquim

    2014-05-01

    The mammalian target of rapamycin inhibitor (mTORI) everolimus and the tyrosine kinase inhibitor (TKI) axitinib are the only two post-first-line treatment options for metastatic renal cell carcinoma (mRCC) licensed at present. Extrapolation of robust phase III studies suggests that median progression-free survival (PFS) is similar between agents. This presents a dilemma for the physician planning treatment for their patients with mRCC: should they be treated with a TKI-mTORI or a TKI-TKI sequence? The lack of direct comparison between axitinib and everolimus leaves the clinician without clear guidance on the optimal choice in second-line therapy. In phase III studies, both post first-line everolimus and axitinib have been shown to delay disease progression; however, cumulative toxicity with sequential use of TKIs may result in more treatment interruptions or dose reductions or increased likelihood of adverse events. While everolimus exerts a tolerability advantage, axitinib is associated with higher response rate and a similar PFS benefit. Proven superiority cannot be used to guide treatment sequence selection in mRCC. Instead, therapeutic planning requires us to take a long-term view of our patient's treatment that includes quality of life and a balance between symptom control, adverse event management and avoidance of unnecessary drug interruptions or dose reductions. In the absence of curative therapies, sustaining a patient's quality of life is a major goal throughout the course of treatment and choosing a second-line agent that is able to adequately achieve this by limiting adverse events should be a priority. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Preparation of arginine-glycine-aspartic acid-modified biopolymeric nanoparticles containing epigalloccatechin-3-gallate for targeting vascular endothelial cells to inhibit corneal neovascularization.

    Science.gov (United States)

    Chang, Che-Yi; Wang, Ming-Chen; Miyagawa, Takuya; Chen, Zhi-Yu; Lin, Feng-Huei; Chen, Ko-Hua; Liu, Guei-Sheung; Tseng, Ching-Li

    2017-01-01

    Neovascularization (NV) of the cornea can disrupt visual function, causing ocular diseases, including blindness. Therefore, treatment of corneal NV has a high public health impact. Epigalloccatechin-3-gallate (EGCG), presenting antiangiogenesis effects, was chosen as an inhibitor to treat human vascular endothelial cells for corneal NV treatment. An arginine-glycine-aspartic acid (RGD) peptide-hyaluronic acid (HA)-conjugated complex coating on the gelatin/EGCG self-assembly nanoparticles (GEH-RGD NPs) was synthesized for targeting the α v β 3 integrin on human umbilical vein endothelial cells (HUVECs) in this study, and a corneal NV mouse model was used to evaluate the therapeutic effect of this nanomedicine used as eyedrops. HA-RGD conjugation via COOH and amine groups was confirmed by 1 H-nuclear magnetic resonance and Fourier-transform infrared spectroscopy. The average diameter of GEH-RGD NPs was 168.87±22.5 nm with positive charge (19.7±2 mV), with an EGCG-loading efficiency up to 95%. Images of GEH-RGD NPs acquired from transmission electron microscopy showed a spherical shape and shell structure of about 200 nm. A slow-release pattern was observed in the nanoformulation at about 30% after 30 hours. Surface plasmon resonance confirmed that GEH-RGD NPs specifically bound to the integrin α v β 3 . In vitro cell-viability assay showed that GEH-RGD efficiently inhibited HUVEC proliferation at low EGCG concentrations (20 μg/mL) when compared with EGCG or non-RGD-modified NPs. Furthermore, GEH-RGD NPs significantly inhibited HUVEC migration down to 58%, lasting for 24 hours. In the corneal NV mouse model, fewer and thinner vessels were observed in the alkali-burned cornea after treatment with GEH-RGD NP eyedrops. Overall, this study indicates that GEH-RGD NPs were successfully developed and synthesized as an inhibitor of vascular endothelial cells with specific targeting capacity. Moreover, they can be used in eyedrops to inhibit angiogenesis in corneal NV

  11. Targeted delivery of Cyclosporine A by polymeric nanocarriers improves the therapy of inflammatory bowel disease in a relevant mouse model.

    Science.gov (United States)

    Melero, Ana; Draheim, Christina; Hansen, Steffi; Giner, Elisa; Carreras, Juan José; Talens-Visconti, Raquel; Garrigues, Teresa María; Peris, José Esteban; Recio, Ma Carmen; Giner, Rosa; Lehr, Claus-Michael

    2017-10-01

    The therapy of inflammatory bowel diseases is still rather inefficient, and about 80% of patients require surgery at some stage. Improving the treatments by more efficient medication is, therefore, an urgent medical need. The objective of this project was to demonstrate targeted delivery of Cyclosporine-A (CYA) to the inflamed areas of the intestinal mucosa after oral administration, enabling improved alleviation of the symptoms and, at the same time, reduced systemic drug absorption and associated adverse effects. As had already been demonstrated in previous studies, nano- to micrometer-sized drug particles will accumulate at inflamed mucosal areas, providing a platform for such purposes. CYA as incorporated in poly-(lactic-co-glycolic-Acid) (PLGA) nano- and mirocarriers, respectively, each homogeneous in size and providing controlled drug release over 24h at intestinal pH-value. For comparative reasons, a commercial formulation (Sandimmun Neoral®) was included in the study. In an acute model of DSS-induced inflammation in Balb/c mice, up to three doses were administered for each formulation: 50mg/kg, 25mg/kg and 12.5mg/kg. Drug-free particles were included as control. The following parameters were evaluated: body weight, colon length, colon weight/length ratio, cytokine expression and histological analysis. Plasma levels of CYA were analysed to compare systemic bioavailability. While disease parameters, such as, e.g. colon length, always improved with an optimum dose of 25mg/kg, the commercial and the microparticulate formulations led to measurable plasma levels and adverse effects in terms of body weight loss at the highest dose. In contrast, when administering the same doses as nanoparticles, plasma concentrations remained always below the detection limit, and the body weight of the animals remained unchanged. In conclusion, this study corroborates the potential of nanocarriers enabling an improved topical delivery of CYA to the inflamed gut mucosa after oral

  12. Molecular network of ChIP-Seq-based NF-κB p65 target genes involves diverse immune functions relevant to the immunopathogenesis of multiple sclerosis.

    Science.gov (United States)

    Satoh, Jun-Ichi

    2014-01-01

    The transcription factor nuclear factor-kappa B (NF-κB) acts as a central regulator of immune response, stress response, cell proliferation, and apoptosis. Aberrant regulation of NF-κB function triggers development of cancers, metabolic diseases, and autoimmune diseases. We attempted to characterize a global picture of the NF-κB target gene network relevant to the immunopathogenesis of multiple sclerosis (MS). We identified the comprehensive set of 918 NF-κB p65 binding sites on protein-coding genes from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset of TNFα-stimulated human B lymphoblastoid cells. The molecular network was studied by a battery of pathway analysis tools of bioinformatics. The GenomeJack genome viewer showed that NF-κB p65 binding sites were accumulated in promoter (35.5%) and intronic (54.9%) regions with an existence of the NF-κB consensus sequence motif. A set of 52 genes (5.7%) corresponded to known NF-κB targets by database search. KEGG, PANTHER, and Ingenuity Pathways Analysis (IPA) revealed that the NF-κB p65 target gene network is linked to regulation of immune functions and oncogenesis, including B cell receptor signaling, T cell activation pathway, Toll-like receptor signaling, and apoptosis signaling, and molecular mechanisms of cancers. KeyMolnet indicated an involvement of the complex crosstalk among core transcription factors in the NF-κB p65 target gene network. Furthermore, the set of NF-κB p65 target genes included 10 genes among 98 MS risk alleles and 49 molecules among 709 MS brain lesion-specific proteins. These results suggest that aberrant regulation of NF-κB-mediated gene expression, by inducing dysfunction of diverse immune functions, is closely associated with development and progression of MS. © 2013 Elsevier B.V. All rights reserved.

  13. Deletion of the Protein Kinase A/Protein Kinase G Target SMTNL1 Promotes an Exercise-adapted Phenotype in Vascular Smooth Muscle*S⃞

    Science.gov (United States)

    Wooldridge, Anne A.; Fortner, Christopher N.; Lontay, Beata; Akimoto, Takayuki; Neppl, Ronald L.; Facemire, Carie; Datto, Michael B.; Kwon, Ashley; McCook, Everett; Li, Ping; Wang, Shiliang; Thresher, Randy J.; Miller, Sara E.; Perriard, Jean-Claude; Gavin, Timothy P.; Hickner, Robert C.; Coffman, Thomas M.; Somlyo, Avril V.; Yan, Zhen; Haystead, Timothy A. J.

    2008-01-01

    In vivo protein kinases A and G (PKA and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smoothelin-like protein 1 (SMTNL1), a novel in vivo target of PKG/PKA, in mediating vascular adaptations to exercise. Aortas from smtnl1-/- mice exhibited strikingly enhanced vasorelaxation before exercise, similar in extent to that achieved after endurance training of wild-type littermates. Additionally, contractile responses to α-adrenergic agonists were greatly attenuated. Immunological studies showed SMTNL1 is expressed in smooth muscle and type 2a striated muscle fibers. Consistent with a role in adaptations to exercise, smtnl1-/- mice also exhibited increased type 2a fibers before training and better performance after forced endurance training compared smtnl1+/+ mice. Furthermore, exercise was found to reduce expression of SMTNL1, particularly in female mice. In both muscle types, SMTNL1 is phosphorylated at Ser-301 in response to adrenergic signals. In vitro SMTNL1 suppresses myosin phosphatase activity through a substrate-directed effect, which is relieved by Ser-301 phosphorylation. Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity. PMID:18310078

  14. Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.

    Science.gov (United States)

    Wooldridge, Anne A; Fortner, Christopher N; Lontay, Beata; Akimoto, Takayuki; Neppl, Ronald L; Facemire, Carie; Datto, Michael B; Kwon, Ashley; McCook, Everett; Li, Ping; Wang, Shiliang; Thresher, Randy J; Miller, Sara E; Perriard, Jean-Claude; Gavin, Timothy P; Hickner, Robert C; Coffman, Thomas M; Somlyo, Avril V; Yan, Zhen; Haystead, Timothy A J

    2008-04-25

    In vivo protein kinases A and G (PKA and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smoothelin-like protein 1 (SMTNL1), a novel in vivo target of PKG/PKA, in mediating vascular adaptations to exercise. Aortas from smtnl1(-/-) mice exhibited strikingly enhanced vasorelaxation before exercise, similar in extent to that achieved after endurance training of wild-type littermates. Additionally, contractile responses to alpha-adrenergic agonists were greatly attenuated. Immunological studies showed SMTNL1 is expressed in smooth muscle and type 2a striated muscle fibers. Consistent with a role in adaptations to exercise, smtnl1(-/-) mice also exhibited increased type 2a fibers before training and better performance after forced endurance training compared smtnl1(+/+) mice. Furthermore, exercise was found to reduce expression of SMTNL1, particularly in female mice. In both muscle types, SMTNL1 is phosphorylated at Ser-301 in response to adrenergic signals. In vitro SMTNL1 suppresses myosin phosphatase activity through a substrate-directed effect, which is relieved by Ser-301 phosphorylation. Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity.

  15. miR-125b targets DNMT3b and mediates p53 DNA methylation involving in the vascular smooth muscle cells proliferation induced by homocysteine

    Energy Technology Data Exchange (ETDEWEB)

    Cao, ChengJian [Key Laboratory of Basic Research in Cardio-Cerebral Vascular Diseases, Ningxia Medical University, Yinchuan (China); Zhang, HuiPing [Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan (China); Zhao, Li [Department of Medical Laboratory, Ningxia Medical University, Yinchuan (China); Zhou, Longxia [Department of Basic Medicine, Ningxia Medical University, Yinchuan (China); Zhang, Minghao; Xu, Hua [Key Laboratory of Basic Research in Cardio-Cerebral Vascular Diseases, Ningxia Medical University, Yinchuan (China); Department of Basic Medicine, Ningxia Medical University, Yinchuan (China); Han, Xuebo [Department of Medical Laboratory, Ningxia Medical University, Yinchuan (China); Li, Guizhong; Yang, Xiaoling [Key Laboratory of Basic Research in Cardio-Cerebral Vascular Diseases, Ningxia Medical University, Yinchuan (China); Department of Basic Medicine, Ningxia Medical University, Yinchuan (China); Jiang, YiDeng, E-mail: jyjcyxy@yeah.net [Key Laboratory of Basic Research in Cardio-Cerebral Vascular Diseases, Ningxia Medical University, Yinchuan (China); Department of Basic Medicine, Ningxia Medical University, Yinchuan (China)

    2016-09-10

    MicroRNAs (miRNAs) are short non-coding RNA and play crucial roles in a wide array of biological processes, including cell proliferation, differentiation and apoptosis. Our previous studies found that homocysteine(Hcy) can stimulate the proliferation of vascular smooth muscle cells (VSMCs), however, the underlying mechanisms were not fully elucidated. Here, we found proliferation of VSMCs induced by Hcy was of correspondence to the miR-125b expression reduced both in vitro and in the ApoE knockout mice, the hypermethylation of p53, its decreased expression, and DNA (cytosine-5)-methyltransferase 3b (DNMT3b) up-regulated. And, we found DNMT3b is a target of miR-125b, which was verified by the Dual-Luciferase reporter assay and western blotting. Besides, the siRNA interference for DNMT3b significantly decreased the methylation level of p53, which unveiled the causative role of DNMT3b in p53 hypermethylation. miR-125b transfection further confirmed its regulative roles on p53 gene methylation status and the VSMCs proliferation. Our data suggested that a miR-125b-DNMT3b-p53 signal pathway may exist in the VSMCs proliferation induced by Hcy.

  16. miR-503 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting the insulin receptor.

    Science.gov (United States)

    Bi, Rui; Ding, Fangbao; He, Yi; Jiang, Lianyong; Jiang, Zhaolei; Mei, Ju; Liu, Hao

    2016-12-01

    Abnormal proliferation and migration of vascular smooth muscle cells (VSMC) is a common feature of disease progression in atherosclerosis. Here, we investigated the potential role of miR-503 in platelet-derived growth factor (PDGF)-induced proliferation and migration of human aortic smooth muscle cells and the underlying mechanisms of action. miR-503 expression was significantly downregulated in a dose- and time-dependent manner following PDGF treatment. Introduction of miR-503 mimics into cultured SMCs significantly attenuated cell proliferation and migration induced by PDGF. Bioinformatics analyses revealed that the insulin receptor (INSR) is a target candidate of miR-503. miR-503 suppressed luciferase activity driven by a vector containing the 3'-untranslated region of INSR in a sequence-specific manner. Downregulation of INSR appeared critical for miR-503-mediated inhibitory effects on PDGF-induced cell proliferation and migration in human aortic SMCs. Based on the collective data, we suggest a novel role of miR-503 as a regulator of VSMC proliferation and migration through modulating INSR. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Targeting Vascular Endothelial Growth Factor Receptor 2 and Protein Kinase D1 Related Pathways by a Multiple Kinase Inhibitor in Angiogenesis and Inflammation Related Processes In Vitro

    Science.gov (United States)

    Varga, Attila; Gyulavári, Pál; Greff, Zoltán; Futosi, Krisztina; Németh, Tamás; Simon-Szabó, Laura; Kerekes, Krisztina; Szántai-Kis, Csaba; Brauswetter, Diána; Kokas, Márton; Borbély, Gábor; Erdei, Anna; Mócsai, Attila; Kéri, György; Vántus, Tibor

    2015-01-01

    Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways. PMID:25874616

  18. Targeting vascular endothelial growth factor receptor 2 and protein kinase D1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro.

    Directory of Open Access Journals (Sweden)

    Attila Varga

    Full Text Available Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2 and protein kinase D1 (PKD1 signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways.

  19. Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice

    Science.gov (United States)

    2010-01-01

    Background The objective of this study was to develop a ligand-targeted photodynamic therapy (tPDT) by conjugating factor VII (fVII) protein with photosensitiser verteporfin in order to overcome the poor selectivity and enhance the effect of non-targeted PDT (ntPDT) for cancer. fVII is a natural ligand for receptor tissue factor (TF) with high affinity and specificity. The reason for targeting receptor TF for the development of tPDT is that TF is a common but specific target on angiogenic tumour vascular endothelial cells (VEC) and many types of tumour cells, including solid tumours and leukaemia. Methods Murine factor VII protein (mfVII) containing a mutation (Lys341Ala) was covalently conjugated via a cross linker EDC with Veterporfin (VP) that was extracted from liposomal Visudyne, and then free VP was separated by Sephadex G50 spin columns. fVII-tPDT using mfVII-VP conjugate, compared to ntPDT, was tested in vitro for the killing of breast cancer cells and VEGF-stimulated VEC and in vivo for inhibiting the tumour growth of breast tumours in a mouse xenograft model. Results We showed that: (i) fVII protein could be conjugated with VP without affecting its binding activity; (ii) fVII-tPDT could selectively kill TF-expressing breast cancer cells and VEGF-stimulated angiogenic HUVECs but had no side effects on non-TF expressing unstimulated HUVEC, CHO-K1 and 293 cells; (iii) fVII targeting enhanced the effect of VP PDT by three to four fold; (iii) fVII-tPDT induced significantly stronger levels of apoptosis and necrosis than ntPDT; and (iv) fVII-tPDT had a significantly stronger effect on inhibiting breast tumour growth in mice than ntPDT. Conclusions We conclude that the fVII-targeted VP PDT that we report here is a novel and effective therapeutic with improved selectivity for the treatment of breast cancer. Since TF is expressed on many types of cancer cells including leukaemic cells and selectively on angiogenic tumour VECs, fVII-tPDT could have broad

  20. Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice

    Directory of Open Access Journals (Sweden)

    Rao Benqiang

    2010-05-01

    Full Text Available Abstract Background The objective of this study was to develop a ligand-targeted photodynamic therapy (tPDT by conjugating factor VII (fVII protein with photosensitiser verteporfin in order to overcome the poor selectivity and enhance the effect of non-targeted PDT (ntPDT for cancer. fVII is a natural ligand for receptor tissue factor (TF with high affinity and specificity. The reason for targeting receptor TF for the development of tPDT is that TF is a common but specific target on angiogenic tumour vascular endothelial cells (VEC and many types of tumour cells, including solid tumours and leukaemia. Methods Murine factor VII protein (mfVII containing a mutation (Lys341Ala was covalently conjugated via a cross linker EDC with Veterporfin (VP that was extracted from liposomal Visudyne, and then free VP was separated by Sephadex G50 spin columns. fVII-tPDT using mfVII-VP conjugate, compared to ntPDT, was tested in vitro for the killing of breast cancer cells and VEGF-stimulated VEC and in vivo for inhibiting the tumour growth of breast tumours in a mouse xenograft model. Results We showed that: (i fVII protein could be conjugated with VP without affecting its binding activity; (ii fVII-tPDT could selectively kill TF-expressing breast cancer cells and VEGF-stimulated angiogenic HUVECs but had no side effects on non-TF expressing unstimulated HUVEC, CHO-K1 and 293 cells; (iii fVII targeting enhanced the effect of VP PDT by three to four fold; (iii fVII-tPDT induced significantly stronger levels of apoptosis and necrosis than ntPDT; and (iv fVII-tPDT had a significantly stronger effect on inhibiting breast tumour growth in mice than ntPDT. Conclusions We conclude that the fVII-targeted VP PDT that we report here is a novel and effective therapeutic with improved selectivity for the treatment of breast cancer. Since TF is expressed on many types of cancer cells including leukaemic cells and selectively on angiogenic tumour VECs, fVII-tPDT could have

  1. High pressure inactivation of relevant target microorganisms in poultry meat products and the evaluation of pressure-induced protein denaturation of marinated poultry under different high pressure treatments

    Science.gov (United States)

    Schmidgall, Johanna; Hertel, Christian; Bindrich, Ute; Heinz, Volker; Toepfl, Stefan

    2011-03-01

    In this study, the possibility of extending shelf life of marinated poultry meat products by high pressure processing was evaluated. Relevant spoilage and pathogenic strains were selected and used as target microorganisms (MOs) for challenge experiments. Meat and brine were inoculated with MOs and treated at 450 MPa, 4 °C for 3 min. The results of inactivation show a decreasing pressure tolerance in the series Lactobacillus > Arcobacter > Carnobacterium > Bacillus cereus > Brochothrix thermosphacta > Listeria monocytogenes. Leuconostoc gelidum exhibited the highest pressure tolerance in meat. A protective effect of poultry meat was found for L. sakei and L. gelidum. In parallel, the influence of different marinade formulations (pH, carbonates, citrates) on protein structure changes during a pressure treatment was investigated. Addition of sodium carbonate shows a protection against denaturation of myofibrillar proteins and provides a maximum water-holding capacity. Caustic marinades allowed a higher retention of product characteristics than low-pH marinades.

  2. Trimer hydroxylated quinone (IIIHyQ) derived from apocynin targets cysteine residues of p47phox preventing the activation of human vascular NADPH oxidase

    Science.gov (United States)

    Mora-Pale, Mauricio; Joon-Kwon, Seok; Linhardt, Robert J.; Dordick, Jonathan S.

    2012-01-01

    Enzymatic derived oligophenols from apocynin can be effective inhibitors of human vascular NADPH oxidase. An isolated IIIHyQ has been shown to inhibit endothelial NADPH oxidase with an IC50 ~30 nM. In vitro studies demonstrated that IIIHyQ is capable on disrupting the interaction between p47phox and p22phox, thereby blocking the activation of the Nox2 isoform. Herein, we report the role of key cysteine residues in p47phox as targets for the IIIHyQ. Incubation of p47phox with IIIHyQ results in a decrease of ~80% of the protein free cysteine residues; similar results were observed using 1,2- and 1,4-naphthoquinoes, while apocynin was unreactive. Mutants of p47phox, where each Cys was individually replaced by Ala (at residues 111, 196 and 378) and Gly (at residue 98), were generated to evaluate their individual importance in IIIHyQ-mediated inhibition of p47phox interaction with p22phox. Specific Michael addition on Cys196, within the N-SH3 domain, by the IIIHyQ is critical for disrupting the p47phox-p22phox interaction. When a C196A mutation was tested, the IIIHyQ was unable to disrupt the p47phox-p22phox interaction. However, the IIIHyQ was effective at disrupting this interaction with the other mutants, displaying IC50 values (4.9, 21.0, and 2.3 μM for the C111A, C378A, and C98G mutants, respectively) comparable to that of wild type p47phox. PMID:22240153

  3. Trimer hydroxylated quinone derived from apocynin targets cysteine residues of p47phox preventing the activation of human vascular NADPH oxidase.

    Science.gov (United States)

    Mora-Pale, Mauricio; Kwon, Seok Joon; Linhardt, Robert J; Dordick, Jonathan S

    2012-03-01

    Enzymatically derived oligophenols from apocynin can be effective inhibitors of human vascular NADPH oxidase (Nox). An isolated trimer hydroxylated quinone (IIIHyQ) has been shown to inhibit endothelial NADPH oxidase with an IC(50) ~30 nM. In vitro studies demonstrated that IIIHyQ is capable of disrupting the interaction between p47(phox) and p22(phox), thereby blocking the activation of the Nox2 isoform. Herein, we report the role of key cysteine residues in p47(phox) as targets for the IIIHyQ. Incubation of p47(phox) with IIIHyQ results in a decrease of ~80% of the protein free cysteine residues; similar results were observed using 1,2- and 1,4-naphthoquinones, whereas apocynin was unreactive. Mutants of p47(phox), in which each Cys was individually replaced by Ala (at residues 111, 196, and 378) or Gly (at residue 98), were generated to evaluate their individual importance in IIIHyQ-mediated inhibition of p47(phox) interaction with p22(phox). Specific Michael addition on Cys196, within the N-SH3 domain, by the IIIHyQ is critical for disrupting the p47(phox)-p22(phox) interaction. When a C196A mutation was tested, the IIIHyQ was unable to disrupt the p47(phox)-p22(phox) interaction. However, the IIIHyQ was effective at disrupting this interaction with the other mutants, displaying IC(50) values (4.9, 21.0, and 2.3μM for the C111A, C378A, and C98G mutants, respectively) comparable to that of wild-type p47(phox). Copyright © 2011 Elsevier Inc. All rights reserved.

  4. [Vascular dementia

    NARCIS (Netherlands)

    Leeuw, H.F. de; Gijn, J. van

    2004-01-01

    Vascular dementia is one of the most frequently occurring dementia syndromes. Its prevalence is about 5% among subjects above 85 years of age. Elevated blood pressure and atherosclerosis are the most important risk factors. According to international criteria, vascular dementia usually occurs within

  5. Epidermal growth factor receptor variant III in head and neck squamous cell carcinoma is not relevant for targeted therapy and irradiation.

    Science.gov (United States)

    Thomas Koch, Dominik; Pickhard, Anja; Gebel, Lena; Buchberger, Anna Maria S; Bas, Murat; Mogler, Carolin; Reiter, Rudolf; Piontek, Guido; Wirth, Markus

    2017-05-16

    The epidermal growth factor receptor (EGFR) is an important regulator of cell growth and survival, and is highly variable in tumor cells. The most prevalent variation of the EGFR extracellular domain is the EGFR variant III (EGFRvIII). Some studies imply that EGFRvIII may be responsible for the poor response to the monoclonal EGFR-antibody Cetuximab, used therapeutically in head and neck squamous cell carcinoma (HNSCC). Due to inconsistent data in the literature regarding EGFRvIII prevalence and clinical relevance in HNSCC, especially its predictive value, we examined EGFRvIII-transfected cell lines and patient tissue samples. In contrast to other recent publications, we were able to demonstrate EGFRvIII expression in HNSCC. However, we noted that the different detection methods yielded inconsistent results. Furthermore, our EGFRvIII transfected and EGFR wild type cell lines exhibited similar characteristics and response rates in the performed in vitro experiments. We conducted various inhibition and combined irradiation experiments using three EGFRvIII-transfected cell lines. Moreover, a patient cohort of 149 cases consisting of formalin fixed and paraffin embedded (FFPE) and fresh-frozen specimens was assayed via reverse transcriptase PCR (rtPCR) with gel electrophoresis and sequencing for EGFRvIII prevalence. In the rtPCR assays, we used five previously published EGFRvIII primers and EGFRvIII-positive glioblastoma tissue as a positive control. In addition, immunohistochemical staining was conducted. EGFRvIII can be detected in HNSCC patient samples. Nevertheless, the low prevalence and similar response rates to targeted drugs and irradiation in vitro cast doubt regarding the clinical relevance of EGFRvIII in HNSCC.

  6. Vascular ring

    DEFF Research Database (Denmark)

    Schmidt, Anne Mette S; Larsen, Signe H; Hjortdal, Vibeke E

    2018-01-01

    BACKGROUND: Vascular ring is a rare cause of recurrent respiratory infections, dysphagia and stridor. Surgical repair is considered safe but the long-term outcomes are unclear. The purpose of this study was to investigate the mortality and morbidity following vascular ring surgery in a single...... age of 1.4 years (range 0.008-64 years) were operated for vascular ring. Median follow-up was 6.8 years (range 2.4-34 years). Presenting symptoms were stridor (52%), dysphagia or vomiting (52%) and recurrent respiratory infections (48%). There were no early or late deaths. Three months postoperatively...

  7. Visualizing the Acute Effects of Vascular-Targeted Therapy In Vivo Using Intravital Microscopy and Magnetic Resonance Imaging: Correlation with Endothelial Apoptosis, Cytokine Induction, and Treatment Outcome

    Directory of Open Access Journals (Sweden)

    Mukund Seshadri

    2007-02-01

    Full Text Available The acute effects of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA were investigated in vivo using intravital microscopy (IVM and magnetic resonance imaging (MRI. Changes in vascular permeability and blood flow of syngeneic CT-26 murine colon adenocarcinomas were assessed at 4 and 24 hours after DMXAA treatment (30 mg/kg, i.p. and correlated with induction of tumor necrosis factor-α (TNF-α, endothelial damage [CD31/terminal deoxynucleotidyl transferase (TdT], and treatment outcome. Intravital imaging revealed a marked increase in vascular permeability 4 hours after treatment, consistent with increases in intratumoral mRNA and protein levels of TNF-α. Parallel contrast-enhanced MRI studies showed a ~ 4-fold increase in longitudinal relaxation rates (ΔR1, indicative of increased contrast agent accumulation within the tumor. Dualimmunostained tumor sections (CD31/TdT revealed evidence of endothelial apoptosis at this time point. Twenty-four hours after treatment, extensive hemorrhage and complete disruption of vascular architecture were observed with IVM, along with a significant reduction in ΔR1 and virtual absence of CD31 immunostaining. DMXAA-induced tumor vascular damage resulted in significant long-term (60-day cures compared to untreated controls. Multimodality imaging approaches are useful in visualizing the effects of antivascular therapy in vivo. Such approaches allow cross validation and correlation of findings with underlying molecular changes contributing to treatment outcome.

  8. Plasma N-Terminal Probrain Natriuretic Peptide, Vascular Endothelial Growth Factor, and Cardiac Troponin I as Novel Biomarkers of Hypertensive Disease and Target Organ Damage in Cats.

    Science.gov (United States)

    Bijsmans, E S; Jepson, R E; Wheeler, C; Syme, H M; Elliott, J

    2017-05-01

    In the absence of ocular target organ damage (ocular-TOD), diagnosis of hypertension is challenging in cats. Biomarkers would provide additional support for the diagnosis of hypertension. Vascular endothelial growth factor (VEGF), N-terminal probrain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), and urine protein-to-creatinine ratio (UPC) are predictors of systemic hypertension, will be increased in cats with hypertension with or without ocular-TOD, and will decrease with antihypertensive treatment. Plasma VEGF, NT-proBNP, and cTnI concentrations and UPC were determined in healthy geriatric cats, normotensive cats with chronic kidney disease (CKD), hypertensive cats with evidence of hypertensive retinopathy (HT-ocular-TOD), and hypertensive cats without hypertensive ocular-TOD (HT-noTOD). Comparisons among groups were performed. Multivariable binary logistic regression models were built to identify independent biomarkers of hypertension and ocular-TOD. Receiver operator characteristic (ROC) curves were drawn to assess clinical use. Cats with HT-ocular-TOD had significantly higher VEGF than all other groups (P cats (P cats had significantly lower cTnI than all other groups (P < .05). No differences were found among groups for UPC (P = .08). Cardiac troponin I and VEGF were independent predictors of hypertension (P < .05), but none of the biomarkers were independent predictors of ocular-TOD. N-terminal probrain natriuretic peptide concentrations decreased with antihypertensive treatment (P < .001). The ROC curves indicated that none of the biomarkers met the criteria to function as diagnostic tests for the diagnosis of hypertension or associated ocular-TOD. Despite statistical significance and changes with ocular-TOD, antihypertensive treatment, or both, VEGF, NT-proBNP, and cTnI did not function as useful diagnostic tests for hypertension. Persistently increased systolic blood pressure (SBP) measurements in combination with fundoscopy remains the

  9. Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis.

    Science.gov (United States)

    Tschochner, Monika; Leary, Shay; Cooper, Don; Strautins, Kaija; Chopra, Abha; Clark, Hayley; Choo, Linda; Dunn, David; James, Ian; Carroll, William M; Kermode, Allan G; Nolan, David

    2016-01-01

    Epstein-Barr virus (EBV) infection represents a major environmental risk factor for multiple sclerosis (MS), with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1)-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome. Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan) and candidates were evaluated for cross recognition with human brain proteins. EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577), and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis. This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of immunogenic

  10. Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Monika Tschochner

    Full Text Available Epstein-Barr virus (EBV infection represents a major environmental risk factor for multiple sclerosis (MS, with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome.Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan and candidates were evaluated for cross recognition with human brain proteins.EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off. In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577, and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis.This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of

  11. Vascular anomalies

    Directory of Open Access Journals (Sweden)

    Murthy Jyotsna

    2005-01-01

    Full Text Available Management of vascular anomalies is an emerging multidisciplinary, super-specialisation field involving several surgical, medical and radiological specialties. Over the years, development in this field has been limited because of complex nomenclature and lack of consensus on the best practice for treatment of some of the more complex vascular anomalies. It was only in 1996 that the International Society of the Study of Vascular Anomalies defined nomenclature for the anomalies and gave clear guidelines on management, allowing for improved clinical practices. As in all fields of clinical medicine, the correct diagnosis of the vascular anomalies is essential to choose the appropriate treatment. This paper gives clear guidelines for diagnosis, understanding of the anomalies and discusses their management.

  12. Vascular Dementia

    OpenAIRE

    Maria Alekseyevna Cherdak; O V Uspenskaya

    2015-01-01

    This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S0140-6736(15)00463-8 Vascular dementia is one of the most common causes of dementia after Alzheimer's disease, causing around 15% of cases. However, unlike Alzheimer's disease, there are no licensed treatments for vascular dementia. Progress in the specialty has been difficult because of uncertainties over disease classification and diagnostic criteria, controversy over the e...

  13. Vascular Vertigo

    Directory of Open Access Journals (Sweden)

    Mazyar Hashemilar

    2017-02-01

    Full Text Available Vertigo is a common complaint in neurology and medicine. The most common causes of vertigo are benign paroxysmal positional vertigo, vestibular neuritis, Meniere’s disease, and vascular disorders. Vertigo of vascular origin is usually limited to migraine, transient ischemic attacks, and ischemic or hemorrhagic stroke. Vascular causes lead to various central or peripheral vestibular syndromes with vertigo. This review provides an overview of epidemiology and clinical syndromes of vascular vertigo. Vertigo is an illusion of movement caused by asymmetrical involvement of the vestibular system by various causes. Migraine is the most frequent vascular disorder that causes vertigo in all age groups. Vertigo may occur in up to 25% of patients with migraine. The lifetime prevalence of migrainous vertigo is almost 1%. Cerebrovascular disorders are estimated to account for 3% to 7% of patients with vertigo. Vestibular paroxysmia has been diagnosed in 1.8% to 4% of cases in various dizziness units. Vasculitic disorders are rare in the general population, but vertigo may be seen in almost up to 50% of patients with different vasculitic syndromes. Conclusions: Migraine, cerebrovascular disorders especially involving the vertebrobasilar territory, cardiocirculatory diseases, neurovascular compression of the eighth nerve, and vasculitis are vascular causes of vertigo syndromes.

  14. Vascular Access Procedures

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Vascular Access Procedures A vascular access procedure inserts a flexible, ... the limitations of Vascular Access Procedures? What are Vascular Access Procedures? A vascular access procedure involves the insertion ...

  15. Vascular Access for Hemodialysis

    Science.gov (United States)

    ... Adequacy Eating & Nutrition for Hemodialysis Vascular Access for Hemodialysis What is a vascular access? A vascular access ... Set Up the Vascular Access Well before Starting Hemodialysis Patients should set up a vascular access well ...

  16. What Is Vascular Disease?

    Science.gov (United States)

    ... Policy What Is Vascular Disease? What Is Vascular Disease? Vascular disease is any abnormal condition of the blood ... Privacy Policy × Your ticket for the: What Is Vascular Disease? Title What Is Vascular Disease? USD Close Print

  17. Intensity modulated radiation therapy (IMRT: differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

    Directory of Open Access Journals (Sweden)

    Delclos Marc E

    2011-06-01

    covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. Conclusions For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.

  18. [Vascular trauma].

    Science.gov (United States)

    Furuya, T; Nobori, M; Tanaka, N

    1999-07-01

    Vascular trauma is essentially acute arterial obstruction, often combined with hemorrhage, fracture, and infection. It can be both life-threatening and limb-threatening and needs an emergency operation. In vascular trauma patient, multiple fracture and organ injury, such as brain, lung, liver, spleen, kidney, or gastrointestinal tract should be evaluated to decide treatment priority. When the pulse distal from the injured site is absent or diminished, vascular trauma is most likely and reconstruction should be accomplished within "the golden time (6-8 hours)". Intimal damage followed by platelet aggregation and thrombus formation will necessitate resection and repair of the site instead of simple thrombectomy. Although autogenous vein is the first choice, artificial graft can be implanted for short segment in non-infected field.

  19. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.

    Science.gov (United States)

    Mendel, Dirk B; Laird, A Douglas; Xin, Xiaohua; Louie, Sharianne G; Christensen, James G; Li, Guangmin; Schreck, Randall E; Abrams, Tinya J; Ngai, Theresa J; Lee, Leslie B; Murray, Lesley J; Carver, Jeremy; Chan, Emily; Moss, Katherine G; Haznedar, Joshua O; Sukbuntherng, Juthamas; Blake, Robert A; Sun, Li; Tang, Cho; Miller, Todd; Shirazian, Sheri; McMahon, Gerald; Cherrington, Julie M

    2003-01-01

    One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo, SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor beta phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50-100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo. Constant inhibition of VEGFR2 and PDGF receptor beta phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.

  20. VASCULAR SURGERY

    African Journals Online (AJOL)

    Venous thromboembolism (VTE) is a complex and serious condition encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), usually in the lower extremities.1,2. Thromboses can result from venous stasis, vascular injury or hypercoagulability, and those involving the deep veins proximal to the knee are ...

  1. Mast cells promote lung vascular remodelling in pulmonary hypertension.

    Science.gov (United States)

    Hoffmann, J; Yin, J; Kukucka, M; Yin, N; Saarikko, I; Sterner-Kock, A; Fujii, H; Leong-Poi, H; Kuppe, H; Schermuly, R T; Kuebler, W M

    2011-06-01

    Left heart disease (LHD) frequently causes lung vascular remodelling and pulmonary hypertension (PH). Yet pharmacological treatment for PH in LHD is lacking and its pathophysiological basis remains obscure. We aimed to identify candidate mechanisms of PH in LHD and to test their relevance and therapeutic potential. In rats, LHD was induced by supracoronary aortic banding. Whole genome microarray analyses were performed, candidate genes were confirmed by RT-PCR and Western blots and functional relevance was tested in vivo by genetic and pharmacological strategies. In lungs of LHD rats, mast cell activation was the most prominently upregulated gene ontology cluster. Mast cell gene upregulation was confirmed at RNA and protein levels and remodelled vessels showed perivascular mast cell accumulations. In LHD rats treated with the mast cell stabiliser ketotifen, or in mast cell deficient Ws/Ws rats, PH and vascular remodelling were largely attenuated. Both strategies also reduced PH and vascular remodelling in monocrotaline-induced pulmonary arterial hypertension, suggesting that the role of mast cells extends to non-cardiogenic PH. In PH of different aetiologies, mast cells accumulate around pulmonary blood vessels and contribute to vascular remodelling and PH. Mast cells and mast cell-derived mediators may present promising targets for the treatment of PH.

  2. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice

    DEFF Research Database (Denmark)

    Kamoun, Walid S; Ley, Carsten D; Farrar, Christian T

    2009-01-01

    by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage...... infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4(+)CD45(+) cells. However, by controlling edema, cediranib significantly increased survival of mice...

  3. Peripheral and central arterial pressure and its relationship to vascular target organ damage in carotid artery, retina and arterial stiffness. Development and validation of a tool. The Vaso risk study

    Directory of Open Access Journals (Sweden)

    Patino-Alonso Maria C

    2011-04-01

    Full Text Available Abstract Background Ambulatory blood pressure monitoring (ABPM shows a better correlation to target organ damage and cardiovascular morbidity-mortality than office blood pressure. A loss of arterial elasticity and an increase in carotid artery intima-media thickness (IMT has been associated with increased cardiovascular morbidity-mortality. Tools have been developed that allow estimation of the retinal arteriovenous index but not all studies coincide and there are contradictory results in relation to the evolution of the arteriosclerotic lesions and the caliber of the retinal vessels. The purpose of this study is to analyze the relationship between peripheral and central arterial pressure (clinic and ambulatory and vascular structure and function as evaluated by the carotid artery intima-media thickness, retina arteriovenous index, pulse wave velocity (PWV and ankle-brachial index in patients with and without type 2 diabetes. In turn, software is developed and validated for measuring retinal vessel thickness and automatically estimating the arteriovenous index. Methods/Design A cross-sectional study involving a control group will be made, with a posterior 4-year follow-up period in primary care. The study patients will be type 2 diabetics, with a control group of non-diabetic individuals. Consecutive sampling will be used to include 300 patients between 34-75 years of age and no previous cardiovascular disease, one-half being assigned to each group. Main measurements: age, gender, height, weight and abdominal circumference. Lipids, creatinine, microalbuminuria, blood glucose, HbA1c, blood insulin, high sensitivity C-reactive protein and endothelial dysfunction markers. Clinic and ambulatory blood pressure monitoring. Carotid ultrasound to evaluate IMT, and retinography to evaluate the arteriovenous index. ECG to assess left ventricle hypertrophy, ankle-brachial index, and pulse wave analysis (PWA and pulse wave velocity (PWV with the Sphigmocor

  4. Message in a Microbottle: Modulation of Vascular Inflammation and Atherosclerosis by Extracellular Vesicles.

    Science.gov (United States)

    van der Vorst, Emiel P C; de Jong, Renske J; Donners, Marjo M P C

    2018-01-01

    Extracellular vesicles (EVs) have emerged as a novel intercellular communication system. By carrying bioactive lipids, miRNAs and proteins they can modulate target cell functions and phenotype. Circulating levels of EVs are increased in inflammatory conditions, e.g., cardiovascular disease patients, and their functional contribution to atherosclerotic disease development is currently heavily studied. This review will describe how EVs can modulate vascular cell functions relevant to vascular inflammation and atherosclerosis, particularly highlighting the role of EV-associated proteolytic activity and effector proteins involved. Furthermore, we will discuss key questions and challenges, especially for EV-based therapeutics.

  5. Message in a Microbottle: Modulation of Vascular Inflammation and Atherosclerosis by Extracellular Vesicles

    Directory of Open Access Journals (Sweden)

    Emiel P. C. van der Vorst

    2018-01-01

    Full Text Available Extracellular vesicles (EVs have emerged as a novel intercellular communication system. By carrying bioactive lipids, miRNAs and proteins they can modulate target cell functions and phenotype. Circulating levels of EVs are increased in inflammatory conditions, e.g., cardiovascular disease patients, and their functional contribution to atherosclerotic disease development is currently heavily studied. This review will describe how EVs can modulate vascular cell functions relevant to vascular inflammation and atherosclerosis, particularly highlighting the role of EV-associated proteolytic activity and effector proteins involved. Furthermore, we will discuss key questions and challenges, especially for EV-based therapeutics.

  6. Pathophysiology of vascular dementia

    Directory of Open Access Journals (Sweden)

    Rizzo Claudia

    2009-11-01

    Full Text Available Abstract The concept of Vascular Dementia (VaD has been recognized for over a century, but its definition and diagnostic criteria remain unclear. Conventional definitions identify the patients too late, miss subjects with cognitive impairment short of dementia, and emphasize consequences rather than causes, the true bases for treatment and prevention. We should throw out current diagnostic categories and describe cognitive impairment clinically and according to commonly agreed instruments that document the demographic data in a standardized manner and undertake a systematic effort to identify the underlying aetiology in each case. Increased effort should be targeted towards the concept of and criteria for Vascular Cognitive Impairment and Post-Stroke Dementia as well as for genetic factors involved, especially as these categories hold promise for early prevention and treatment.

  7. Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice

    OpenAIRE

    Rao Benqiang; Hu Zhiwei; Chen Shimin; Duanmu Jinzhong

    2010-01-01

    Abstract Background The objective of this study was to develop a ligand-targeted photodynamic therapy (tPDT) by conjugating factor VII (fVII) protein with photosensitiser verteporfin in order to overcome the poor selectivity and enhance the effect of non-targeted PDT (ntPDT) for cancer. fVII is a natural ligand for receptor tissue factor (TF) with high affinity and specificity. The reason for targeting receptor TF for the development of tPDT is that TF is a common but specific target on angio...

  8. Diabetes and Retinal Vascular Dysfunction

    Directory of Open Access Journals (Sweden)

    Eui Seok Shin

    2014-01-01

    Full Text Available Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR. We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR.

  9. Enhanced vesicular stomatitis virus (VSVΔ51 targeting of head and neck cancer in combination with radiation therapy or ZD6126 vascular disrupting agent

    Directory of Open Access Journals (Sweden)

    Alajez Nehad M

    2012-06-01

    Full Text Available Abstract Background Head and neck squamous cell carcinoma (HNSCC is the 5th most common cancer worldwide. Locally advanced HNSCC are treated with either radiation or chemo-radiotherapy, but still associated with high mortality rate, underscoring the need to develop novel therapies. Oncolytic viruses have been garnering increasing interest as anti-cancer agents due to their preferential killing of transformed cells. In this study, we evaluated the therapeutic potential of mutant vesicular stomatitis virus (VSVΔ51 against the human hypopharyngeal FaDu tumour model in vitro and in vivo. Results Our data demonstrated high toxicity of the virus against FaDu cells in vitro, which was associated with induction of apoptosis. In vivo, systemic injection of 1 × 109 pfu had minimal effect on tumour growth; however, when combined with two doses of ionizing radiation (IR; 5 Gy each or a single injection of the vascular disrupting agent (ZD6126, the virus exhibited profound suppression of tumour growth, which translated to a prolonged survival in the treated mice. Concordantly, VSVΔ51 combined with ZD6126 led to a significant increase in viral replication in these tumours. Conclusions Our data suggest that the combinations of VSVΔ51 with either IR or ZD6126 are potentially novel therapeutic opportunities for HNSCC.

  10. A systematic review of economic evaluations of Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors, mammalian target of rapamycin inhibitors and Programmed Death-1 inhibitors in metastatic renal cell cancer.

    Science.gov (United States)

    Petrou, Panagiotis

    2018-02-16

    The therapeutic categories of Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors, mammalian target of rapamycin inhibitors and Programmed Death-1 inhibitors have transformed the treatment of metastatic renal cell cancer. Nevertheless, this comes at an increased cost, in tandem with similar fiscal pressures in the broader oncology sector, which may jeopardize the sustainability of health systems. Areas covered To this direction, the economic evaluation of these agents is essential for rational and efficient resource allocation. The aim of this study is to glean, assess and present an outline of the available cost-effectiveness studies of these agents in the management of metastatic renal cell cancer. Expert Commentary We concluded that the results of economic evaluation are pertinent, apart from the product under evaluation, to the country setting as well.

  11. Optimal treatment of vascular birthmarks.

    Science.gov (United States)

    Werner, Jochen A; Dünne, Anja A; Lippert, Burkard M; Folz, Benedikt J

    2003-01-01

    Optimal functional and cosmetic outcomes for vascular lesions require a thorough preoperative diagnosis of vascular anomalies, since correct classification of each vascular lesion has a direct influence on the treatment of choice. Many different classification systems have been discussed controversially. Based on clinical practicality and significant accuracy of forecast with regard to the clinical course of a lesion, Mulliken and Glowacki's biologic classification gained most clinical relevance and has become accepted as the official classification scheme by the International Society for the Study of Vascular Anomalies (ISSVA). Based on comprehensive description of relevant literature results, the current communication shall give an overview of differing, internationally accepted treatments. Although conservative management can be proposed for uncomplicated hemangiomas occurring in infancy, the proliferative progression of these lesions provides an adequate indication for treatment, while vascular malformations, which usually persist throughout life, always require therapeutic intervention if they start to cause clinical symptoms. Based on individual parameters (such as diameter, location and growth dynamics), different treatments, including cryotherapy, corticosteroids, laser therapy, sclerotherapy, surgery, and/or embolization, can be performed successfully. Currently, however, none of these treatments represents the solitary treatment of choice.

  12. Quantitative targeted and retrospective data analysis of relevant pesticides, antibiotics and mycotoxins in bakery products by liquid chromatography-single-stage Orbitrap mass spectrometry.

    Science.gov (United States)

    De Dominicis, Emiliano; Commissati, Italo; Gritti, Elisa; Catellani, Dante; Suman, Michele

    2015-01-01

    In addition to 'traditional' multi-residue and multi-contaminant multiple reaction monitoring (MRM) mass spectrometric techniques devoted to quantifying a list of targeted compounds, the global food industry requires non-targeted methods capable of detecting other possible potentially hazardous compounds. Ultra-high-performance liquid chromatography combined with a single-stage Orbitrap high-resolution mass spectrometer (UHPLC-HRMS Exactive™-Orbitrap Technology) was successfully exploited for the complete selective and quantitative determination of 33 target compounds within three major cross categories (pesticides, antibiotics and mycotoxins) in bakery matrices (specifically milk, wheat flour and mini-cakes). Resolution was set at 50 000 full width at half maximum (FWHM) to achieve the right compromise between an adequate scan speed and selectivity, allowing for the limitations related to the necessary generic sample preparation approach. An exact mass with tolerance of 5 ppm and minimum peak threshold of 10 000 units were fixed as the main identification conditions, including retention time and isotopic pattern as additional criteria devoted to greatly reducing the risk of false-positive findings. The full validation for all the target analytes was performed: linearity, intermediate repeatability and recovery (28 analytes within 70-120%) were positively assessed; furthermore, limits of quantification between 5 and 100 µg kg(-1) (with most of the analytes having a limit of detection below 6 µg kg(-1)) indicate good performance, which is compatible with almost all the regulatory needs. Naturally contaminated and fortified mini-cakes, prepared through combined use of industrial and pilot plant production lines, were analysed at two different concentration levels, obtaining good overall quantitative results and providing preliminary indications of the potential of full-scan HRMS cluster analysis. The effectiveness of this analytical approach was also tested in

  13. Biophysical characterization of Acacia caesia-fabricated silver nanoparticles: effectiveness on mosquito vectors of public health relevance and impact on non-target aquatic biocontrol agents.

    Science.gov (United States)

    Benelli, Giovanni; Kadaikunnan, Shine; Alharbi, Naiyf S; Govindarajan, Marimuthu

    2017-02-05

    Mosquito-borne diseases lead to serious public health concerns in tropical and sub-tropical countries worldwide, due to development of mosquito resistance to synthetic pesticides, non-target effects of pesticides, and socioeconomic reasons. Currently, green nanotechnology is a promising research field, showing a wide range of potential applications in vector control programs. The employ of natural products as reducing agents to fabricate insecticidal nanocomposites is gaining research attention worldwide, due to low costs and high effectiveness. Interestingly, biophysical features of green-synthesized nanoparticles strongly differ when different botanicals are employed for nanosynthesis. In this study, a cheap Acacia caesia leaf extract was employed to fabricate silver nanoparticles (Ag NPs) with ovicidal, larvicidal, and adulticidal toxicity against three mosquito vectors, Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus. Ag NPs were analyzed by various biophysical methods, including spectroscopy (UV-visible spectrophotometry, XRD, FTIR, EDX) and microscopy (SEM, TEM, AFM) techniques. High acute larvicidal potential was observed against larvae of An. subpictus (LC50 = 10.33 μg/ml), Ae. albopictus (LC50 = 11.32 μg/ml), and Cx. tritaeniorhynchus (LC50 = 12.35 μg/ml). Ag NPs completely inhibited egg hatchability on three vectors at 60, 75, and 90 μg/ml, respectively. In adulticidal assays, LD50 values were 18.66, 20.94, and 22.63 μg/ml. If compared to mosquito larvae, Ag NPs were safer to three non-target aquatic biocontrol agents, with LC50 ranging from 684 to 2245 μg/ml. Overall, our study highlights the potential of A. caesia as an abundant and cheap bioresource to fabricate biogenic Ag NPs effective against mosquito young instars and adults, with moderate impact on non-target aquatic biocontrol agents.

  14. In vivo tumor targeting and imaging with anti-vascular endothelial growth factor antibody-conjugated dextran-coated iron oxide nanoparticles.

    Science.gov (United States)

    Hsieh, Wan-Ju; Liang, Chan-Jung; Chieh, Jen-Jie; Wang, Shu-Huei; Lai, I-Rue; Chen, Jyh-Horng; Chang, Fu-Hsiung; Tseng, Wei-Kung; Yang, Shieh-Yueh; Wu, Chau-Chung; Chen, Yuh-Lien

    2012-01-01

    Active targeting by specific antibodies combined with nanoparticles is a promising technology for cancer imaging and detection by magnetic resonance imaging (MRI). The aim of the present study is to investigate whether the systemic delivery of antivascular endothelial growth factor antibodies conjugating to the surface of functionalized supermagnetic iron oxide nanoparticles (anti-VEGF-NPs) led to target-specific accumulation in the tumor. The VEGF expression in human colon cancer and in Balb/c mice bearing colon cancers was examined by immunohistochemistry. The distribution of these anti-VEGF-NPs particles or NPs particles were evaluated by MRI at days 1, 2, or 9 after the injection into the jugular vein of Balb/c mice bearing colon cancers. Tumor and normal tissues (liver, spleen, lung, and kidney) were collected and were examined by Prussian blue staining to determine the presence and distribution of NPs in the tissue sections. VEGF is highly expressed in human and mouse colon cancer tissues. MRI showed significant changes in the T*(2) signal and T(2) relaxation in the anti-VEGF-NP- injected-mice, but not in mice injected with NP alone. Examination of paraffin sections of tumor tissues stained for the iron constituent of the NPs with Prussian blue revealed a strong blue reaction in the tumors of anti-VEGF-NP-treated mice, but only a weak reaction in mice injected with NPs. In both groups, at all time points, Prussian blue-stained liver and spleen sections showed only light staining, while stained cells were rarely detected in kidney and lung sections. Transmission electron microscopy showed that many more electron-dense particles were present in endothelial cells, tumor cells, and extracellular matrix in tumor tissues in mice injected with anti-VEGF-NPs than in NP-injected mice. These results demonstrated in vivo tumor targeting and efficient accumulation of anti-VEGF-NPs in tumor tissues after systemic delivery in a colon cancer model, showing that anti

  15. Carbonic Anhydrase 9 Expression Increases with Vascular Endothelial Growth Factor–Targeted Therapy and Is Predictive of Outcome in Metastatic Clear Cell Renal Cancer

    Science.gov (United States)

    Stewart, Grant D.; O’Mahony, Fiach C.; Laird, Alexander; Rashid, Sukaina; Martin, Sarah A.; Eory, Lel; Lubbock, Alexander L.R.; Nanda, Jyoti; O’Donnell, Marie; Mackay, Alan; Mullen, Peter; McNeill, S. Alan; Riddick, Antony C.P.; Aitchison, Michael; Berney, Daniel; Bex, Axel; Overton, Ian M.; Harrison, David J.; Powles, Thomas

    2014-01-01

    Background There is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy. Objective To explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome. Design, setting, and participants Multiple frozen samples from primary tumours were taken from sunitinib-naïve (n = 22) and sunitinib-treated mccRCC patients (n = 23) for protein analysis. A cohort (n = 86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings. Intervention Three cycles of sunitinib 50 mg (4 wk on, 2 wk off). Outcome measurements and statistical analysis Reverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression. Results and limitations Differential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy. PMID:24821582

  16. Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Kathleen M. Keefe

    2017-03-01

    Full Text Available Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI. We focus on nerve growth factor (NGF, brain derived neurotrophic factor (BDNF, and neurotrophin-3 (NT-3, and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord.

  17. Network pharmacology-based and clinically relevant prediction of the active ingredients and potential targets of Chinese herbs in metastatic breast cancer patients.

    Science.gov (United States)

    Mao, Yu; Hao, Jian; Jin, Zi-Qi; Niu, Yang-Yang; Yang, Xue; Liu, Dan; Cao, Rui; Wu, Xiong-Zhi

    2017-04-18

    Chinese Herbal Medicine (CHM) plays a significant role in breast cancer treatment. We conduct the study to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV breast cancer.Survival benefit of CHM was verified by Kaplan-Meier method and Cox regression analysis. A bivariate correlation analysis was used to find and establish the effect of herbs in complex CHM formulas. A network pharmacological approach was adopted to explore the potential mechanisms of CHM.Patients in the CHM group had a median survival time of 55 months, which was longer than the 23 months of patients in the non-CHM group. Cox regression analysis indicated that CHM was an independent protective factor. Correlation analysis showed that 10 herbs were strongly correlated with favorable survival outcomes (Pherbs might achieve anti-breast cancer activity primarily through inhibiting HSP90, ERα and TOP-II related pathways.

  18. [Alzheimer's disease and vascular dementia].

    Science.gov (United States)

    Nagata, Ken

    2014-04-01

    Alzheimer's disease (AD) and vascular dementia (VaD) are the two major forms of dementia in the elderly, and they had been separated categorically on the basis of pathogenetic mechanisms and clinical operationalized criteria. However, it was claimed that this strict separation might steered toward the overdiagnosis of vascular dementia, this dichotomy has been reevaluated in the light of recent epidemiological and neuropathological knowledge. Cerebrovascular disease (CVD) is now considered as one of the vascular risk factors to the onset and evolution of Alzheimer's disease. Futhermore, the term "AD with CVD" has been used to classify patients fulfilling the clinical criteria for possible AD and who also present clinical or brain imaging evidence of relevant CVD.

  19. Recommendations for Developing Contextually Relevant HIV/AIDS Prevention Strategies Targeting African-Born Immigrants and Refugees in the United States.

    Science.gov (United States)

    Kingori, Caroline; Esquivel, Camila LeMaster; Hassan, Qorsho; Elmi, Abdul; Mukasa, Bakali; Reece, Michael

    2016-10-01

    African-born immigrants and refugees have HIV infection rates six times higher than any other minority groups in the United States. Despite the increase in the population size and diversity of Somali immigrants and refugees in the United States, Somalis are one of the medically underserved population subgroups in this region. The lack of aggregate HIV infection rates among African-born immigrants, for example, Somali refugees, is a cause for alarm and calls for more research to be conducted in this subgroup. The purpose of this article was to examine contextually relevant HIV prevention strategies that will enhance HIV prevention among Somali immigrant/refugee young adults in the United States. Using the grounded theory approach, a convenience sample of 27 immigrant/refugee young adults was recruited in central Ohio. Recommendations for potential HIV prevention strategies emerged under two main categories: (1) internal community resources and (2) external platforms. Study findings support a collaborative approach involving community leaders (parents, elders, religious leaders) and educational (schools), media, and healthcare settings to tailor HIV prevention strategies that meet the needs of the priority group.

  20. MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1.

    Science.gov (United States)

    Liu, Zhiguo; Liu, Yuguang; Li, Lianling; Xu, Zhenkuan; Bi, Baibin; Wang, Yunyan; Li, Jian Yi

    2014-10-01

    The aberrant expression of microRNAs (miRNAs) is always associated with tumor development and progression. Microvascular proliferation is one of the unique pathologic features of glioblastoma (GBM) . In this study, the microvasculature from GBM or normal brain tissue derived from neurosurgeries was purified and total RNA was isolated from purified microvasculature. The difference of miRNA expression profiles between glioblastoma microvasculature and normal brain capillaries was investigated. It was found that miR-7-5p in GBM microvessels was significantly reduced compared with that in normal brain capillaries. In the in vitro experiments, overexpression of miR-7-5p significantly inhibited human umbilical vein endothelial cell proliferation. Forced expression of miR-7-5p in human umbilical vein endothelial cells in vitro significantly reduced the protein level of RAF1 and repressed the activity of the luciferase, a reporter vector carrying the 3'-untranslated region of RAF1. These findings indicate that RAF1 is one of the miR-7-5p target genes. Furthermore, a significant inverse correlation between miR-7-5p expression and RAF1 protein level in GBM microvasculature was found. These data suggest that miR-7-5p functions as a tumor suppressor gene to regulate GBM microvascular endothelial cell proliferation potentially by targeting the RAF1 oncogene, implicating an important role for miR-7-5p in the pathogenesis of GBM. It may serve as a guide for the antitumor angiogenesis drug development.

  1. Protecting against vascular disease in brain

    Science.gov (United States)

    2011-01-01

    Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease. PMID:21335467

  2. Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2–mediated angiogenesis

    Science.gov (United States)

    2013-01-01

    Background Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo. Methods We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo. Results Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. Conclusion Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies. PMID:23895055

  3. Vascular calcification: Inducers and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Donghyun, E-mail: dhlee@cau.ac.kr [Department of Biomedical Engineering, Division of Integrative Engineering, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756 (Korea, Republic of)

    2011-09-15

    Highlights: {center_dot} Types of vascular calcification processes. {center_dot} Inducers of vascular calcification. {center_dot} Inhibitors of vascular calcifications. {center_dot} Clinical utility for vascular calcification therapy. {center_dot} Implications for the development of new tissue engineering strategies. - Abstract: Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.

  4. Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.

    Science.gov (United States)

    Nectoux, J; Fichou, Y; Rosas-Vargas, H; Cagnard, N; Bahi-Buisson, N; Nusbaum, P; Letourneur, F; Chelly, J; Bienvenu, T

    2010-07-01

    More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

  5. CDC25A Protein Stability Represents a Previously Unrecognized Target of HER2 Signaling in Human Breast Cancer: Implication for a Potential Clinical Relevance in Trastuzumab Treatment

    Directory of Open Access Journals (Sweden)

    Emanuela Brunetto

    2013-06-01

    Full Text Available The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2 in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007. Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005. Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort. Our findings highlight a link between HER2 and CDC25A that positively modulates HER2- targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

  6. Korrek, volledig, relevant

    DEFF Research Database (Denmark)

    Bergenholtz, Henning; Gouws, Rufus

    2007-01-01

    as detrimental to the status of a dictionary as a container of linguistic knowledge. This paper shows that, from a lexicographic perspective, such a distinction is not relevant. What is important is that definitions should contain information that is relevant to and needed by the target users of that specific......In explanatory dictionaries, both general language dictionaries and dictionaries dealing with languages for special purposes, the lexicographic definition is an important item to present the meaning of a given lemma. Due to a strong linguistic bias, resulting from an approach prevalent in the early...

  7. Polyphenolics from açaí ( Euterpe oleracea Mart.) and red muscadine grape (Vitis rotundifolia ) protect human umbilical vascular Endothelial cells (HUVEC) from glucose- and lipopolysaccharide (LPS)-induced inflammation and target microRNA-126.

    Science.gov (United States)

    Noratto, Giuliana D; Angel-Morales, Gabriela; Talcott, Stephen T; Mertens-Talcott, Susanne U

    2011-07-27

    Endothelial anti-inflammatory effects of açaí (Ac) and red muscadine grape (Gp) polyphenolics have not been extensively investigated. It was hypothesized that polyphenolics from Ac and Gp exert comparable protective effects in human vascular endothelial cells (HUVEC) upon inflammatory stress. Furthermore, this study investigated whether microRNAs relevant to endothelial function might be regulated by Ac and Gp. Results showed that Ac and Gp (5-20 mg gallic acid equivalent/L) protected HUVEC against glucose-induced oxidative stress and inflammation. Glucose-induced expression of interleukin-6 and -8 was down-regulated by Ac and Gp at mRNA and protein levels. Upon lipopolysaccharide (LPS; 1 μg/L)-induced inflammation, Ac and Gp inhibited gene expression of adhesion molecules and NF-κB activation to similar extents, although Gp was more effective in decreasing PECAM-1 and ICAM-1 protein. Of the screened microRNAs, only microRNA-126 expression was found to be modulated by Ac and Gp as the underlying mechanism to inhibit gene and protein expression of VCAM-1.

  8. Pediatric vascularized composite allotransplantation.

    Science.gov (United States)

    Doumit, Gaby; Gharb, Bahar Bassiri; Rampazzo, Antonio; Papay, Francis; Siemionow, Maria Z; Zins, James E

    2014-10-01

    Vascularized composite allotransplantation (VCA) has experienced a growing acceptance, which has led to a debate centered on extending the indications of the procedure to include pediatric patients. The aim of this article was to discuss such indications based on the evidence in pediatric solid organ transplantation, reconstructive surgery in children, and VCA in adult patients. Papers published on the outcomes of pediatric solid organ transplantation, growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, facial fractures, and outcomes after repair of peripheral nerves in children were reviewed. Although the outcomes of solid organ transplantation in children have improved, the transplanted organs continue to have a limited lifespan. Long-term immunosuppressive therapy exposes the patients to an increased lifetime risk of infections, diabetes, hypertension, dyslipidemia, cardiovascular disease, and malignancy. Growth impairment and learning disabilities are other relevant drawbacks, which affect the pediatric recipients. Nonadherence to medication is a common cause of graft dysfunction and loss among the adolescent transplant recipients. Rejection episodes, hospitalizations, and medication adverse effects contribute negatively to the quality of life of the patients. Although normal growth after limb transplantation could be expected, pediatric facial transplant recipients may present with arrest of growth of transplanted midfacial skeleton. Considering the non-life-threatening nature of the conditions that lead to eligibility for VCA, it is suggested that it is premature to extend the indications of VCA to include pediatric patients under the currently available immunosuppressive protocols.

  9. Proatherogenic pathways leading to vascular calcification

    Energy Technology Data Exchange (ETDEWEB)

    Mazzini, Michael J. [Department of Cardiology, Boston University Medical Center, Boston, MA (United States); Schulze, P. Christian [Department of Medicine, Boston University Medical Center, Boston, MA (United States)]. E-mail: christian.schulze@bmc.org

    2006-03-15

    Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. The pathogenesis of atherosclerosis involves local vascular injury, inflammation and oxidative stress as well as vascular calcification. Vascular calcification has long been regarded as a degenerative process leading to mineral deposition in the vascular wall characteristic for late stages of atherosclerosis. However, recent studies identified vascular calcification in early stages of atherosclerosis and its occurrence has been linked to clinical events in patients with cardiovascular disease. Its degree correlates with local vascular inflammation and with the overall impact and the progression of atherosclerosis. Over the last decade, diverse and highly regulated molecular signaling cascades controlling vascular calcification have been described. Local and circulating molecules such as osteopontin, osteoprogerin, leptin and matrix Gla protein were identified as critical regulators of vascular calcification. We here review the current knowledge on molecular pathways of vascular calcification and their relevance for the progression of cardiovascular disease.

  10. Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation.

    Science.gov (United States)

    Shawky, Noha M; Segar, Lakshman

    2017-05-01

    Activation of nuclear factor erythroid 2-related factor 2 (Nrf2, a transcription factor) and/or inhibition of mammalian target of rapamycin (mTOR) are implicated in the suppression of vascular smooth muscle cell (VSMC) proliferation. The present study has examined the likely regulatory effects of sulforaphane (SFN, an antioxidant) on Nrf2 activation and platelet-derived growth factor (PDGF)-induced mTOR signaling in VSMCs. Using human aortic VSMCs, nuclear extraction and siRNA-mediated downregulation studies were performed to determine the role of Nrf2 on SFN regulation of PDGF-induced proliferative signaling. Immunoprecipitation and/or immunoblot studies were carried out to determine how SFN regulates PDGF-induced mTOR/p70S6K/S6 versus ERK and Akt signaling. Immunohistochemical analysis was performed to determine SFN regulation of S6 phosphorylation in the injured mouse femoral artery. SFN (5μM) inhibits PDGF-induced activation of mTOR without affecting mTOR association with raptor in VSMCs. While SFN inhibits PDGF-induced phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTOR), it does not affect ERK or Akt phosphorylation. In addition, SFN diminishes exaggerated phosphorylation of S6 ribosomal protein (a downstream target of p70S6K) in VSMCs in vitro and in the neointimal layer of injured artery in vivo. Although SFN promotes Nrf2 accumulation to upregulate cytoprotective genes (e.g., heme oxygenase-1 and thioredoxin-1), downregulation of endogenous Nrf2 by target-specific siRNA reveals an Nrf2-independent effect for SFN-mediated inhibition of mTOR/p70S6K/S6 signaling and suppression of VSMC proliferation. Strategies that utilize local delivery of SFN at the lesion site may limit restenosis after angioplasty by targeting mTOR/p70S6K/S6 axis in VSMCs independent of Nrf2 activation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Repeated Measurement of Absolute and Relative Judgments of Loudness: Clinical Relevance for Prescriptive Fitting of Aided Target Gains for soft, Comfortable, and Loud, But Ok Sound Levels.

    Science.gov (United States)

    Formby, Craig; Payne, JoAnne; Yang, Xin; Wu, Delphanie; Parton, Jason M

    2017-02-01

    judgments bisect the measured levels judged for soft and for loud, but OK sounds. (4) Loudness judgments within the same loudness category varied across listeners within group by as much as 50 to 60 dB. Such large variation in judgments of loudness is problematic, especially because hearing-impaired listeners are known to exhibit similarly large ranges of intersubject response variation and, yet, poplar prescriptive fitting strategies continue to use average rather than individual loudness data to fit nonlinear hearing aids. The primary conclusions drawn from these findings are that reliable absolute judgments of soft and loud, but OK are clinically practical and economical to measure and, from these judgments, good estimates of comfortable loudness can also be predicted for individuals or for groups of listeners. Such loudness data, as measured as described in this report, offer promise for streamlining and enhancing prescriptive fitting of nonlinear hearing aids to target gain settings for soft (audible), comfortable, and loud, but OK (tolerable) sound inputs for the individual listener.

  12. Plant Vascular Biology 2013: vascular trafficking.

    Science.gov (United States)

    Ursache, Robertas; Heo, Jung-Ok; Helariutta, Ykä

    2014-04-01

    About 200 researchers from around the world attended the Third International Conference on Plant Vascular Biology (PVB 2013) held in July 2013 at the Rantapuisto Conference Center, in Helsinki, Finland (http://www.pvb2013.org). The plant vascular system, which connects every organ in the mature plant, continues to attract the interest of researchers representing a wide range of disciplines, including development, physiology, systems biology, and computational biology. At the meeting, participants discussed the latest research advances in vascular development, long- and short-distance vascular transport and long-distance signalling in plant defence, in addition to providing a context for how these studies intersect with each other. The meeting provided an opportunity for researchers working across a broad range of fields to share ideas and to discuss future directions in the expanding field of vascular biology. In this report, the latest advances in understanding the mechanism of vascular trafficking presented at the meeting have been summarized.

  13. The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases.

    Science.gov (United States)

    Ta, Hang T; Truong, Nghia P; Whittaker, Andrew K; Davis, Thomas P; Peter, Karlheinz

    2018-01-01

    Vascular-targeted drug delivery is a promising approach for the treatment of atherosclerosis, due to the vast involvement of endothelium in the initiation and growth of plaque, a characteristic of atherosclerosis. One of the major challenges in carrier design for targeting cardiovascular diseases (CVD) is that carriers must be able to navigate the circulation system and efficiently marginate to the endothelium in order to interact with the target receptors. Areas covered: This review draws on studies that have focused on the role of particle size, shape, and density (along with flow hemodynamics and hemorheology) on the localization of the particles to activated endothelial cell surfaces and vascular walls under different flow conditions, especially those relevant to atherosclerosis. Expert opinion: Generally, the size, shape, and density of a particle affect its adhesion to vascular walls synergistically, and these three factors should be considered simultaneously when designing an optimal carrier for targeting CVD. Available preliminary data should encourage more studies to be conducted to investigate the use of nano-constructs, characterized by a sub-micrometer size, a non-spherical shape, and a high material density to maximize vascular wall margination and minimize capillary entrapment, as carriers for targeting CVD.

  14. The anti-diabetic drug metformin inhibits vascular endothelial growth factor expression via the mammalian target of rapamycin complex 1/hypoxia-inducible factor-1α signaling pathway in ELT-3 cells.

    Science.gov (United States)

    Tadakawa, Mari; Takeda, Takashi; Li, Bin; Tsuiji, Kenji; Yaegashi, Nobuo

    2015-01-05

    The aim of this study was to elucidate whether metformin can regulate the expression of vascular endothelial growth factor (VEGF) in rat-derived uterine leiomyoma cells (ELT-3 cells). In vitro studies were conducted using ELT-3 cells. Under normoxic conditions, metformin suppressed VEGF protein levels in the supernatant and cells in a dose-dependent manner. In hypoxia-mimicking conditions, VEGF and hypoxia-inducible factor-1α (HIF-1α) proteins were both highly expressed and were suppressed by the metformin treatment. Metformin did not affect HIF-1α mRNA levels, which indicated that its effects occurred at the post-translational level. Metformin inhibited mammalian target of rapamycin complex 1 (mTORC1) activity by phosphorylating the mTORC1 component raptor. This study revealed the anti-angiogenic activity of metformin in ELT-3 cells by suppressing the expression of VEGF via the mTORC1/HIF-1α pathway. These results indicate that metformin may represent an effective alternative in the future treatment of uterine leiomyomas. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream pathways of receptor tyrosine kinases involving phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine hemangiosarcoma cell lines.

    Science.gov (United States)

    Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Sakai, Hiroki; Takagi, Satoshi

    2016-07-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm with no current effective treatment. Previous studies showed that receptor tyrosine kinases and molecules within their downstream pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (m-TOR) or mitogen-activated protein kinase (MAPK) were overexpressed in canine, human, and murine tumors, including HSA. The present study investigated the effects of inhibitors of these pathways in canine splenic and hepatic HSA cell lines using assays of cell viability and apoptosis. Inhibitors of the MAPK pathway did not affect canine HSA cell viability. However, cell viability was significantly reduced by exposure to inhibitors of vascular endothelial growth factor receptor 2 and the PI3K/Akt/m-TOR pathway; these inhibitors also induced apoptosis in these cell lines. These results suggest that these inhibitors reduce the proliferation of canine HSA cells by inducing apoptosis. Further study of these inhibitors, using xenograft mouse models of canine HSA, are warranted to explore their potential for clinical application.

  16. MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.

    Science.gov (United States)

    Zhang, Zi-Wei; Guo, Rui-Wei; Lv, Jin-Lin; Wang, Xian-Mei; Ye, Jin-Shan; Lu, Ni-Hong; Liang, Xing; Yang, Li-Xia

    2017-04-29

    Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Vascular pathology in the throwing athlete.

    Science.gov (United States)

    Dugas, J R; Weiland, A J

    2000-08-01

    Vascular pathology in the upper extremity of a throwing athlete comprises a spectrum of serious disorders apt to threaten the patient's career and the viability of the involved parts. Such pathology includes digital vessel thrombosis, proximal thrombosis with distal embolization, vessel aneurysm, and vessel compression, such as in thoracic outlet syndrome and quadrilateral space syndrome. This article provides a description of vascular disorders prone to result from sports activities and a review of published data relevant to throwing athletes. Recognition of vascular compromise as a cause for dead arm syndrome or painful digital dysfunction among athletes is essential to prevent the grave consequences of progressive ischemia.

  18. Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

    NARCIS (Netherlands)

    Kuijper, Arno; Groep, P. van der; Wall, E. van der; Diest, P.J. van

    2005-01-01

    INTRODUCTION Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance

  19. Vascular complications in orthopedic surgery.

    Science.gov (United States)

    Chervu, A; Quinones-Baldrich, W J

    1988-10-01

    Vascular complications may be seen secondary to trauma or in the perioperative period following elective surgery. Prompt recognition and correction of these problems are of utmost importance to assure functional viability of the affected extremity. Evaluation may be complicated by the presence of preexisting atherosclerotic occlusive disease in the elderly patient. Relevant points in the history and physical examination include mechanism of injury, preexisting disease, evaluation of motor and sensory function, and presence and character of pulses. Noninvasive vascular studies should be obtained in all patients. Absolute indications for angiography include absent pulses, signs and symptoms of ischemia, a bruit, and a posterior knee dislocation; decreased pulses, a significant hematoma, and proximity of the fracture fragment are relative indications. Controversial issues in the management of combined orthopedic and vascular injuries include the use of internal versus external fixation, the use of prosthetic versus autogenous material, and the need for venous reconstruction. Popliteal artery trauma is still associated with a high limb loss rate, and careful evaluation of knee injuries is necessary. Vascular compromise may also complicate joint replacement surgery. These complications are preventable, and management is greatly simplified by a detailed preoperative evaluation.

  20. Collagen vascular disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001223.htm Collagen vascular disease To use the sharing features on this page, ... previously said to have "connective tissue" or "collagen vascular" disease. We now have names for many specific conditions ...

  1. Mechanisms of Vascular Aging: New Perspectives

    Science.gov (United States)

    Kaley, Gabor; de Cabo, Rafael; Sonntag, William E.; Csiszar, Anna

    2010-01-01

    This review focuses on molecular, cellular, and functional changes that occur in the vasculature during aging; explores the links between mitochondrial oxidative stress, inflammation, and development of vascular disease in the elderly patients; and provides a landscape of molecular mechanisms involved in cellular oxidative stress resistance, which could be targeted for the prevention or amelioration of unsuccessful vascular aging. Practical interventions for prevention of age-associated vascular dysfunction and disease in old age are considered here based on emerging knowledge of the effects of anti-inflammatory treatments, regular exercise, dietary interventions, and caloric restriction mimetics. PMID:20576649

  2. Bypass materials in vascular surgery

    Directory of Open Access Journals (Sweden)

    Willich, Stephan N.

    2006-03-01

    Full Text Available Introduction: Arteriosclerotic changes can lead to circulatory disturbances in various areas of the human vascular system. In addition to pharmacological therapy and the management of risk factors (e. g. hypertension, diabetes, lipid metabolism disorders, and lifestyle, surgical interventions also play an important role in the treatment of arteriosclerosis. Long-segment arterial occlusions, in particular, can be treated successfully with bypass sur-gery. A number of different materials are available for this type of operation, such as autologous vein or pros-thetic grafts comprised of polytetrafluoroethylene (PTFE or Dacron®. Prosthetic materials are used especially in the treatment of peripheral artery disease, such as in aortoiliac or femoropopliteal bypass surgery. The present report will thus focus on this area in order to examine the effectiveness of different bypass materials. Among the efforts being made to refine the newly introduced DRG system in Germany, analysing the different bypass materials used in vascular surgery is particularly important. Indeed, in its current version the German DRG system does not distinguish between bypass materials in terms of reimbursement rates. Differences in cost structures are thus of especial interest to hospitals in their budget calculations, whereas both private and statutory health insurance funds are primarily interested in long-term results and their costs. Objectives: The goal of this HTA is to compare the different bypass materials used in vascular surgery in terms of their medical efficiency and cost-effectiveness, as well as with regard to their ethical, social and legal implications. In addition, this report aims to point out the areas in which further medical, epidemiological and health economic research is still needed. Methods: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information

  3. Clinical Relevance of Adipokines

    Directory of Open Access Journals (Sweden)

    Matthias Blüher

    2012-10-01

    Full Text Available The incidence of obesity has increased dramatically during recent decades. Obesity increases the risk for metabolic and cardiovascular diseases and may therefore contribute to premature death. With increasing fat mass, secretion of adipose tissue derived bioactive molecules (adipokines changes towards a pro-inflammatory, diabetogenic and atherogenic pattern. Adipokines are involved in the regulation of appetite and satiety, energy expenditure, activity, endothelial function, hemostasis, blood pressure, insulin sensitivity, energy metabolism in insulin sensitive tissues, adipogenesis, fat distribution and insulin secretion in pancreatic β-cells. Therefore, adipokines are clinically relevant as biomarkers for fat distribution, adipose tissue function, liver fat content, insulin sensitivity, chronic inflammation and have the potential for future pharmacological treatment strategies for obesity and its related diseases. This review focuses on the clinical relevance of selected adipokines as markers or predictors of obesity related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.

  4. World Federation of Vascular Societies: presidential address

    DEFF Research Database (Denmark)

    Sillesen, Henrik Hegaard

    2010-01-01

    The presidential address describes briefly the history of the World Federation for Vascular Societies (WFVS) and its objectives. Vascular Surgery today includes interventional procedures (open surgical and endovascular) in addition to risk factor reduction and medical treatment. It is equally imp...... throughout the world. In addition, for introduction of new treatments, training issues and dissemination of science a global organisation like the WFVS is needed.......The presidential address describes briefly the history of the World Federation for Vascular Societies (WFVS) and its objectives. Vascular Surgery today includes interventional procedures (open surgical and endovascular) in addition to risk factor reduction and medical treatment. It is equally....... Similar, in order to be able to train with relevant case mix and numbers, and in order always to have both complex open and endovascular skills on call 24 hours per day, 365 days a year, centralisation into larger units is necessary. The WFVS is important simply looking at the huge demographic differences...

  5. [Menopause: Hypertension and vascular disease].

    Science.gov (United States)

    Zilberman, J M

    2018-01-28

    Hypertension is the main cardiovascular risk factor affecting 25% of women. Hormone changes and hypertension after menopause may lead to higher target organ damage and cardiovascular disease such as increased arterial stiffness, coronary diseases, chronic heart failure and stroke. The physiopathological mechanisms involved in the development of hypertension and cardiovascular diseases in menopausal women are controversial. There are pharmacokinetic and pharmacodynamic differences in both sexes, the women have more coughing when using the converting-enzyme inhibitors, more cramps when using thiazide diuretics and more oedema in the inferior limbs when using calcium antagonists. The aim of this review is to analyse possible physiopathological mechanisms involved in hypertension after menopause and to gain a better understanding of the biological effects mediated by vascular ageing in women when the level of oestrogen protective effect decreases over the vascular system. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    National Research Council Canada - National Science Library

    Chen, Bin; He, Chong

    2006-01-01

    .... We found that vascular targeting photodynamic therapy (PDT), a modality involving the combination of a photosensitizer and laser light, is able to disrupt tumor vascular barrier, a significant hindrance to drug delivery...

  7. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    National Research Council Canada - National Science Library

    Chen, Bin; He, Chong

    2007-01-01

    .... We found that vascular targeting photodynamic therapy (PDT), a modality involving the combination of a photosensitizer and laser light, is able to disrupt tumor vascular barrier, a significant hindrance to drug delivery...

  8. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

    Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

    2000-01-01

    The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... was moderately reproduced (kappa = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all...

  9. Uterine vascular lesions.

    Science.gov (United States)

    Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

    2013-01-01

    Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management.

  10. Vascular biology of preeclampsia.

    Science.gov (United States)

    Myatt, L; Webster, R P

    2009-03-01

    Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, resolves on delivery of the placenta. Normal pregnancy is itself characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. This is exacerbated in preeclampsia with an associated breakdown of compensatory mechanisms, eventually leading to placental and vascular dysfunction. The underlying pathology of preeclampsia is thought to be a relatively hypoxic or ischemic placenta. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can interact to produce peroxynitrite a powerful prooxidant that covalently modifies proteins by nitration of tyrosine residues, to possibly alter vascular function in preeclampsia. The linkage between placental hypoxia and maternal vascular dysfunction has been proposed to be via placental syncytiotrophoblast basement membranes shed by the placenta or via angiogenic factors which include soluble flt1 and endoglin secreted by the placenta that bind vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in the maternal circulation. There is also abundant evidence of altered reactivity of the maternal and placental vasculature and of the altered production of autocoids in preeclampsia. The occurrence of preeclampsia is increased in women with preexisting vascular disease and confers a long-term risk for development of cardiovascular disease. The vascular stress test of pregnancy thus identifies those women with a previously unrecognized at risk vascular system and promotes the development of preeclampsia. Preexisting maternal vascular dysfunction intensified by placental factors is possibly responsible for the individual pathologies of preeclampsia.

  11. Nanotechnology and its relationship to interventional radiology. Part II: Drug Delivery, Thermotherapy, and Vascular Intervention.

    Science.gov (United States)

    Power, Sarah; Slattery, Michael M; Lee, Michael J

    2011-08-01

    Nanotechnology can be defined as the design, creation, and manipulation of structures on the nanometer scale. This two-part review is intended to acquaint the interventionalist with the field of nanotechnology, and provide an overview of potential applications, while highlighting advances relevant to interventional radiology. Part 2 of the article concentrates on drug delivery, thermotherapy, and vascular intervention. In oncology, advances in drug delivery allow for improved efficacy, decreased toxicity, and greater potential for targeted therapy. Magnetic nanoparticles show potential for use in thermotherapy treatments of various tumours, and the effectiveness of radiofrequency ablation can be enhanced with nanoparticle chemotherapy agents. In vascular intervention, much work is focused on prevention of restenosis through developments in stent technology and systems for localised drug delivery to vessel walls. Further areas of interest include applications for thrombolysis and haemostasis.

  12. Nanotechnology and its relationship to interventional radiology. Part II: Drug Delivery, Thermotherapy, and Vascular Intervention.

    LENUS (Irish Health Repository)

    Power, Sarah

    2012-02-01

    Nanotechnology can be defined as the design, creation, and manipulation of structures on the nanometer scale. This two-part review is intended to acquaint the interventionalist with the field of nanotechnology, and provide an overview of potential applications, while highlighting advances relevant to interventional radiology. Part 2 of the article concentrates on drug delivery, thermotherapy, and vascular intervention. In oncology, advances in drug delivery allow for improved efficacy, decreased toxicity, and greater potential for targeted therapy. Magnetic nanoparticles show potential for use in thermotherapy treatments of various tumours, and the effectiveness of radiofrequency ablation can be enhanced with nanoparticle chemotherapy agents. In vascular intervention, much work is focused on prevention of restenosis through developments in stent technology and systems for localised drug delivery to vessel walls. Further areas of interest include applications for thrombolysis and haemostasis.

  13. Nanotechnology and its Relationship to Interventional Radiology. Part II: Drug Delivery, Thermotherapy, and Vascular Intervention.

    LENUS (Irish Health Repository)

    Power, Sarah

    2010-09-16

    Nanotechnology can be defined as the design, creation, and manipulation of structures on the nanometer scale. This two-part review is intended to acquaint the interventionalist with the field of nanotechnology, and provide an overview of potential applications, while highlighting advances relevant to interventional radiology. Part 2 of the article concentrates on drug delivery, thermotherapy, and vascular intervention. In oncology, advances in drug delivery allow for improved efficacy, decreased toxicity, and greater potential for targeted therapy. Magnetic nanoparticles show potential for use in thermotherapy treatments of various tumours, and the effectiveness of radiofrequency ablation can be enhanced with nanoparticle chemotherapy agents. In vascular intervention, much work is focused on prevention of restenosis through developments in stent technology and systems for localised drug delivery to vessel walls. Further areas of interest include applications for thrombolysis and haemostasis.

  14. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

    Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

    2000-01-01

    years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...

  15. Why relevance theory is relevant for lexicography

    DEFF Research Database (Denmark)

    Bothma, Theo; Tarp, Sven

    2014-01-01

    This article starts by providing a brief summary of relevance theory in information science in relation to the function theory of lexicography, explaining the different types of relevance, viz. objective system relevance and the subjective types of relevance, i.e. topical, cognitive, situational...... that is very important for lexicography as well as for information science, viz. functional relevance. Since all lexicographic work is ultimately aimed at satisfying users’ information needs, the article then discusses why the lexicographer should take note of all these types of relevance when planning a new...... dictionary project, identifying new tasks and responsibilities of the modern lexicographer. The article furthermore discusses how relevance theory impacts on teaching dictionary culture and reference skills. By integrating insights from lexicography and information science, the article contributes to new...

  16. Vascular cognitive impairment and vascular dementia

    Directory of Open Access Journals (Sweden)

    Klavdija Ovčar

    2017-09-01

    Full Text Available In the developed world, five to ten percent of people older than 65 years have dementia. One fifth of dementia etiologies are due to vascular brain lesions (VaD – vascular dementia. A milder form is called vascular cognitive impairment (VCI. The main clinical criteria for VaD are: 1. cognitive decline verified with standardized cognitive test/scale, 2. evidence of the associated vascular brain lesion, 3. excluded reversible causes of cognitive decline. The main risk factors for VaD are age, atherosclerosis, diabetes and hypertension. They play a key role in pathogenesis of the cognitive impairment. Depending on the damaged brain region, different cognitive domains may be affected with or without other neurological signs. These diversities in the clinical picture challenge the correct diagnosis. Unique feature of VaD is its progression, which can be stopped, if patients receive an appropriate treatment.The treatment of VCI and VaD symptoms is similar to that in Alzheimer’s disease. More importantly, VCI may be slowed down or even stopped with proper secondary stroke prevention and good rehabilitation. The most efficient is primary stroke prevention with healthy lifestyle and treatment of acquired risk factors.

  17. Vascular disease burden in Indian subjects with vascular dementia.

    Science.gov (United States)

    Chandra, Mina; Anand, Kuljeet Singh

    2015-01-01

    Vascular disease factors like hypertension, diabetes mellitus, dyslipidaemia, and ischaemic heart disease contribute to the development of vascular dementia. As comorbidity of vascular disease factors in vascular dementia is common, we investigated the vascular disease burden in subjects with vascular dementia. To investigate the vascular disease burden due to four vascular disease factors: hypertension, diabetes mellitus, dyslipidaemia, and ischaemic heart disease in Indian subjects with vascular dementia. In this study, 159 subjects with probable vascular dementia (as per NINDS-AIREN criteria) attending the memory clinic at a tertiary care hospital were assessed for the presence of hypertension, diabetes mellitus, dyslipidaemia, and ischaemic heart disease using standardised operational definitions and for severity of dementia on the Clinical Dementia Rating (CDR) scale. The data obtained was subjected to appropriate statistical analysis. Dyslipidaemia (79.25 per cent) was the most common vascular disease factor followed by hypertension (73.58 per cent), ischaemic heart disease (58.49 per cent), and diabetes mellitus (40.80 per cent). Most subjects (81.1 per cent) had two or more vascular disease factors. Subjects with more severe dementia had more vascular disease factors (sig 0.001). People with moderate to severe dementia have a significantly higher vascular disease burden; therefore, higher vascular disease burden may be considered as a poor prognostic marker in vascular dementia. Subjects with vascular dementia and their caregivers must manage cognitive impairment and ADL alongside managing serious comorbid vascular diseases that may worsen the dementia.

  18. Vascular remodelling in asthma.

    Science.gov (United States)

    Walters, Eugene Haydn; Soltani, Amir; Reid, David William; Ward, Chris

    2008-02-01

    We review the recent literature, focusing on 2006 and 2007, to produce an update on the patho-biology of angiogenesis and vascular endothelial growth factor in the asthmatic airway. In terms of conceptual development in asthma research, airway inflammation and remodelling have been regarded as separate processes or perhaps as sequential, with early inflammation leading later to remodelling. Recent insights identify a central role for vascular endothelial growth factor in stimulating both inflammation and vascular remodelling coincidentally, with the full panoply of vascular endothelial growth factor mediated events being complex and wide. Both nitric oxide and matrix metalloproteinase-9 induction may be important downstream pathogenic mechanisms. Virus-mediated exacerbations are a prime manifestation of the oscillating trajectory of clinical asthma. The early stimulation of vascular endothelial growth factor production is probably a central aetiological mechanism, with secondary inflammation and angiogenesis. The time scale of the latter, especially, fits with the time scale of clinico-physiological changes after exacerbation. These vascular endothelial growth factor induced changes are potentially modifiable with therapy. Insights into the importance of vascular endothelial growth factor and angiogenesis in asthma pathogenesis now lead to potential new therapeutic possibilities and elucidate why recent advances in asthma therapeutics have been so successful.

  19. Deep learning relevance

    DEFF Research Database (Denmark)

    Lioma, Christina; Larsen, Birger; Petersen, Casper

    2016-01-01

    train a Recurrent Neural Network (RNN) on existing relevant information to that query. We then use the RNN to "deep learn" a single, synthetic, and we assume, relevant document for that query. We design a crowdsourcing experiment to assess how relevant the "deep learned" document is, compared...... to existing relevant documents. Users are shown a query and four wordclouds (of three existing relevant documents and our deep learned synthetic document). The synthetic document is ranked on average most relevant of all....

  20. Targeted Temperature Management at 33°C Versus 36°C and Impact on Systemic Vascular Resistance and Myocardial Function After Out-of-Hospital Cardiac Arrest

    DEFF Research Database (Denmark)

    Bro-Jeppesen, John; Hassager, Christian; Wanscher, Michael

    2014-01-01

    BACKGROUND: Cardiovascular dysfunction is common after out-of-hospital cardiac arrest as part of the postcardiac arrest syndrome, and hypothermia may pose additional impact on hemodynamics. The aim was to investigate systemic vascular resistance index (SVRI), cardiac index, and myocardial perform...... because of lower heart rate with unaffected left ventricular systolic function compared with 36°C. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01020916....

  1. Understanding Vascular Endothelium

    OpenAIRE

    Gimbrone, Michael A.

    2014-01-01

    Understanding Vascular Endothelium : Nature’s Container for Blood The entire cardiovascular system, from the chambers of the heart to the smallest capillaries of peripheral tissues, is lined by a single-cell-thick continuous layer—the vascular endothelium. For many years, this gossamer membrane was thought to function largely as an inert barrier, passively separating the reactive components of the circulating blood from the cells and connective tissue matrix of the various organs of the body....

  2. Hypercholesterolaemia and vascular dementia

    OpenAIRE

    Appleton, Jason P.; Scutt, Polly; Sprigg, Nikola; Bath, Philip M.

    2017-01-01

    Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors–diabetes, hypercholesterolaemia, hypertension and smoking–are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet no...

  3. Unravelling the complexities of vascular smooth muscle ion channels

    DEFF Research Database (Denmark)

    Jepps, Thomas A

    2017-01-01

    Which ion channel is the most important for regulating vascular tone? Which one is responsible for controlling the resting membrane potential or repolarization? Which channels are recruited by different intracellular signalling pathways or change in certain vascular diseases? Many different ion...... to off-target effects. As cardiovascular diseases are expected to increase worldwide to epidemic proportions, ion channel research and the hunt for the next major therapeutic target to treat different vascular diseases has never been more important. However, I believe that the question we should now...

  4. Antioxidants and vascular health.

    Science.gov (United States)

    Bielli, Alessandra; Scioli, Maria Giovanna; Mazzaglia, Donatella; Doldo, Elena; Orlandi, Augusto

    2015-12-15

    Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial β-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L-carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies.

  5. Activated mineralocorticoid receptor regulates micro-RNA-29b in vascular smooth muscle cells.

    Science.gov (United States)

    Bretschneider, Maria; Busch, Bianca; Mueller, Daniel; Nolze, Alexander; Schreier, Barbara; Gekle, Michael; Grossmann, Claudia

    2016-04-01

    Inappropriately activated mineralocorticoid receptor (MR) is a risk factor for vascular remodeling with unclear molecular mechanism. Recent findings suggest that post-transcriptional regulation by micro-RNAs (miRs) may be involved. Our aim was to search for MR-dependent miRs in vascular smooth muscle cells (VSMCs) and to explore the underlying molecular mechanism and the pathologic relevance. We detected that aldosteroneviathe MR reduces miR-29bin vivoin murine aorta and in human primary and cultured VSMCs (ED50= 0.07 nM) but not in endothelial cells [quantitative PCR (qPCR), luciferase assays]. This effect was mediated by an increased decay of miR-29b in the cytoplasm with unchanged miR-29 family member or primary-miR levels. Decreased miR-29b led to an increase in extracellular matrix measured by ELISA and qPCR and enhanced VSMC migration in single cell-tracking experiments. Additionally, cell proliferation and the apoptosis/necrosis ratio (caspase/lactate dehydrogenase assay) was modulated by miR-29b. Enhanced VSMC migration by aldosterone required miR-29b regulation. Control experiments were performed with scrambled RNA and empty plasmids, by comparing aldosterone-stimulated with vehicle-incubated cells. Overall, our findings provide novel insights into the molecular mechanism of aldosterone-mediated vascular pathogenesis by identifying miR-29b as a pathophysiologic relevant target of activated MR in VSMCs and by highlighting the importance of miR processing for miR regulation.-Bretschneider, M., Busch, B., Mueller, D., Nolze, A., Schreier, B., Gekle, M., Grossmann, C. Activated mineralocorticoid receptor regulates micro-RNA-29b in vascular smooth muscle cells. © FASEB.

  6. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck

    2013-05-01

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  7. Design and development of multilayer vascular graft

    Science.gov (United States)

    Madhavan, Krishna

    2011-07-01

    Vascular graft is a widely-used medical device for the treatment of vascular diseases such as atherosclerosis and aneurysm as well as for the use of vascular access and pediatric shunt, which are major causes of mortality and morbidity in this world. Dysfunction of vascular grafts often occurs, particularly for grafts with diameter less than 6mm, and is associated with the design of graft materials. Mechanical strength, compliance, permeability, endothelialization and availability are issues of most concern for vascular graft materials. To address these issues, we have designed a biodegradable, compliant graft made of hybrid multilayer by combining an intimal equivalent, electrospun heparin-impregnated poly-epsilon-caprolactone nanofibers, with a medial equivalent, a crosslinked collagen-chitosan-based gel scaffold. The intimal equivalent is designed to build mechanical strength and stability suitable for in vivo grafting and to prevent thrombosis. The medial equivalent is designed to serve as a scaffold for the activity of the smooth muscle cells important for vascular healing and regeneration. Our results have shown that genipin is a biocompatible crosslinker to enhance the mechanical properties of collagen-chitosan based scaffolds, and the degradation time and the activity of smooth muscle cells in the scaffold can be modulated by the crosslinking degree. For vascular grafting and regeneration in vivo, an important design parameter of the hybrid multilayer is the interface adhesion between the intimal and medial equivalents. With diametrically opposite affinities to water, delamination of the two layers occurs. Physical or chemical modification techniques were thus used to enhance the adhesion. Microscopic examination and graft-relevant functional characterizations have been performed to evaluate these techniques. Results from characterization of microstructure and functional properties, including burst strength, compliance, water permeability and suture

  8. Application study of medical robots in vascular intervention.

    Science.gov (United States)

    Lu, Wang-sheng; Xu, Wu-yi; Zhang, Jing; Liu, Da; Wang, Da-min; Jia, Po; Li, Zhi-cao; Wang, Tian-miao; Zhang, Da-peng; Tian, Zeng-min; Zeng, Yanjun

    2011-09-01

    Based on the background of minimally invasive surgery and applications of medical robots, a vascular interventional robotic system has been developed that can be used in the field of vascular intervention. The robotic system comprises a propulsion system, an image navigation system and a virtual surgery training system. Integration of the three systems constitutes a vascular intervention prototype robotic system used to carry out in vitro vascular intervention and animal experiments. On a transparent glass vascular model, a catheter was shown to enter an arbitrary branch of the vascular model with catheter motion meeting the requirements of clinical vascular intervention surgery (VIS); i.e. error band of catheter motion experiments, 1.33-2.00 mm (4F-6F) diameter catheters were selectively inserted successfully into predefined targets in the animal, such as the renal, cardiovascular and cerebrovascular artery. Compared with conventional manual surgery, the time for robotic surgery is a little longer. There were no operative complications in the animal experiments. These simulation and animal study results demonstrate that this vascular interventional robotic system allows doctors to perform angiography remotely and prevents them from radiation exposure. The system may be the basis for further clinical applications of vascular intervention. Copyright © 2011 John Wiley & Sons, Ltd.

  9. Brain Tumor Tropism of Transplanted Human Neural Stem Cells Is Induced by Vascular Endothelial Growth Factor

    Directory of Open Access Journals (Sweden)

    Nils Ole Schmidt

    2005-06-01

    Full Text Available The transplantation of neural stem cells (NSCs offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumorupregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.

  10. Vascularized epiphyseal transplant.

    Science.gov (United States)

    Innocenti, Marco; Delcroix, Luca; Romano, G Federico; Capanna, Rodolfo

    2007-01-01

    In skeletally immature patients, the transfer of vascularized epiphysis along with a variable amount of adjoining diaphysis may provide the potential for growth of such a graft, preventing future limb length discrepancy. This article describes the authors' experience with the vascularized transfer of the proximal fibular epiphysis in the reconstruction of large bone defects including the epiphysis in a series of 27 patients ranging in age from 2 to 11 years. The follow-up, ranging from 2 to 14 years, has been long enough to allow some evaluation of the validity, indications, and limits of this reconstructive option.

  11. Bioinspired Nanonetworks for Targeted Cancer Drug Delivery.

    Science.gov (United States)

    Raz, Nasibeh Rady; Akbarzadeh-T, Mohammad-R; Tafaghodi, Mohsen

    2015-12-01

    A biomimicry approach to nanonetworks is proposed here for targeted cancer drug delivery (TDD). The swarm of bioinspired nanomachines utilizes the blood distribution network and chemotaxis to carry drug through the vascular system to the cancer site, recognized by a high concentration of vascular endothelial growth factor (VEGF). Our approach is multi-scale and includes processes that occur both within cells and with their neighbors. The proposed bionanonetwork takes advantage of several organic processes, some of which already occur within the human body, such as a plate-like structure similar to those of red blood cells for more environmental contact; a berry fruit architecture for its internal multi-foams architecture; the penetrable structure of cancer cells, tissue, as well as the porous structure of the capillaries for drug penetration; state of glycocalyx for ligand-receptor adhesion; as well as changes in pH state of blood and O 2 release for nanomachine communication. For a more appropriate evaluation, we compare our work with a conventional chemotherapy approach using a mathematical model of cancer under actual experimental parameter settings. Simulation results show the merits of the proposed method in targeted cancer therapy by improving the densities of the relevant cancer cell types and VEGF concentration, while following more organic and natural processes.

  12. Endothelial microparticles: Sophisticated vesicles modulating vascular function

    Science.gov (United States)

    Curtis, Anne M; Edelberg, Jay; Jonas, Rebecca; Rogers, Wade T; Moore, Jonni S; Syed, Wajihuddin; Mohler, Emile R

    2015-01-01

    Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation. PMID:23892447

  13. Hypercholesterolaemia and vascular dementia.

    Science.gov (United States)

    Appleton, Jason P; Scutt, Polly; Sprigg, Nikola; Bath, Philip M

    2017-07-15

    Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors-diabetes, hypercholesterolaemia, hypertension and smoking-are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet not fully understood. Similarly, the effects of lipids and lipid-lowering therapy on preventing or treating dementia remain unclear; the few trials that have assessed lipid-lowering therapy for preventing (two trials) or treating (four trials) dementia found no evidence to support the use of lipid-lowering therapy for these indications. It is appropriate to treat those patients with vascular risk factors that meet criteria for lipid-lowering therapy for the primary and secondary prevention of cardiovascular and cerebrovascular events, and in line with current guidelines. Managing the individual patient in a holistic manner according to his or her own vascular risk profile is recommended. Although the paucity of randomized controlled evidence makes for challenging clinical decision making, it provides multiple opportunities for on-going and future research, as discussed here. © 2017 The Author(s).

  14. Depression in vascular dementia.

    NARCIS (Netherlands)

    Naarding, P.; Koning, I. de; Kooten, F. van; Dippel, D.W.; Janzing, J.G.E.; Mast, R.C. van der; Koudstaal, P.J.

    2003-01-01

    OBJECTIVE: To study the presence of different dimensions of depression in subjects with vascular dementia. BACKGROUND: After a stroke, cognitive, affective and behavioural disturbances are common. It has been suggested that the nature of affective symptomatology can help to differentiate organic

  15. Vascular management in rotationplasty.

    Science.gov (United States)

    Mahoney, Craig R; Hartman, Curtis W; Simon, Pamela J; Baxter, B Timothy; Neff, James R

    2008-05-01

    The Van Nes rotationplasty is a useful limb-preserving procedure for skeletally immature patients with distal femoral or proximal tibial malignancy. The vascular supply to the lower limb either must be maintained and rotated or transected and reanastomosed. We asked whether there would be any difference in the ankle brachial index or complication rate for the two methods of vascular management. Vessels were resected with the tumor in seven patients and preserved and rotated in nine patients. One amputation occurred in the group in which the vessels were preserved. Four patients died secondary to metastatic disease diagnosed preoperatively. The most recent ankle brachial indices were 0.96 and 0.82 for the posterior tibial and dorsalis pedis arteries, respectively, in the reconstructed group. The ankle brachial indices were 0.98 and 0.96 for the posterior tibial and dorsalis pedis arteries, respectively, in the rotated group. Outcomes appear similar using both methods of vascular management and one should not hesitate to perform an en bloc resection when there is a question of vascular involvement.

  16. Renal posttransplant's vascular complications

    Directory of Open Access Journals (Sweden)

    Bašić Dragoslav

    2003-01-01

    Full Text Available INTRODUCTION Despite high graft and recipient survival figures worldwide today, a variety of technical complications can threaten the transplant in the postoperative period. Vascular complications are commonly related to technical problems in establishing vascular continuity or to damage that occurs during donor nephrectomy or preservation [13]. AIM The aim of the presenting study is to evaluate counts and rates of vascular complications after renal transplantation and to compare the outcome by donor type. MATERIAL AND METHODS A total of 463 kidneys (319 from living related donor LD and 144 from cadaveric donor - CD were transplanted during the period between June 1975 and December 1998 at the Urology & Nephrology Institute of Clinical Centre of Serbia in Belgrade. Average recipients' age was 33.7 years (15-54 in LD group and 39.8 (19-62 in CD group. Retrospectively, we analyzed medical records of all recipients. Statistical analysis is estimated using Hi-squared test and Fischer's test of exact probability. RESULTS Major vascular complications including vascular anastomosis thrombosis, internal iliac artery stenosis, internal iliac artery rupture obliterant vasculitis and external iliac vein rupture were analyzed. In 25 recipients (5.4% some of major vascular complications were detected. Among these cases, 22 of them were from CD group vs. three from LD group. Relative rate of these complications was higher in CD group vs. LD group (p<0.0001. Among these complications dominant one was vascular anastomosis thrombosis which occurred in 18 recipients (17 from CD vs. one from LD. Of these recipients 16 from CD lost the graft, while the rest of two (one from each group had lethal outcome. DISCUSSION Thrombosis of renal allograft vascular anastomosis site is the most severe complication following renal transplantation. In the literature, renal allograft thrombosis is reported with different incidence rates, from 0.5-4% [14, 15, 16]. Data from the

  17. Ultrasound for vascular access in pediatric patients.

    Science.gov (United States)

    Schindler, Ehrenfried; Schears, Gregory J; Hall, Stuart R; Yamamoto, Tomohiro

    2012-10-01

    In pediatric patients vascular access is often more difficult than in adults because of the smaller size of the vessels and the inability of the patient to cooperate without deep sedation or general anesthesia. Therefore Ultrasound has already become an invaluable tool for vascular access, but the full potential of ultrasound has yet to be fully realized. Improvements in image quality and a better understanding of optimal insertion techniques continue to help clinicians safely and efficiently place catheters with fewer complications. The probes used for the vascular access are mainly linear and convex type. Higher- frequency ultrasound provides a vivid image; however, the signals are remarkably attenuated. Therefore, the choice of the probe with appropriate frequency is essential. As blood vessels are relatively easily identified with ultrasound, ultrasound-guided vascular access does not require as sharp images as ultrasound-guided nerve block. For pediatric vascular access, the linear probe with 5-15 MHz, 2-5 cm depth is ideal and adequate for almost all cases. Ultrasound-guided vascular access has two main approaches: 'long-axis' or 'in-plane approach' and 'short-axis' or 'transverse approach'. The long-axis approach visualizes the vessel along the insertion pathway and is commonly used to monitor the entire approach of the needle into the vessel. The short-axis approach is easier to show the positional relationship and depth of target vessels, but it is much harder to follow the needle tip within the tissues. The use of 'real-time' ultrasound has been shown to increase first insertion success, reduce access time, have a higher overall success, and reduce arterial puncture. As the technology continues to improve the use of ultrasound will become as ubiquitous as the lines themselves. © 2012 Blackwell Publishing Ltd.

  18. Oxidative stress and vascular inflammation in aging.

    Science.gov (United States)

    El Assar, Mariam; Angulo, Javier; Rodríguez-Mañas, Leocadio

    2013-12-01

    Vascular aging, a determinant factor for cardiovascular disease and health status in the elderly, is now viewed as a modifiable risk factor. Impaired endothelial vasodilation is a early hallmark of arterial aging that precedes the clinical manifestations of vascular dysfunction, the first step to cardiovascular disease and influencing vascular outcomes in the elderly. Accordingly, the preservation of endothelial function is thought to be an essential determinant of healthy aging. With special attention on the effects of aging on the endothelial function, this review is focused on the two main mechanisms of aging-related endothelial dysfunction: oxidative stress and inflammation. Aging vasculature generates an excess of the reactive oxygen species (ROS), superoxide and hydrogen peroxide, that compromise the vasodilatory activity of nitric oxide (NO) and facilitate the formation of the deleterious radical, peroxynitrite. Main sources of ROS are mitochondrial respiratory chain and NADPH oxidases, although NOS uncoupling could also account for ROS generation. In addition, reduced antioxidant response mediated by erythroid-2-related factor-2 (Nrf2) and downregulation of mitochondrial manganese superoxide dismutase (SOD2) contributes to the establishment of chronic oxidative stress in aged vessels. This is accompanied by a chronic low-grade inflammatory phenotype that participates in defective endothelial vasodilation. The redox-sensitive transcription factor, nuclear factor-κB (NF-κB), is upregulated in vascular cells from old subjects and drives a proinflammatory shift that feedbacks oxidative stress. This chronic NF-κB activation is contributed by increased angiotensin-II signaling and downregulated sirtuins and precludes adequate cellular response to acute ROS generation. Interventions targeted to recover endogenous antioxidant capacity and cellular stress response rather than exogenous antioxidants could reverse oxidative stress-inflammation vicious cycle in

  19. Vascular manifestations of Behcet's disease

    Directory of Open Access Journals (Sweden)

    Regina Georgiyeva Goloeva

    2010-01-01

    Conclusion. Vascular disorders in BD were diagnosed in one fourth of the patients, mainly in young male patients. Severe thromboses with the development of chronic venous insignificance, Budd-Chiari syndrome, pulmonary and iliac artery aneurysms, and arterial thromboses were observed in male patients only. Vascular events were associated with erythema nodosum and epididymitis; in these concomitances, the vascular risk was substantially increased. Vascular death rates were 2,2%.

  20. Engineering vascularized skeletal muscle tissue

    NARCIS (Netherlands)

    Levenberg, Shulamit; Rouwkema, Jeroen; Macdonald, Mara; Garfein, Evan S.; Kohane, Daniel S.; Darland, Diane C.; Marini, Robert; van Blitterswijk, Clemens; Mulligan, Richard C.; D'Amore, Patricia A.; Langer, Robert

    2005-01-01

    One of the major obstacles in engineering thick, complex tissues such as muscle is the need to vascularize the tissue in vitro. Vascularization in vitro could maintain cell viability during tissue growth, induce structural organization and promote vascularization upon implantation. Here we describe

  1. Drug treatment of hypertension: focus on vascular health

    OpenAIRE

    Cameron, Alan C.; Lang, Ninian N.; Touyz, Rhian M.

    2016-01-01

    Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by...

  2. Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification.

    Science.gov (United States)

    Mokas, Sophie; Larivière, Richard; Lamalice, Laurent; Gobeil, Stéphane; Cornfield, David N; Agharazii, Mohsen; Richard, Darren E

    2016-09-01

    Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG-4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1α subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  3. The Vascular Depression Hypothesis: Mechanisms Linking Vascular Disease with Depression

    Science.gov (United States)

    Taylor, Warren D.; Aizenstein, Howard J.; Alexopoulos, George S.

    2013-01-01

    The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes. PMID:23439482

  4. Macrophage migration inhibitory factor induces vascular leakage via autophagy

    Directory of Open Access Journals (Sweden)

    Hong-Ru Chen

    2015-01-01

    Full Text Available Vascular leakage is an important feature of acute inflammatory shock, which currently has no effective treatment. Macrophage migration inhibitory factor (MIF is a pro-inflammatory cytokine that can induce vascular leakage and plays an important role in the pathogenesis of shock. However, the mechanism of MIF-induced vascular leakage is still unclear. In this study, using recombinant MIF (rMIF, we demonstrated that MIF induced disorganization and degradation of junction proteins and increased the permeability of human endothelial cells in vitro. Western blotting analysis showed that rMIF treatment induced LC3 conversion and p62 degradation. Inhibition of autophagy with a PI3K inhibitor (3-MA, a ROS scavenger (NAC or autophagosomal-lysosomal fusion inhibitors (bafilomycin A1 and chloroquine rescued rMIF-induced vascular leakage, suggesting that autophagy mediates MIF-induced vascular leakage. The potential involvement of other signaling pathways was also studied using different inhibitors, and the results suggested that MIF-induced vascular leakage may occur through the ERK pathway. In conclusion, we showed that MIF triggered autophagic degradation of endothelial cells, resulting in vascular leakage. Inhibition of MIF-induced autophagy may provide therapeutic targets against vascular leakage in inflammatory shock.

  5. Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system.

    Science.gov (United States)

    Kaur, H; Carvalho, J; Looso, M; Singh, P; Chennupati, R; Preussner, J; Günther, S; Albarrán-Juárez, J; Tischner, D; Classen, S; Offermanns, S; Wettschureck, N

    2017-06-16

    G-protein-coupled receptor (GPCR) expression is extensively studied in bulk cDNA, but heterogeneity and functional patterning of GPCR expression in individual vascular cells is poorly understood. Here, we perform a microfluidic-based single-cell GPCR expression analysis in primary smooth muscle cells (SMC) and endothelial cells (EC). GPCR expression is highly heterogeneous in all cell types, which is confirmed in reporter mice, on the protein level and in human cells. Inflammatory activation in murine models of sepsis or atherosclerosis results in characteristic changes in the GPCR repertoire, and we identify functionally relevant subgroups of cells that are characterized by specific GPCR patterns. We further show that dedifferentiating SMC upregulate GPCRs such as Gpr39, Gprc5b, Gprc5c or Gpr124, and that selective targeting of Gprc5b modulates their differentiation state. Taken together, single-cell profiling identifies receptors expressed on pathologically relevant subpopulations and provides a basis for the development of new therapeutic strategies in vascular diseases.

  6. Brain Vascular Imaging Techniques

    Directory of Open Access Journals (Sweden)

    Bàrbara Laviña

    2016-12-01

    Full Text Available Recent major improvements in a number of imaging techniques now allow for the study of the brain in ways that could not be considered previously. Researchers today have well-developed tools to specifically examine the dynamic nature of the blood vessels in the brain during development and adulthood; as well as to observe the vascular responses in disease situations in vivo. This review offers a concise summary and brief historical reference of different imaging techniques and how these tools can be applied to study the brain vasculature and the blood-brain barrier integrity in both healthy and disease states. Moreover, it offers an overview on available transgenic animal models to study vascular biology and a description of useful online brain atlases.

  7. Plant Vascular Biology 2010

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Biao

    2014-11-17

    This grant supported the Second International Conference on Plant Vascular Biology (PVB 2010) held July 24-28, 2010 on the campus of Ohio State University, Columbus, Ohio. Biao Ding (Ohio State University; OSU) and David Hannapel (Iowa State University; ISU) served as co-chairs of this conference. Biao Ding served as the local organizer. PVB is defined broadly here to include studies on the biogenesis, structure and function of transport systems in plants, under conditions of normal plant growth and development as well as of plant interactions with pathogens. The transport systems cover broadly the xylem, phloem, plasmodesmata and vascular cell membranes. The PVB concept has emerged in recent years to emphasize the integrative nature of the transport systems and approaches to investigate them.

  8. Vascular cognitive impairment

    Directory of Open Access Journals (Sweden)

    N.V. Vakhnina

    2014-01-01

    Full Text Available Vascular pathology of the brain is the second most common cause of cognitive impairment after Alzheimer's disease. The article describes the modern concepts of etiology, pathogenetic mechanisms, clinical features and approaches to diagnosis and therapy of vascular cognitive impairment (VCI. Cerebrovascular accident, chronic cerebral circulatory insufficiency and their combination, sometimes in combination with a concomitant neurodegenerative process, are shown to be the major types of brain lesions leading to VCI. The clinical presentation of VCI is characterized by the neuropsychological status dominated by impairment of the executive frontal functions (planning, control, attention in combination with focal neurological symptoms. The diagnosis is based on comparing of the revealed neuropsychological and neurological features with neuroimaging data. Neurometabolic, acetylcholinergic, glutamatergic, and other vasoactive drugs and non-pharmacological methods are widely used to treat VCI. 

  9. Pathophysiology of vascular dementia

    OpenAIRE

    Rizzo Claudia; Duro Giovanni; Iemolo Francesco; Castiglia Laura; Hachinski Vladimir; Caruso Calogero

    2009-01-01

    Abstract The concept of Vascular Dementia (VaD) has been recognized for over a century, but its definition and diagnostic criteria remain unclear. Conventional definitions identify the patients too late, miss subjects with cognitive impairment short of dementia, and emphasize consequences rather than causes, the true bases for treatment and prevention. We should throw out current diagnostic categories and describe cognitive impairment clinically and according to commonly agreed instruments th...

  10. Targeting RAGE Signaling in Inflammatory Disease.

    Science.gov (United States)

    Hudson, Barry I; Lippman, Marc E

    2018-01-29

    The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA. RAGE can also act as an innate immune sensor of microbial pathogen-associated molecular pattern molecules (PAMPs) including bacterial endotoxin, respiratory viruses, and microbial DNA. RAGE is expressed at low levels under normal physiology, but it is highly upregulated under chronic inflammation because of the accumulation of various RAGE ligands. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammation and progression of diabetic vascular complications, cardiovascular disease (CVD), and cancer progression and metastasis. The clinical relevance of RAGE in inflammatory disease is being demonstrated in emerging clinical trials of novel small-molecule RAGE inhibitors.

  11. Pulmonary vascular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Fedullo, P.F.; Shure, D.

    1987-03-01

    A wide range of pulmonary vascular imaging techniques are available for the diagnostic evaluation of patients with suspected pulmonary vascular disease. The characteristics of any ideal technique would include high sensitivity and specificity, safety, simplicity, and sequential applicability. To date, no single technique meets these ideal characteristics. Conventional pulmonary angiography remains the gold standard for the diagnosis of acute thromboembolic disease despite the introduction of newer techniques such as digital subtraction angiography and magnetic resonance imaging. Improved noninvasive lower extremity venous testing methods, particularly impedance plethysmography, and ventilation-perfusion scanning can play significant roles in the noninvasive diagnosis of acute pulmonary emboli when properly applied. Ventilation-perfusion scanning may also be useful as a screening test to differentiate possible primary pulmonary hypertension from chronic thromboembolic pulmonary hypertension. And, finally, angioscopy may be a useful adjunctive technique to detect chronic thromboembolic disease and determine operability. Optimal clinical decision-making, however, will continue to require the proper interpretation of adjunctive information obtained from the less-invasive techniques, applied with an understanding of the natural history of the various forms of pulmonary vascular disease and with a knowledge of the capabilities and shortcomings of the individual techniques.

  12. Update on Vascular Dementia.

    Science.gov (United States)

    Khan, Ayesha; Kalaria, Raj N; Corbett, Anne; Ballard, Clive

    2016-09-01

    Vascular dementia (VaD) is a major contributor to the dementia syndrome and is described as having problems with reasoning, planning, judgment, and memory caused by impaired blood flow to the brain and damage to the blood vessels resulting from events such as stroke. There are a variety of etiologies that contribute to the development of vascular cognitive impairment and VaD, and these are often associated with other dementia-related pathologies such as Alzheimer disease. The diagnosis of VaD is difficult due to the number and types of lesions and their locations in the brain. Factors that increase the risk of vascular diseases such as stroke, high blood pressure, high cholesterol, and smoking also raise the risk of VaD. Therefore, controlling these risk factors can help lower the chances of developing VaD. This update describes the subtypes of VaD, with details of their complex presentation, associated pathological lesions, and issues with diagnosis, prevention, and treatment. © The Author(s) 2016.

  13. Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease

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    Raouf A. Khalil

    2013-03-01

    Full Text Available Blood pressure (BP is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN. In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i, which forms a complex with calmodulin, activates myosin light chain (MLC kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC. PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK and MAPK kinase (MEK, a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in

  14. Relevance Matrices in LVQ

    NARCIS (Netherlands)

    Schneider, Petra; Biehl, Michael; Hammer, Barbara; Verleysen, Michel

    2007-01-01

    We propose a new matrix learning scheme to extend Generalized Relevance Learning Vector Quantization (GRLVQ). By introducing a full matrix of relevance factors in the distance measure, correlations between different features and their importance for the classification scheme can be taken into

  15. Towards organ printing: engineering an intra-organ branched vascular tree.

    Science.gov (United States)

    Visconti, Richard P; Kasyanov, Vladimir; Gentile, Carmine; Zhang, Jing; Markwald, Roger R; Mironov, Vladimir

    2010-03-01

    Effective vascularization of thick three-dimensional engineered tissue constructs is a problem in tissue engineering. As in native organs, a tissue-engineered intra-organ vascular tree must be comprised of a network of hierarchically branched vascular segments. Despite this requirement, current tissue-engineering efforts are still focused predominantly on engineering either large-diameter macrovessels or microvascular networks. We present the emerging concept of organ printing or robotic additive biofabrication of an intra-organ branched vascular tree, based on the ability of vascular tissue spheroids to undergo self-assembly. The feasibility and challenges of this robotic biofabrication approach to intra-organ vascularization for tissue engineering based on organ-printing technology using self-assembling vascular tissue spheroids including clinically relevantly vascular cell sources are analyzed. It is not possible to engineer 3D thick tissue or organ constructs without effective vascularization. An effective intra-organ vascular system cannot be built by the simple connection of large-diameter vessels and microvessels. Successful engineering of functional human organs suitable for surgical implantation will require concomitant engineering of a 'built in' intra-organ branched vascular system. Organ printing enables biofabrication of human organ constructs with a 'built in' intra-organ branched vascular tree.

  16. Diagnosis of vascular cognitive impairment and its main categories.

    Science.gov (United States)

    Rodríguez García, P L; Rodríguez García, D

    2015-05-01

    A review of current criteria for the diagnosis of categories related with vascular cognitive impairment, in particular the nomenclature, diagnostic criteria, and differential clinical-radiological findings. The criteria for the diagnosis of vascular cognitive impairment have evolved, but available criteria were designed basically for differentiating between vascular dementia and dementia due to Alzheimer disease, and for research purposes. Nevertheless, in clinical practice precise elements are required for: 1) Clinical diagnosis of dementia and mild cognitive impairment; 2) Clinical and neuroimaging criteria for identification of the various cerebrovascular lesions associated with cognitive dysfunction, and 3) A formulation of the aetiogenic-pathogenic relationship between cognitive impairment and cerebrovascular lesions. For this reason, a review was carried out on the diagnostic elements of vascular cognitive impairment categories, classification, and their most relevant characteristics. It highlights the characteristic for the diagnosis of multi-infarction dementia, strategic single infarct dementia, small vessel disease with dementia, mixed dementia, and vascular mild cognitive impairment. Standardisation is required, by a multidisciplinary expert team, as regards nomenclature and criteria for the diagnosis of the full spectrum associated with vascular cognitive impairment and especially for vascular dementia and its categories. Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  17. [How Treatable is Vascular Dementia?].

    Science.gov (United States)

    Mori, Etsuro

    2016-04-01

    Vascular dementia is an umbrella term, encompassing the pathological changes in the brain due to cerebrovascular disease that result in dementia. Vascular dementia is the second most common form of dementia, after Alzheimer's disease. In this paper, I outline the concept of vascular dementia, the key aspects of the disease that are yet to be clarified, and the current status of clinical trials. Assessing these factors, I discuss how treatable vascular dementia presently is. Use of the term'vascular dementia'is riddled with uncertainties regarding disease classification, and non-standardized diagnostic criteria. There are difficulties in determining the exact relationship between cerebrovascular pathology and cognitive impairment. The comorbid effects of Alzheimer's pathology in some individuals also present an obstacle to reliable clinical diagnosis, and hinder research into effective management approaches. Vascular dementia is preventable and treatable, as there are established primary and secondary prevention measures for the causative cerebrovascular diseases, such as vascular risk factor intervention, antiplatelet therapy, and anticoagulation, amongst others. However, unlike Alzheimer's disease, there are no established symptomatic treatments for vascular dementia. Clinical trials of cholinesterase inhibitors and memantine indicate that they produce small cognitive benefits in patients with vascular dementia, though the exact clinical significance of these is uncertain. Data are insufficient to support the widespread use of these drugs in vascular dementia. Rehabilitation and physical and cognitive exercise may be beneficial, but evidence of cognitive benefit and relief of neuropsychiatric symptoms due to exercise is lacking.

  18. Evidence-based medical research on diagnostic criteria and screening technique of vascular mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Xia-wei LIU

    2015-07-01

    Full Text Available Background Vascular mild cognitive impairment (VaMCI is the prodromal syndrome of vascular dementia (VaD and key target for drug treatment. There is controversy over the diagnostic criteria and screening tools of VaMCI, which affects its clinical diagnosis. This paper aims to explore the clinical features, diagnostic criteria and screening technique of VaMCI.  Methods Taking "vascular mild cognitive impairment OR vascular cognitive impairment no dementia" as retrieval terms, search in PubMed database from January 1997 to March 2015 and screen relevant literatures concerning VaMCI. According to Guidance for the Preparation of Neurological Management Guidelines revised by European Federation of Neurological Societies (EFNS in 2004, evidence grading was performed on literatures. Results A total of 32 literatures in English were selected according to inclusion and exclusion criteria, including 3 guidelines and consensus and 29 clinical studies. Seven literatures (2 on Level Ⅰ, 5 on Level Ⅱ studied on neuropsychological features in VaMCI patients and found reduced processing speed and executive function impairment were main features. Two literatures reported the diagnostic criteria of VaMCI, including VaMCI criteria published by American Heart Association (AHA/American Stroke Association (ASA in 2011 and "Diagnostic Criteria for Vascular Cognitive Disorders" published by International Society for Vascular Behavioral and Cognitive Disorders (VASCOG in 2014. Fifteen literatures (4 on LevelⅠ, 11 on Level Ⅱ described the diagnostic criteria of VaMCI used in clinical research, from which 6 operational diagnostic items were extracted. Fourteen literatures (4 on Level Ⅰ, 10 on Level Ⅱ described neuropsychological assessment tools for VaMCI screening, and found the 5-minute protocol recommended by National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN was being good consistency with other neuropsychological

  19. A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.

    Science.gov (United States)

    Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

    2016-11-08

    Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.

  20. Culturally Relevant Cyberbullying Prevention

    OpenAIRE

    Phillips, Gregory John

    2017-01-01

    In this action research study, I, along with a student intervention committee of 14 members, developed a cyberbullying intervention for a large urban high school on the west coast. This high school contained a predominantly African American student population. I aimed to discover culturally relevant cyberbullying prevention strategies for African American students. The intervention committee selected video safety messages featuring African American actors as the most culturally relevant cyber...

  1. [Estrogens and vascular thrombosis].

    Science.gov (United States)

    Colmou, A

    1982-09-01

    The incidence of thromboses among young women has increased with widespread use of oral contraceptives (OCs) due to the significant thromboembolic risk of estrogen. Estrogens intervene at the vascular, platelet, and plasma levels as a function of hormonal variations in the menstrual cycle, increasing the aggregability of the platelets and thrombocytes, accelerating the formation of clots, and decreasing the amount of antithrombin III. Estrogens are used in medicine to treat breast and prostate cancers and in gynecology to treat dysmenorrhea, during the menopause, and in contraception. Smoking, cardiovascular disease and hypertension, hypercholesterolemia, and diabetes are contraindicators to estrogen use. Thrombosis refers to blockage of a blood vessel by a clot or thrombus. Before estrogens are prescribed, a history of phlebitis, obesity, hyperlipidemia, or significant varicosities should be ruled out. A history of venous thrombosis, hyperlipoproteinemia, breast nodules, serious liver condition, allergies to progesterone, and some ocular diseases of vascular origin definitively rule out treatment with estrogens. A family history of infarct, embolism, diabetes, cancer, or vascular accidents at a young age signals a need for greater patient surveillance. All patients receiving estrogens should be carefully observed for signs of hypertension, hypercholesterolemia, hypercoagulability, or diabetes. Nurses have a role to play in carefully eliciting the patient's history of smoking, personal and family medical problems, and previous and current laboratory results, as well as in informing the patients of the risks and possible side effects of OCs, especially for those who smoke. Nurses should educate patients receiving estrogens, especially those with histories of circulatory problems, to avoid standing in 1 position for prolonged periods, avoid heat which is a vasodilator, avoid obesity, excercise regularly, wear appropriate footgear, and follow other good health

  2. Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma.

    Directory of Open Access Journals (Sweden)

    Orit Itzhaki

    Full Text Available Vasculogenic mimicry (VM describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin, which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin, which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti neoplastic effects in a variety of malignancies.

  3. Vascular Contributions to Cognitive Impairment and Dementia

    Science.gov (United States)

    Gorelick, Philip B.; Scuteri, Angelo; Black, Sandra E.; DeCarli, Charles; Greenberg, Steven M.; Iadecola, Costantino; Launer, Lenore J.; Laurent, Stephane; Lopez, Oscar L.; Nyenhuis, David; Petersen, Ronald C.; Schneider, Julie A.; Tzourio, Christophe; Arnett, Donna K.; Bennett, David A.; Chui, Helena C.; Higashida, Randall T.; Lindquist, Ruth; Nilsson, Peter M.; Roman, Gustavo C.; Sellke, Frank W.; Seshadri, Sudha

    2013-01-01

    Background and Purpose This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Methods Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee. Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed

  4. The pathobiology of vascular dementia.

    Science.gov (United States)

    Iadecola, Costantino

    2013-11-20

    Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Vascular Access Guidelines: Summary, Rationale, and Controversies.

    Science.gov (United States)

    Sequeira, Adrian; Naljayan, Mihran; Vachharajani, Tushar J

    2017-03-01

    Dialysis vascular access management in the United States changed significantly after National Kidney Foundation-Kidney Disease Outcome Quality Initiative (NKF-KDOQI) clinical practice guidelines were first published in 1997. The Centers for Medicare and Medicaid Service adopted these guidelines and in collaboration with the End-Stage Renal Disease Networks established the Fistula First Breakthrough Initiative (FFBI) in 2003 to improve the rate of arteriovenous fistula use over arteriovenous graft and central venous catheter in the dialysis population. The implementation of guidelines and FFBI has led to a significant increase in the arteriovenous fistula use in the prevalent dialysis population. The guidelines are criticized for being opinion based and often impractical. Over the past 2 decades, the patient population undergoing dialysis has become older with complex comorbidities and challenges for creating an ideal vascular access. Advancing knowledge about access pathophysiology, improved treatment options, and improved process of care with team approach model point toward diminishing relevance of few of the existing guidelines. Moreover, several guidelines remain controversial and may be leading to clinical decisions that may be unfavorable to the patients. The review discusses the historical aspect of vascular access care in the United States and evolution of current practice standards and controversies surrounding few of these guidelines in the current time. Published by Elsevier Inc.

  6. Anaesthesia for vascular emergencies.

    Science.gov (United States)

    Ellard, L; Djaiani, G

    2013-01-01

    Patients presenting with vascular emergencies including acute aortic syndrome, ruptured thoracic or abdominal aortic aneurysms, thoracic aortic trauma and acute lower limb ischaemia have a high risk of peri-operative morbidity and mortality. Although anatomical suitability is not universal, endovascular surgery may improve mortality and the results of ongoing randomised controlled trials are awaited. Permissive hypotension pre-operatively should be the standard of care with the systolic blood pressure kept to 50-100 mmHg as long as consciousness is maintained. The benefit of local anaesthesia over general anaesthesia is not definitive and this decision should be tailored for a given patient and circumstance. Cerebrospinal fluid drainage for prevention of paraplegia is often impractical in the emergency setting and is not backed by strong evidence; however, it should be considered postoperatively if symptoms develop. We discuss the pertinent anaesthetic issues when a patient presents with a vascular emergency and the impact that endovascular repair has on anaesthetic management. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.

  7. Spinal Cord Vascular Disease

    Directory of Open Access Journals (Sweden)

    Abdoreza Ghoreishi

    2017-02-01

    Full Text Available The spinal cord is subject to many of the same vascular diseases that involve the brain, but its anatomy and embryology render it susceptible to some syndromes that do not have intracranial counterparts.The embryonic arterial supply to the spinal cord derives from intradural vessels that enter at each spinal level and divide to follow the dorsal and ventral roots. SPINAL CORD ISCHEMIA: The midthoracic levels of the spinal cord are traditionally considered to be the most vulnerable to compromise from hypoperfusion, but more recent evidence suggests that the lower thoracic cord is at greater risk . The actual prevalence of spinal cord infarction is unknown, but is generally cited as representing 1% to 2% of all central neurovascular events and 5% to 8% of all acute myelopathies. Weakness (100%, sensory loss (89%, back pain at onset (82%, and urinary complaints requiring catheterization (75% were the most common symptoms of cord ischemia at the time of presentation . Weakness most commonly affects both legs. Examination typically reveals flaccid paresis accompanied by diminished superficial and tendon reflexes below the level of the lesion. Preservation of strength and reflexes suggests the rare syndrome of posterior spinal artery territory infarction. Weakness most commonly affects both legs. Examination typically reveals flaccid paresis accompanied by diminished superficial and tendon reflexes below the level of the lesion. Preservation of strength and reflexes suggests the rare syndrome of posterior spinal artery territory infarction.   Aortic pathologies with regional hemodynamic compromise are the most common cause of spinal cord infarction, accounting for 30% to 40% of cases.                                                                                 The medical management of spinal cord ischemia is generally supportive and focused on reducing risk for

  8. Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective

    Directory of Open Access Journals (Sweden)

    Stefania Bellini

    2017-12-01

    Full Text Available Heat shock proteins (HSPs are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective.

  9. Neurite Mistargeting and Inverse Order of Intraretinal Vascular Plexus Formation Precede Subretinal Vascularization in Vldlr Mutant Mice.

    Directory of Open Access Journals (Sweden)

    Verity Johnson

    Full Text Available In the retina blood vessels are required to support a high metabolic rate, however, uncontrolled vascular growth can lead to impaired vision and blindness. Subretinal vascularization (SRV, one type of pathological vessel growth, occurs in retinal angiomatous proliferation and proliferative macular telangiectasia. In these diseases SRV originates from blood vessels within the retina. We use mice with a targeted disruption in the Vldl-receptor (Vldlr gene as a model to study SRV with retinal origin. We find that Vldlr mRNA is strongly expressed in the neuroretina, and we observe both vascular and neuronal phenotypes in Vldlr-/- mice. Unexpectedly, horizontal cell (HC neurites are mistargeted prior to SRV in this model, and the majority of vascular lesions are associated with mistargeted neurites. In Foxn4-/- mice, which lack HCs and display reduced amacrine cell (AC numbers, we find severe defects in intraretinal capillary development. However, SRV is not suppressed in Foxn4-/-;Vldlr-/- mice, which reveals that mistargeted HC neurites are not required for vascular lesion formation. In the absence of VLDLR, the intraretinal capillary plexuses form in an inverse order compared to normal development, and subsequent to this early defect, vascular proliferation is increased. We conclude that SRV in the Vldlr-/- model is associated with mistargeted neurites and that SRV is preceded by altered retinal vascular development.

  10. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.

    Science.gov (United States)

    Kalaria, Raj N

    2016-05-01

    dementia associated with cerebral small vessel disease. Greater understanding of the neurochemical and molecular investigations is needed to better define microvascular disease and vascular substrates of dementia. The investigation of relevant animal models would be valuable in exploring the pathogenesis as well as prevention of the vascular causes of cognitive impairment.

  11. Alpha particle induced reactions on {sup nat}Cr up to 39 MeV: Experimental cross-sections, comparison with theoretical calculations and thick target yields for medically relevant {sup 52g}Fe production

    Energy Technology Data Exchange (ETDEWEB)

    Hermanne, A.; Adam Rebeles, R. [Cyclotron Laboratory, Vrije Universiteit Brussel, Brussel 1090 (Belgium); Tárkányi, F.; Takács, S. [Institute of Nuclear Research, Hungarian Academy of Science, 4026 Debrecen (Hungary)

    2015-08-01

    Thin {sup nat}Cr targets were obtained by electroplating, using 23.75 μm Cu foils as backings. In five stacked foil irradiations, followed by high resolution gamma spectroscopy, the cross sections for production of {sup 52g}Fe, {sup 49,51cum}Cr, {sup 52cum,54,56cum}Mn and {sup 48cum}V in Cr and {sup 61}Cu,{sup 68}Ga in Cu were measured up to 39 MeV incident α-particle energy. Reduced uncertainty is obtained by simultaneous remeasurement of the {sup nat}Cu(α,x){sup 67,66}Ga monitor reactions over the whole energy range. Comparisons with the scarce literature values and results from the TENDL-2013 on-line library, based on the theoretical code family TALYS-1.6, were made. A discussion of the production routes for {sup 52g}Fe with achievable yields and contamination rates was made.

  12. Temporary vascular shunting in vascular trauma: A 10-year review ...

    African Journals Online (AJOL)

    Five patients with non-viable limbs had the vessel ligated. Conclusions. A TIVS in the damage control setting is both life- and limb-saving. These shunts can be inserted safely in a facility without access to a surgeon with vascular surgery experience if there is uncontrollable bleeding or the delay to definitive vascular surgery ...

  13. Temporary vascular shunting in vascular trauma: A 10-year review ...

    African Journals Online (AJOL)

    part of a damage control procedure, 7 patients were referred from a hospital without access to vascular surgical facilities with the TIVS in situ, and in the remaining 6 patients the TIVS was inserted during repair of a lower limb fracture with an associated vascular injury. Damage control procedure. Twenty-two patients had a ...

  14. Additive Manufacturing of Vascular Grafts and Vascularized Tissue Constructs.

    Science.gov (United States)

    Elomaa, Laura; Yang, Yunzhi Peter

    2017-10-01

    There is a great need for engineered vascular grafts among patients with cardiovascular diseases who are in need of bypass therapy and lack autologous healthy blood vessels. In addition, because of the severe worldwide shortage of organ donors, there is an increasing need for engineered vascularized tissue constructs as an alternative to organ transplants. Additive manufacturing (AM) offers great advantages and flexibility of fabrication of cell-laden, multimaterial, and anatomically shaped vascular grafts and vascularized tissue constructs. Various inkjet-, extrusion-, and photocrosslinking-based AM techniques have been applied to the fabrication of both self-standing vascular grafts and porous, vascularized tissue constructs. This review discusses the state-of-the-art research on the use of AM for vascular applications and the key criteria for biomaterials in the AM of both acellular and cellular constructs. We envision that new smart printing materials that can adapt to their environment and encourage rapid endothelialization and remodeling will be the key factor in the future for the successful AM of personalized and dynamic vascular tissue applications.

  15. Nutrition and vascular dementia.

    Science.gov (United States)

    Perez, L; Heim, L; Sherzai, A; Jaceldo-Siegl, K; Sherzai, A

    2012-04-01

    The objective of this review was to elucidate the relationship between VaD and various nutritional factors based on epidemiological studies. Vascular dementia (VaD) is the second most common type of dementia. The prevalence of VaD continues to increase as the US population continues to grow and age. Currently, control of potential risk factors is believed to be the most effective means of preventing VaD. Thus, identification of modifiable risk factors for VaD is crucial for development of effective treatment modalities. Nutrition is one of the main modifiable variables that may influence the development of VaD. A systematic review of literature was conducted using the PubMed, Web of Science, and CINAHL Plus databases with search parameters inclusive of vascular dementia, nutrition, and vascular cognitive impairment (VCI). Fourteen articles were found that proposed a potential role of specific nutritional components in VaD. These components included antioxidants, lipids, homocysteine, folate, vitamin B12, and fish consumption. Antioxidants, specifically Vitamin E and C, and fatty fish intake were found to be protective against VaD risk. Fried fish, elevated homocysteine, and lower levels of folate and vitamin B12 were associated with increased VaD. Evidence for dietary lipids was inconsistent, although elevated midlife serum cholesterol may increase risk, while late-life elevated serum cholesterol may be associated with decreased risk of VaD. Currently, the most convincing evidence as to the relationship between VaD and nutrition exists for micronutrients, particularly Vitamin E and C. Exploration of nutrition at the macronutrient level and additional long term prospective cohort studies are warranted to better understand the role of nutrition in VaD disease development and progression. At present, challenges in this research include limitations in sample size, which was commonly cited. Also, a variety of diagnostic criteria for VaD were employed in the studies

  16. The Danish Vascular Registry, Karbase

    Directory of Open Access Journals (Sweden)

    Eldrup N

    2016-10-01

    Full Text Available Nikolaj Eldrup,1,2 Charlotte Cerqueira,3 Louise de la Motte,2,4 Lisbet Knudsen Rathenborg,2,4 Allan K Hansen2,5 1Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, 2Karbase, The Danish Vascular Registry, Aarhus, 3Registry Support Centre (East – Epidemiology and Biostatistics, Research Centre for Prevention and Health, Capital Region of Denmark, 4Department of Vascular Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 5Department of Vascular Surgery, Aalborg University Hospital, Aalborg, Denmark Aim: The Danish Vascular Registry (DVR, Karbase, is monitoring arterial and advanced vein interventions conducted at all vascular departments in Denmark. The main aim of the DVR is to improve the quality of treatment for patients undergoing vascular surgery in Denmark by using the registry for quality assessment and research. Study population: All patients undergoing vascular interventions (surgical and endovascular at any vascular department in Denmark are registered in the DVR. The DVR was initiated in 1989, and each year, ~9,000 procedures are added. By January 2016, .180,000 procedures have been recorded. Since 2001, data completeness has been .90% (compared to the Danish National Patient Register. Main variables: Variables include information on descriptive patient data (ie, age, sex, height, and weight and comorbidity (ie, previous cardiovascular disease and diabetes. Process variable includes waiting time (time from event to medical contact and treatment and the type of procedures conducted. Outcome variables for in-hospital complications (ie, wound complications, myocardial infarction, stroke, amputation, respiratory complications, and renal insufficiency and 30-day patency are submitted. Variables for medical treatment (antithrombotic and statin treatment, amputation, and survival are extracted from nationwide, administrative registers. Conclusion: The DVR reports outcome on key indicators for

  17. Potential Therapeutics for Vascular Cognitive Impairment and Dementia.

    Science.gov (United States)

    Sun, Miao-Kun

    2017-10-16

    As the human lifespan increases, the number of people affected by age-related dementia is growing at an epidemic pace. Vascular pathology dramatically affects cognitive profiles, resulting in dementia and cognitive impairment. While vascular dementia itself constitutes a medical challenge, hypoperfusion/vascular risk factors enhance amyloid toxicity and other memory-damaging factors and hasten Alzheimer's disease (AD) and other memory disorders' progression, as well as negatively affect treatment outcome. Few therapeutic options are, however, currently available to improve the prognosis of patients with vascular dementia and cognitive impairment, mixed AD dementia with vascular pathology, or other memory disorders. Emerging evidence, however, indicates that, like AD and other memory disorders, synaptic impairment underlies much of the memory impairment in the cognitive decline of vascular cognitive impairment and vascular dementia. Effective rescues of the memory functions might be achieved through synaptic and memory therapeutics, targeting distinct molecular signaling pathways that support the formation of new synapses and maintaining their connections. Potential therapeutic agents include: 1) memory therapeutic agents that rescue synaptic and memory functions after the brain insults; 2) anti-pathologic therapeutics and an effective management of vascular risk factors; and 3) preventative therapeutic agents that achieve memory therapy through functional enhancement. Their development and potential as clinically effective memory therapeutics for vascular cognitive impairment and dementia are discussed in this review. These therapeutic agents are also likely to benefit patients with AD and/or other types of memory disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. The Relevance of Literature.

    Science.gov (United States)

    Dunham, L. L.

    1971-01-01

    The "legacy" of the humanities is discussed in terms of relevance, involvement, and other philosophical considerations. Reasons for studying foreign literature in language classes are developed in the article. Comment is also made on attitudes and ideas culled from the writings of Clifton Fadiman, Jean Paul Sartre, and James Baldwin. (RL)

  19. Is Information Still Relevant?

    Science.gov (United States)

    Ma, Lia

    2013-01-01

    Introduction: The term "information" in information science does not share the characteristics of those of a nomenclature: it does not bear a generally accepted definition and it does not serve as the bases and assumptions for research studies. As the data deluge has arrived, is the concept of information still relevant for information…

  20. Diagnostic criteria for vascular dementia

    NARCIS (Netherlands)

    Scheltens, P.; Hijdra, A. H.

    1998-01-01

    The term vascular dementia implies the presence of a clinical syndrome (dementia) caused by, or at least assumed to be caused by, a specific disorder (cerebrovascular disease). In this review, the various sets of criteria used to define vascular dementia are outlined. The various sets of criteria

  1. Dynamic adaption of vascular morphology

    DEFF Research Database (Denmark)

    Okkels, Fridolin; Jacobsen, Jens Christian Brings

    2012-01-01

    The structure of vascular networks adapts continuously to meet changes in demand of the surrounding tissue. Most of the known vascular adaptation mechanisms are based on local reactions to local stimuli such as pressure and flow, which in turn reflects influence from the surrounding tissue. Here ...

  2. Caffeine's Vascular Mechanisms of Action

    Directory of Open Access Journals (Sweden)

    Darío Echeverri

    2010-01-01

    Full Text Available Caffeine is the most widely consumed stimulating substance in the world. It is found in coffee, tea, soft drinks, chocolate, and many medications. Caffeine is a xanthine with various effects and mechanisms of action in vascular tissue. In endothelial cells, it increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predominantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. In addition, it blocks the adenosine receptors present in the vascular tissue to produce vasoconstriction. In this paper the main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial.

  3. The Danish Vascular Registry, Karbase

    DEFF Research Database (Denmark)

    Eldrup, Nikolaj; Cerqueira, Charlotte; de la Motte, Louise

    2016-01-01

    AIM: The Danish Vascular Registry (DVR), Karbase, is monitoring arterial and advanced vein interventions conducted at all vascular departments in Denmark. The main aim of the DVR is to improve the quality of treatment for patients undergoing vascular surgery in Denmark by using the registry...... for quality assessment and research. STUDY POPULATION: All patients undergoing vascular interventions (surgical and endovascular) at any vascular department in Denmark are registered in the DVR. The DVR was initiated in 1989, and each year, ∼9,000 procedures are added. By January 2016, >180,000 procedures...... have been recorded. Since 2001, data completeness has been >90% (compared to the Danish National Patient Register). MAIN VARIABLES: Variables include information on descriptive patient data (ie, age, sex, height, and weight) and comorbidity (ie, previous cardiovascular disease and diabetes). Process...

  4. Social media in vascular surgery.

    Science.gov (United States)

    Indes, Jeffrey E; Gates, Lindsay; Mitchell, Erica L; Muhs, Bart E

    2013-04-01

    There has been a tremendous growth in the use of social media to expand the visibility of various specialties in medicine. The purpose of this paper is to describe the latest updates on some current applications of social media in the practice of vascular surgery as well as existing limitations of use. This investigation demonstrates that the use of social networking sites appears to have a positive impact on vascular practice, as is evident through the incorporation of this technology at the Cleveland Clinic and by the Society for Vascular Surgery into their approach to patient care and physician communication. Overall, integration of social networking technology has current and future potential to be used to promote goals, patient awareness, recruitment for clinical trials, and professionalism within the specialty of vascular surgery. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  5. Noninfarct vascular dementia and Alzheimer dementia spectrum.

    Science.gov (United States)

    Emery, V Olga; Gillie, Edward X; Smith, Joseph A

    2005-03-15

    Vascular dementia is an overarching superordinate category of which multiinfarct vascular dementia is only one subtype. To contribute to the definition of vascular dementia, method involved investigation of mental status, oral language and comprehension in 81 consecutive vascular patients comprising two vascular samples: cerebral infarct sample (n=43) and cerebral noninfarct sample (n=38). To determine baseline, method also involved investigation of 36 demographically equivalent normal elderly. Results indicate both vascular samples performed significantly worse than normal elderly. Results further indicate there were no robust, reliable, significant differences between cerebral infarct and cerebral noninfarct patients. The lack of significant differences between cerebral infarct and cerebral noninfarct vascular samples brings into focus the ambiguous transition between diffuse, generalized disease and the multifocality underlying the vascular dementia-Alzheimer dementia spectrum. Cross-cutting infarct and noninfarct vascular populations were vascular factors of arteriosclerosis, abnormal blood pressure, diabetes mellitus, abnormal electrocardiogram, peripheral vascular disease, and other variables implicated in the distal causality of both infarct and noninfarct vascular dementias. Results indicate cerebral infarction is not the only path to the final common phenotype of vascular dementia. Vascular dementia is reconceptualized so as to include noninfarct vascular dementia: vascular dementia caused by underlying vascular factors other than cerebral infarction. It is suggested that one form of the subtype of noninfarct vascular dementia is Alzheimer-type vascular dementia.

  6. Role of Endogenous Sulfur Dioxide in Regulating Vascular Structural Remodeling in Hypertension

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2016-01-01

    Full Text Available Sulfur dioxide (SO2, an emerging gasotransmitter, was discovered to be endogenously generated in the cardiovascular system. Recently, the physiological effects of endogenous SO2 were confirmed. Vascular structural remodeling (VSR, an important pathological change in many cardiovascular diseases, plays a crucial role in the pathogenesis of the diseases. Here, the authors reviewed the research progress of endogenous SO2 in regulating VSR by searching the relevant data from PubMed and Medline. In spontaneously hypertensive rats (SHRs and pulmonary hypertensive rats, SO2/aspartate aminotransferase (AAT pathway was significantly altered. SO2 inhibited vascular smooth muscle cell (VSMC proliferation, promoted apoptosis, inhibited the synthesis of extracellular collagen but promoted its degradation, and enhanced antioxidative capacity, thereby playing a significant role in attenuating VSR. However, the detailed mechanisms needed to be further explored. Further studies in this field would be important for the better understanding of the pathogenesis of systemic hypertension and pulmonary hypertension. Also, clinical trials are needed to demonstrate if SO2 would be a potential therapeutic target in cardiovascular diseases.

  7. Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress.

    Science.gov (United States)

    Pearson-Leary, J; Eacret, D; Chen, R; Takano, H; Nicholas, B; Bhatnagar, S

    2017-06-27

    During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, we used nonbiased analyses of microRNAs in the ventral hippocampus (vHPC) to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat. In the vHPC of active coping rats, miR-455-3p level was increased, while miR-30e-3p level was increased in the vHPC of passive coping rats. Pathway analyses identified inflammatory and vascular remodeling pathways as enriched by genes targeted by these microRNAs. Utilizing several independent markers for blood vessels, inflammatory processes and neural activity in the vHPC, we found that SL/vulnerable rats exhibit increased neural activity, vascular remodeling and inflammatory processes that include both increased blood-brain barrier permeability and increased number of microglia in the vHPC relative to control and resilient rats. To test the relevance of these changes for the development of the vulnerable phenotype, we used pharmacological approaches to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. Collectively, these results show that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the vHPC. These results suggest that dampening inflammatory processes by administering anti-inflammatory agents reduces

  8. Adiponectin as a potential biomarker of vascular disease.

    Science.gov (United States)

    Ebrahimi-Mamaeghani, Mehrangiz; Mohammadi, Somayeh; Arefhosseini, Seyed Rafie; Fallah, Parviz; Bazi, Zahra

    2015-01-01

    The increasing prevalence of diabetes and its complications heralds an alarming situation worldwide. Obesity-associated changes in circulating adiponectin concentrations have the capacity to predict insulin sensitivity and are a link between obesity and a number of vascular diseases. One obvious consequence of obesity is a decrease in circulating levels of adiponectin, which are associated with cardiovascular disorders and associated vascular comorbidities. Human and animal studies have demonstrated decreased adiponectin to be an independent risk factor for cardiovascular disease. However, in animal studies, increased circulating adiponectin alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction, and diabetic cardiac tissue disorders. Further, metabolism of a number of foods and medications are affected by induction of adiponectin. Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health. Understanding the molecular mechanisms underlying the regulation of adiponectin secretion and signaling is critical for designing new therapeutic strategies. This review summarizes the recent evidence for the physiological role and clinical significance of adiponectin in vascular health, identification of the receptor and post-receptor signaling events related to the protective effects of the adiponectin system on vascular compartments, and its potential use as a target for therapeutic intervention in vascular disease.

  9. Perivascular fat, AMP-activated protein kinase and vascular diseases.

    Science.gov (United States)

    Almabrouk, T A M; Ewart, M A; Salt, I P; Kennedy, S

    2014-02-01

    Perivascular adipose tissue (PVAT) is an active endocrine and paracrine organ that modulates vascular function, with implications for the pathophysiology of cardiovascular disease (CVD). Adipocytes and stromal cells contained within PVAT produce mediators (adipokines, cytokines, reactive oxygen species and gaseous compounds) with a range of paracrine effects modulating vascular smooth muscle cell contraction, proliferation and migration. However, the modulatory effect of PVAT on the vascular system in diseases, such as obesity, hypertension and atherosclerosis, remains poorly characterized. AMP-activated protein kinase (AMPK) regulates adipocyte metabolism, adipose biology and vascular function, and hence may be a potential therapeutic target for metabolic disorders such as type 2 diabetes mellitus (T2DM) and the vascular complications associated with obesity and T2DM. The role of AMPK in PVAT or the actions of PVAT have yet to be established, however. Activation of AMPK by pharmacological agents, such as metformin and thiazolidinediones, may modulate the activity of PVAT surrounding blood vessels and thereby contribute to their beneficial effect in cardiometabolic diseases. This review will provide a current perspective on how PVAT may influence vascular function via AMPK. We will also attempt to demonstrate how modulating AMPK activity using pharmacological agents could be exploited therapeutically to treat cardiometabolic diseases. © 2013 The British Pharmacological Society.

  10. The influence of perivascular adipose tissue on vascular homeostasis.

    Science.gov (United States)

    Szasz, Theodora; Bomfim, Gisele Facholi; Webb, R Clinton

    2013-01-01

    The perivascular adipose tissue (PVAT) is now recognized as an active contributor to vascular function. Adipocytes and stromal cells contained within PVAT are a source of an ever-growing list of molecules with varied paracrine effects on the underlying smooth muscle and endothelial cells, including adipokines, cytokines, reactive oxygen species, and gaseous compounds. Their secretion is regulated by systemic or local cues and modulates complex processes, including vascular contraction and relaxation, smooth muscle cell proliferation and migration, and vascular inflammation. Recent evidence demonstrates that metabolic and cardiovascular diseases alter the morphological and secretory characteristics of PVAT, with notable consequences. In obesity and diabetes, the expanded PVAT contributes to vascular insulin resistance. PVAT-derived cytokines may influence key steps of atherogenesis. The physiological anticontractile effect of PVAT is severely diminished in hypertension. Above all, a common denominator of the PVAT dysfunction in all these conditions is the immune cell infiltration, which triggers the subsequent inflammation, oxidative stress, and hypoxic processes to promote vascular dysfunction. In this review, we discuss the currently known mechanisms by which the PVAT influences blood vessel function. The important discoveries in the study of PVAT that have been made in recent years need to be further advanced, to identify the mechanisms of the anticontractile effects of PVAT, to explore the vascular-bed and species differences in PVAT function, to understand the regulation of PVAT secretion of mediators, and finally, to uncover ways to ameliorate cardiovascular disease by targeting therapeutic approaches to PVAT.

  11. Vascular pathology: Cause or effect in Alzheimer disease?

    Science.gov (United States)

    Rius-Pérez, S; Tormos, A M; Pérez, S; Taléns-Visconti, R

    2015-09-15

    Alzheimer disease (AD) is the main cortical neurodegenerative disease. The incidence of this disease increases with age, causing significant medical, social and economic problems, especially in countries with ageing populations. This review aims to highlight existing evidence of how vascular dysfunction may contribute to cognitive impairment in AD, as well as the therapeutic possibilities that might arise from this evidence. The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. The link between neurodegeneration and vascular dysfunction pathways has provided new drug targets and therapeutic approaches that will add to the treatments for AD. It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  12. Mechanisms for suppressing NADPH oxidase in the vascular wall

    Directory of Open Access Journals (Sweden)

    Gregory J Dusting

    2005-03-01

    Full Text Available Oxidative stress underlies many forms of vascular disease as well as tissue injury following ischemia and reperfusion. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex as expressed in vascular cells differs from that in phagocytic leucocytes both in biochemical structure and functions. The crucial flavin-containing catalytic subunits, Nox1 and Nox4, are not found in leucocytes, but are highly expressed in vascular cells and upregulated with vascular remodeling, such as that found in hypertension and atherosclerosis. The difference in catalytic subunits offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic functions carried out by reactive oxygen and nitrogen species. Nitric oxide and targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack, than are conventional antioxidants. The roles of Nox isoforms in other inflammatory conditions are yet to be explored.

  13. Contemporary vascular smartphone medical applications.

    Science.gov (United States)

    Carter, Thomas; O'Neill, Stephen; Johns, Neil; Brady, Richard R W

    2013-08-01

    Use of smartphones and medical mHealth applications (apps) within the clinical environment provides a potential means for delivering elements of vascular care. This article reviews the contemporary availability of apps specifically themed to major vascular diseases and the opportunities and concerns regarding their integration into practice. Smartphone apps relating to major vascular diseases were identified from the app stores for the 6 most popular smartphone platforms, including iPhone, Android, Blackberry, Nokia, Windows, and Samsung. Search terms included peripheral artery (arterial) disease, varicose veins, aortic aneurysm, carotid artery disease, amputation, ulcers, hyperhydrosis, thoracic outlet syndrome, vascular malformation, and lymphatic disorders. Forty-nine vascular-themed apps were identified. Sixteen (33%) were free of charge. Fifteen apps (31%) had customer satisfaction ratings, but only 3 (6%) had greater than 100. Only 13 apps (27%) had documented medical professional involvement in their design or content. The integration of apps into the delivery of care has the potential to benefit vascular health care workers and patients. However, high-quality apps designed by clinicians with vascular expertise are currently lacking and represent an area of concern in the mHealth market. Improvement in the quality and reliability of these apps will require the development of robust regulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

    National Research Council Canada - National Science Library

    Yuhui Huang; Jianping Yuan; Elda Righi; Walid S. Kamoun; Marek Ancukiewicz; Jean Nezivar; Michael Santosuosso; John D. Martin; Margaret R. Martin; Fabrizio Vianello; Pierre Leblanc; Lance L. Munn; Peigen Huang; Dan G. Duda; Dai Fukumura; Rakesh K. Jain; Mark C. Poznansky

    2012-01-01

    ... may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2...

  15. Depression in vascular dementia.

    Science.gov (United States)

    Naarding, Paul; de Koning, Inge; dan Kooten, Fop; Dippel, Diederik W J; Janzing, Joost G E; van der Mast, Rose C; Koudstaal, Peter J

    2003-04-01

    To study the presence of different dimensions of depression in subjects with vascular dementia. After a stroke, cognitive, affective and behavioural disturbances are common. It has been suggested that the nature of affective symptomatology can help to differentiate organic from psychological depression. Cognitive and affective symptoms were assessed in 78 stroke patients and a principal component analysis was performed on these symptoms. Also, a discriminant analysis was carried out to establish the contribution of different symptoms on the diagnosis 'depressive disorder' and 'dementia'. (1) Principal component analysis revealed three distinct sub-syndromes: one with predominantly mood symptoms, one with essentially psychomotor symptoms, and one with vegetative symptoms; (2) mood, psychomotor and vegetative symptoms were all independently and strongly related to a diagnosis of major depressive disorder according to DSM-III-R criteria; (3) the psychomotor factor was also firmly associated with dementia; and (4) discriminant analysis gave further support for our conclusion that some of the depressive features, in particular the psychomotor factor, are at least partly related to the organic brain damage from stroke. The results indicate that different dimensions of depression could be discerned in a group of stroke patients and that the symptom profile of depression in these patients can be affected by the presence of dementia. Copyright 2003 John Wiley & Sons, Ltd.

  16. Epigenetic Diabetic Vascular Complications

    Directory of Open Access Journals (Sweden)

    Ali Ahmadzadeh-Amiri

    2016-01-01

    Full Text Available Diabetic vascular complications (DVC influence several vital organ systems including cardiovascular, renal, ocular and nervous systems making it a major public health problem. Although extensive researches were performed in this field, the exact mechanisms responsible for these organ damages in diabetes remain obscure. Several metabolic disturbances have been involved in its complication and change in genes associated with these pathways occurred. Gene expression to produce a biologically active protein can be controlled by transcriptional and translational alteration on the head of genes without change in nucleotide composition. These epigenetic adjustments are steady, but possibly reversible and can be transmitted to future generation. Gene expression can be regulated by three epigenetic mechanisms including DNA methylation, histone modifications and noncoding microRNAs (miRNAs activity. Epigenetic studies must be directed to better realize the role of epigenetic changes to the etiology of DVC and knowledge of epigenetic would play a pivotal role in the application of individualized medicine. Application and development of high technology sequencing combined with more sensitive and advanced methodologies for epigenome studying help to determine specific epigenetic events that stimulate gene responses in patients with diabetes mellitus.

  17. [Extremity vascular traumas].

    Science.gov (United States)

    Angelini, Romeo; Rutolo, Ferdinando; Cozzolino, Giuseppe; D'Amario, Vanessa; Spigonardo, Francesca

    2005-01-01

    The Authors report on a series of 61 vascular traumas treated over a 7 years, separated in two groups. The first one includes 35 cases, that are street accidents, on the work and gunshot wounds. The second group includes 26 iatrogenic causes due to arterial catheterism. All patients underwent ecocolor Doppler directly in the operating theatre and, when this diagnostic procedure was not enough, pre-operating angiography was used (10 cases of complex traumas of the lower limb). One death was reported far each groups (3.27%). In 55 cases (90.1%), limb savage was achieved. In the others 4 (6.93%) of the first group, limb demolition was necessary for different causes. In the first group, severe neurological sequelaes were observed in 2 cases and motor deficits caused by tendon lesions in 1 case. The good results obtained are the result of the short ischemic interval between the acute event and treatment, thanks to a multidisciplinary approach of a specific equipe, that is rapid as possible.

  18. Prevalence, Correlates, and Prognosis of Healthy Vascular Aging in a Western Community-Dwelling Cohort: The Framingham Heart Study.

    Science.gov (United States)

    Niiranen, Teemu J; Lyass, Asya; Larson, Martin G; Hamburg, Naomi M; Benjamin, Emelia J; Mitchell, Gary F; Vasan, Ramachandran S

    2017-08-01

    Hypertension and increased vascular stiffness are viewed as inevitable parts of aging. To elucidate whether the age-related decrease in vascular function is avoidable, we assessed the prevalence, correlates, and prognosis of healthy vascular aging (HVA) in 3196 Framingham Study participants aged ≥50 years. We defined HVA as absence of hypertension and pulse wave velocity lifestyle, maintaining normal vascular function beyond 70 years of age is challenging. Although our data are observational, our findings support prevention strategies targeting modifiable factors and behaviors and obesity, in particular, to prevent or delay vascular aging and the associated risk of CVD. © 2017 American Heart Association, Inc.

  19. Vascular injuries during gynecological laparoscopy: the vascular surgeon's advice

    Directory of Open Access Journals (Sweden)

    Marcello Barbosa Barros

    Full Text Available CONTEXT: Iatrogenic vascular problems due to laparoscopy are a well recognized problem and lead to significant repercussions. In this context, a ten-year review of cases topic is presented, based on experience gained while heading two important vascular surgery services. CASES: Five patients with vascular injuries during elective laparoscopy are described. These patients presented with seven lesions of iliac vessels. All cases were evaluated immediately and required laparotomy, provisional hemostasis and urgent attendance by a vascular surgeon. Direct suturing was performed in three cases. One aortoiliac bypass and one ilioiliac reversed venous graft were made. Venous lesions were sutured. One case of a point-like perforation of the small bowel was found. There were no deaths and no complications during the postoperative period. DISCUSSION: Important points on this subject are made, and advice is given. There needs to be immediate recognition of the vascular injury, and expert repair by a vascular surgeon is recommended, in order to significantly reduce the degree of complications.

  20. Trauma vascular, visión del cirujano vascular

    Directory of Open Access Journals (Sweden)

    Dr. D. Cristián Salas

    2011-09-01

    Full Text Available El 3% de todas las lesiones en trauma tiene un componente vascular. Con los conflictos armados del siglo pasado se lograron grandes avances en este campo. A partir de la Guerra de Vietnam gracias a las mejoras en el manejo prehospitalario, traslado de pacientes, y avances en técnica quirúrgica se lograron tasas de sobrevida y de amputaciones que se han mantenido estables hasta la fecha. El diagnóstico de lesiones vasculares en extremidades se realiza con el examen físico, sin embargo las lesiones de vasos torácicos y abdominales requieren de imágenes de apoyo, siempre que el paciente se encuentre estabilizado, generalmente tomografía axial computada. La mayoría de las lesiones vasculares son por trauma penetrante, comprometiendo principalmente las extremidades. Con el desarrollo de los procedimientos invasivos vasculares en los últimos años se ha observado un aumento de lesiones vasculares iatrogénicas. Hoy en día muchos pacientes con trauma vascular son manejados por vía endovascular.

  1. Role of preoperative vascular ultrasonography in hemodialysis vascular access operation.

    Science.gov (United States)

    Siribumrungwong, Boonying; Tomtitchong, Prakitpunthu; Kanpirom, Kitti

    2010-12-01

    Preoperative vascular mapping increase rate of successful hemodialysis vascular access operation. Several studies recommend using this procedure routinely. But some studies recommend using this procedure in selected patients. So this study aims to determine the impacts of preoperative vascular mapping in unfavorable-examined patients. 55 patients were studied retrospectively from August 2006 to October 2009. Before April 2008, the operative plans were based on physical examination (group 1). After April 2008, the surgeon did preoperative vascular mapping prior to the operation in unfavorable-examined patients (group 2). The results were compared. There were high maturation rates in favorable-examined patients. In unfavorable-examined patients, preoperative vascular mapping can identified nonpalpable favorable vein which successful maturation of 18.75%. Complementary duplex scan decrease rate of unsuccessful operation significantly (p = 0.037) but does not increase maturation rate. Careful physical examination is important part before operation. Preoperative vascular mapping has benefit only in patients with unfavorable-examined patients. It finds some nonpalpable favorable vein and decrease unsuccessful exploration.

  2. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia.

    Science.gov (United States)

    Iadecola, Costantino

    2010-09-01

    There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier, and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

  3. Regional intensity of vascular care and lower extremity amputation rates

    Science.gov (United States)

    Goodney, Philip P.; Holman, Kerianne; Henke, Peter K.; Travis, Lori L.; Dimick, Justin B.; Stukel, Therese A.; Fisher, Elliott. S.; Birkmeyer, John D.

    2013-01-01

    -risk patients, especially African-American diabetic patients residing in low-intensity vascular care regions, represent an important target for systematic efforts to reduce amputation risk. PMID:23375611

  4. ( Elaeis guineensis Jacq ) vascular wilt

    African Journals Online (AJOL)

    Effet de la jachére sur l'expérimentation de la fusariose vasculaire du palmier à huile ( Elaeis guineensis Jacq ) : Effects of the fallow in the expression of oil-palm ( Elaeis guineensis Jacq ) vascular wilt.

  5. Lifestyle choices and endothelial function: risk and relevance.

    Science.gov (United States)

    Wang, Jingli; Widlansky, Michael E

    2009-04-01

    Cardiovascular disease remains the leading cause of death and disability in industrialized nations. The risk of cardiovascular disease is significantly reduced by lifestyle choices that promote cardiovascular health. Epidemiological data demonstrate that poor dietary choices, lack of exercise, smoking, obesity, stress, and pollution all increase cardiovascular risk. Poor habits and choices also have been shown to have adverse effects on vascular endothelial homeostasis leading to the development of endothelial dysfunction. Endothelial dysfunction includes broad regulatory changes leading to the expression of a vasoconstrictive, pro-thrombotic, and pro-inflammatory phenotype of the vascular endothelium. Interest in assessing lifestyle interventions as they relate to endothelial function has been encouraged by data demonstrating that measurements of endothelial function in easily accessible vascular beds such as the brachial artery correlate with risk for future cardiovascular events. Given the logistical difficulties and costs of performing large scale clinical trials assessing the ability of many lifestyle interventions designed to reduce cardiovascular risk, employing measures of endothelial function as a surrogate outcome for cardiovascular risk has allowed researchers to determine the biological plausibility of epidemiological data in this area with smaller studies. Newer study techniques, including genomic methodologies, now allow for better delineation of the mechanisms by which lifestyle choices affect the vascular endothelium and of the role of genetic variation in modifying these effects. This review discusses the effects of lifestyle choices on vascular endothelial function, the role and relevance of using studies that assess endothelial function in assessing cardiovascular risk, and future research directions in this area.

  6. Heritability of Retinal Vascular Fractals

    DEFF Research Database (Denmark)

    Vergmann, Anna Stage; Broe, Rebecca; Kessel, Line

    2017-01-01

    Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. Methods: This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50°, disc-centered fundus photographs, the reti...... vasculature may affect the retinal response to potential vascular disease in later life....

  7. Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report.

    Science.gov (United States)

    Shah, Ravi; Yeri, Ashish; Das, Avash; Courtright-Lim, Amanda; Ziegler, Olivia; Gervino, Ernest; Ocel, Jeffrey; Quintero-Pinzon, Pablo; Wooster, Luke; Bailey, Cole Shields; Tanriverdi, Kahraman; Beaulieu, Lea M; Freedman, Jane E; Ghiran, Ionita; Lewis, Gregory D; Van Keuren-Jensen, Kendall; Das, Saumya

    2017-12-01

    Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community. Copyright © 2017 the American Physiological Society.

  8. The Danish Vascular Registry, Karbase

    Science.gov (United States)

    Eldrup, Nikolaj; Cerqueira, Charlotte; de la Motte, Louise; Rathenborg, Lisbet Knudsen; Hansen, Allan K

    2016-01-01

    Aim The Danish Vascular Registry (DVR), Karbase, is monitoring arterial and advanced vein interventions conducted at all vascular departments in Denmark. The main aim of the DVR is to improve the quality of treatment for patients undergoing vascular surgery in Denmark by using the registry for quality assessment and research. Study population All patients undergoing vascular interventions (surgical and endovascular) at any vascular department in Denmark are registered in the DVR. The DVR was initiated in 1989, and each year, ∼9,000 procedures are added. By January 2016, >180,000 procedures have been recorded. Since 2001, data completeness has been >90% (compared to the Danish National Patient Register). Main variables Variables include information on descriptive patient data (ie, age, sex, height, and weight) and comorbidity (ie, previous cardiovascular disease and diabetes). Process variable includes waiting time (time from event to medical contact and treatment) and the type of procedures conducted. Outcome variables for in-hospital complications (ie, wound complications, myocardial infarction, stroke, amputation, respiratory complications, and renal insufficiency) and 30-day patency are submitted. Variables for medical treatment (antithrombotic and statin treatment), amputation, and survival are extracted from nationwide, administrative registers. Conclusion The DVR reports outcome on key indicators for monitoring the quality at all vascular departments in Denmark for the purpose of quality improvement. Furthermore, data are available for research and are being used in international collaborations on changes in clinical practices. PMID:27822118

  9. [Cutaneous vascular anomalies in children].

    Science.gov (United States)

    Yilmaz, L; Kacenelenbogen, N

    2015-09-01

    Vascular anomalies, which are erroneously categorized under the term angiomas, are a highly heterogeneous group of lesions that are poorly understood and affect a mean of 5 to 10 % of children. The fortuitous discovery of propranolol's efficacy in one of these entities has made them a topical issue. The paper's main objective is to inform family doctors of the various types of vascular anomalies, clarify their classification, and provide a common terminology. Its secondary objective is to provide a decision tree that enables primary care doctors to avoid diagnostic pitfalls, successfully detect cases, and optimize management. Systematic review. According to a recent study, 71,3 % of publications use the term hemangioma erroneously, regardless of the authors' field. The key for family doctors is to use one international classification only, that of the International Society for the Study of Vascular Anomalies (ISSVA), in order to facilitate management and comprehension between the different healthcare levels. The diagnosis of vascular anomalies is clinical in 90 % of cases, so all family doctors can, whilst using a decision tree, diagnose a vascular anomaly and refer only those that are complex for specialist care. The most common vascular anomaly is infantile hemangioma in infants, which spontaneously regresses around the age of 5-7 years in 90 % of cases. Watchful waiting and regular follow-up suffice, therefore, in such settings.

  10. The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications.

    Science.gov (United States)

    Qi Nan, Wu; Ling, Zhang; Bing, Chen

    2015-06-01

    The telomere-telomerase system plays an important role in the pathogenesis and disease progression of diabetes mellitus as well as in its vascular complications. Recent studies suggest that telomere shortening and abnormal telomerase activity occur in patients with diabetes mellitus, and targeting the telomere-telomerase system has become a prospective treatment for diabetes mellitus and its vascular complications. This review highlights the significance of the telomere-telomerase system and supports its role as a possible therapeutic target for patients with diabetes mellitus and its vascular complications Areas covered: This review covers the advances in understanding the telomere-telomerase system over the last 30 years and its significance in diabetes mellitus. In addition, it provides knowledge regarding the significance of the telomere-telomerase system in diabetes mellitus and its vascular complications as well as its role and mechanisms in oxidative stress, cell therapy and antioxidant activity Expert opinion: The telomere-telomerase system may be a potential therapeutic target that can protect against DNA damage and apoptosis in patients with diabetes mellitus and its vascular complications. DNA damage and apoptosis are associated with oxidative stress and are involved in the dysfunction of pancreatic β cells, insulin resistance, and its vascular complications. Abnormalities in the telomere-telomerase system may be associated with diabetes mellitus and its vascular complications. Therapies targeting telomere-telomerase system, telomerase reverse transcriptase transfection and alterative telomere lengthening must be identified before gene therapy can commence.

  11. Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease

    OpenAIRE

    Bradley, Jessica M.; Islam, Kazi N.; Polhemus, David J.; Donnarumma, Erminia; Brewster, Luke P.; Tao, Ya-Xiong; Goodchild, Traci T.; Lefer, David J.

    2015-01-01

    In a clinically relevant porcine model of metabolic syndrome and peripheral vascular disease, treatment with a novel sustained-release nitrite formulation restored cardiac endothelial nitric oxide synthase, enhancing myocardial nitrite levels, reduced oxidative stress, and improved ex vivo coronary vascular function via endothelium-independent vasodilation mechanism in obese Ossabaw swine.

  12. The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts

    Science.gov (United States)

    Hoshi, Ryan A.; Van Lith, Robert; Jen, Michele C.; Allen, Josephine B.; Lapidos, Karen A.; Ameer, Guillermo

    2014-01-01

    Prosthetic vascular grafts do not mimic the antithrombogenic properties of native blood vessels and therefore have higher rates of complications that involve thrombosis and restenosis. We developed an approach for grafting bioactive heparin, a potent anticoagulant glycosaminoglycan, to the lumen of ePTFE vascular grafts to improve their interactions with blood and vascular cells. Heparin was bound to aminated poly(1,8-octanediol-co-citrate) (POC) via its carboxyl functional groups onto POC-modified ePTFE grafts. The bioactivity and stability of the POC-immobilized heparin (POC–Heparin) were characterized via platelet adhesion and clotting assays. The effects of POC–Heparin on the adhesion, viability and phenotype of primary endothelial cells (EC), blood outgrowth endothelial cells (BOECs) obtained from endothelial progenitor cells (EPCs) isolated from human peripheral blood, and smooth muscle cells were also investigated. POC–Heparin grafts maintained bioactivity under physiologically relevant conditions in vitro for at least one month. Specifically, POC–Heparin-coated ePTFE grafts significantly reduced platelet adhesion and inhibited whole blood clotting kinetics. POC–Heparin supported EC and BOEC adhesion, viability, proliferation, NO production, and expression of endothelial cell-specific markers von Willebrand factor (vWF) and vascular endothelial-cadherin (VE-cadherin). Smooth muscle cells cultured on POC–Heparin showed increased expression of α-actin and decreased cell proliferation. This approach can be easily adapted to modify other blood contacting devices such as stents where antithrombogenicity and improved endothelialization are desirable properties. PMID:23069711

  13. Deep dorsal vein arterialisation in vascular impotence.

    Science.gov (United States)

    Wespes, E; Corbusier, A; Delcour, C; Vandenbosch, G; Struyven, J; Schulman, C C

    1989-11-01

    A series of 12 patients with vasculogenic impotence (4 arterial lesions; 8 arterial and venous lesions) underwent deep dorsal vein arterialisation after pre-operative assessment by a multidisciplinary approach. Cumulative graft patency was 58% (7 of 12 patients) up to 21 months but only 4 patients developed almost normal erections. Digital angiography, with and without the intracavernous injection of papaverine, was performed during follow-up to determine the vascular physiological status. At flaccidity, the corpora cavernosa were never opacified in the absence of a venocorporeal shunt. The penile glans was always visualised. Opacification of the deep dorsal vein and the circumflex system decreased with penile rigidity, resulting from their compression between Buck's fascia and the tunica albuginea. Intracavernous pressure recorded before and after the surgical procedure showed a marked increase when a caverno-venous shunt was performed. Hypervascularisation of the glans occurred in 2 cases. The relevance of this new surgical technique and its functional mechanism are discussed.

  14. Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding

    Science.gov (United States)

    Reinert, Rachel B.; Cai, Qing; Hong, Ji-Young; Plank, Jennifer L.; Aamodt, Kristie; Prasad, Nripesh; Aramandla, Radhika; Dai, Chunhua; Levy, Shawn E.; Pozzi, Ambra; Labosky, Patricia A.; Wright, Christopher V. E.; Brissova, Marcela; Powers, Alvin C.

    2014-01-01

    Neurovascular alignment is a common anatomical feature of organs, but the mechanisms leading to this arrangement are incompletely understood. Here, we show that vascular endothelial growth factor (VEGF) signaling profoundly affects both vascularization and innervation of the pancreatic islet. In mature islets, nerves are closely associated with capillaries, but the islet vascularization process during embryonic organogenesis significantly precedes islet innervation. Although a simple neuronal meshwork interconnects the developing islet clusters as they begin to form at E14.5, the substantial ingrowth of nerve fibers into islets occurs postnatally, when islet vascularization is already complete. Using genetic mouse models, we demonstrate that VEGF regulates islet innervation indirectly through its effects on intra-islet endothelial cells. Our data indicate that formation of a VEGF-directed, intra-islet vascular plexus is required for development of islet innervation, and that VEGF-induced islet hypervascularization leads to increased nerve fiber ingrowth. Transcriptome analysis of hypervascularized islets revealed an increased expression of extracellular matrix components and axon guidance molecules, with these transcripts being enriched in the islet-derived endothelial cell population. We propose a mechanism for coordinated neurovascular development within pancreatic islets, in which endocrine cell-derived VEGF directs the patterning of intra-islet capillaries during embryogenesis, forming a scaffold for the postnatal ingrowth of essential autonomic nerve fibers. PMID:24574008

  15. Early Detection System of Vascular Disease and Its Application Prospect

    Directory of Open Access Journals (Sweden)

    Huan Liu

    2016-01-01

    Full Text Available Markers of imaging, structure, and function reflecting vascular damage, integrating a long time accumulation effect of traditional and unrecognized cardiovascular risk factors, can be regarded as surrogate endpoints of target organ damage before the occurrence of clinical events. Prevention of cardiovascular disease requires risk stratification and treatment of traditional risk factors, such as smoking, hypertension, hyperlipidemia, and diabetes. However, traditional risk stratification is not sufficient to provide accurate assessment of future cardiovascular events. Therefore, vascular injury related parameters obtained by ultrasound or other noninvasive devices, as a surrogate parameter of subclinical cardiovascular disease, can improve cardiovascular risk assessment and optimize the preventive treatment strategy. Thus, we will summarize the research progress and clinical application of early assessment technology of vascular diseases in the present review.

  16. New vascular disrupting agents in upper gastrointestinal malignancies.

    Science.gov (United States)

    Quatrale, A E; Porcelli, L; Gnoni, A; Numico, G; Paradiso, A; Azzariti, A

    2014-01-01

    Antivascular approaches aim to cause rapid and catastrophic shutdown in the vascular function of the tumour, leading to extensive tumour cell death. Tumour vascular disrupting agents (VDAs) are a new class of cancer therapies that target the existing vasculature of tumours, taking advantage of the relative instability of tumour vasculature and its supporting structures. Treatment with VDAs induces a rapid collapse and regression of tumour vessels, with a consequent deprivation of blood and oxygen which leads to ischemic or hemorrhagic necrosis of the tumour. In this review, an overview of the most recently developed vascular disrupting agents is reported, focusing on the biological effects exerted by these compounds on endothelial cells and tumour vasculature, potentially effective in the treatment of several malignancies including upper gastrointestinal tumours. In particular, we have focused on the antimitotic agent combretastatin and its numerous synthetic analogues such as combretastatin A-4-phosphate, OXI4503, and AVE8062, and on the colchicine analogue ZD6126.

  17. Vascular aging and hemodynamic stability in the intraoperative period

    Directory of Open Access Journals (Sweden)

    Ferrante S. Gragasin

    2012-04-01

    Full Text Available The proportion of elderly people in the population is steadily increasing, and the inevitable consequence is that this subpopulation is more frequently represented in common medical procedures and surgeries. Understanding the circulatory changes that accompany the aging process is therefore becoming increasingly timely and relevant. In this short review, we discuss aspects of vascular control in aging that are particularly relevant in the maintenance of intraoperative hemodynamic stability. We subsequently review the effects of certain notable anesthetic agents with respect to the aging vasculature.

  18. Molecular biomarkers of vascular dysfunction in obstructive sleep apnea.

    Directory of Open Access Journals (Sweden)

    Elzbieta Kaczmarek

    Full Text Available Untreated and long-lasting obstructive sleep apnea (OSA may lead to important vascular abnormalities, including endothelial cell (EC dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (microvasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation, and human dermal microvascular (HMVEC and coronary artery endothelial cells (HCAEC cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS, tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20, hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75% compared to mildly hypoxemic OSA patients (SaO2 75%-90% and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1 expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.

  19. The influence of perivascular adipose tissue on vascular homeostasis

    Directory of Open Access Journals (Sweden)

    Szasz T

    2013-03-01

    Full Text Available Theodora Szasz,1 Gisele Facholi Bomfim,2 R Clinton Webb1 1Department of Physiology, Georgia Regents University, Augusta, USA; 2Department of Pharmacology, University of São Paulo, São Paulo, Brazil Abstract: The perivascular adipose tissue (PVAT is now recognized as an active contributor to vascular function. Adipocytes and stromal cells contained within PVAT are a source of an ever-growing list of molecules with varied paracrine effects on the underlying smooth muscle and endothelial cells, including adipokines, cytokines, reactive oxygen species, and gaseous compounds. Their secretion is regulated by systemic or local cues and modulates complex processes, including vascular contraction and relaxation, smooth muscle cell proliferation and migration, and vascular inflammation. Recent evidence demonstrates that metabolic and cardiovascular diseases alter the morphological and secretory characteristics of PVAT, with notable consequences. In obesity and diabetes, the expanded PVAT contributes to vascular insulin resistance. PVAT-derived cytokines may influence key steps of atherogenesis. The physiological anticontractile effect of PVAT is severely diminished in hypertension. Above all, a common denominator of the PVAT dysfunction in all these conditions is the immune cell infiltration, which triggers the subsequent inflammation, oxidative stress, and hypoxic processes to promote vascular dysfunction. In this review, we discuss the currently known mechanisms by which the PVAT influences blood vessel function. The important discoveries in the study of PVAT that have been made in recent years need to be further advanced, to identify the mechanisms of the anticontractile effects of PVAT, to explore the vascular-bed and species differences in PVAT function, to understand the regulation of PVAT secretion of mediators, and finally, to uncover ways to ameliorate cardiovascular disease by targeting therapeutic approaches to PVAT. Keywords: adipokines

  20. Adiponectin as a potential biomarker of vascular disease

    Directory of Open Access Journals (Sweden)

    Ebrahimi-Mamaeghani M

    2015-01-01

    the receptor and post-receptor signaling events related to the protective effects of the adiponectin system on vascular compartments, and its potential use as a target for therapeutic intervention in vascular disease.Keywords: obesity, adiponectin, vascular disease

  1. Phytochemical genistein in the regulation of vascular function: new insights.

    Science.gov (United States)

    Si, Hongwei; Liu, Dongmin

    2007-01-01

    Genistein, a natural bioactive compound derived from legumes, has drawn wide attention during the last decade because of its potentially beneficial effects on some human degenerative diseases. It has a weak estrogenic effect and is a well-known non-specific tyrosine kinase inhibitor at pharmacological doses. Epidemiological studies show that genistein intake is inversely associated with the risk of cardiovascular diseases. Data from animal and in vitro studies suggest a protective role of genistein in cardiovascular events. However, the mechanisms of the genistein action on vascular protective effects are unclear. Past extensive studies exploring its hypolipidemic effect resulted in contradictory data. Genistein also is a relatively poor antioxidant. However, genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte-endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis. Recent studies found that genistein exerts a novel non-genomic action by targeting on important signaling molecules in vascular endothelial cells (ECs). Genistein rapidly activates endothelial nitric oxide synthase and production of nitric oxide in ECs. This genistein effect is novel since it is independent of its known effects, but mediated by the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cascade. Further studies demonstrated that genistein directly stimulates the plasma membrane-associated adenylate cyclases, leading to activation of the cAMP signaling pathway. In addition, genistein activates peroxisome proliferator-activated receptors, ligand-activated nuclear receptors important to normal vascular function. Furthermore, genistein reduces reactive oxygen species (ROS) by attenuating the expression of ROS-producing enzymes. These new findings reveal the novel roles for genistein in the regulation of vascular function and provide a basis for further

  2. Recruiting women to vascular surgery and other surgical specialties.

    Science.gov (United States)

    Dageforde, Leigh Anne; Kibbe, Melina; Jackson, Gretchen Purcell

    2013-01-01

    Vascular surgery is a subspecialty that attracts future surgeons with challenging technical procedures and complex decision making. Despite its appeal, continued promotion of the field is necessary to recruit and retain the best and brightest candidates. Recruitment of medical students and residents may be limited by the lifestyle inherent to vascular surgery and the length of residency training. The young adults of the current applicant and resident pool differ from prior generations in their desire for hands-on mentoring, aspirations to affect change daily, a penchant for technology, and strong emphasis on work-life balance. Furthermore, the percentage of women pursuing careers in vascular surgery is not representative of the eligible workforce. Women are now the majority of graduates in all of higher education, and thus, vascular surgery may need to make a concerted effort to appeal to women in order to attract the most talented young professionals to the field. Recruiting strategies for both men and women of Generation Y should target a diverse group of potential candidates with an awareness of the unique characteristics and needs of this generation of rising surgeons. Copyright © 2013 Society for Vascular Surgery. All rights reserved.

  3. Concomitant vascular and neurodegenerative pathologies double the risk of dementia.

    Science.gov (United States)

    Azarpazhooh, Mahmoud Reza; Avan, Abolfazl; Cipriano, Lauren E; Munoz, David G; Sposato, Luciano A; Hachinski, Vladimir

    2017-09-30

    The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%-86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  4. Diagnosis and treatment of vascular damage in dementia.

    Science.gov (United States)

    Biessels, Geert Jan

    2016-05-01

    This paper provides an overview of cognitive impairment due to vascular brain damage, which is referred to as vascular cognitive impairment (VCI). Over the past decades, we have seen marked progress in detecting VCI, both through maturation of diagnostic concepts and through advances in brain imaging, especially MRI. Yet in daily practice, it is often challenging to establish the diagnosis, particularly in patients where there is no evident temporal relation between a cerebrovascular event and cognitive dysfunction. Because vascular damage is such a common cause of cognitive dysfunction, it provides an obvious target for treatment. In patients whose cognitive dysfunction follows directly after a stroke, the etiological classification of this stroke will direct treatment. In many patients however, VCI develops due to so-called "silent vascular damage," without evident cerebrovascular events. In these patients, small vessel diseases (SVDs) are the most common cause. Yet no SVD-specific treatments currently exist, which is due to incomplete understanding of the pathophysiology. This review addresses developments in this field. It offers a framework to translate diagnostic criteria to daily practice, addresses treatment, and highlights some future perspectives. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau, and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Imaging of peripheral vascular disease

    Directory of Open Access Journals (Sweden)

    Mo Al-Qaisi

    2009-03-01

    Full Text Available Mo Al-Qaisi1, David M Nott1, David H King1, Sam Kaddoura2, Mo Hamady31Charing Cross Hospital, London, UK; 2Royal Brompton Hospital, London, UK; 3St. Mary’s Hospital, London, UKAbstract: This illustrated review article gives an evidence-based update on the different modalities used for imaging peripheral vascular disease (duplex ultrasound, computed tomography angiography, magnetic resonance angiography, and digital subtraction angiography. After discussing the latest technological developments for each modality, their limitations are also highlighted. The evidence is presented for the various modalities’ roles in the imaging of peripheral vascular disease, including problem-solving applications. The strengths and weaknesses of each modality are therefore critically appraised, including the salient technological, clinical, and financial aspects. This review allows the general and specialist practitioner to make an informed decision on how best to deploy imaging tests in peripheral vascular disease as part of an evidence-based approach. The article concludes with a rational imaging algorithm for the investigation of peripheral vascular disease.Keywords: imaging, peripheral, vascular, duplex, angiography, arterial 

  6. Trauma vascular, visión del cirujano vascular

    OpenAIRE

    Dr. D. Cristián Salas

    2011-01-01

    El 3% de todas las lesiones en trauma tiene un componente vascular. Con los conflictos armados del siglo pasado se lograron grandes avances en este campo. A partir de la Guerra de Vietnam gracias a las mejoras en el manejo prehospitalario, traslado de pacientes, y avances en técnica quirúrgica se lograron tasas de sobrevida y de amputaciones que se han mantenido estables hasta la fecha. El diagnóstico de lesiones vasculares en extremidades se realiza con el examen físico, sin embargo las lesi...

  7. Extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities: A retrospective study of 352 patients.

    Science.gov (United States)

    Sohns, Jan M; Menke, Jan; Bergau, Leonard; Weiss, Bernhard G; Schmuck, Sebastian; Weiberg, Desiree; Staab, Wieland; Derlin, Thorsten; Dorenkamp, Marc; Sohns, Christian

    2017-01-01

    Background The aim of this study was to assess the prevalence and clinical significance of extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities. Materials and methods Three hundred fifty-two patients underwent abdominal, pelvic and lower extremity 1.5 T magnetic resonance angiography. Clinically relevant vascular and extra-vascular findings were identified. Relevant vascular findings were classified as stenosis, occlusion, aneurysm, sclerosis, dissection or vasculitis. Relevant extra-vascular findings were categorized as 'safe' (Group A), intermediate - requiring additional investigation - (Group B) and malignant/endangering - requiring change of therapy (Group C). Results A total of 2152 clinically relevant vascular findings was identified (6.1/patient). The most frequent vascular finding was femoral artery stenosis (10.6%). Four hundred fifty-one extra-vascular findings were observed (1.3/patient) and classified into Group A (78%), Group B (19.5%) and Group C findings (2.4%). The most frequent malignant findings were lung cancer, lymphoma, osteosarcoma, hepatocellular carcinoma and renal cell carcinoma (7/352 patients). Conclusions Extravascular findings are frequently encountered in magnetic resonance angiography performed for vascular indications. Clinically relevant findings are seen in a substantial part of patients and should prompt further diagnostic work-up.

  8. Is relevance theory applicable to proverbs’ translation?

    Directory of Open Access Journals (Sweden)

    Pegulescu Anca-Mariana

    2016-01-01

    Full Text Available Translation, viewed as a multi-faceted task, can arise different types of difficulties. Proverbs have been considered special patterns, displaying sometimes hidden meanings or suggesting morals issuing from a particular example. These paremic units - the proverbs - conveyed feelings, states of mind, behaviours or ‘metaphorical descriptions of certain situations’(Krikmann. Starting from Savory’s list of pair-wise contradictory translation principles, I intend to prove that the link between different ‘forms’ and their ‘contents’ lies in the principle of relevance when referring to proverbs. Even if relevance theory is not a theory of linguistic structure - and many translation problems imply structural mismatches - relevance theory offers insights about contextual information. Proverbs are seen as texts in themselves. My analysis will target the ethnofields of ‘to buy’ and ‘to sell’ in English proverbs and their Romanian corresponding versions.

  9. Basic Vascular Neuroanatomy of the Brain and Spine: What the General Interventional Radiologist Needs to Know

    OpenAIRE

    Prince, Ethan A.; Ahn, Sun Ho

    2013-01-01

    This article is intended to provide a review of clinically relevant neurovascular anatomy. A solid understanding of the vascular anatomy of the brain and spine are essential for the safe and effective performance of neurointerventional radiology. Key concepts to master include collateral pathways and anastomoses between the external and internal carotid circulation, the Circle of Willis as a route to otherwise inaccessible intracranial vascular distributions, and the origin of spinal arterial...

  10. Mesoderm/mesenchyme homeobox gene l promotes vascular smooth muscle cell phenotypic modulation and vascular remodeling.

    Science.gov (United States)

    Wu, Bing; Zhang, Lei; Zhu, Yun-He; Zhang, You-En; Zheng, Fei; Yang, Jian-Ye; Guo, Ling-Yun; Li, Xing-Yuan; Wang, Lu; Tang, Jun-Ming; Chen, Shi-You; Wang, Jia-Ning

    2018-01-15

    To investigate the role of mesoderm/mesenchyme homeobox gene l (Meox1) in vascular smooth muscle cells (SMCs) phenotypic modulation during vascular remodeling. By using immunostaining, Western blot, and histological analyses, we found that Meox1 was up-regulated in PDGF-BB-treated SMCs in vitro and balloon injury-induced arterial SMCs in vivo. Meox1 knockdown by shRNA restored the expression of contractile SMCs phenotype markers including smooth muscle α-actin (α-SMA) and calponin. In contrast, overexpression of Moex1 inhibited α-SMA and calponin expressions while inducing the expressions of synthetic SMCs phenotype markers such as matrix gla protein, osteopontin, and proliferating cell nuclear antigen. Mechanistically, Meox1 mediated the SMCs phenotypic modulation through FAK-ERK1/2 signaling, which appears to induce autophagy in SMCs. In vivo, knockdown of Meox1 attenuated injury-induced neointima formation and promoted SMCs contractile proteins expressions. Meox1 knockdown also reduced the number of proliferating SMCs, suggesting that Meox1 was important for SMCs proliferation in vivo. Moreover, knockdown of Meox1 attenuated ERK1/2 signaling and autophagy markers expressions, suggesting that Meox1 may promote SMCs phenotypic modulation via ERK1/2 signaling-autophagy in vivo. Our data indicated that Meox1 promotes SMCs phenotypic modulation and injury-induced vascular remodeling by regulating the FAK-ERK1/2-autophagy signaling cascade. Thus, targeting Meox1 may be an attractive approach for treating proliferating vascular diseases. Copyright © 2017. Published by Elsevier B.V.

  11. Heritability of Retinal Vascular Fractals

    DEFF Research Database (Denmark)

    Vergmann, Anna Stage; Broe, Rebecca; Kessel, Line

    2017-01-01

    , the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the retinal......Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. Methods: This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50°, disc-centered fundus photographs......, the retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficients. Falconer's formula and quantitative genetic models were used to determine the genetic component of variation. Results: The mean...

  12. Fetal origin of vascular aging

    Directory of Open Access Journals (Sweden)

    Shailesh Pitale

    2011-01-01

    Full Text Available Aging is increasingly regarded as an independent risk factor for development of cardiovascular diseases such as atherosclerosis and hypertension and their complications (e.g. MI and Stroke. It is well known that vascular disease evolve over decades with progressive accumulation of cellular and extracellular materials and many inflammatory processes. Metabolic syndrome, obesity and diabetes are conventionally recognized as risk factors for development of coronary vascular disease (CVD. These conditions are known to accelerate ageing process in general and vascular ageing in particular. Adverse events during intrauterine life may programme organ growth and favour disease later in life, popularly known as, ′Barker′s Hypothesis′. The notion of fetal programming implies that during critical periods of prenatal growth, changes in the hormonal and nutritional milieu of the conceptus may alter the full expression of the fetal genome, leading to permanent effects on a range of physiological.

  13. Does aldosterone play a significant role for regulation of vascular tone?

    DEFF Research Database (Denmark)

    Lyngsø, Kristina Sanne; Assersen, Kasper Bostlund; Dalgaard, Emil Geertsen

    2016-01-01

    receptors (MR) are present in endothelial and vascular smooth muscle cells and MR-independent pathways are also involved. The vascular effects of aldosterone are complex, both concentration, temporal and spatial aspects are relevant. The acute response includes vasodilation through endothelial nitric oxide...... of reactive oxygen radicals, endothelia Na-influx and smooth muscle calcium channel expression and perivascular cells, e.g. mast cells, also participate. Moreover, the vascular effect of aldosterone depends on the status of the endothelium which is likely cause of the very different responses to aldosterone...

  14. Vascular education and training in Asia.

    Science.gov (United States)

    Jirasiritham, Sopon

    2008-12-01

    Cardiovascular diseases have become more prevalent and threatening to the health of the population of Asia due to the rapidly growing number of aging people. The Asian Society for Vascular Surgery unites 13 member organizations: Japan, Korea, China, India, Hong Kong, Singapore, Malaysia, Taiwan, Bangladesh, Philippines, Saudi Arabia, Indonesia, and Thailand. The essential mission of the Asian Society for Vascular Surgery is to improve training in vascular surgery to increase the number of competent vascular surgeons in Asia. Almost every member country has its own vascular training program. Most curricula for vascular surgery training are composed of basic vascular research, clinical vascular medicine, vascular investigation, and open and endovascular surgery, with the period of training ranging from 2 to 4 years.

  15. Vascular Gene Expression: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Angélica Concepción eMartínez-Navarro

    2013-07-01

    Full Text Available The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a primitive vascular tissue (a lycophyte, as well as from others that lack a true vascular tissue (a bryophyte, and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non- vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

  16. Target Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — [Part of the ATLAS user facility.] The Physics Division operates a target development laboratory that produces targets and foils of various thickness and substrates,...

  17. Angioembolisation in vaginal vascular malformation.

    Directory of Open Access Journals (Sweden)

    Srivastava D

    2001-01-01

    Full Text Available Vaginal arteriovenous malformations are rare entities and their most common presentation is vaginal haemorrhage. This case report describes a 22-year-old woman who presented at 20 weeks of gestation with slow growing soft and tender swelling at anterior vaginal wall. Diagnosis was confirmed as vaginal vascular malformation on contrast enhanced magnetic resonance imaging. The mass did not subside after delivery and patient developed dyspareunia. It was successfully treated by angioembolisation using polyvinyl alcohol particles. Angioembolisation being safe and effective should be the treatment of first choice for symptomatic vaginal vascular malformation.

  18. Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension.

    Science.gov (United States)

    Touyz, Rhian M

    2008-03-01

    Magnesium, an essential intracellular cation, is critically involved in many biochemical reactions involved in the regulation of vascular tone and integrity. Decreased magnesium concentration has been implicated in altered vascular reactivity, endothelial dysfunction, vascular inflammation, and structural remodeling, processes important in vascular changes and target organ damage associated with hypertension. Until recently, very little was known about mechanisms regulating cellular magnesium homeostasis, and processes controlling transmembrane magnesium transport had been demonstrated only at the functional level. Two cation channels of the transient receptor potential melastatin (TRPM) cation channel family have now been identified as magnesium transporters, TRPM6 and TRPM7. These unique proteins, termed chanzymes because they possess a channel and a kinase domain, are differentially expressed, with TRPM6 being found primarily in epithelial cells and TRPM7 occurring ubiquitously. Vascular TRPM7 is modulated by vasoactive agents, pressure, stretch, and osmotic changes and may be a novel mechanotransducer. In addition to its magnesium transporter function, TRPM7 has been implicated as a signaling kinase involved in vascular smooth muscle cell growth, apoptosis, adhesion, contraction, cytoskeletal organization, and migration, important processes involved in vascular remodeling associated with hypertension and other vascular diseases. Emerging evidence suggests that vascular TRPM7 function may be altered in hypertension. This review discusses the importance of magnesium in vascular biology and implications in hypertension and highlights the transport systems, particularly TRPM6 and TRPM7, which may play a role in the control of vascular magnesium homeostasis. Since the recent identification and characterization of Mg2+-selective transporters, there has been enormous interest in the field. However, there is still a paucity of information, and much research is needed

  19. Cilia Control Vascular Mural Cell Recruitment in Vertebrates

    Directory of Open Access Journals (Sweden)

    Xiaowen Chen

    2017-01-01

    Full Text Available Vascular mural cells (vMCs are essential components of the vertebrate vascular system, controlling blood vessel maturation and homeostasis. Discrete molecular mechanisms have been associated with vMC development and differentiation. The function of hemodynamic forces in controlling vMC recruitment is unclear. Using transgenic lines marking developing vMCs in zebrafish embryos, we find that vMCs are recruited by arterial-fated vessels and that the process is flow dependent. We take advantage of tissue-specific CRISPR gene targeting to demonstrate that hemodynamic-dependent Notch activation and the ensuing arterial genetic program is driven by endothelial primary cilia. We also identify zebrafish foxc1b as a cilia-dependent Notch-specific target that is required within endothelial cells to drive vMC recruitment. In summary, we have identified a hemodynamic-dependent mechanism in the developing vasculature that controls vMC recruitment.

  20. Sleep and vascular disorders.

    Science.gov (United States)

    Plante, Gérard E

    2006-10-01

    It is not surprising that cardiovascular diseases such as congestive heart failure and coronary insufficiency can give rise to varying degrees of sleep impairment; it is less readily appreciated that certain physiologic events occurring during sleep-as well as long-term unsatisfactory sleep-may cause or increase the risk of cardiovascular conditions such as hypertension, atherosclerosis, stroke, and cardiac arrythmias. Heart rate abnormalities during sleep in normotensive subjects predict later cardiovascular disease, and their early identification alerts the physician to undertake preventive measures. Maneuvers, such as induction of hypoxia, can elicit abnormal blood pressure responses during sleep, and such responses have been used to identify impending cardiovascular problems that could become therapeutic targets. The spontaneously hypertensive rat has been used to examine the effect of sympathetic nervous system (SNS) activity on the heart under a variety of experimental conditions, including quiet and paradoxical sleep. The results have disclosed significant differences between the responses of spontaneously hypertensive rats and normal rats to SNS stimulation. Exploration of other pathophysiologic pathways affected by exposure to light and dark, including those responsive to the cyclic production of melatonin, will improve our understanding of the effect of disruptions of the circadian cycle on cardiovascular function. There is growing evidence that melatonin can influence important processes such as fluid, nitrogen, and acid-base balance. Human subjects whose nocturnal arterial blood pressure fails to show the "normal" decrement during sleep ("nondippers") are also prone to sleep poorly, exhibit increased SNS activity during sleep, and have an increased risk of total and cardiovascular disease mortality. Chronic sleep deficit is now known to be a risk factor for obesity and may contribute to the visceral form of obesity that underlies the metabolic syndrome

  1. Vascular ultrasound for atherosclerosis imaging

    NARCIS (Netherlands)

    C.L. de Korte (Chris); H.H.G. Hansen (Hendrik); A.F.W. van der Steen (Ton)

    2011-01-01

    textabstractCardiovascular disease is a leading cause of death in the Western world. Therefore, detection and quantification of atherosclerotic disease is of paramount importance to monitor treatment and possible prevention of acute events. Vascular ultrasound is an excellent technique to assess the

  2. Signaling circuitry in vascular morphogenesis.

    Science.gov (United States)

    Warren, Carmen M; Iruela-Arispe, M Luisa

    2010-05-01

    In this mini-review, we have highlighted the recent breakthroughs in growth factor signaling that have made conceptual changes in our understanding of how blood vessels are formed. Studies conducted over the past few years have focused on understanding the cell biology of vascular morphogenesis. The major themes include characterization of the different cell types that comprise a vascular sprout, as well as the regulatory influence of cell-cell and cell-matrix interactions on signaling outcomes. In addition, novel trends have emerged, including nonconventional ways in which vascular endothelial growth factor contributes to cell survival and metabolic balance. The growth of new capillary sprouts from a preexisting vascular network requires a highly coordinated cellular response to both growth factors and morphogens. This response is sensed and triggered by cell surface receptors responsible for the activation of an intracellular cascade that efficiently initiates migration and proliferation programs. While the molecular players that coordinate these effects have been identified, recent findings have expanded our understanding of how context, in particular cell-cell and cell-matrix interactions, affects endothelial cell responses to growth factors.

  3. Intestinal vascular anomalies in children.

    Science.gov (United States)

    Frémond, B; Yazbeck, S; Dubois, J; Brochu, P; Garel, L; Ouimet, A

    1997-06-01

    Vascular anomalies are an uncommon cause of gastrointestinal bleeding in childhood. Confusing nomenclature has made objective comparisons of published cases difficult and has interfered with an established consensus regarding diagnosis and therapeutic modalities. The purpose of this study was to clarify the situation by reviewing the records of all children who had intestinal vascular anomalies who were referred to our institution from 1975 to 1995. Thirteen lesions were identified in nine children (five boys and four girls). The median age at clinical onset was 8 years. Only two patients presented with a complex syndrome (Klippel-Trenaunay, 1; Osler-Rendu-Weber, 1). Diagnosis, location, and extension of these anomalies was only possible by angiography, which indicated that seven patients had isolated venous malformations and two had arteriovenous malformations. Because the lesions did not involve the serosa, intraoperative localization was a major problem. The main findings were a few slightly dilated mesenteric veins. Treatment was conservative in four children and surgical in five. Pathological findings on resected bowel demonstrated dilated and abnormal veins in the mucosa and submucosa. Selective angiography should not be delayed in patients with gastrointestinal bleeding if results of all other investigations are negative. Because these lesions are rarely recognizable on operative inspection, precise preoperative angiographic localization of intestinal vascular anomalies is essential to allow for a safe and limited resection of the involved bowel segment. Based on a better understanding of the natural history of these lesions, a classification of vascular anomalies of intestines in children is proposed.

  4. Silk Biomaterials with Vascularization Capacity.

    Science.gov (United States)

    Han, Hongyan; Ning, Hongyan; Liu, Shanshan; Lu, Qiang; Fan, Zhihai; Lu, Haijun; Lu, Guozhong; Kaplan, David L

    2016-01-20

    Functional vascularization is critical for the clinical regeneration of complex tissues such as kidney, liver or bone. The immobilization or delivery of growth factors has been explored to improve vascularization capacity of tissue engineered constructs, however, the use of growth factors has inherent problems such as the loss of signaling capability and the risk of complications such as immunological responses and cancer. Here, a new method of preparing water-insoluble silk protein scaffolds with vascularization capacity using an all aqueous process is reported. Acid was added temporally to tune the self-assembly of silk in lyophilization process, resulting in water insoluble scaffold formation directly. These biomaterials are mainly noncrystalline, offering improved cell proliferation than previously reported silk materials. These systems also have appropriate softer mechanical property that could provide physical cues to promote cell differentiation into endothelial cells, and enhance neovascularization and tissue ingrowth in vivo without the addition of growth factors. Therefore, silk-based degradable scaffolds represent an exciting biomaterial option, with vascularization capacity for soft tissue engineering and regenerative medicine.

  5. Markers of Early Vascular Ageing.

    Science.gov (United States)

    Kotsis, Vasilios; Antza, Christina; Doundoulakis, Ioannis; Stabouli, Stella

    2017-01-01

    Cardiovascular damage is clinically manifested as coronary artery disease, heart failure, stroke and peripheral artery disease. The prevalence of these adverse conditions is higher with advancing age. Although many patients present cardiovascular damage late in their life, it is common to see patients with early atherosclerosis in cardiovascular intensive care units at ages lower than 50 years in men and 55 for women. In this review of the literature we identified risk factors of early vascular damage. The classic risk factors such as age, gender, diabetes mellitus, dyslipidemia, smoking, alcohol, hypertension, obesity, family history and newer biomarkers such as hs-CRP, folic acid, homocysteine, fibrinogen are neither strong nor predictive of the individual patient's risk to present early cardiovascular disease. All these risk factors have been used to propose risk scores for possible future events but we still lack a single strong marker indicating new onset of disease that will predict the future independently of the classical factors. The role of vascular imaging techniques to identify patients with subclinical atherosclerotic vascular damage before clinical disease, including the effect of known and unknown risk factors on the vascular tree, seems to be very important for intensifying preventive measures in high risk patients. Early arteriosclerosis measured from pulse wave velocity is associated with reduced arterial elasticity and is associated with future cardiovascular events. Vascular measurements may better represent the continuum of cardiovascular disease from a young healthy to an aged diseased vessel that is going to produce adverse clinical events. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Basic vascular neuroanatomy of the brain and spine: what the general interventional radiologist needs to know.

    Science.gov (United States)

    Prince, Ethan A; Ahn, Sun Ho

    2013-09-01

    This article is intended to provide a review of clinically relevant neurovascular anatomy. A solid understanding of the vascular anatomy of the brain and spine are essential for the safe and effective performance of neurointerventional radiology. Key concepts to master include collateral pathways and anastomoses between the external and internal carotid circulation, the Circle of Willis as a route to otherwise inaccessible intracranial vascular distributions, and the origin of spinal arterial blood supply. These concepts will be highlighted using clinical angiographic examples with discussion of relevant embryology and pathology as needed.

  7. Mechanisms involved in the aging-induced vascular dysfunction

    Directory of Open Access Journals (Sweden)

    Mariam eEl Assar De La Fuente

    2012-05-01

    Full Text Available Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1 the reduction of nitric oxide (NO bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO-; (2 the possible sources involved in the enhancement of oxidative stress; (3 the increased activity of cyclooxygenase-derived vasoconstrictor compounds; and (4 the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, as well as sirtuins are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people.

  8. Pediatric central nervous system vascular malformations

    Energy Technology Data Exchange (ETDEWEB)

    Burch, Ezra A. [Brigham and Women' s Hospital, Department of Radiology, Boston, MA (United States); Orbach, Darren B. [Boston Children' s Hospital, Neurointerventional Radiology, Boston, MA (United States)

    2015-09-15

    Pediatric central nervous system (CNS) vascular anomalies include lesions found only in the pediatric population and also the full gamut of vascular lesions found in adults. Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some CNS vascular lesions that occur in adults, such as arteriovenous malformation, have somewhat distinct manifestations in children, and those are also discussed. Additionally, children with CNS vascular malformations often have associated broader vascular conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia, and capillary malformation-arteriovenous malformation syndrome (related to the RASA1 mutation). The treatment of pediatric CNS vascular malformations has greatly benefited from advances in endovascular therapy, including technical advances in adult interventional neuroradiology. Dramatic advances in therapy are expected to stem from increased understanding of the genetics and vascular biology that underlie pediatric CNS vascular malformations. (orig.)

  9. Subclinical hypothyroidism after vascular complicated pregnancy

    NARCIS (Netherlands)

    Zanden, M. van der; Hop-de Groot, R.J.; Sweep, F.C.; Ross, H.A.; Heijer, M. den; Spaanderman, M.E.A.

    2013-01-01

    OBJECTIVE: Women with a history of vascular complicated pregnancy are at risk for developing remote cardiovascular disease. It is associated with underlying cardiovascular risk factors both jeopardizing trophoblast and vascular function. Subclinical hypothyroidism may relate to both conditions.

  10. ESRD QIP - Vascular Access - Payment Year 2018

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset includes facility details, performance rates, vascular access topic measure score, and the state and national average measure scores for the vascular...

  11. NEURO-VASCULAR INJURIES ASSOCIATED WITH LIMB ...

    African Journals Online (AJOL)

    hi-tech

    2000-12-01

    Dec 1, 2000 ... Results: Road traffic accidents were the main cause of fractures associated with neuro- vascular ... the patients with vascular or nerve injury associated with fractures .... of traumatic aorto-iliac dissection injury in a child with.

  12. Ultrastructure: effects of melanin pigment on target specificity using a pulsed dye laser (577 nm)

    Energy Technology Data Exchange (ETDEWEB)

    Tong, A.K.; Tan, O.T.; Boll, J.; Parrish, J.A.; Murphy, G.F.

    1987-06-01

    It has been shown recently that brief pulses of 577 nm radiation from the tunable dye laser are absorbed selectively by oxyhemoglobin. This absorption is associated with highly specific damage to superficial vascular plexus blood vessels in those with lightly pigmented (type I-II) skin. To determine whether pigmentary differences in the overlying epidermis influence this target specificity, we exposed both type I (fair) and type V (dark) normal human skin to varying radiant exposure doses over 1.5-microsecond pulse durations from the tunable dye laser at a wavelength of 577 nm. Using ultrastructural techniques, we found in type I skin that even clinical subthreshold laser exposures caused reproducible alterations of erythrocytes and adjacent dermal vascular endothelium without comparable damage to the overlying epidermis. In contrast, degenerated epidermal basal cells represented the predominant form of cellular damage after laser exposure of type V skin at comparable doses. We conclude that epidermal melanin and vascular hemoglobin are competing sites for 577 nm laser absorption and damage, and that the target specificity of the 577 nm tunable dye laser is therefore influenced by variations in epidermal pigmentation. This finding is relevant to the clinical application of the tunable dye laser in the ablative treatment of vascular lesions. We also found on ultrastructure that the presence of electron-lucent circular structures of approximately 800 A in diameter were observed only at and above clinical threshold doses in those with type I skin and at the highest dose of 2.75 J/cm2 in type V skin. It has been proposed that these structures might be heat-fixed molds of water vapor. Both this and ultrastructural changes of epidermal basal cells demonstrate mechanisms responsible for alteration of tissue after exposure to 577 nm, which are discussed.

  13. Self-management of vascular risk factors

    OpenAIRE

    Sol-de Rijk, B.G.M.

    2009-01-01

    Summary The aim of this thesis was to provide insight into the potential of a self-management approach in treatment of vascular risk factors and to develop a self-management intervention. Furthermore to examine if this intervention, based on self-efficacy promoting theory, is effective in reducing vascular risk factors in patients with established vascular diseases. Patients with different manifestations of vascular diseases appeared to have high levels of self-efficacy concerning the self-ma...

  14. Vascular smooth muscle function: defining the diabetic vascular phenotype.

    Science.gov (United States)

    Bruno, Rosa Maria; Ghiadoni, Lorenzo

    2013-10-01

    In this issue of Diabetologia, a meta-analysis performed by Montero and co-authors (Diabetologia doi 10.1007/s00125-013-2974-1 ) demonstrates a significant impairment of vascular smooth muscle (VSM) function in type 2 diabetic patients. Endothelial function and VSM function between type 2 diabetic and healthy individuals were associated, especially in the microcirculation, confirming the hypothesis that unresponsiveness of VSM cells to NO may amplify the consequences of reduced NO availability. This study suggests a novel interpretation for endothelial dysfunction in diabetic patients, indicating VSM cells as key players. Causative mechanisms of VSM dysfunction, which seems to be a feature of the vascular phenotype of type 2 diabetes mellitus, are largely unexplored in humans. Future studies should also address the crucial issue of the prognostic significance of VSM dysfunction in diabetic patients, and possibly in other conditions characterised by high cardiovascular risk.

  15. Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: an immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors.

    Science.gov (United States)

    Miettinen, Markku; Rikala, Maarit-Sarlomo; Rys, Janusz; Lasota, Jerzy; Wang, Zeng-Feng

    2012-04-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is a primary responder to vascular endothelial growth factor signal and thereby regulates endothelial migration and proliferation. This receptor is expressed in endothelial cells and in some vascular tumors, but many reports also detail its expression in carcinomas and lymphomas. VEGFR2 is a potential cell-type marker, and data on VEGFR2 expression may also have therapeutic significance in view of recent availability of VEGFR2 inhibitors. In this study, we immunohistochemically examined 262 vascular endothelial and 1640 nonvascular tumors and selected non-neoplastic tissues with a VEGFR2-specific rabbit monoclonal antibody 55B11. In early human embryo, VEFGR2 was expressed in endothelia of developing capillaries and in the thoracic duct, great vessels, hepatic sinusoids, epidermis, and mesothelia. In late first trimester fetus peripheral soft tissues, VEGFR2 was restricted to capillary endothelia, chondrocytes, and superficial portion of the epidermis. In normal adult tissues, it was restricted to endothelia and mesothelia. VEGFR2 was consistently expressed in angiosarcomas, Kaposi sarcomas, and retiform hemangioendotheliomas. It was detected in only half of epithelioid hemangioendotheliomas (15/27), usually focally. VEGFR2 was strongly expressed in most capillary hemangiomas and weakly or focally in cavernous, venous, and spindle cell hemangiomas and in lymphangiomas. Malignant epithelial mesothelioma was found to be a unique epithelial neoplasm with a strong and nearly consistent VEGFR2 expression, including membrane staining (35/38). Approximately 10% of squamous cell carcinomas and 23% of pulmonary adenocarcinomas contained focal positivity. The only nonendothelial mesenchymal tumors found to be VEGFR2 positive were biphasic synovial sarcoma (focal epithelial expression) and chordoma. All melanomas and lymphomas were negative. VEGFR2 is a promising marker for malignant vascular tumors and malignant

  16. Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia.

    Science.gov (United States)

    Ashino, Takashi; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2013-04-01

    Reactive oxygen species are important mediators for platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells, whereas excess reactive oxygen species-induced oxidative stress contributes to the development and progression of vascular diseases, such as atherosclerosis. Activation of the redox-sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is pivotal in cellular defense against oxidative stress by transcriptional upregulation of antioxidant proteins. This study aimed to elucidate the role of Nrf2 in PDGF-mediated vascular smooth muscle cell migration and neointimal hyperplasia. PDGF promoted nuclear translocation of Nrf2, followed by the induction of target genes, including NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, and thioredoxin-1. Nrf2 depletion by small interfering RNA enhanced PDGF-promoted Rac1 activation and reactive oxygen species production and persistently phosphorylated downstream extracellular signal-regulated kinase-1/2. Nrf2 depletion enhanced vascular smooth muscle cell migration in response to PDGF and wound scratch. In vivo, Nrf2-deficient mice showed enhanced neointimal hyperplasia in a wire injury model. These findings suggest that the Nrf2 system is important for PDGF-stimulated vascular smooth muscle cell migration by regulating reactive oxygen species elimination, which may contribute to neointimal hyperplasia after vascular injury. Our findings provide insight into the Nrf2 system as a novel therapeutic target for vascular remodeling and atherosclerosis.

  17. Specificity of haemostasis abnormalities for vascular phenotypes.

    Science.gov (United States)

    Lowe, G D; Haverkate, F

    1998-01-01

    Atherothrombosis is a systemic disease, hence it is difficult to prove the specificity of haemostasis abnormality for any single vascular phenotype. Associations between haemostatic variables and any given phenotype, e.g. (vascular) dementia, should be interpreted with caution, given the overlaps of vascular disease phenotypes, risk factors, and haemostatic variables.

  18. 21 CFR 870.4450 - Vascular clamp.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Vascular clamp. 870.4450 Section 870.4450 Food and... CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4450 Vascular clamp. (a) Identification. A vascular clamp is a surgical instrument used to occlude a blood vessel temporarily. (b) Classification. Class II...

  19. Hippocampal atrophy in subcortical vascular dementia

    NARCIS (Netherlands)

    van de Pol, L.A.; Gertz, H.J.; Scheltens, P.; Wolf, H

    2011-01-01

    Background and Purpose: New research criteria for subcortical vascular dementia (SVaD) have been suggested to define a more homogeneous subgroup of vascular dementia. Hippocampal (Hc) atrophy is a hallmark of Alzheimer's disease (AD), but it also occurs in other dementia disorders including vascular

  20. Systematic review of the risk of adverse outcomes associated with vascular endothelial growth factor inhibitors for the treatment of cancer.

    Directory of Open Access Journals (Sweden)

    Labib Imran Faruque

    Full Text Available BACKGROUND: Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi, focusing on those with vascular pathogenesis. METHODS AND FINDINGS: We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism, hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR. We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078 on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%. Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0, arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0; hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16, and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65. The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials. CONCLUSIONS: VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk

  1. Transient receptor potential melastatin 7 (TRPM7) cation channels, magnesium and the vascular system in hypertension.

    Science.gov (United States)

    Yogi, Alvaro; Callera, Glaucia E; Antunes, Tayze T; Tostes, Rita C; Touyz, Rhian M

    2011-01-01

    Decreased Mg(2+) concentration has been implicated in altered vascular reactivity, endothelial dysfunction and structural remodeling, processes important in vascular changes and target organ damage associated with hypertension. Unlike our knowledge of other major cations, mechanisms regulating cellular Mg(2+) handling are poorly understood. Until recently little was known about protein transporters controlling transmembrane Mg(2+) influx. However, new research has uncovered a number of genes and proteins identified as transmembrane Mg(2+) transporters, particularly transient receptor potential melastatin (TRPM) cation channels, TRPM6 and TRPM7. Whereas TRPM6 is found primarily in epithelial cells, TRPM7 is ubiquitously expressed. Vascular TRPM7 has been implicated as a signaling kinase involved in vascular smooth muscle cell growth, apoptosis, adhesion, contraction, cytoskeletal organization and migration, and is modulated by vasoactive agents, pressure, stretch and osmotic changes. Emerging evidence suggests that vascular TRPM7 function might be altered in hypertension. The present review discusses the importance of Mg(2+) in vascular biology in hypertension and focuses on transport systems, mainly TRPM7, that might play a role in the control of vascular Mg(2+) homeostasis. Elucidation of the relationship between the complex systems responsible for regulation of Mg(2+) homeostasis, the role of TRPM7 in vascular signaling, and the cardiovascular impact will be important for understanding the clinical implications of hypomagnesemia in cardiovascular disease.

  2. Near-infraread spectroscopy during peripheral vascular surgery

    DEFF Research Database (Denmark)

    Schroeder, Torben Veith; Eiberg, Jonas Peter; Vogt, Katja

    1997-01-01

    Original,Near-infraread spectroscopy,Vascular disease,Vascular by-pass surgery,Perioperative oxymetry......Original,Near-infraread spectroscopy,Vascular disease,Vascular by-pass surgery,Perioperative oxymetry...

  3. Magnesium Counteracts Vascular Calcification: Passive Interference or Active Modulation?

    Science.gov (United States)

    Ter Braake, Anique D; Shanahan, Catherine M; de Baaij, Jeroen H F

    2017-08-01

    Over the last decade, an increasing number of studies report a close relationship between serum magnesium concentration and cardiovascular disease risk in the general population. In end-stage renal disease, an association was found between serum magnesium and survival. Hypomagnesemia was identified as a strong predictor for cardiovascular disease in these patients. A substantial body of in vitro and in vivo studies has identified a protective role for magnesium in vascular calcification. However, the precise mechanisms and its contribution to cardiovascular protection remain unclear. There are currently 2 leading hypotheses: first, magnesium may bind phosphate and delay calcium phosphate crystal growth in the circulation, thereby passively interfering with calcium phosphate deposition in the vessel wall. Second, magnesium may regulate vascular smooth muscle cell transdifferentiation toward an osteogenic phenotype by active cellular modulation of factors associated with calcification. Here, the data supporting these major hypotheses are reviewed. The literature supports both a passive inorganic phosphate-buffering role reducing hydroxyapatite formation and an active cell-mediated role, directly targeting vascular smooth muscle transdifferentiation. However, current evidence relies on basic experimental designs that are often insufficient to delineate the underlying mechanisms. The field requires more advanced experimental design, including determination of intracellular magnesium concentrations and the identification of the molecular players that regulate magnesium concentrations in vascular smooth muscle cells. © 2017 American Heart Association, Inc.

  4. Human Stem Cell-Derived Endothelial-Hepatic Platform for Efficacy Testing of Vascular-Protective Metabolites from Nutraceuticals.

    Science.gov (United States)

    Narmada, Balakrishnan Chakrapani; Goh, Yeek Teck; Li, Huan; Sinha, Sanjay; Yu, Hanry; Cheung, Christine

    2017-03-01

    Atherosclerosis underlies many cardiovascular and cerebrovascular diseases. Nutraceuticals are emerging as a therapeutic moiety for restoring vascular health. Unlike small-molecule drugs, the complexity of ingredients in nutraceuticals often confounds evaluation of their efficacy in preclinical evaluation. It is recognized that the liver is a vital organ in processing complex compounds into bioactive metabolites. In this work, we developed a coculture system of human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and human pluripotent stem cell-derived hepatocytes (hPSC-HEPs) for predicting vascular-protective effects of nutraceuticals. To validate our model, two compounds (quercetin and genistein), known to have anti-inflammatory effects on vasculatures, were selected. We found that both quercetin and genistein were ineffective at suppressing inflammatory activation by interleukin-1β owing to limited metabolic activity of hPSC-ECs. Conversely, hPSC-HEPs demonstrated metabolic capacity to break down both nutraceuticals into primary and secondary metabolites. When hPSC-HEPs were cocultured with hPSC-ECs to permit paracrine interactions, the continuous turnover of metabolites mitigated interleukin-1β stimulation on hPSC-ECs. We observed significant reductions in inflammatory gene expressions, nuclear translocation of nuclear factor κB, and interleukin-8 production. Thus, integration of hPSC-HEPs could accurately reproduce systemic effects involved in drug metabolism in vivo to unravel beneficial constituents in nutraceuticals. This physiologically relevant endothelial-hepatic platform would be a great resource in predicting the efficacy of complex nutraceuticals and mechanistic interrogation of vascular-targeting candidate compounds. Stem Cells Translational Medicine 2017;6:851-863. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  5. Angiogenesis, Cancer, and Vascular Aging

    OpenAIRE

    Junji Moriya; Tohru Minamino

    2017-01-01

    Several lines of evidence have revealed that the angiogenic response to ischemic injury declines with age, which might account for the increased morbidity and mortality of cardiovascular disease (CVD) among the elderly. While impairment of angiogenesis with aging leads to delayed wound healing or exacerbation of atherosclerotic ischemic diseases, it also inhibits the progression of cancer. Age-related changes of angiogenesis have been considered to at least partly result from vascular aging o...

  6. Vascular access registry of Serbia: a 4-year experience.

    Science.gov (United States)

    Jemcov, Tamara; Dimkovic, Nada

    2017-02-01

    Adequate and functional long-term vascular access (VA) is pivotal for the efficient hemodialysis (HD). It has been shown that the most reliable VA is autogenous arteriovenous fistulas (AVFs) as compared with arteriovenous grafts (AVGs) and vascular catheters (VCs). The vascular access register (VAR) has been established since 2010, and the 4-year trend of VA in Serbia is presented in this paper. All HD centers in Serbia provided their data by fulfilling the questionnaire that included prevalent and incident HD patients on December 31, 2010-1013. AVF is the most frequent prevalent VA (89.5-93.1 %) and also the most frequent newly created VA (87-89 %) during the observational period. The number of preemptive AVF is increasing, but it is still low (7.8 % in 2010 and 14.6 % in 2013). The percentage of incident AVG is constant (~3.4 %) as well as the number of permanent VC (8.2 % in 2010 and 7.8 % in 2013). The number of incident patients who started HD with AVF is decreasing (from 37 to 27 %), and the number of urgent start with VC is on the increase (from 63 to 73 %). In almost all relevant dialysis centers, vascular access is created by surgeons. Temporal VCs are placed by anesthesiologists (all centers), nephrologists (up to 25 % of centers) and vascular surgeons (up to 20 %). VCs are located mainly in jugular vein, but the number of femoral catheters remains high (up to 69 %). Although we have favorable data, the VAR is of a great importance and ensures continuous quality improvement.

  7. Author disclosure of conflict of interest in vascular surgery journals.

    Science.gov (United States)

    Forbes, Thomas L

    2011-09-01

    Advances in vascular surgery are increasingly technology-driven, and the relationships between surgeons and the medical device industry can be complex. This study reviewed conflict of interest (COI) disclosure in the vascular surgery journals regarding several selected technology-driven topics, including endovascular stent grafts (EV), carotid artery stenting (CAS), and peripheral arterial interventions (PI), to suggest further directions. Authors' COI disclosures were reviewed from all clinical papers published in 2008 and 2009 in each of six vascular surgery journals, and pertaining to three selected topics (EV, CAS, and PI). Rate of COI disclosure was evaluated as a function of journal, topic, article type (randomized trial, case series, case report, review, or meta-analysis), and authors' region of origin. Secondarily, consistency of authors' disclosure was evaluated by reviewing papers by the same author and of the same topic. Six hundred thirty-five papers were reviewed from the six journals. A COI was declared in 125 (19.7%) of these papers. This rate differed between journals (range, 3.2%-34.1%; P author writing papers describing the same general topic. COI disclosure was consistent in the majority of these instances (72.4%), but inconsistent in 32 cases (27.6%). The most common (P = .006) inconsistencies involved the same type of article in different journals (46.9%), or in the same journal (25%). Rates of disclosure of COI, and inconsistencies in disclosure in the vascular surgery literature are at least partially due to differences in journals' reporting policies, while a smaller proportion of these inconsistencies are due to individual author behavior. Journals should adopt a consistent requirement for a separate COI declaration where all relevant financial arrangements are disclosed. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  8. Vascular Aging and Arterial Stiffness

    Directory of Open Access Journals (Sweden)

    Luana de Rezende Mikael

    Full Text Available Abstract Cardiovascular diseases (CVD account annually for almost one third of all deaths worldwide. Among the CVD, systemic arterial hypertension (SAH is related to more than half of those outcomes. Type 2 diabetes mellitus is an independent risk factor for SAH because it causes functional and structural damage to the arterial wall, leading to stiffness. Several studies have related oxidative stress, production of free radicals, and neuroendocrine and genetic changes to the physiopathogenesis of vascular aging. Indirect ways to analyze that aging process have been widely studied, pulse wave velocity (PWV being considered gold standard to assess arterial stiffness, because there is large epidemiological evidence of its predictive value for cardiovascular events, and it requires little technical knowledge to be performed. A pulse wave is generated during each cardiac contraction and travels along the arterial bed until finding peripheral resistance or any bifurcation point, determining the appearance of a reflected wave. In young individuals, arteries tend to be more elastic, therefore, the reflected wave occurs later in the cardiac cycle, reaching the heart during diastole. In older individuals, however, the reflected wave occurs earlier, reaching the heart during systole. Because PWV is an important biomarker of vascular damage, highly valuable in determining the patient’s global cardiovascular risk, we chose to review the articles on vascular aging in the context of cardiovascular risk factors and the tools available to the early identification of that damage.

  9. Therapeutic Targeting of Fibroblast Growth Factor Receptors in Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Mikito Inokuchi

    2015-01-01

    Full Text Available Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC, although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2 have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs, including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.

  10. User perspectives on relevance criteria

    DEFF Research Database (Denmark)

    Maglaughlin, Kelly L.; Sonnenwald, Diane H.

    2002-01-01

    implications for relevance feedback in information retrieval systems, suggesting that systems accept and utilize multiple positive and negative relevance criteria from users. Systems designers may want to focus on supporting content criteria followed by full text criteria as these may provide the greatest cost...

  11. Vascularization regenerative medicine and tissue engineering

    CERN Document Server

    Brey, Eric M

    2014-01-01

    A Complex and Growing Field The study of vascularization in tissue engineering and regenerative medicine (TERM) and its applications is an emerging field that could revolutionize medical approaches for organ and tissue replacement, reconstruction, and regeneration. Designed specifically for researchers in TERM fields, Vascularization: Regenerative Medicine and Tissue Engineering provides a broad overview of vascularization in TERM applications. This text summarizes research in several areas, and includes contributions from leading experts in the field. It defines the difficulties associated with multicellular processes in vascularization and cell-source issues. It presents advanced biomaterial design strategies for control of vascular network formation and in silico models designed to provide insight not possible in experimental systems. It also examines imaging methods that are critical to understanding vascularization in engineered tissues, and addresses vascularization issues within the context of specific...

  12. Relevance of Allergy in Adult Asthma

    Science.gov (United States)

    Mathur, Sameer K.; Viswanathan, Ravi K.

    2014-01-01

    Recent studies on asthma have demonstrated multiple phenotypes of asthma, based on the clinical characteristics of the disease. With the current interest in personalized medicine, the question arises whether the presence of allergic sensitization has any relevance for these phenotypes and the management of asthma. This review will examine the current knowledge of asthma phenotypes and the impact of atopy on asthma diagnosis and severity in adults. In addition, this review will address whether therapies targeted at the atopic axis help improve asthma outcomes, including lung function indices and exacerbations. PMID:24643812

  13. Intrahepatic Vascular Anatomy in Rats and Mice--Variations and Surgical Implications.

    Directory of Open Access Journals (Sweden)

    Constanze Sänger

    Full Text Available The intra-hepatic vascular anatomy in rodents, its variations and corresponding supplying and draining territories in respect to the lobar structure of the liver have not been described. We performed a detailed anatomical imaging study in rats and mice to allow for further refinement of experimental surgical approaches.LEWIS-Rats and C57Bl/6N-Mice were subjected to ex-vivo imaging using μCT. The image data were used for semi-automated segmentation to extract the hepatic vascular tree as prerequisite for 3D visualization. The underlying vascular anatomy was reconstructed, analysed and used for determining hepatic vascular territories.The four major liver lobes have their own lobar portal supply and hepatic drainage territories. In contrast, the paracaval liver is supplied by various small branches from right and caudate portal veins and drains directly into the vena cava. Variations in hepatic vascular anatomy were observed in terms of branching pattern and distance of branches to each other. The portal vein anatomy is more variable than the hepatic vein anatomy. Surgically relevant variations were primarily observed in portal venous supply.For the first time the key variations of intrahepatic vascular anatomy in mice and rats and their surgical implications were described. We showed that lobar borders of the liver do not always match vascular territorial borders. These findings are of importance for the design of new surgical procedures and for understanding eventual complications following hepatic surgery.

  14. Endothelial C-type natriuretic peptide maintains vascular homeostasis.

    Science.gov (United States)

    Moyes, Amie J; Khambata, Rayomand S; Villar, Inmaculada; Bubb, Kristen J; Baliga, Reshma S; Lumsden, Natalie G; Xiao, Fang; Gane, Paul J; Rebstock, Anne-Sophie; Worthington, Roberta J; Simone, Michela I; Mota, Filipa; Rivilla, Fernando; Vallejo, Susana; Peiró, Concepción; Sánchez Ferrer, Carlos F; Djordjevic, Snezana; Caulfield, Mark J; MacAllister, Raymond J; Selwood, David L; Ahluwalia, Amrita; Hobbs, Adrian J

    2014-09-01

    The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor-C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

  15. Endothelial C-type natriuretic peptide maintains vascular homeostasis

    Science.gov (United States)

    Moyes, Amie J.; Khambata, Rayomand S.; Villar, Inmaculada; Bubb, Kristen J.; Baliga, Reshma S.; Lumsden, Natalie G.; Xiao, Fang; Gane, Paul J.; Rebstock, Anne-Sophie; Worthington, Roberta J.; Simone, Michela I.; Mota, Filipa; Rivilla, Fernando; Vallejo, Susana; Peiró, Concepción; Sánchez Ferrer, Carlos F.; Djordjevic, Snezana; Caulfield, Mark J.; MacAllister, Raymond J.; Selwood, David L.; Ahluwalia, Amrita; Hobbs, Adrian J.

    2014-01-01

    The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor–C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders. PMID:25105365

  16. Clinical characteristics associated with readmission among patients undergoing vascular surgery.

    Science.gov (United States)

    Engelbert, Travis L; Fernandes-Taylor, Sara; Gupta, Prateek K; Kent, K Craig; Matsumura, Jon

    2014-05-01

    Readmission after a vascular surgery intervention is frequent, costly, and often considered preventable. Vascular surgery outcomes have recently been scrutinized by Medicare because of the high rates of readmission. We determined patient and clinical characteristics associated with readmission in a cohort of vascular surgery patients. From 2009 to 2013, the medical records of all patients (n = 2505) undergoing interventions by the vascular surgery service at a single tertiary care institution were retrospectively reviewed. Sociodemographic and clinical characteristics were examined for association with 30-day readmission to the same institution. The 30-day readmission rate to the same institution was 9.7 % (n = 244). Procedures most likely to result in readmission were below-knee (25%), foot (22%), and toe amputations (19%), as well as lower extremity revascularization (22%). Patients covered by Medicaid (16.8%) and Medicare (10.0%) were most likely to be readmitted, followed by fee-for-service (9.5%), self-pay (8.0%), and health maintenance organizations (5.5%; P vs 6.2% low severity; P vs 6.1 days, respectively; P vs 9.5% without intensive care unit stay; P institutions must identify high-risk patients. Efforts should focus on subgroups undergoing selected interventions (amputations, lower extremity revascularization), those with urgent admissions, and patients with extended hospital stays. Patients in need of postacute care upon discharge are especially prone to readmission, requiring special attention to discharge planning and coordination of postdischarge care. By focusing on subgroups at risk for readmission, preventative resources can be efficiently targeted. Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  17. Therapeutic issues in vascular dementia: studies, designs and approaches.

    Science.gov (United States)

    Black, Sandra E

    2007-03-01

    Vascular dementia (VaD) is a heterogeneous disorder resulting from various cerebrovascular diseases (CVD) causing cognitive impairment that reflects severity and location of damage. Epidemiological studies suggest VaD is the second commonest cause of dementia, but autopsy series report that pure VaD is infrequent, while combined CVD and Alzheimer's Disease(AD) is likely the commonest pathological-dementia correlate. Both diseases share vascular risk factors and benefit from their treatment. The most widely used diagnostic criteria for VaD are highly specific but not sensitive. Vascular Cognitive Impairment (VCI) is a dynamic, evolving concept that embraces VaD, Vascular Cognitive Impairment No Dementia (VCIND) and mixed AD and CVD. Clinical trials to date have focused on probable and possible VaD with beneficial effects evident for different drug classes, including cholinergic agents and NMDA agonists. Limitations have included use of cognitive tools suitable for AD that are insensitive to executive dysfunction. Disease heterogeneity has not been adequately controlled and subtypes require further study. Diagnostic VaD criteria now 13 years old need updating. More homogeneous subgroups need to be defined and therapeutically targeted to improve cognitive-behavioural outcomes including optimal control of vascular risk factors. More sensitive testing of executive function outlined in recent VCI Harmonization criteria and longer trial duration are needed to discern meaningful effects. Imaging criteria must be well-defined, with centralized review and standardized protocols. Serial scanning with quantification of tissue atrophy and lesion burden is becoming feasible, and cognitive interventions, including rehabilitation pharmacotherapy, with drugs strategically coupled to cognitive -behavioural treatments, hold promise and need further development.

  18. Mitoprotection attenuates myocardial vascular impairment in porcine metabolic syndrome.

    Science.gov (United States)

    Yuan, Fang; Hedayat, Ahmad F; Ferguson, Christopher M; Lerman, Amir; Lerman, Lilach O; Eirin, Alfonso

    2017-12-01

    The metabolic syndrome (MetS) leads to cardiac vascular injury, which may reflect in increased retention of endothelial progenitor cells (EPC). Coronary endothelial cell (EC) mitochondria partly regulate vascular function and structure. We hypothesized that chronic mitoprotection would preserve EC mitochondria and attenuate coronary vascular injury and dysfunction in swine MetS. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (ELAM, 0.1mg/kg SC q.d), and lean controls (n=6 each). Cardiac remodeling and function were assessed in vivo by multi-detector-CT, and coronary artery and sinus blood samples collected. EC mitochondrial density, apoptosis, oxidative stress, endothelial nitric oxide (eNOS) immunoreactivity, myocardial microvascular density (3D micro-CT), and coronary endothelial function (organ bath) were assessed ex-vivo. The number and arteriovenous gradient of CD34+/KDR+ EPC was calculated by FACS (a negative net gradient indicating EPC retention). MetS and MetS+ELAM pigs developed similar MetS (obesity, hyperlipidemia, insulin resistance, and hypertension). EC mitochondrial density decreased in MetS compared to lean, but normalized in MetS+ELAM. ELAM also attenuated EC oxidative stress and apoptosis, and improved subendocardial microvascular density. ELAM-induced vasculoprotection was reflected in decreased coronary retention of EPC. ELAM also partly improved eNOS immunoreactivity, coronary endothelial function, and vessel maturity, whereas myocardial perfusion was unaffected. Chronic mitoprotection improved coronary EC mitochondrial density and decreased vascular remodeling and dysfunction. Yet, additional mitochondria-independent mechanisms likely contribute to MetS-induced cardiac vascular injury.

  19. An overview of methods for vascular mapping in the planning of free flaps

    NARCIS (Netherlands)

    Smit, Jeroen M.; Klein, Steven; Werker, Paul M. N.

    Introduction: The aim of this overview is to describe the various methods for vascular mapping of flaps together with their advantages and drawbacks. Materials and methods: The PubMed database was used. Relevant search terms included 'flap' in combination with 'hand-held Doppler' (HHD), 'colour

  20. Vascular Care in Patients With Alzheimer Disease With Cerebrovascular Lesions Slows Progression of White Matter Lesions on MRI The Evaluation of Vascular Care in Alzheimer's Disease (EVA) Study

    NARCIS (Netherlands)

    Richard, E.; Gouw, A.A.; Scheltens, P.; van Gool, W.A.

    2010-01-01

    Background and Purpose:White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in

  1. Vascular Care in Patients With Alzheimer Disease With Cerebrovascular Lesions Slows Progression of White Matter Lesions on MRI The Evaluation of Vascular Care in Alzheimer's Disease (EVA) Study

    NARCIS (Netherlands)

    Richard, Edo; Gouw, Alida A.; Scheltens, Philip; van Gool, Willem A.

    2010-01-01

    Background and Purpose-White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in

  2. Ghrelin improves vascular autophagy in rats with vascular calcification.

    Science.gov (United States)

    Xu, Mingming; Liu, Lin; Song, Chenfang; Chen, Wei; Gui, Shuyan

    2017-06-15

    This study aimed to investigate whether ghrelin ameliorated vascular calcification (VC) through improving autophagy. VC model was induced by nicotine plus vitamin D 3 in rats and β-glycerophosphate in vascular smooth muscle cell (VSMC). Calcium deposition was detected by von Kossa staining or alizarin red S staining. ALP activity was also detected. Western blot was used to assess the protein expression. Ghrelin treatment attenuated the elevation of calcium deposition and ALP activity in VC model both in vivo and in vitro. Interesting, the protein levels of autophagy markers, LC3 and beclin1 were significantly upregulated by ghrelin in VC model. An autophagy inhibitor, 3-methyladenine blocks the ameliorative effect of ghrelin on VC. Furthermore, protein expressions of phosphate-AMPK were increased by ghrelin treatment both in calcified aorta and VSMC. The effect of ghrelin on autophagy induction and VC attenuation was prevented by AMPK inhibitor, compound C. Our results suggested that ghrelin improved autophagy through AMPK activation, which was resulted in VC amelioration. These data maybe throw light on prevention and therapy of VC. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Effect of vascular burden as measured by vascular indexes upon vascular dementia: a matched case-control study

    OpenAIRE

    Takahashi, Paul Y; Caldwell, Casey R; Targonski, Paul V

    2012-01-01

    Paul Y Takahashi, Casey R Caldwell, Paul V TargonskiPrimary Care Internal Medicine, Mayo Clinic, Rochester MN, USABackground: Vascular dementia (VaD) is a challenging illness that affects the lives of older adults and caregivers. It is unclear how multiple vascular risk factor exposures (polyvascular disease) affect VaD.Purpose: To determine the relationship between multiple vascular risk exposures, as counted on an index in cases with VaD, compared with healthy age-/gender-matched controls.M...

  4. Clinical relevance in anesthesia journals

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Møller, Ann M

    2006-01-01

    The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles....

  5. Relevance theory: pragmatics and cognition.

    Science.gov (United States)

    Wearing, Catherine J

    2015-01-01

    Relevance Theory is a cognitively oriented theory of pragmatics, i.e., a theory of language use. It builds on the seminal work of H.P. Grice(1) to develop a pragmatic theory which is at once philosophically sensitive and empirically plausible (in both psychological and evolutionary terms). This entry reviews the central commitments and chief contributions of Relevance Theory, including its Gricean commitment to the centrality of intention-reading and inference in communication; the cognitively grounded notion of relevance which provides the mechanism for explaining pragmatic interpretation as an intention-driven, inferential process; and several key applications of the theory (lexical pragmatics, metaphor and irony, procedural meaning). Relevance Theory is an important contribution to our understanding of the pragmatics of communication. © 2014 John Wiley & Sons, Ltd.

  6. [Research status quo and progression in targeted therapy for advanced gastric cancer].

    Science.gov (United States)

    Feng, Rui; Zhang, Xiaotian; Yang, Sheng

    2016-10-25

    With the deeper research of the proliferation, invasion and metastasis mechanisms of the gastric cancer, targeted therapy has become a hot spot in this field. The exploration of targeted agents for gastric cancer is mainly concentrated upon the drugs that target human epidermal growth factor receptor (HER) family, the vascular endothelial growth factor (VEGF), the phosphatidylinositol 3-kinase-protein kinase/mammalian target of rapamycin (PI3K/mTOR) and the NF-κB signaling pathways. The targeted drugs relevant to HER family include the Cetuximab, Nimotuzumab, Matuzumab, Panitumumab and Erlotinib which are aimed at HER-1, the Trastuzumab, Pertuzumab and T-DM1 (trastuzumab emtansine) which are aimed at HER-2, and the Lapatinib and Afatinib which are the multi-target agents of HER. The agents which target VEGF signaling pathway include the anti-VEGF monoclonal antibody (Bevacizumab), the anti-VEGFR drugs (Ramucirumab, Apatinib, Sorafenib, Sunitinib and cediranib), and the recombinant fusion protein (Aflibercept). The LY294002, BEZ235 and Everolimus which are aimed at PI3K/mTOR signaling pathway have shown great promise. Bortezomib has been researched more as a new agent which targets NF-κB signaling pathway. Currently, only Trastuzumab, Ramucirumab and Apatinib have been completed the stage 3 clinical trials and succeeded. In future, researches should focus on multi-target agents or applications in combination treatment. This review collects the recent researches and the clinical trials to summarize the current state and progress of research on gastric cancer targeted therapy.

  7. Vascular dementia: Facts and controversies

    Directory of Open Access Journals (Sweden)

    Pavlović Aleksandra

    2013-01-01

    Full Text Available Vascular dementia (VaD is the second most frequent dementia after Alzheimer’s disease, and is diagnosed during lifetime in 20% of demented patients. Five­year survival rate in VaD is 39%, while it is estimated to be 75% in healthy persons of the same age. It is therefore important to make correct diagnosis of VaD early in the course of the disease. Risk factors for VaD are identical to stroke risk factors, and there are significant possibilities for the prevention of vascular cognitive decline. Cognitive decline develops acutely or step­by­step within three months after stroke, but more gradual progression of intellectual decline is also possible. Neurological examination can reveal pyramidal and extrapyramidal signs, pseudobulbar palsy, gait disturbance and urinary incontinence. Neuropsychological profile comprises the loss of cognitive set shifting, decline in word fluency, verbal learning difficulties, perseverations, difficulties in complex figure copying, and in patients with cortically located lesions also problems with speech and praxia. The basis of the diagnosis is, besides history, neurological examination and neuropsychological assessment, computed tomography and/ or magnetic resonance brain imaging. Vascular risk factors control is the most important measure in VaD prevention. Modern guidelines for the treatment of cognitive decline in VaD emphasize that donepezil can be useful in the improvement of cognitive status at the level of Class IIa recommendation at the level of evidence A, while memantine may be useful in patients with mixed VaD and Alzheimer’s disease dementia. [Projekat Ministarstva nauke Republike Srbije, br. 175022 i br. 175033

  8. MIGRAINE AND STROKE: VASCULAR COMORBIDITY

    Directory of Open Access Journals (Sweden)

    Donata eGuidetti

    2014-10-01

    Full Text Available Several comorbidities are associated to migraine.Recent meta-analyses have consistently demonstrated a relationship between migraine and stroke, which is well-defined for ischaemic stroke and migraine with aura, even stronger in females on oral contraceptives or smokers. However, there seems to be no clear-cut association between stroke in migraineurs and the common vascular risk factors, at least in the young adult population. Migraineurs also run an increased risk of hemorrhagic stroke, while the association between migraine and cardiovascular disease remains poorly defined.Another aspect is the relationship between migraine and the presence of silent brain lesions. It has been demonstrated that there is an increased frequency of ischaemic lesions in the white matter of migraineurs, especially silent infarcts in the posterior circulation territory in patients with at least 10 attacks per month. Although there is a higher prevalence of patent foramen ovale (PFO in migraineurs, the relationship between migraine and PFO remains controversial and PFO closure is not a recommended procedure to prevent migraine. As an increased frequency of cervical artery dissections has been observed in migrainous patients, it has been hypothesized that migraine may represent a predisposing factor for cervical artery dissection. There still remains the question as to whether migraine should be considered a true vascular disease or if the comorbidity between migraine and cerebrovascular disease may have underlying shared risk factors or pathophysiological mechanisms. Although further studies are required to clarify this issue, current evidence supports a clinical management where MA patients should be screened for other concomitant vascular risk factors and treated accordingly.

  9. Clinical relevance in anesthesia journals

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Møller, Ann M

    2006-01-01

    The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles.......The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles....

  10. Spinal vascular malformations; Spinale Gefaessmalformationen

    Energy Technology Data Exchange (ETDEWEB)

    Yilmaz, U. [Universitaetsklinikum des Saarlandes, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Homburg/Saar (Germany)

    2012-05-15

    Spinal vascular malformations are a group of rare diseases with different clinical presentations ranging from incidental asymptomatic findings to progressive tetraplegia. This article provides an overview about imaging features as well as clinical and therapeutic aspects of spinal arteriovenous malformations, cavernomas and capillary telangiectasia. (orig.) [German] Spinale Gefaessmalformationen sind eine Gruppe seltener Erkrankungen mit unterschiedlichen klinischen Praesentationen, die vom asymptomatischen Zufallsbefund bis zur progredienten Tetraparese reichen. Dieser Artikel gibt einen Ueberblick ueber radiologische Befunde sowie klinische und therapeutische Aspekte von spinalen arteriovenoesen Malformationen, Kavernomen und kapillaeren Teleangiektasien. (orig.)

  11. Vascular comorbidities in multiple sclerosis

    DEFF Research Database (Denmark)

    Thormann, Anja; Magyari, Melinda; Koch-Henriksen, Nils

    2016-01-01

    To investigate the occurrence of vascular comorbidities before and after the clinical onset of multiple sclerosis. In this combined case–control and cohort study, all Danish born citizens with onset of multiple sclerosis 1980–2005 were identified from the Danish Multiple Sclerosis Registry...... and randomly matched with controls regarding year of birth, gender, and municipality on January 1st in the year of multiple sclerosis (MS) onset (index date). Individual-level information on comorbidities was obtained from several independent nationwide registries and linked to the study population by unique...

  12. A Unique Immunofluorescence Protocol to Detect Protein Expression in Vascular Tissues: Tacking a Long Standing Pathological Hitch

    Directory of Open Access Journals (Sweden)

    Puneet GANDHI

    2018-01-01

    Full Text Available Objective: Autofluorescence induced interference is one of the major drawbacks in immunofluorescence analysis of formalin-fixed paraffin-embedded tissues, as it decreases the signal-to-noise ratio of specific labeling. Apart from aldehyde-fixation induced artifacts; collagen and elastin, red blood cells and endogenous fluorescent pigment lipofuscin are prime sources of autofluorescence in vascular and aging tissues. We describe herein, an optimized indirect-immunofluorescence method for archival formalin-fixed paraffin-embedded tissues tissues and cryo sections, using a combination of 3-reagents in a specific order, to achieve optimal fluorescence signals and imaging. Material and Method: Human telomerase reverse transcriptase, a protein implicated as a proliferation marker, was chosen relevant to its expression in solid tumors along with 3 other intracellular proteins exhibiting nuclear and/or cytoplasmic expression. Staining was performed on 10 glioma tissue sections along with 5 of their cryo sections, 5 sections each of hepatocellular, lung, papillary-thyroid and renal cell carcinoma, with 10 non-malignant brain tissue samples serving as control. Specimens were imaged using epifluorescence microscopy, followed by software-based quantification of fluorescence signals for statistical analysis and validation. Results: We observed that the combined application of sodium-borohydride followed by crystal violet before antigen retrieval and a Sudan black B treatment after secondary antibody application proved to be most efficacious for masking autofluorescence/non-specific background in vascular tissues. Conclusion: This unique trio-methodology provides quantifiable observations with maximized fluorescence signal intensity of the target protein for longer retention time of the signal even after prolonged storage. The results can be extrapolated to other human tissues for different protein targets.

  13. Correlation between penile cavernosal artery blood flow and retinal vascular findings in arteriogenic erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Ahmed M Emarah

    2010-09-01

    Full Text Available Ahmed M Emarah1, Shawky M El-Haggar2, Ihab A Osman2, Abdel Wahab S Khafagy21Departments of Ophthalmology, 2Andrology and Sexology, Cairo University Hospital, EgyptObjectives: Arteriogenic erectile dysfunction (ED is a target organ disease of atherosclerosis, and therefore might be a predictor of systemic atherosclerosis. Being systemic, it might be possible to evaluate the extent of atherosclerosis from retinal vascular findings. We investigated the possible correlation between penile cavernosal artery blood flow and retinal vascular findings in patients with arteriogenic ED.Patients and methods: Sixty patients with ED were divided according to the peak systolic velocity (PSV in their penile cavernosal arteries into two groups; Group A included 30 patients with PSV less than 25 cm/sec, and Group B included 30 patients with PSV more than 35 cm/sec. Blood flow in the penile cavernosal artery was measured with color Doppler ultrasonography. All patients were assessed by ocular fundus examination under amydriatic conditions to evaluate retinal vascular atherosclerotic changes using Hyman’s classification.Results: Evidence of retinal vascular atherosclerotic changes was found in 19 patients (63.3% in Group A and in 10 patients (33.3% in Group B.Conclusions: Our study confirms the possibility of predicting penile arterial vascular status in patients with ED from their retinal vascular findings by using amydriatic simple, practical funduscopy.Keywords: erectile dysfunction, atherosclerosis, retinal vascular atherosclerosis

  14. Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery.

    Directory of Open Access Journals (Sweden)

    Desmond B S Pink

    Full Text Available The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM, a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2 peptide fragment or vascular endothelial growth factor (VEGF. VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.

  15. [Vascular depression, limits of the concept].

    Science.gov (United States)

    Lebert, Florence

    2004-09-01

    The concept of vascular depression has recently been reassessed and more clearly delineated. The diagnostic criteria for vascular depression require a major depression associated with evidence of confluent or diffuse vascular lesions in the subcortical regions on MRI. The clinical symptoms are not specific, but they are often associated with mild cognitive decline. Ischemia is probably the main factor for vascular depression, but the relationship between ischemic lesions and clinical symptoms remains not well explained. The apolipoproteine E genotype is not a risk factor for vascular depression, but it is associated with more severe hyperintensities on MRI. A pharmacological resistance has been described in vascular depression, but, in recent studies, clinical improvement has been observed with antidepressants in more than 80% of cases. A neuropsychological follow-up is recommended, because dementia may appear with 25% of patients.

  16. Uncooled infrared camera for the noninvasive visualization of the vascular flow in an anastomotic vessel during neurological surgery: technical note.

    Science.gov (United States)

    Otani, Naoki; Ishihara, Miya; Nakai, Kanji; Fujita, Masanori; Wada, Kojiro; Mori, Kentaro

    2014-06-17

    We herein present our experience to assess intraoperative confirmation of vascular patency with an uncooled infrared camera in extracranial-intracranial (EC-IC) bypass surgery. This camera had distinguishing characteristics, including its small size, light weight, and adequate temperature resolution (camera to assess the vascular flow of the end-to-side anastomosis model in rats. In addition, we evaluated the vascular flow in continuous clinical series using this infrared camera during EC-IC bypass in 14 patients (17 sides). This infrared camera offers real-time information on the vascular patency of end-to-side anastomosis vessels of all relevant diameters. The spatial resolution and image quality are satisfactory, and the procedure can be safely repeatable. We have shown that the infrared camera could be a new and feasible technology for intraoperative imaging of the vascular flow and is considered to be clinically useful during cerebrovascular surgery.

  17. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study.

    Science.gov (United States)

    Richard, Edo; Gouw, Alida A; Scheltens, Philip; van Gool, Willem A

    2010-03-01

    White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs and prevents occurrence of new infarcts. A randomized controlled clinical trial, including 123 subjects, compared vascular care with standard care in patients with Alzheimer disease with cerebrovascular lesions on MRI. Progression of WMLs, lacunes, medial temporal lobe atrophy, and global cortical atrophy were semiquantitatively scored after 2-year follow-up. Sixty-five subjects (36 vascular care, 29 standard care) had a baseline and a follow-up MRI and in 58 subjects, a follow-up scan could not be obtained due to advanced dementia or death. Subjects in the vascular care group had less progression of WMLs as measured with the WML change score (1.4 versus 2.3, P=0.03). There was no difference in the number of new lacunes or change in global cortical atrophy or medial temporal lobe atrophy between the 2 groups. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs. Treatment aimed at vascular risk factors in patients with early Alzheimer disease may be beneficial, possibly in an even earlier stage of the disease.

  18. The metabolic vascular syndrome - guide to an individualized treatment.

    Science.gov (United States)

    Hanefeld, Markolf; Pistrosch, Frank; Bornstein, Stefan R; Birkenfeld, Andreas L

    2016-03-01

    In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil.

  19. Elevated TATA-binding protein expression drives vascular endothelial growth factor expression in colon cancer

    Science.gov (United States)

    Johnson, Sandra A.S.; Lin, Justin J.; Walkey, Christopher J.; Leathers, Michael P.; Coarfa, Cristian; Johnson, Deborah L.

    2017-01-01

    The TATA-binding protein (TBP) plays a central role in eukaryotic gene transcription. Given its key function in transcription initiation, TBP was initially thought to be an invariant protein. However, studies showed that TBP expression is upregulated by oncogenic signaling pathways. Furthermore, depending on the cell type, small increases in cellular TBP amounts can induce changes in cellular growth properties towards a transformed phenotype. Here we sought to identify the specific TBP-regulated gene targets that drive its ability to induce tumorigenesis. Using microarray analysis, our results reveal that increases in cellular TBP concentrations produce selective alterations in gene expression that include an enrichment for genes involved in angiogenesis. Accordingly, we find that TBP levels modulate VEGFA expression, the master regulator of angiogenesis. Increases in cellular TBP amounts induce VEGFA expression and secretion to enhance cell migration and tumor vascularization. TBP mediates changes in VEGFA transcription requiring its recruitment at a hypoxia-insensitive proximal TSS, revealing a mechanism for VEGF regulation under non-stress conditions. The results are clinically relevant as TBP expression is significantly increased in both colon adenocarcinomas as well as adenomas relative to normal tissue. Furthermore, TBP expression is positively correlated with VEGFA expression. Collectively, these studies support the idea that increases in TBP expression contribute to enhanced VEGFA transcription early in colorectal cancer development to drive tumorigenesis. PMID:28415573

  20. Placental hemostasis and sterile inflammation: New insights into gestational vascular disease.

    Science.gov (United States)

    Kohli, Shrey; Isermann, Berend

    2017-03-01

    Activation of the coagulation and inflammatory systems are physiologically occurring during pregnancy. However, excess activation of either system is well documented in gestational vascular diseases (GVD). GVD are placenta-mediated pregnancy complications and a major cause of feto-maternal morbidity and mortality. The causal relevance of excess coagulation and inflammatory responses for GVD remains largely unknown. Deciphering the causal relationship of excess coagulation and inflammation in GVD may allow conceptualizing new therapeutic approaches to combat GVD. Platelet activation and procoagulant extracellular vesicles (EVs) provide a link between coagulation and inflammation and their activation or generation in GVD is well established. As recently shown EVs cause sterile placental inflammation by activating maternal platelets that release ATP and activate purinergic receptor signaling and NLRP3 inflammasome in the embryonic trophoblast. This thrombo-inflammatory mechanism suggests a novel link between coagulation activation and sterile inflammation in GVD. These findings highlight a role of anti-platelet therapies in GVD. In addition, targeting the inflammasome alone or in combination with platelet inhibition may provide a new therapeutic strategy in GVD. © 2017 Elsevier Ltd. All rights reserved.

  1. Vascular smooth muscle cell apoptosis promotes transplant arteriosclerosis through inducing the production of SDF-1α.

    Science.gov (United States)

    Li, J; Liu, S; Li, W; Hu, S; Xiong, J; Shu, X; Hu, Q; Zheng, Q; Song, Z

    2012-08-01

    Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild-type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF-1α from apoptotic and neighboring viable cells, resulting in increased SDF-1α in the culture media. Conditioned media from Ltv-p53-transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF-1α-dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus-mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF-1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90(+)CD105(+) double-positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF-1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  2. Vascular adaption to physical inactivity in humans

    OpenAIRE

    Bleeker, M.W.P.

    2006-01-01

    This thesis presents studies on vascular adaptation to physical inactivity and deconditioning. Although it is clear that physical inactivity is an important risk factor for cardiovascular disease, the underlying physiological mechanisms have not yet been elucidated. In contrast to physical inactivity, exercise decreases the risk for cardiovascular disease. This beneficial effect of exercise is partly due to changes in vascular function and structure. However, far less is known about vascular ...

  3. Enhanced Recovery after Vascular Surgery

    Directory of Open Access Journals (Sweden)

    Milena D. Stojanovic

    2018-01-01

    Full Text Available The beginnings of the enhanced recovery after surgery (ERAS program were first developed for patients in colorectal surgery, and after it was established as the standard of care in this surgical field, it began to be applied in many others surgical areas. This is multimodal, evidence-based approach program and includes simultaneous optimization of preoperative status of patients, adequate selection of surgical procedure and postoperative management. The aim of this program is to reduce complications, the length of hospital stay and to improve the patients outcome. Over the past decades, special attention was directed to the postoperative management in vascular surgery, especially after major vascular surgery because of the great risk of multiorgan failure, such as: respiratory failure, myocardial infarction, hemodynamic instability, coagulopathy, renal failure, neurological disorders, and intra-abdominal complications. Although a lot of effort was put into it, there is no unique acceptable program for ERAS in this surgical field, and there is still a need to point out the factors responsible for postoperative outcomes of these patients. So far, it is known that special attention should be paid to already existing diseases, type and the duration of the surgical intervention, hemodynamic and fluid management, nutrition, pain management, and early mobilization of patients.

  4. Neuroradiological findings in vascular dementia

    Energy Technology Data Exchange (ETDEWEB)

    Guermazi, Ali; Miaux, Yves; Suhy, Joyce; Pauls, Jon; Lopez, Ria [Synarc, Inc., Department of Radiology Services, San Francisco, CA (United States); Rovira-Canellas, Alex [Hospital General Universitari Vall d' Hebron, Unita de Resonancia Magnetica, Barcelona (Spain); Posner, Holly [Eisai, Inc., Teaneck, NJ (United States)

    2007-01-15

    There are multiple diagnostic criteria for vascular dementia (VaD) that may define different populations. Utilizing the criteria of the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) has provided improved consistency in the diagnosis of VaD. The criteria include a table listing brain imaging lesions associated with VaD. The different neuroradiological aspects of the criteria are reviewed based on the imaging data from an ongoing large-scale clinical trial testing a new treatment for VaD. The NINDS-AIREN criteria were applied by a centralized imaging rater to determine eligibility for enrollment in 1,202 patients using brain CT or MRI. Based on the above data set, the neuroradiological features that are associated with VaD and that can result from cerebral small-vessel disease with extensive leukoencephalopathy or lacunae (basal ganglia or frontal white matter), or may be the consequence of single strategically located infarcts or multiple infarcts in large-vessel territories, are illustrated. These features may also be the consequence of global cerebral hypoperfusion, intracerebral hemorrhage, or other mechanisms such as genetically determined arteriopathies. Neuroimaging confirmation of cerebrovascular disease in VaD provides information about the topography and severity of vascular lesions. Neuroimaging may also assist with the differential diagnosis of dementia associated with normal pressure hydrocephalus, chronic subdural hematoma, arteriovenous malformation or tumoral diseases. (orig.)

  5. Mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis.

    Science.gov (United States)

    Enns, Winnie; von Rossum, Anna; Choy, Jonathan

    2015-05-17

    Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

  6. Renal vascular and thrombotic effects of cyclosporine.

    Science.gov (United States)

    Remuzzi, G; Bertani, T

    1989-04-01

    Cyclosporine A (CyA) given to prevent xenograft rejection induces renal function impairment. In the last few years many studies have been devoted to understanding the mechanism(s) of CyA-induced renal insufficiency. In humans, several specific findings--interstitial fibrosis, toxic tubulopathy, peritubular capillary congestion, arteriolopathy--have been associated with CyA administration. It is now recognized that CyA renal toxicity mainly manifests under three different syndromes: (1) acute reversible decrease in glomerular filtration rate (GFR), (2) acute microvascular disease with the pattern of thrombotic microangiopathy, and (3) chronic irreversible renal damage. This review analyzes the available evidence that the clinical syndromes of CyA nephrotoxicity are related to changes induced by CyA on renal vessels. Experimental studies have failed to document that the activation of renin-angiotensin axis or sympathetic nervous system plays a relevant role in the development of CyA-associated renal vasoconstriction, which is the main causal factor of acute reversible decrease in GFR, whereas it is possible that changes in arachidonic acid metabolites with vasoactive properties contribute to this CyA-induced phenomenon. In this context, findings of increased urinary TxB2 and protective effect of TxA2 receptor blocking are of particular interest. Since the introduction of CyA in clinical practice, a syndrome of thrombotic microangiopathy resembling hemolytic uremic syndrome/thrombotic thrombocytopenic purpura has been recognized in humans and reproduced in experimental animals. This is a rare form of vascular toxicity attributed to CyA which may have a poor prognosis and possibly results from a direct toxic effect of CyA on vascular endothelium. The syndrome of chronic progressive deterioration of renal function associated with CyA was first recognized in humans. Until recently the possibility of reproducing this syndrome in animals in order to better understand its

  7. Vascular tumors and malformations in children, Introduction.

    Science.gov (United States)

    Maguiness, Sheilagh M

    2016-03-01

    Over the past decade, I have been amazed at the growth in the field of vascular anomalies. The recognition of vascular birthmarks as a defined area of medicine is a relatively recent event. The International Society for the Study of Vascular Anomalies (ISSVA) was founded by Drs John Mulliken and Anthony Young in the late 1970s. Mulliken and Glowacki's sentinel 1982 paper on the biologic classification of vascular anomalies further established the field, by providing clarity of nomenclature and unifying concepts that had previously been lacking. ©2016 Frontline Medical Communications.

  8. [Diagnosis and management of vascular anomalies].

    Science.gov (United States)

    Philandrianos, C; Degardin, N; Casanova, D; Petit, P; Bartoli, J-M; Bardot, J; Magalon, G

    2011-06-01

    Vascular anomalies are a complex pathological group. They are especially difficult to study because of confusion in the terminology used. The classification developed by the International Society for the Study of Vascular Anomalies (ISSVA) in 1996 allows using a common scientific language. There are two groups of lesions: vascular tumor and vascular malformation. The management of these anomalies is difficult and must involve an interdisciplinary approach including specialists in plastic surgery, radiology, pediatry and dermatology. We propose a simplified approach for the management of these pathologies. This approach is coming from the experience of Marseille (France) multidisciplinary team. Copyright © 2009 Elsevier Masson SAS. All rights reserved.

  9. Tumor vascular disruption using various radiation types

    Directory of Open Access Journals (Sweden)

    JJ Bevelacqua

    2014-04-01

    Full Text Available The feasibility of disrupting a tumor’s vascular structure with various radiation types and radionuclides is investigated. Calculated absorbed dose profiles for photons and 4He ions suggest that low-energy beta-gamma and alpha emitting radionuclides can deposit sufficient absorbed dose to disrupt a tumor’s vascular structure while minimizing the dose outside the blood vessel. Candidate radionuclides uniformly distributed in microspheres are theoretically investigated with respect to their vascular disruption potential and to offer an alternative to 90Y microsphere therapy. Requisite activities of candidate low-energy beta-gamma and alpha emitting radionuclides to facilitate vascular disruption are calculated.

  10. Vascular function in health, hypertension, and diabetes

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Gliemann, Lasse; Hellsten, Ylva

    2015-01-01

    muscle, which can affect muscle function. Central aspects in the vascular impairments are alterations in the formation of prostacyclin, the bioavailability of NO and an increased formation of vasoconstrictors and reactive oxygen species (ROS). Regular physical activity effectively improves vascular...... to the formation of vasodilators such as nitric oxide (NO) and prostacyclin. In essential hypertension and type II diabetes, the endothelial function and regulation of vascular tone is impaired with consequent increases in peripheral vascular resistance and inadequate regulation of oxygen supply to the skeletal...

  11. Patient knowledge of risk factors 18 months after a nurse-led vascular intervention

    LENUS (Irish Health Repository)

    Tone, J M

    2011-01-01

    Background and aims: Eighteen months after the completion of a vascular risk intervention study, the authors aimed to ascertain whether participants who attended the intensive, nurse-led group had better retention of knowledge of diabetes and heart disease compared with those who had undergone standard diabetes care. Method: A knowledge-based questionnaire was sent to participants who completed the vascular risk intervention study, 94 from the intensive, nurse-led group and 94 from the standard care group. Results: A response rate of 75% was achieved. Although more participants in the intensive group achieved recommended vascular risk targets, there was no increase in retained knowledge of vascular risks. A high proportion of the total cohort could not quantify targets for blood pressure (67.2%), cholesterol (65.1%) or HbA1c (68.1%). Conclusion: In this cohort of people with type 2 diabetes, knowledge retention regarding treatment targets was poor. Education programmes should stress awareness of vascular risk factors and diabetes.

  12. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  13. Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function.

    Science.gov (United States)

    Terao, Junji

    2017-09-01

    Nowadays dietary flavonoids attract much attention in the prevention of chronic diseases. Epidemiological and intervention studies strongly suggest that flavonoid intake has beneficial effects on vascular health. It is unlikely that flavonoids act as direct antioxidants, although oxidative stress profoundly contributes to vascular impairment leading to cardiovascular diseases. Instead, flavonoids may exert their function by tuning the cellular redox state to an adaptive response or tolerable stress. However, the optimum intake of flavonoids from supplements or diet has not been clarified yet, because a number of exogenous and endogenous factors modulating their bioavailability affect their vascular function. This review will focus on the current knowledge of the bioavailability and vascular function of quercetin as a representative of antioxidative flavonoids. Current intervention studies imply that intake of quercetin-rich onion improves vascular health. Onion may be superior to quercetin supplement from the viewpoint of quercetin bioavailability, probably because the food matrix enhances the intestinal absorption of quercetin. α-Glucosylation increases its bioavailability by elevating the accessibility to the absorptive cells. Prenylation may enhance bioaccumulation at the target site by increasing the cellular uptake. However, these chemical modifications do not guarantee health benefits to the vascular system. Dietary quercetin is exclusively present as their conjugated form in the blood stream. Quercetin may exert its vascular function as an aglycone within macrophage cells after inflammation-induced deconjugation and as conjugated metabolites by targeting endothelial cells. The relationship between the bioavailability and bio-efficacy should be clarified, to evaluate the vascular function of a wide variety of dietary flavonoids. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Short-term Physical Inactivity Impairs Vascular Function

    Science.gov (United States)

    Nosova, Emily V.; Yen, Priscilla; Chong, Karen C.; Alley, Hugh F.; Stock, Eveline O.; Quinn, Alex; Hellmann, Jason; Conte, Michael S.; Owens, Christopher D.; Spite, Matthew; Grenon, S. Marlene

    2014-01-01

    Introduction Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening and increased vascular inflammation. Methods Five healthy subjects (4 males and 1 female) underwent 5 days of bed rest (BR) to simulate inactivity. Measurements of vascular function [flow-mediated vasodilation (FMD) to evaluate endothelial function; applanation tonometry to assess arterial resistance], inflammation and metabolism were made before BR, daily during BR and after 2 recovery days. Subjects maintained an isocaloric diet throughout. Results Bed rest led to significant decreases in brachial artery and femoral artery FMD [Brachial: 11 ± 3% pre-BR vs. 9 ± 2% end-BR, P=0.04; Femoral: 4 ± 1% vs. 2 ± 1%, P=0.04]. The central augmentation index increased with BR [−4 ± 9% vs. 5 ± 11%, P=0.03]. Diastolic blood pressure (DBP) increased [58 ± 7 mmHg vs. 62 ± 7 mmHg, P=0.02], while neither systolic blood pressure nor heart rate changed. 15-HETE, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged. Conclusions Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased DBP, and an increase in 15-HETE. We speculate that inactivity promotes a vascular “deconditioning” state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored. PMID:24630521

  15. Relevance of ellipse eccentricity for camera calibration

    Science.gov (United States)

    Mordwinzew, W.; Tietz, B.; Boochs, F.; Paulus, D.

    2015-05-01

    Plane circular targets are widely used within calibrations of optical sensors through photogrammetric set-ups. Due to this popularity, their advantages and disadvantages are also well studied in the scientific community. One main disadvantage occurs when the projected target is not parallel to the image plane. In this geometric constellation, the target has an elliptic geometry with an offset between its geometric and its projected center. This difference is referred to as ellipse eccentricity and is a systematic error which, if not treated accordingly, has a negative impact on the overall achievable accuracy. The magnitude and direction of eccentricity errors are dependent on various factors. The most important one is the target size. The bigger an ellipse in the image is, the bigger the error will be. Although correction models dealing with eccentricity have been available for decades, it is mostly seen as a planning task in which the aim is to choose the target size small enough so that the resulting eccentricity error remains negligible. Besides the fact that advanced mathematical models are available and that the influence of this error on camera calibration results is still not completely investigated, there are various additional reasons why bigger targets can or should not be avoided. One of them is the growing image resolution as a by-product from advancements in the sensor development. Here, smaller pixels have a lower S/N ratio, necessitating more pixels to assure geometric quality. Another scenario might need bigger targets due to larger scale differences whereas distant targets should still contain enough information in the image. In general, bigger ellipses contain more contour pixels and therefore more information. This supports the target-detection algorithms to perform better even at non-optimal conditions such as data from sensors with a high noise level. In contrast to rather simple measuring situations in a stereo or multi-image mode, the impact

  16. Implementation of a vascular access quality programme improves vascular access care

    NARCIS (Netherlands)

    van Loon, M.; van der Mark, W.; Beukers, N.; de Bruin, C.; Blankestijn, P. J.; Huisman, R. M.; Zijlstra, J. J.; van der Sande, F. M.; Tordoir, J. H. M.

    Introduction. In the Netherlands an access quality improvement plan (QIP) was introduced by vascular access coordinators (VAC) with the aim to decrease vascular access-related complications by preemptive intervention of malfunctioning accesses. A vascular access QIP was established in 24 centres

  17. Relevance in the science classroom: A multidimensional analysis

    Science.gov (United States)

    Hartwell, Matthew F.

    While perceived relevance is considered a fundamental component of adaptive learning, the experience of relevance and its conceptual definition have not been well described. The mixed-methods research presented in this dissertation aimed to clarify the conceptual meaning of relevance by focusing on its phenomenological experience from the students' perspective. Following a critical literature review, I propose an identity-based model of perceived relevance that includes three components: a contextual target, an identity target, and a connection type, or lens. An empirical investigation of this model that consisted of two general phases was implemented in four 9th grade-biology classrooms. Participants in Phase 1 (N = 118) completed a series of four open-ended writing activities focused on eliciting perceived personal connections to academic content. Exploratory qualitative content analysis of a 25% random sample of the student responses was used to identify the main meaning-units of the proposed model as well as different dimensions of student relevance perceptions. These meaning-units and dimensions provided the basis for the construction of a conceptual mapping sentence capturing students' perceived relevance, which was then applied in a confirmatory analysis to all other student responses. Participants in Phase 2 (N = 139) completed a closed survey designed based on the mapping sentence to assess their perceived relevance of a biology unit. The survey also included scales assessing other domain-level motivational processes. Exploratory factor analysis and non-metric multidimensional scaling indicated a coherent conceptual structure, which included a primary interpretive relevance dimension. Comparison of the conceptual structure across various groups (randomly-split sample, gender, academic level, domain-general motivational profiles) provided support for its ubiquity and insight into variation in the experience of perceived relevance among students of different

  18. Preoperative vascular access evaluation for haemodialysis patients.

    Science.gov (United States)

    Kosa, Sarah D; Al-Jaishi, Ahmed A; Moist, Louise; Lok, Charmaine E

    2015-09-30

    Haemodialysis treatment requires reliable vascular access. Optimal access is provided via functional arteriovenous fistula (fistula), which compared with other forms of vascular access, provides superior long-term patency, requires few interventions, has low thrombosis and infection rates and cost. However, it has been estimated that between 20% and 60% of fistulas never mature sufficiently to enable haemodialysis treatment. Mapping blood vessels using imaging technologies before surgery may identify vessels that are most suitable for fistula creation. We compared the effect of conducting routine radiological imaging evaluation for vascular access creation preoperatively with standard care without routine preoperative vessel imaging on fistula creation and use. We searched Cochrane Kidney and Transplant's Specialised Register to 14 April 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We included randomised controlled trials (RCTs) that enrolled adult participants (aged ≥ 18 years) with chronic or end-stage kidney disease (ESKD) who needed fistulas (both before dialysis and after dialysis initiation) that compared fistula maturation rates relating to use of imaging technologies to map blood vessels before fistula surgery with standard care (no imaging). Two authors assessed study quality and extracted data. Dichotomous outcomes, including fistula creation, maturation and need for catheters at dialysis initiation, were expressed as risk ratios (RR) with 95% confidence intervals (CI). Continuous outcomes, such as numbers of interventions required to maintain patency, were expressed as mean differences (MD). We used the random-effects model to measure mean effects. Four studies enrolling 450 participants met our inclusion criteria. Overall risk of bias was judged to be low in one study, unclear in two, and high in one.There was no significant differences in the number of fistulas that were successfully created (4

  19. Mechanic’s hands revisited: is this sign still useful for diagnosis in patients with lung involvement of collagen vascular diseases?

    OpenAIRE

    Sohara, Erei; Saraya, Takeshi; Sato, Shinji; Tsujimoto, Naoki; Watanabe, Takayasu; Takata, Saori; Tanaka, Yasutaka; Ishii, Haruyuki; Takizawa, Hajime; Goto, Hajime

    2014-01-01

    Background The presence of “mechanic’s hands” is one of the clinical clues for collagen vascular diseases. However, the exact relevance of “mechanic’s hands” in collagen vascular diseases has not been well documented. The aim of this study was to clarify the relevance of “mechanic’s hands” to collagen vascular diseases including various skin lesions and interstitial pneumonia. Methods A retrospective review of the medical records of patients with “mechanic’s hands” at our hospital between Apr...

  20. Head and neck vascular anomalies. A multidisciplinary approach and diagnostic criteria.

    Science.gov (United States)

    Moneghini, L; Sangiorgio, V; Tosi, D; Colletti, G; Melchiorre, F; Baraldini, V; Graziani, D; Alfano, R M; Vercellio, G; Bulfamante, G

    2017-03-01

    Vascular anomalies represent a heterogeneous group of pathologies of the circulatory system that can affect any type of hematic and /or lymphatic vessel of different diameter or anatomic site. The extreme variability of tissue types and districts involved by these lesions determines a wide heterogeneity of clinical manifestations, resulting in involvement of different medical expertise. In this context, a commonly agreed terminology is crucial for the appropriate evaluation and multidisciplinary management of patients. The ISSVA Classification that has its roots in the previous Classification of Mulliken and Glowacky distinguishes vascular anomalies in two main groups: vascular tumors and vascular malformations. In head and neck, where vascular anomalies are the most common benign lesions of infancy and childhood, correct diagnosis with the use of unequivocal terminology is more crucial for treatment considering the relevance of structures that can be involved. The aim of this work has been to clarify information and knowledges currently available in the field of vascular anomalies. Referring to ISSVA Classification, clinico- histopathological aspects of each entity have been elucidated. © Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.

  1. Adiposity, adipocytokines & microvesicles in the etiology of vascular disease

    NARCIS (Netherlands)

    Kanhai, D.A.N.I.S.

    2013-01-01

    Vascular disease, in this thesis the terms vascular and cardiovascular are used interchangeably, is the number 1 cause of death worldwide. In 2008, 30% of all mortality had a vascular origin. Vascular mortality rates after a first manifestation of vascular disease are decreasing in Western society,

  2. FPGA controlled artificial vascular system

    Directory of Open Access Journals (Sweden)

    Laqua D.

    2015-09-01

    Full Text Available Monitoring the oxygen saturation of an unborn child is an invasive procedure, so far. Transabdominal fetal pulse oximetry is a promising method under research, used to estimate the oxygen saturation of a fetus noninvasively. Due to the nature of the method, the fetal information needs to be extracted from a mixed signal. To properly evaluate signal processing algorithms, a phantom modeling fetal and maternal blood circuits and tissue layers is necessary. This paper presents an improved hardware concept for an artificial vascular system, utilizing an FPGA based CompactRIO System from National Instruments. The experimental model to simulate the maternal and fetal blood pressure curve consists of two identical hydraulic circuits. Each of these circuits consists of a pre-pressure system and an artificial vascular system. Pulse curves are generated by proportional valves, separating these two systems. The dilation of the fetal and maternal artificial vessels in tissue substitutes is measured by transmissive and reflective photoplethysmography. The measurement results from the pressure sensors and the transmissive optical sensors are visualized to show the functionality of the pulse generating systems. The trigger frequency for the maternal valve was set to 1 per second, the fetal valve was actuated at 0.7 per second for validation. The reflective curve, capturing pulsations of the fetal and maternal circuit, was obtained with a high power LED (905 nm as light source. The results show that the system generates pulse curves, similar to its physiological equivalent. Further, the acquired reflective optical signal is modulated by the alternating diameter of the tubes of both circuits, allowing for tests of signal processing algorithms.

  3. Impact of inflammation on vascular disease in hypertension.

    Science.gov (United States)

    Virdis, Agostino; Dell'Agnello, Umberto; Taddei, Stefano

    2014-07-01

    Low grade inflammation exerts a crucial pathogenic role in hypertension and cardiovascular disease. A large body of evidence indicates that innate and adaptive immune systems, and in particular T cells, are involved. A balance between T-effector lymphocytes and Treg lymphocytes represents a crucial regulatory mechanism that, when altered, favours blood pressure elevation and organ damage development. Of note, Treg lymphocytes exert important anti-inflammatory properties, whose activities guarantees vascular homeostasis and protects the vessel wall from the development of atherosclerosis. In humans, most of evidence ascertaining essential hypertension as a condition of chronic low-grade inflammatory status revealed a strict and independent association between CRP, TNF-α, IL-6 or adhesion molecules and vascular changes in essential hypertensive patients. Evidence of involvement of the immune system in vasculature from patients with hypertension or cardiovascular disease starts to appear in literature. Further investigation on immunity, including the role of T-lymphocytes, will help develop of new therapeutic targets that may improve outcomes in hypertension and cardiovascular disease and discover novel approaches in the treatment of hypertension and vascular disease. Copyright © 2014. Published by Elsevier Ireland Ltd.

  4. Bio-chemo-mechanical models of vascular mechanics

    Science.gov (United States)

    Kim, Jungsil; Wagenseil, Jessica E.

    2014-01-01

    Models of vascular mechanics are necessary to predict the response of an artery under a variety of loads, for complex geometries, and in pathological adaptation. Classic constitutive models for arteries are phenomenological and the fitted parameters are not associated with physical components of the wall. Recently, microstructurally-linked models have been developed that associate structural information about the wall components with tissue-level mechanics. Microstructurally-linked models are useful for correlating changes in specific components with pathological outcomes, so that targeted treatments may be developed to prevent or reverse the physical changes. However, most treatments, and many causes, of vascular disease have chemical components. Chemical signaling within cells, between cells, and between cells and matrix constituents affects the biology and mechanics of the arterial wall in the short- and long-term. Hence, bio-chemo-mechanical models that include chemical signaling are critical for robust models of vascular mechanics. This review summarizes bio-mechanical and bio-chemo-mechanical models with a focus on large elastic arteries. We provide applications of these models and challenges for future work. PMID:25465618

  5. The importance of being relevant

    Directory of Open Access Journals (Sweden)

    Snehlata eJaswal

    2012-08-01

    Full Text Available This review aims at an understanding of the binding process by synthesizing the extant perspectives regarding binding. It begins with a consideration of the biological explanations of binding, viz., conjunctive coding, synchrony, and reentrant mechanisms. Thereafter binding is reviewed as a psychological process guided by top down signals. The stages and types of binding proposed by various researchers are discussed in this section. The next section introduces Working Memory as the executive directing the top-down signals. After that it is described how Working Memory works by selecting relevant sensory input, followed by a detailed consideration of the debate regarding objects vs. features with the conclusion that relevance is the key factor determining what is processed. The next section considers other factors affecting the selection of relevant input. Then, we shift focus to describe what happens to irrelevant input – whether it is discarded at the outset or is gradually inhibited, and whether inhibition is a perceptual or post-perceptual process. The concluding section describes the process of binding as currently understood on the basis of the literature included in the review. To summarize, it appears that initially the ‘object’ is conceptualized as an instantaneous bundle of all features. However, only relevant features of stimuli are gradually integrated to form a stable representation of the object. Concomitantly, irrelevant features are removed from the object representations. Empirical evidence suggests that the inhibition of irrelevant features occurs over time and is thus presumably a process within Working Memory.

  6. Regularization in Matrix Relevance Learning

    NARCIS (Netherlands)

    Schneider, Petra; Bunte, Kerstin; Stiekema, Han; Hammer, Barbara; Villmann, Thomas; Biehl, Michael

    A In this paper, we present a regularization technique to extend recently proposed matrix learning schemes in learning vector quantization (LVQ). These learning algorithms extend the concept of adaptive distance measures in LVQ to the use of relevance matrices. In general, metric learning can

  7. Making Plant Biology Curricula Relevant.

    Science.gov (United States)

    Hershey, David R.

    1992-01-01

    Reviews rationale, purposes, challenges, and relevance of hands-on, plant biology curricula that have been developed in response to the limited use of plants in biology education. Discusses methods to maintain both instructional rigor and student interest in the following topics: cut flowers, container-growing media, fertilizers, hydroponics,…

  8. BIBLE TRANSLATION AND RELEVANCE THEORY

    African Journals Online (AJOL)

    Wilss's text book (Wilss 1982) suggests that the situation in general translation theory is not very different. It was precisely this model of communication theory that was challenged by Sperber and Wilson's relevance theory (Sperber & Wilson 1986; see also Wilson & Sperber 1987). Set within this context this paper seeks to ...

  9. Lexicography and the Relevance Criterion

    African Journals Online (AJOL)

    This will be done within the framework of the function theory .... Gouws (2011) supports this vision and stresses that learning from each other .... specific type of need, e.g. to solve a communicative or cognitive problem, ..... According to Borlund (2000) "the judgement of situational relevance ..... Management 36(4): 533-550.

  10. Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation.

    Directory of Open Access Journals (Sweden)

    Iván eRodríguez

    2014-09-01

    Full Text Available Physiological vascular function regulation is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the main risk factors of cardiovascular pathology, where the imbalance between the synthesis of vasodilator and vasoconstrictor molecules is common in the development of vascular disorders in systemic and placental circulation. In the placenta, an organ without autonomic innervations, the local control of vascular tone is critical for maintenance of fetal growth and mechanisms that underlie shear stress response induced by blood flow are essential during pregnancy. In this field, shear stress induced by moderate exercise is one of the most important mechanisms to improve vascular function through nitric oxide (NO synthesis and stimulation of mechanical response of endothelial cells triggered by ion channels, caveolae, endothelial NO synthase (eNOS and vascular endothelial growth factor (VEGF, among others. The demand for oxygen and nutrients by tissues and organs, especially in placentation and pregnancy, determines blood flow parameters and physiological adaptations of vascular beds for covering metabolic requirements. In this regard, moderate exercise versus sedentarism shows potential benefits for improving vascular function associated with the enhancement of molecular mechanisms induced by shear stress. In this review, we collect evidence about molecular bases of physiological response to shear stress in order to highlight the relevance of moderate exercise-training for vascular health in adult and fetal life.

  11. Vascular permeability alterations induced by arsenic.

    Science.gov (United States)

    Chen, Shih-Chieh; Tsai, Ming-Hsien; Wang, Hsiu-Jen; Yu, Hsin-Su; Chang, Louis W

    2004-01-01

    The impact of arsenic on the integrity of blood vessels in vivo via in situ exposure (local injection) of arsenic was investigated. Vascular permeability changes were evaluated by means of the Evans blue assay and the India ink tracer techniques. Rats were intravenously injected with Evans blue followed by intradermal injections of various doses of sodium arsenite on the back skins of the animals. Evans blue at different time points was extracted and assayed as indices of vascular leakage. Skin at various time point injection sites was sampled for arsenic measurement via graphite furnace atomic absorption spectroscopy. Our time course study with Evans blue technique demonstrated a biphasic pattern of vascular permeability change: an early phase of permeability reduction and a later phase of permeability promotion at all dose levels tested. The India ink tracer technique also demonstrated a time-correlated increase in vascular labelling in the tissues examined, signifying an increase in vascular leakage with time. Moreover, we found that despite an early increase in tissue arsenic content at time of injection, tissue arsenic declined rapidly and returned to near control levels after 30-60 min. Thus, an inverse correlation between tissue arsenic content and the extent of vascular permeability was apparent. This study provides the first demonstration that in situ exposure to arsenic will produce vascular dysfunction (vascular leakage) in vivo.

  12. Functional preservation of vascular smooth muscle tissue

    Science.gov (United States)

    Alexander, W. C.; Hutchins, P. M.; Kimzey, S. L.

    1973-01-01

    The ionic and cellular feedback relationships operating to effect the vascular decompensatory modifications were examined to reveal procedures for implementing protective measures guarding against vascular collapse when returning from a weightless environment to that of the earth's gravity. The surgical procedures for preparing the rat cremaster, and the fixation methods are described. Abstracts of publications resulting from this research are included.

  13. VASCULAR EFFECTS OF KETAMINE IN ISOLATED RABBIT ...

    African Journals Online (AJOL)

    Daniel Owu

    Summary: The precise mechanism by which ketamine induces relaxation of vascular smooth muscle is not clear. The goal of this study was to further characterize the vascular actions of ketamine in rabbit aortic smooth muscles. Ring segments (2mm) of rabbit aortae were suspended in 20ml organ baths containing ...

  14. Arteriovenous Malformations and Other Vascular Malformation Syndromes

    Science.gov (United States)

    Whitehead, Kevin J.; Smith, Matthew C. P.; Li, Dean Y.

    2013-01-01

    Vascular malformations are a disruption of the normal vascular pattern in which it is expected that a capillary network of microscopic vessels lies interposed between high-pressure arteries that deliver blood and thin-walled veins that collect low-pressure blood for return to the heart. In the case of arteriovenous malformations, arteries or arterioles connect directly to the venous collection system, bypassing any capillary bed. Clinical consequences result from rupture and hemorrhage, from dramatically increased blood flow, or from the loss of capillary functions such as nutrient exchange and filtering function. These malformations can occur sporadically or as a component of inherited vascular malformation syndromes. In these and other hereditary vascular malformation syndromes, genetic studies have identified proteins and pathways involved in vascular morphogenesis and development. A common theme observed is that vascular malformations result from disruption in pathways involved in vascular stability. Here we review the vascular malformations and pathways involved in hereditary hemorrhagic telangiectasia, capillary malformation–arteriovenous malformation, cerebral cavernous malformations, and mucocutaneous venous malformations. PMID:23125071

  15. Non-suture methods of vascular anastomosis

    NARCIS (Netherlands)

    Zeebregts, CJ; Heijmen, RH; van den Dungen, JJ; van Schilfgaarde, R

    Background: The main aim of performing a vascular anastomosis is to achieve maximal patency rates. An important factor to achieve that goal is to minimize damage to the vessel walls. Sutures inevitably induce vascular wall damage, which influences the healing of the anastomosis. Over time, several

  16. Vascular birthmarks of infancy: resolving nosologic confusion.

    Science.gov (United States)

    Hand, Jennifer L; Frieden, Ilona J

    2002-04-01

    The terminology describing congenital vascular birthmarks has been a source of confusion in the medical literature. Mulliken and Glowacki [1982: Plas. Recons. Surg. 69:412-422] published a biologic classification system which has become the most widely accepted framework for classifying vascular birthmarks and is accepted as the official classification schema by the International Society for the Study of Vascular Anomalies (ISSVA). In this study, we evaluate the current nosology of vascular birthmarks used in standard medical genetics reference texts compared with the accepted Mulliken ISSVA framework. In five sources examined, a variety of terms were used to describe congenital vascular anomalies. The degree of agreement with accepted ISSVA classification varied both within and among texts, with agreement as low as 22% and as high as 75%. In all texts, hemangioma was the most commonly used term, appearing 79 times. Use of the term "hemangioma" had the lowest rate of agreement with the ISSVA classification criteria, with agreement in 23% of citations. The terms "vascular malformation" and "port-wine stain" were used less frequently, but with a much higher degree of agreement with the ISSVA classification: 82% and 66%, respectively. These results establish that nosologic confusion is widespread even in standard genetic reference texts. In particular, the term "hemangioma" is used imprecisely. The ISSVA classification system provides an extremely useful framework for geneticists to classify vascular birthmarks in their evaluation of infants and children with vascular anomalies in order to provide more accurate evaluation, prognosis, and genetic counseling. Copyright 2002 Wiley-Liss, Inc.

  17. Hemorrhage Control for Major Traumatic Vascular Injuries

    Science.gov (United States)

    2016-10-01

    and it is unclear if this contributed to the high (46%) mortality in OPEN patients with thoracic aortic injury. Intra- abdominal arterial hemorrhage...Endovascular therapy for overcoming challenges presented with blunt abdominal aortic injury. Vascular and endovascular surgery 2012;46:329-331. 23...systematically define the clinical and logistical issues surrounding traditional open vascular surgery and catheter-based hemorrhage control. The

  18. Vascular dementia | Connor | African Journal of Psychiatry

    African Journals Online (AJOL)

    Vascular dementia (VaD) is a common but heterogeneous condition in which there is a clear temporal relationship between the dementia and vascular disease. It may result from multiple large or small vessel strokes or a single strategic stroke. Subcortical ischaemic VaD includes multiple lacunes and subcortical ...

  19. Evaluation of Peripheral Vascular Calcification and Serum ...

    African Journals Online (AJOL)

    Introduction: Vascular calcification is a risk factor for cardiovascular mortality in the general population. It is highly prevalent in end stage renal disease (ESRD) patients. Low magnesium (Mg) levels have been reported to have a strong association with vascular calcification in hemodialysis (HD) patients. The aims of this ...

  20. Management Strategies in Hemodialysis Vascular Access

    NARCIS (Netherlands)

    J. van der Linden (Joke)

    2006-01-01

    textabstractSince the introduction of the AV fistula and the use of interposition graft little improvement has been made in the vascular access field. Still, vascular access related complications, are one of the most important reasons for patient hospitalization, morbidity and even mortality

  1. Reconstructive vascular surgery below the knee

    DEFF Research Database (Denmark)

    Rasmussen, L B; Jelnes, R; Sager, P

    1986-01-01

    In a series of 38 consecutive patients with advanced peripheral vascular disease (i.e. rest pain) reconstructive vascular surgery was performed with the distal anastomosis below the knee. Ankle/arm pressure index (AAI) was 0.28 (0.11-0.47) preoperatively; accumulated graft patency rate was 0.47 (SD...

  2. Percutaneous Treatment of Peripheral Vascular Malformations

    NARCIS (Netherlands)

    E. van der Linden (Edwin)

    2011-01-01

    textabstractVascular malformations arise from errors in the morphological processes that shape the embryonic vascular system during fetal development. These developmental errors result in abnormal clusters of blood vessels. Although these lesions are present at birth, they might not become visible

  3. Pure neuritic leprosy: Current status and relevance.

    Science.gov (United States)

    Rao, P Narasimha; Suneetha, Sujai

    2016-01-01

    Pure neuritic leprosy has always been an enigma due to its clinical and management ambiguities. Although only the Indian Association of Leprologist's classification recognizes 'pure neuritic leprosy' as a distinct sub group of leprosy, cases nonetheless are reported from various countries of Asia, Africa, South America and Europe, indicating its global relevance. It is important to maintain pure neuritic leprosy as a subgroup as it constitutes a good percentage of leprosy cases reported from India, which contributes to more than half of global leprosy numbers. Unfortunately, a high proportion of these patients present with Grade 2 disability at the time of initial reporting itself due to the early nerve involvement. Although skin lesions are absent by definition, when skin biopsies were performed from the skin along the distribution of the affected nerve, a proportion of patients demonstrated leprosy pathology, revealing sub-clinical skin involvement. In addition on follow-up, skin lesions are noted to develop in up to 20% of pure neuritic leprosy cases, indicating its progression to manifest cutaneous disease. Over the decades, the confirmation of diagnosis of pure neuritic leprosy has been subjective, however, with the arrival and use of high-resolution ultrasonography (HRUS) for nerve imaging, we have a tool not only to objectively measure and record the nerve thickening but also to assess the morphological alterations in the nerve including echo texture, fascicular pattern and vascularity. Management of pure neuritic leprosy requires multidrug therapy along with appropriate dose of systemic corticosteroids, for both acute and silent neuritis. Measures for pain relief, self-care of limbs and physiotherapy are important to prevent as well as manage disabilities in this group of patients.

  4. Pure neuritic leprosy: Current status and relevance

    Directory of Open Access Journals (Sweden)

    P Narasimha Rao

    2016-01-01

    Full Text Available Pure neuritic leprosy has always been an enigma due to its clinical and management ambiguities. Although only the Indian Association of Leprologist's classification recognizes 'pure neuritic leprosy' as a distinct sub group of leprosy, cases nonetheless are reported from various countries of Asia, Africa, South America and Europe, indicating its global relevance. It is important to maintain pure neuritic leprosy as a subgroup as it constitutes a good percentage of leprosy cases reported from India, which contributes to more than half of global leprosy numbers. Unfortunately, a high proportion of these patients present with Grade 2 disability at the time of initial reporting itself due to the early nerve involvement. Although skin lesions are absent by definition, when skin biopsies were performed from the skin along the distribution of the affected nerve, a proportion of patients demonstrated leprosy pathology, revealing sub-clinical skin involvement. In addition on follow-up, skin lesions are noted to develop in up to 20% of pure neuritic leprosy cases, indicating its progression to manifest cutaneous disease. Over the decades, the confirmation of diagnosis of pure neuritic leprosy has been subjective, however, with the arrival and use of high-resolution ultrasonography (HRUS for nerve imaging, we have a tool not only to objectively measure and record the nerve thickening but also to assess the morphological alterations in the nerve including echo texture, fascicular pattern and vascularity. Management of pure neuritic leprosy requires multidrug therapy along with appropriate dose of systemic corticosteroids, for both acute and silent neuritis. Measures for pain relief, self-care of limbs and physiotherapy are important to prevent as well as manage disabilities in this group of patients.

  5. NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Dumas, Sébastien J; Bru-Mercier, Gilles; Courboulin, Audrey; Quatredeniers, Marceau; Rücker-Martin, Catherine; Antigny, Fabrice; Nakhleh, Morad K; Ranchoux, Benoit; Gouadon, Elodie; Vinhas, Maria-Candida; Vocelle, Matthieu; Raymond, Nicolas; Dorfmüller, Peter; Fadel, Elie; Perros, Frédéric; Humbert, Marc; Cohen-Kaminsky, Sylvia

    2018-02-14

    Background -Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N-methyl-D-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells, but its role in PAH is unknown. Methods -We assessed the status of the glutamate-NMDAR axis in the pulmonary arteries of PAH patients and controls, through mass spectrometry imaging, western blotting and immunohistochemistry. We measured the glutamate release from cultured pulmonary vascular cells using enzymatic assays, and analyzed NMDAR regulation/phosphorylation through western blot experiments. The effect of NMDAR blockade on human pulmonary arterial smooth muscle cell (hPASMC) proliferation was determined using a BrdU incorporation assay. We assessed the role of NMDARs in vascular remodeling associated to pulmonary hypertension (PH), both in smooth muscle-specific NMDAR knockout mice exposed to chronic hypoxia and in the monocrotaline rat model of PH using NMDAR blockers. Results -We report glutamate accumulation, upregulation of the NMDAR, and NMDAR engagement reflected by increases in GluN1-subunit phosphorylation, in the pulmonary arteries of human PAH patients. K v channel inhibition and ETAR activation amplified calcium-dependent glutamate release from hPASMCs, and ETAR and PDGFR activation led to NMDAR engagement, highlighting crosstalk between the glutamate-NMDAR axis and major PAH-associated pathways. The PDGF-BB-induced proliferation of hPASMCs involved NMDAR activation and phosphorylated GluN1 subunit localization to cell-cell contacts, consistent with glutamatergic communication between

  6. PanVascular medicine. 2. ed.

    Energy Technology Data Exchange (ETDEWEB)

    Lanzer, Peter (ed.) [Health Care Center Bitterfeld (Germany). Division of Cardiovascular Disease

    2015-06-01

    Vascular management and care has become a truly multidisciplinary enterprise as the number of specialists involved in the treatment of patients with vascular diseases has steadily increased. While in the past, treatments were delivered by individual specialists, in the twenty-first century a team approach is without doubt the most effective strategy. In order to promote professional excellence in this dynamic and rapidly evolving field, a shared knowledge base and interdisciplinary standards need to be established. Pan Vascular Medicine, 2nd edition has been designed to offer such an interdisciplinary platform, providing vascular specialists with state-of-the art descriptive and procedural knowledge. Basic science, diagnostics, and therapy are all comprehensively covered. In a series of succinct, clearly written chapters, renowned specialists introduce and comment on the current international guidelines and present up-to-date reviews of all aspects of vascular care.

  7. Fundamental principles of vascular network topology.

    Science.gov (United States)

    Kopylova, Veronika S; Boronovskiy, Stanislav E; Nartsissov, Yaroslav R

    2017-06-15

    The vascular system is arguably the most important biological system in many organisms. Although the general principles of its architecture are simple, the growth of blood vessels occurs under extreme physical conditions. Optimization is an important aspect of the development of computational models of the vascular branching structures. This review surveys the approaches used to optimize the topology and estimate different geometrical parameters of the vascular system. The review is focused on optimizations using complex cost functions based on the minimum total energy principle and the relationship between the laws of growth and precise vascular network topology. Experimental studies of vascular networks in different species are also discussed. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  8. Stem/Progenitor cells in vascular regeneration.

    Science.gov (United States)

    Zhang, Li; Xu, Qingbo

    2014-06-01

    A series of studies has been presented in the search for proof of circulating and resident vascular progenitor cells, which can differentiate into endothelial and smooth muscle cells and pericytes in animal and human studies. In terms of pluripotent stem cells, including embryonic stem cells, iPS, and partial-iPS cells, they display a great potential for vascular lineage differentiation. Development of stem cell therapy for treatment of vascular and ischemic diseases remains a major challenging research field. At the present, there is a clear expansion of research into mechanisms of stem cell differentiation into vascular lineages that are tested in animal models. Although there are several clinical trials ongoing that primarily focus on determining the benefits of stem cell transplantation in ischemic heart or peripheral ischemic tissues, intensive investigation for translational aspects of stem cell therapy would be needed. It is a hope that stem cell therapy for vascular diseases could be developed for clinic application in the future.

  9. Using Polymeric Scaffolds for Vascular Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Alida Abruzzo

    2014-01-01

    Full Text Available With the high occurrence of cardiovascular disease and increasing numbers of patients requiring vascular access, there is a significant need for small-diameter (<6 mm inner diameter vascular graft that can provide long-term patency. Despite the technological improvements, restenosis and graft thrombosis continue to hamper the success of the implants. Vascular tissue engineering is a new field that has undergone enormous growth over the last decade and has proposed valid solutions for blood vessels repair. The goal of vascular tissue engineering is to produce neovessels and neoorgan tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of tissue-engineered implants is that these tissues can grow, remodel, rebuild, and respond to injury. This review describes the development of polymeric materials over the years and current tissue engineering strategies for the improvement of vascular conduits.

  10. Hedgehog and Resident Vascular Stem Cell Fate

    Directory of Open Access Journals (Sweden)

    Ciaran J. Mooney

    2015-01-01

    Full Text Available The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall.

  11. Human perivascular adipose tissue dysfunction as a cause of vascular disease: Focus on vascular tone and wall remodeling.

    Science.gov (United States)

    Ozen, Gulsev; Daci, Armond; Norel, Xavier; Topal, Gokce

    2015-11-05

    Obesity is one of the major risk factors for the development of cardiovascular diseases. It is characterized by excessive or abnormal accumulation of adipose tissue, including depots which surround the blood vessels named perivascular adipose tissue (PVAT). PVAT plays endocrine and paracrine roles by producing large numbers of metabolically vasoactive adipokines. The present review outlines our current understanding of the beneficial roles of PVAT in vascular tone and remodeling in healthy subjects supported by clinical studies, highlighting different factors or mechanisms that could mediate protective effects of PVAT on vascular function. Most studies in humans show that adiponectin is the best candidate for the advantageous effect of PVAT. However, in pathological conditions especially obesity-related cardiovascular diseases, the beneficial effects of PVAT on vascular functions are impaired and transform into detrimental roles. This change is defined as PVAT dysfunction. In the current review, the contribution of PVAT dysfunction to obesity-related cardiovascular diseases has been discussed with a focus on possible mechanisms including an imbalance between beneficial and detrimental adipokines (commonly described as decreased levels of adiponectin and increased levels of leptin or tumor necrosis factor-alpha (TNFα)), increased quantity of adipose tissue, inflammation, cell proliferation and endothelial dysfunction. Finally, novel pharmacotherapeutic targets for the treatment of cardiovascular and metabolic disorders are addressed. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. DNA Damage: A Main Determinant of Vascular Aging

    Directory of Open Access Journals (Sweden)

    Paula K. Bautista-Niño

    2016-05-01

    Full Text Available Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indicate that under conditions during which DNA damage accumulates in an accelerated rate, functional decline of the vasculature takes place in a similar but more rapid or more exaggerated way than occurs in the absence of such conditions. Also epidemiological studies suggest a relationship between DNA maintenance and age-related cardiovascular disease. Accordingly, mouse models of defective DNA repair are means to study the mechanisms involved in biological aging of the vasculature. We here review the evidence of the role of DNA damage in vascular aging, and present mechanisms by which genomic instability interferes with regulation of the vascular tone. In addition, we present potential remedies against vascular aging induced by genomic instability. Central to this review is the role of diverse types of DNA damage (telomeric, non-telomeric and mitochondrial, of cellular changes (apoptosis, senescence, autophagy, mediators of senescence and cell growth (plasminogen activator inhibitor-1 (PAI-1, cyclin-dependent kinase inhibitors, senescence-associated secretory phenotype (SASP/senescence-messaging secretome (SMS, insulin and insulin-like growth factor 1 (IGF-1 signaling, the adenosine monophosphate-activated protein kinase (AMPK-mammalian target of rapamycin (mTOR-nuclear factor kappa B (NFκB axis, reactive oxygen species (ROS vs. endothelial nitric oxide synthase (eNOS-cyclic guanosine monophosphate

  13. Prevention of chronic kidney and vascular disease : Toward global health equity - The Bellagio 2004 Declaration

    NARCIS (Netherlands)

    Dirks, JH; De Zeeuw, D; Agarwal, SK; Atkins, RC; Correa-Rotter, R; D'Amico, G; Bennett, PH; El Nahas, M; Valdes, RH; Kaseje, D; Katz, IJ; Naicker, S; Rodriguez-Iturbe, B; Schieppati, A; Shaheen, F; Sitthi-Amorn, C; Solez, K; Viberti, G; Remuzzi, G; Weening, J.J.

    Chronic kidney disease (CKD) not only reflects target organ injury in systemic vascular disease in the general population and in association with diabetes, hypertension, and smoking, but it is recognized as one of the major risk factors in the pathogenesis and outcome of cardiovascular disease.

  14. Vascular narrowing in pulmonary arterial hypertension is heterogeneous: rethinking resistance

    NARCIS (Netherlands)

    Rol, N.; Timmer, E.M.; Faes, T.J.; Noordegraaf, A.V.; Grunberg, K.; Bogaard, H.J.; Westerhof, N.

    2017-01-01

    In idiopathic pulmonary arterial hypertension (PAH), increased pulmonary vascular resistance is associated with structural narrowing of small (resistance) vessels and increased vascular tone. Current information on pulmonary vascular remodeling is mostly limited to averaged increases in wall

  15. Taking care of your vascular access for hemodialysis

    Science.gov (United States)

    ... below as a reminder. What Is a Vascular Access? A vascular access is an opening made in your skin ... access into your body. Know What Type of Vascular Access You Have There are 3 main types of ...

  16. [Gastric vascular lesions in cirrhosis: gastropathy and antral vascular ectasia].

    Science.gov (United States)

    Casas, Meritxell; Calvet, Xavier; Vergara, Mercedes; Bella, Maria Rosa; Junquera, Félix; Martinez-Bauer, Eva; Campo, Rafael

    2015-02-01

    Portal hypertensive gastropathy (GHP) is a complication of portal hypertension usually associated with liver cirrhosis. The pathogenesis is unclear but the presence of portal hypertension is an essential factor for its development. GHP may be asymptomatic or present as gastrointestinal bleeding or iron deficiency anemia. Endoscopic lesions vary from a mosaic pattern to diffuse red spots; the most common location is the fundus. Treatment is indicated when there is acute or chronic bleeding, as secondary prophylaxis. There is insufficient evidence to recommend primary prophylaxis in patients who have never bled. Drugs that decrease portal pressure, such as non-cardioselective beta-blockers, and/or endoscopic ablative treatments, such as argon-beam coagulation, may be used. The role of transarterial intrahepatic portosystemic shunt) or bypass surgery has been insufficiently analyzed. Antral vascular ectasia (EVA) is a rare entity in liver cirrhosis, whose pathophysiology is still unknown. Clinical presentation is similar to that of GHP and endoscopy usually shows red spots in the antrum. Biopsy is often required to differentiate EVA from GHP. There is no effective medical therapy, so endoscopic ablative therapy and, in severe cases, antrectomy are recommended. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

  17. Targeted Learning

    CERN Document Server

    van der Laan, Mark J

    2011-01-01

    The statistics profession is at a unique point in history. The need for valid statistical tools is greater than ever; data sets are massive, often measuring hundreds of thousands of measurements for a single subject. The field is ready to move towards clear objective benchmarks under which tools can be evaluated. Targeted learning allows (1) the full generalization and utilization of cross-validation as an estimator selection tool so that the subjective choices made by humans are now made by the machine, and (2) targeting the fitting of the probability distribution of the data toward the targe

  18. A Generative Theory of Relevance

    Science.gov (United States)

    2004-09-01

    latent representation space . 2We need the Fubini -Tonelli theorem because the parameter space h is uncountable and the information representation space i...models can be expressed in a simple common form that is a direct consequence of De-Finetti’s representation theorem . We draw several unexpected...who defines relevance in terms of entailment (as in theorem -proving). Suppose G represents a logical proposition corresponding to a user’s request

  19. Directing vascular cell selectivity and hemocompatibility on patterned platforms featuring variable topographic geometry and size.

    Science.gov (United States)

    Ding, Yonghui; Yang, Zhilu; Bi, Cathy W C; Yang, Meng; Xu, Sherry Li; Lu, Xiong; Huang, Nan; Huang, Pingbo; Leng, Yang

    2014-08-13

    It is great challenge to generate multifunctionality of vascular grafts and stents to enable vascular cell selectivity and improve hemocompatibility. Micro/nanopatterning of vascular implant surfaces for such multifunctionality is a direction to be explored. We developed a novel patterned platform featuring two typical geometries (groove and pillar) and six pattern sizes (0.5-50 μm) in a single substrate to evaluate the response of vascular cells and platelets. Our results indicate that targeted multifunctionality can be indeed instructed by rationally designed surface topography. The pillars nonselectively inhibited the growth of endothelial and smooth muscle cells. By contrast, the grooves displayed selective effects: in a size-dependent manner, the grooves enhanced endothelialization but inhibited the growth of smooth muscle cells. Moreover, our studies suggest that topographic cues can affect response of vascular cells by regulating focal adhesion and stress fiber development, which define cytoskeleton organization and cell shape. Notably, both the grooves and the pillars at 1 μm size drastically reduced platelet adhesion and activation. Taken together, these findings suggest that the topographic pattern featuring 1 μm grooves may be the optimal design of surface multifunctionality that favors vascular cell selectivity and improves hemocompatibility.

  20. The Role of Oxidative Stress in the Pathogenesis of Diabetic Vascular Complications

    Directory of Open Access Journals (Sweden)

    Shuji Sasaki

    2012-08-01

    Full Text Available Oxidative stress has been paid increasing attention to as an important causative factor for diabetic vascular complications. Among possible various sources, accumulating evidence has indicated that NAD(PH oxidase may be the most important source for reactive oxygen species production in diabetic vascular tissues. The mechanisms underlying activation and up-regulation of NAD(PH oxidase has been supposed to be mediated by high glucose-induced protein kinase C (PKC activation. In this review article, activation of local renin-angiotensin II system induced by chymase activation is also shown to amplify such a PKC-dependent activation of NAD(PH oxidase. Additionally, human evidence showing the beneficial effect of antioxidants on diabetic vascular complications. Bilirubin has been recognized as a strong endogenous antioxidant. Here markedly lower prevalence of vascular complications is shown in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation. Lastly, statin, angiotensin II receptor blocker, chymase inhibitor, bilirubin and biliverdin, PKC β isoform inhibitor, and glucagon-like peptide-1 analog, are shown to serve as antioxidants and have some beneficial effect on diabetic vascular complications, via inhibiting PKC-NAD(PH oxidase activation, supporting the notion that this mechanism may be an effective therapeutic target for preventing diabetic vascular complications.

  1. A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension

    Science.gov (United States)

    Toba, Michie; Alzoubi, Abdallah; O’Neill, Kealan; Abe, Kohtaro; Urakami, Takeo; Komatsu, Masanobu; Alvarez, Diego; Järvinen, Tero A.H.; Mann, David; Ruoslahti, Erkki; McMurtry, Ivan F.; Oka, Masahiko

    2015-01-01

    A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH. PMID:24401613

  2. Current concepts in the classification, diagnosis and treatment of vascular anomalies.

    Science.gov (United States)

    Ernemann, Ulrike; Kramer, Ulrich; Miller, Stephan; Bisdas, Sotirios; Rebmann, Hans; Breuninger, Helmut; Zwick, Christine; Hoffmann, Jürgen

    2010-07-01

    Patients with extended vascular anomalies may suffer from significant aesthetic and functional impairment and represent a challenge to therapeutic planning, which is best met by an interdisciplinary concept. In agreement with the International Society for the Study of Vascular Anomalies (ISSVA), vascular lesions are classified into haemangiomas as proliferating endothelial tumours on the one hand and congenital vascular malformations on the other. According to the preponderant vascular channels and hemodynamic characteristics, malformations are subdivided into low flow (venous, lymphatic and capillary) lesions and high-flow malformations. Diagnostic imaging should be targeted at the specific structural and functional informations required for treatment planning. The imaging modality of choice to provide these informations is magnetic resonance imaging (MRI) supplemented by magnetic resonance angiography (MRA) with high spatial and temporal resolution. Treatment indications for haemangiomas depend on the proliferative behaviour of the lesion and comprise beta-blockers in order to induce involution as well as cryotherapy, laser and open surgery. Interventional radiological procedures have evolved as an essential element in an interdisciplinary treatment plan for vascular malformations and include percutaneous sclerotherapy with ethanol and OK-432 for venous and lymphatic malformations and transarterial embolization for high-flow lesions. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  3. Current concepts in the classification, diagnosis and treatment of vascular anomalies

    Energy Technology Data Exchange (ETDEWEB)

    Ernemann, Ulrike, E-mail: ulrike.ernemann@med.uni-tuebingen.d [Department of Diagnostic and Interventional Neuroradiology, Radiological Clinic, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen (Germany); Kramer, Ulrich; Miller, Stephan [Department of Diagnostic and Interventional Radiology, Radiological Clinic, University Hospital Tuebingen (Germany); Bisdas, Sotirios [Department of Diagnostic and Interventional Neuroradiology, Radiological Clinic, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen (Germany); Rebmann, Hans [Department of Paediatrics, Children' s Hospital, University Hospital Tuebingen (Germany); Breuninger, Helmut [Department of Dermatology, University Hospital Tuebingen (Germany); Zwick, Christine [Department of Hand, Plastic, Reconstructive and Burns Surgery, BG Trauma Clinic Tuebingen, University Hospital Tuebingen (Germany); Hoffmann, Juergen [Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen (Germany)

    2010-07-15

    Patients with extended vascular anomalies may suffer from significant aesthetic and functional impairment and represent a challenge to therapeutic planning, which is best met by an interdisciplinary concept. In agreement with the International Society for the Study of Vascular Anomalies (ISSVA), vascular lesions are classified into haemangiomas as proliferating endothelial tumours on the one hand and congenital vascular malformations on the other. According to the preponderant vascular channels and hemodynamic characteristics, malformations are subdivided into low flow (venous, lymphatic and capillary) lesions and high-flow malformations. Diagnostic imaging should be targeted at the specific structural and functional informations required for treatment planning. The imaging modality of choice to provide these informations is magnetic resonance imaging (MRI) supplemented by magnetic resonance angiography (MRA) with high spatial and temporal resolution. Treatment indications for haemangiomas depend on the proliferative behaviour of the lesion and comprise {beta}-blockers in order to induce involution as well as cryotherapy, laser and open surgery. Interventional radiological procedures have evolved as an essential element in an interdisciplinary treatment plan for vascular malformations and include percutaneous sclerotherapy with ethanol and OK-432 for venous and lymphatic malformations and transarterial embolization for high-flow lesions.

  4. Correlation between penile cavernosal artery blood flow and retinal vascular findings in arteriogenic erectile dysfunction

    Science.gov (United States)

    Emarah, Ahmed M; El-Haggar, Shawky M; Osman, Ihab A; Khafagy, Abdel Wahab S

    2010-01-01

    Objectives: Arteriogenic erectile dysfunction (ED) is a target organ disease of atherosclerosis, and therefore might be a predictor of systemic atherosclerosis. Being systemic, it might be possible to evaluate the extent of atherosclerosis from retinal vascular findings. We investigated the possible correlation between penile cavernosal artery blood flow and retinal vascular findings in patients with arteriogenic ED. Patients and methods: Sixty patients with ED were divided according to the peak systolic velocity (PSV) in their penile cavernosal arteries into two groups; Group A included 30 patients with PSV less than 25 cm/sec, and Group B included 30 patients with PSV more than 35 cm/sec. Blood flow in the penile cavernosal artery was measured with color Doppler ultrasonography. All patients were assessed by ocular fundus examination under amydriatic conditions to evaluate retinal vascular atherosclerotic changes using Hyman’s classification. Results: Evidence of retinal vascular atherosclerotic changes was found in 19 patients (63.3%) in Group A and in 10 patients (33.3%) in Group B. Conclusions: Our study confirms the possibility of predicting penile arterial vascular status in patients with ED from their retinal vascular findings by using amydriatic simple, practical funduscopy. PMID:20922041

  5. Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases.

    Science.gov (United States)

    Herman, Allison B; Autieri, Michael V

    2017-11-15

    Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing societies, and will increase with an aging and increasingly sedentary society. Vascular disease and atherosclerotic vascular syndromes are essentially inflammatory disorders, and transcriptional and post-transcriptional processes play essential roles in the ability of resident vascular and inflammatory cells to adapt to environmental stimuli. The regulation of mRNA translocation, stability, and translation are key processes of post-transcriptional regulation that permit these cells to rapidly respond to inflammatory stimuli. For the most part, these processes are controlled by elements in the 3'-UTR of labile, proinflammatory transcripts. Since proinflammatory transcripts almost exclusively contain AU-rich elements (AREs), this represents a tightly regulated and specific mechanism for initiation and maintenance of the proinflammatory phenotype. RNA-binding proteins (RBPs) recognize cis elements in 3'-UTR, and regulate each of these processes, but there is little literature exploring the concept that RBPs themselves can be directly regulated by inflammatory stimuli. Conceptually, inflammation-responsive RBPs represent an attractive target of rational therapies to combat vascular inflammatory syndromes. Herein we briefly describe the cellular and molecular etiology of atherosclerosis, and summarize our current understanding of RBPs and their specific roles in regulation of inflammatory mRNA stability. We also detail RBPs as targets of current anti-inflammatory modalities and how this may translate into better treatment for vascular inflammatory diseases. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  6. The inclusion of cognition in vascular risk factor clinical practice guidelines

    Science.gov (United States)

    Rockwood, Kenneth; Middleton, Laura E; Moorhouse, Paige K; Skoog, Ingmar; Black, Sandra E

    2009-01-01

    Background: People with vascular risk factors are at increased risk for cognitive impairment as well as vascular disease. The objective of this study was to evaluate whether vascular risk factor clinical practice guidelines consider cognition as an outcome or in connection with treatment compliance. Methods: Articles from PubMed, EMBASE, and the Cochrane Library were assessed by at least two reviewers and were included if: (1) Either hypertension, high cholesterol, diabetes, or atrial fibrillation was targeted; (2) The guideline was directed at physicians; (3) Adult patients (aged 19 years or older) were targeted; and (4) The guideline was published in English. Of 91 guidelines, most were excluded because they were duplicates, older versions, or focused on single outcomes. Results: Of the 20 clinical practice guidelines that met inclusion criteria, five mentioned cognition. Of these five, four described potential treatment benefits but only two mentioned that cognition may affect compliance. No guidelines adequately described how to screen for cognitive impairment. Conclusion: Despite evidence that links cognitive impairment to vascular risk factors, only a minority of clinical practice guidelines for the treatment of vascular risk factors consider cognition as either an adverse outcome or as a factor to consider in treatment. PMID:19966911

  7. [A new specialty is born: Vascular medicine].

    Science.gov (United States)

    Laroche, J-P

    2016-05-01

    On the 4th of December 2015, the French authorities officially recognized the birth of a specialty in vascular medicine entitled CO-DES cardiology-vascular/vascular Medicine. France is the 7th country to obtain this specialty after Switzerland, Germany, Austria, Czech Republic, Slovakia and Slovenia, six countries in the EEC. It has taken years to achieve a long but exciting experience: we went from hopes to disappointments, sometimes with the blues, but lobbying helping… with sustained confidence. This article tells the story of 30 years of struggle to achieve this vascular medicine specialty. Gaston Bachelard wrote: "Nothing is obvious, nothing is given, all is built." For the construction of vascular medicine, we had to overcome many obstacles, nothing was given to us, everything was conquered. Beware "The specialist is one who knows more and more things about an increasin