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Sample records for advanced human atherosclerotic

  1. Evidence for roles of radicals in protein oxidation in advanced human atherosclerotic plaque.

    PubMed Central

    Fu, S; Davies, M J; Stocker, R; Dean, R T

    1998-01-01

    Oxidative damage might be important in atherogenesis. Oxidized lipids are present at significant concentrations in advanced human plaque, although tissue antioxidants are mostly present at normal concentrations. Indirect evidence of protein modification (notably derivatization of lysine) or oxidation has been obtained by immunochemical methods; the specificities of these antibodies are unclear. Here we present chemical determinations of six protein-bound oxidation products: dopa, o-tyrosine, m-tyrosine, dityrosine, hydroxyleucine and hydroxyvaline, some of which reflect particularly oxy-radical-mediated reaction pathways, which seem to involve mainly the participation of transition- metal ions. We compared the relative abundance of these oxidation products in normal intima, and in human carotid plaque samples with that observed after radiolytically generated hydroxyl radical attack on BSA in vitro. The close similarities in relative abundances in the latter two circumstances indicate that hydroxyl radical damage might occur in plaque. The relatively higher level of dityrosine in plaque than that observed after radiolysis suggests the additional involvement of HOCl-mediated reactions in advanced plaque. PMID:9677308

  2. Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques.

    PubMed Central

    Katz, S S; Shipley, G G; Small, D M

    1976-01-01

    95 individual human atherosclerotic lesions from 26 persons were classified into three groups under the dissecting microscope: fatty streaks, fibrous plaques, and gruel (atheromatous) plaques. Each lesion was isolated by microdissection, its lipid composition determined by chromatography, and the physical states of the lipids identified by polarizing microscopy and in some cases by X-ray diffraction. The composition of each lesion was plotted on the in vitro phase diagram of the major lipids of plaques: cholesterol, cholesterol ester, and phospholipid. The observed physical states were compared with those predicted by the location of the lipid composition on the phase diagram. The most severe lesions (gruel plaques) had an average lipid composition of cholesterol 31.5+/-1.9%, cholesterol ester 47.2+/-2.3%, and phospholipid 15.3+/-0.5%. Their compositions fell within the three-phase zone of the phase diagram, predicting the lipids to be separated into a cholesterol crystal phase, a cholesterol ester oily phase and a phospholipid liquid crystalline phase. In addition to the phospholipid liquid crystalline phase of membranes and myelin-like figures demonstrable by electron microscopy, polarizing microscopy revealed the other two predicted phases, isotropic cholesterol ester-rich droplets and cholesterol crystals. X-ray diffraction studies verified the identity of the crystals as cholesterol monohydrate. Fibrous plaques also had an average lipid composition within the three-phase zone of the phase diagram. Polarizing microscopy revealed the presence of cholesterol monohydrate crystals and lipid droplets in all of these lesions; the droplets were predominately isotropic in 28 of the 31 fibrous plaques. Although these lesions had less free cholesterol and more cholesterol ester than gruel plaques, they were otherwise similar. Fatty streaks had compositions within both the two- and three-phase zones of the phase diagram. Compared with gruel plaques, the fatty streaks

  3. Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody.

    PubMed Central

    Kume, S.; Takeya, M.; Mori, T.; Araki, N.; Suzuki, H.; Horiuchi, S.; Kodama, T.; Miyauchi, Y.; Takahashi, K.

    1995-01-01

    To elucidate the deposition of advanced glycation end products (AGEs) in aortic atherosclerosis, aortic walls were obtained from 25 autopsy cases and examined immunohistochemically and immunoelectron microscopically with a monoclonal antibody specific for AGEs, 6D12. Among the autopsy cases, atherosclerotic lesions were found in the aortas of 22 cases and were composed of diffuse intimal thickening, fatty streaks, atherosclerotic plaques, and/or complicated lesions. In these cases, intracellular AGE accumulation was demonstrated in the intimal lesions of aortic atherosclerosis in 12 cases. Compared with the diffuse intimal thickening, intracellular AGE accumulation was marked in the fatty streaks and atherosclerotic plaques. Immunohistochemical double staining with 6D12 and monoclonal antibodies for macrophages or muscle actin or a polyclonal antibody for scavenger receptors demonstrated that the AGE accumulation in macrophages or their related foam cells was marked in the diffuse intimal thickening and fatty streak lesions and that almost all macrophages and macrophage-derived foam cells possessed scavenger receptors. Immunoelectron microscopic observation revealed the localization of 6D12-positive reaction in lysosomal lipid vacuoles or electron-dense granules of the foam cells. These results indicate that AGE accumulation occurs in macrophages, smooth muscle cells, and their related foam cells. Images Figure 2 Figure 3 Figure 6 PMID:7545874

  4. Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

    PubMed Central

    Hazell, L J; Arnold, L; Flowers, D; Waeg, G; Malle, E; Stocker, R

    1996-01-01

    Oxidation of LDL may contribute to atherogenesis, though the nature of the in vivo oxidant(s) remains obscure. Myeloperoxidase, the enzyme responsible for hypochlorous acid/hypochlorite (HOCl) production in vivo, is present in active form in human atherosclerotic lesions, and HOCl aggregates and transforms LDL into a high-uptake form for macrophages in vitro. Here we demonstrate HOCl-modified proteins in human lesions using an mAb raised against HOCl-modified LDL that recognizes HOCl-oxidized proteins but does not cross-react with Cu2+-, malondialdehyde-, or 4-hydroxynonenal-modified LDL. This antibody detected significantly more material in advanced atherosclerotic lesions than normal arteries, even though azide and methionine were included during sample work-up to inhibit myeloperoxidase and to scavenge HOCl. The epitope(s) recognized was predominantly cell associated and present in monocyte/macrophages, smooth muscle, and endothelial cells. The intima and cholesterol clefts stained more heavily than the center of the thickened vessels; adventitial staining was apparent in some cases. Immunostaining was also detected in a very early lesion from an accident victim, beside healthy areas that were unreactive. LDL oxidized by HOCl in vitro, but not native LDL, effectively competed with the epitopes in lesions for antibody binding. Density centrifugation of plaque homogenates and Western blot analysis showed that, in the apo B-containing lipoprotein fraction, the mAb recognized protein(s) of molecular mass greater than apo B, similar to those produced during oxidation of LDL with HOCl in vitro. Three major proteins were recognized by the anti-HOCl-modified protein antibody but not by an anti-apo B antibody in the apo B-free fraction. Together, these results demonstrate HOCl-oxidized proteins in human atherosclerotic lesions, implicating this oxidant in LDL modification in vivo. PMID:8617887

  5. Differentially expressed genes and canonical pathway expression in human atherosclerotic plaques – Tampere Vascular Study

    PubMed Central

    Sulkava, Miska; Raitoharju, Emma; Levula, Mari; Seppälä, Ilkka; Lyytikäinen, Leo-Pekka; Mennander, Ari; Järvinen, Otso; Zeitlin, Rainer; Salenius, Juha-Pekka; Illig, Thomas; Klopp, Norman; Mononen, Nina; Laaksonen, Reijo; Kähönen, Mika; Oksala, Niku; Lehtimäki, Terho

    2017-01-01

    Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds. PMID:28128285

  6. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions.

    PubMed Central

    Gown, A. M.; Tsukada, T.; Ross, R.

    1986-01-01

    The authors have performed immunocytochemical investigations of the distribution of various cell types in human atherosclerotic plaques using monoclonal antibodies specific to smooth muscle cells (CGA7 [Gown et al, J Cell Biol 1985, 100:807-813] and HHF35 [Tsukada et al, Am J Pathol (In press)] ); lymphocytes (T200 antigen); endothelial cells (Factor VIII and the Ulex europeus agglutinin); and macrophages, the latter with a new macrophage-specific antibody HAM56. All studies were performed on methanol-Carnoy's-fixed, paraffin-embedded tissues. In areas of grossly normal aorta, significant numbers of macrophages were noted within areas of diffuse intimal thickening. The cellular composition of the following three types of raised lesions were analyzed: fibro-fatty lesions, which, despite their gross appearance, consistent with fibrous plaques, were composed almost exclusively of macrophages and lymphocytes and almost devoid of smooth muscle cells; fibrous plaques, which were predominantly composed of smooth muscle cells displaying considerable morphologic heterogeneity and an admixture of blood-borne cells; advanced plaques, which were characterized by complex layers of smooth muscle cells and macrophages with considerable variation from region to region. Also noted were foci of medial and even intimal vascularization subjacent to the more advanced plaques. These studies demonstrate the application of monoclonal antibody technology to the study of the cellular composition of human atherosclerotic lesions. Images Figure 1 Figure 2 p195-a Figure 3 Figure 4 Figure 5 Figure 6 p201-a Figure 7 Figure 8 PMID:3777135

  7. Research Progress on the Risk Factors and Outcomes of Human Carotid Atherosclerotic Plaques

    PubMed Central

    Xiong, Xiang-Dong; Xiong, Wei-Dong; Xiong, Shang-Shen; Chen, Gui-Hai

    2017-01-01

    Objective: Atherosclerosis is an inflammatory process that results in complex lesions or plaques that protrude into the arterial lumen. Carotid atherosclerotic plaque rupture, with distal atheromatous debris embolization, causes cerebrovascular events. This review aimed to explore research progress on the risk factors and outcomes of human carotid atherosclerotic plaques, and the molecular and cellular mechanisms of human carotid atherosclerotic plaque vulnerability for therapeutic intervention. Data Sources: We searched the PubMed database for recently published research articles up to June 2016, with the key words of “risk factors”, “outcomes”, “blood components”, “molecular mechanisms”, “cellular mechanisms”, and “human carotid atherosclerotic plaques”. Study Selection: The articles, regarding the latest developments related to the risk factors and outcomes, atherosclerotic plaque composition, blood components, and consequences of human carotid atherosclerotic plaques, and the molecular and cellular mechanisms of human carotid atherosclerotic plaque vulnerability for therapeutic intervention, were selected. Results: This review described the latest researches regarding the interactive effects of both traditional and novel risk factors for human carotid atherosclerotic plaques, novel insights into human carotid atherosclerotic plaque composition and blood components, and consequences of human carotid atherosclerotic plaque. Conclusion: Carotid plaque biology and serologic biomarkers of vulnerability can be used to predict the risk of cerebrovascular events. Furthermore, plaque composition, rather than lesion burden, seems to most predict rupture and subsequent thrombosis. PMID:28303857

  8. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.

    PubMed Central

    Daugherty, A; Dunn, J L; Rateri, D L; Heinecke, J W

    1994-01-01

    Oxidatively modified lipoproteins have been implicated in atherogenesis, but the mechanisms that promote oxidation in vivo have not been identified. Myeloperoxidase, a heme protein secreted by activated macrophages, generates reactive intermediates that oxidize lipoproteins in vitro. To explore the potential role of myeloperoxidase in the development of atherosclerosis, we determined whether the enzyme was present in surgically excised human vascular tissue. In detergent extracts of atherosclerotic arteries subjected to Western blotting, a rabbit polyclonal antibody monospecific for myeloperoxidase detected a 56-kD protein, the predicted molecular mass of the heavy subunit. Both the immunoreactive protein and authentic myeloperoxidase bound to a lectin-affinity column; after elution with methyl mannoside their apparent molecular masses were indistinguishable by nondenaturing size-exclusion chromatography. Peroxidase activity in detergent extracts of atherosclerotic lesions likewise bound to a lectin column and eluted with methyl mannoside. Moreover, eluted peroxidase generated the cytotoxic oxidant hypochlorous acid (HOCl), indicating that enzymatically active myeloperoxidase was present in lesions. Patterns of immunostaining of arterial tissue with antihuman myeloperoxidase antibodies were similar to those produced by an antimacrophage antibody, and were especially prominent in the shoulder region of transitional lesions. Intense foci of myeloperoxidase immunostaining also appeared adjacent to cholesterol clefts in lipid-rich regions of advanced atherosclerotic lesions. These findings identify myeloperoxidase as a component of human vascular lesions. Because this heme protein can generate reactive species that damage lipids and proteins, myeloperoxidase may contribute to atherogenesis by catalyzing oxidative reactions in the vascular wall. Images PMID:8040285

  9. MR histology of advanced atherosclerotic lesions of ApoE- knockout mice

    NASA Astrophysics Data System (ADS)

    Naumova, A.; Yarnykh, V.; Ferguson, M.; Rosenfeld, M.; Yuan, C.

    2016-02-01

    The purposes of this study were to examine the feasibility of determining the composition of advanced atherosclerotic plaques in fixed ApoE-knockout mice and to develop a time-efficient microimaging protocol for MR histological imaging on mice. Five formalin-fixed transgenic ApoE-knockout mice were imaged at the 9.4T Bruker BioSpec MR scanner using 3D spoiled gradient-echo sequence with an isotropic field of view of 24 mm3; TR 20.8 ms; TE 2.6 ms; flip angle 20°, resulted voxel size 47 × 63 × 94 pm3. MRI examination has shown that advanced atherosclerotic lesions of aorta, innominate and carotid arteries in ApoE-knockout mice are characterized by high calcification and presence of the large fibrofatty nodules. MRI quantification of atherosclerotic lesion components corresponded to histological assessment of plaque composition with a correlation coefficient of 0.98.

  10. Laser ablation of human atherosclerotic plaque without adjacent tissue injury

    NASA Technical Reports Server (NTRS)

    Grundfest, W. S.; Litvack, F.; Forrester, J. S.; Goldenberg, T.; Swan, H. J. C.

    1985-01-01

    Seventy samples of human cadaver atherosclerotic aorta were irradiated in vitro using a 308 nm xenon chloride excimer laser. Energy per pulse, pulse duration and frequency were varied. For comparison, 60 segments were also irradiated with an argon ion and an Nd:YAG laser operated in the continuous mode. Tissue was fixed in formalin, sectioned and examined microscopically. The Nd:YAG and argon ion-irradiated tissue exhibited a central crater with irregular edges and concentric zones of thermal and blast injury. In contrast, the excimer laser-irradiated tissue had narrow deep incisions with minimal or no thermal injury. These preliminary experiments indicate that the excimer laser vaporizes tissue in a manner different from that of the continuous wave Nd:YAG or argon ion laser. The sharp incision margins and minimal damage to adjacent normal tissue suggest that the excimer laser is more desirable for general surgical and intravascular uses than are the conventionally used medical lasers.

  11. Local Effects of Human PCSK9 on the Atherosclerotic Lesion

    PubMed Central

    Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman; Major, Amy S.; Ding, Lei; Zhang, Youmin; DeVay, Rachel M.; Hong, Liang; Fan, Daping; Predazzi, Irene M.; Rashid, Shirya; Linton, MacRae F.; Fazio, Sergio

    2015-01-01

    Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptors (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque in unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition independently of changes in serum cholesterol levels we generated chimeric mice expressing hPCSK9 exclusively from macrophages using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE−/− and LDLR−/− mice, which were then placed on a high fat diet for 8 wk. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPM from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. hPCSK9 was detected in serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE−/− recipient mice while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b and Ly6Chi positive cell numbers in spleens of apoE−/− mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent as PCSK9 protein was not detected in lesions of LDLR−/− recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol

  12. Local effects of human PCSK9 on the atherosclerotic lesion.

    PubMed

    Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman; Major, Amy S; Ding, Lei; Zhang, Youmin; DeVay, Rachel M; Hong, Liang; Fan, Daping; Predazzi, Irene M; Rashid, Shirya; Linton, MacRae F; Fazio, Sergio

    2016-01-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but

  13. Optical detection of structural changes in human carotid atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Korol, R. M.; Canham, P. B.; Finlay, H. M.; Hammond, R. R.; Quantz, M.; Ferguson, G. G.; Liu, L. Y.; Lucas, A. R.

    2005-08-01

    Background: Arterial bifurcations are commonly the sites of developing atherosclerotic plaque that lead to arterial occlusions and plaque rupture (myocardial infarctions and strokes). Laser induced fluorescence (LIF) spectroscopy provides an effective nondestructive method supplying spectral information on extracellular matrix (ECM) protein composition, specifically collagen and elastin. Purpose: To investigate regional differences in the ECM proteins -- collagen I, III and elastin in unstable plaque by analyzing data from laser-induced fluorescence spectroscopy of human carotid endarterectomy specimens. Methods: Gels of ECM protein extracts (elastin, collagen types I & III) were measured as reference spectra and internal thoracic artery segments (extra tissue from bypass surgery) were used as tissue controls. Arterial segments and the endarterectomy specimens (n=21) were cut into 5mm cross-sectional rings. Ten fluorescence spectra per sampling area were then recorded at 5 sites per ring with argon laser excitation (357nm) with a penetration depth of 200 μm. Spectra were normalized to maximum intensity and analyzed using multiple regression analysis. Tissue rings were fixed in formalin (within 3 hours of surgery), sectioned and stained with H&E or Movat's Pentachrome for histological analysis. Spectroscopy data were correlated with immunohistology (staining for elastin, collagen types I, III and IV). Results: Quantitative fluorescence for the thoracic arteries revealed a dominant elastin component on the luminal side -- confirmed with immunohistology and known artery structure. Carotid endarterectomy specimens by comparison had a significant decrease in elastin signature and increased collagen type I and III. Arterial spectra were markedly different between the thoracic and carotid specimens. There was also a significant elevation (p<0.05) of collagen type I distal to the bifurcation compared to proximal tissue in the carotid specimens. Conclusion: Fluorescence

  14. Magnetic characterization of human blood in the atherosclerotic process in coronary arteries

    NASA Astrophysics Data System (ADS)

    Janus, B.; Bućko, M. S.; Chrobak, A.; Wasilewski, J.; Zych, M.

    2011-03-01

    In the last decades there has been an increasing interest in biomagnetism—a field of biophysics concerned with the magnetic properties of living organisms. Biomagnetism focuses on the measurement of magnetic properties of biological samples in the clinical environment. Progress in this field can provide new data for the understanding of the pathomechanism of atherosclerosis and support the diagnostic options for the evaluation and treatment of atherothrombotic complications. Lyophilized human blood samples from patients with atherosclerotic lesions (calcium scoring (CS) CS>0) and without atherosclerotic lesions (CS=0) were magnetically investigated. Magnetic measurements (performed in room and low temperature) indicated significant magnetic differences between these two groups of patients. Atherosclerotic blood samples are characterized by higher concentration of ferrimagnetic particles (magnetite and/or maghemite) and significant changes in the superparamagnetic behaviour. This research presents that magnetometry, in combination with medical research can lead to a better understanding of iron physiology in the atherosclerotic process.

  15. 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: Associations with cerebrovascular symptoms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15-lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovasc...

  16. Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages.

    PubMed

    Miyazaki, A; Sakashita, N; Lee, O; Takahashi, K; Horiuchi, S; Hakamata, H; Morganelli, P M; Chang, C C; Chang, T Y

    1998-10-01

    The acyl coenzyme A:cholesterol acyltransferase (ACAT) gene was first cloned in 1993 (Chang et al, J Biol Chem. 1993;268:20747-20755; designated ACAT-1). Using affinity-purified antibodies raised against the N-terminal portion of human ACAT-1 protein, we performed immunohistochemical localization studies and showed that the ACAT-1 protein was highly expressed in atherosclerotic lesions of the human aorta. We also performed cell-specific localization studies using double immunostaining and showed that ACAT-1 was predominantly expressed in macrophages but not in smooth muscle cells. We then used a cell culture system in vitro to monitor the ACAT-1 expression in differentiating monocytes-macrophages. The ACAT-1 protein content increased by up to 10-fold when monocytes spontaneously differentiated into macrophages. This increase occurred within the first 2 days of culturing the monocytes and reached a plateau level within 4 days of culturing, indicating that the increase in ACAT-1 protein content is an early event during the monocyte differentiation process. The ACAT-1 protein expressed in the differentiating monocytes-macrophages was shown to be active by enzyme assay in vitro. The high levels of ACAT-1 present in macrophages maintained in culture can explain the high ACAT-1 contents found in atherosclerotic lesions. Our results thus support the idea that ACAT-1 plays an important role in differentiating monocytes and in forming macrophage foam cells during the development of human atherosclerosis.

  17. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression.

    PubMed

    Subramanian, Manikandan; Proto, Jonathan D; Matsushima, Glenn K; Tabas, Ira

    2016-12-13

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl(-/-) or wild-type mice were transplanted into lethally irradiated Ldlr(-/-) mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr(-/-) mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis.

  18. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression

    PubMed Central

    Subramanian, Manikandan; Proto, Jonathan D.; Matsushima, Glenn K.; Tabas, Ira

    2016-01-01

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl−/− or wild-type mice were transplanted into lethally irradiated Ldlr−/− mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr−/− mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis. PMID:27958361

  19. Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions

    PubMed Central

    1990-01-01

    The major characteristics of human atherosclerotic lesions are similar to those of a chronic inflammatory reaction, namely fibrosis, mesenchymal cell proliferation, the presence of resident macrophages, and cell necrosis. Atherosclerosis exhibits in addition the feature of lipid (mainly cholesterol) accumulation. The results of the present report demonstrate that a specific cholesterol-containing lipid particle present in human atherosclerotic lesions activates the complement system to completion. Thus, lipid could represent a stimulatory factor for the inflammatory reaction, whose underlying mechanistic basis may be, at least in part, complement activation. The complement-activating lipid was purified from saline extracts of aortic atherosclerotic lesions by sucrose density gradient centrifugation followed by molecular sieve chromatography on Sepharose 2B. It contained little protein other than albumin, was 100-500 nm in size, exhibited an unesterified to total cholesterol ratio of 0.58 and an unesterified cholesterol to phospholipid ratio of 1.2. The lipid, termed lesion lipid complement (LCA), activated the alternative pathway of complement in a dose-dependent manner. Lesion-extracted low density lipoprotein (LDL) obtained during the purification procedure failed to activate complement. Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion. Biochemical and electron microscopic evaluations revealed that much of the C5b-9 present in atherosclerotic lesions is membraneous, rather than fluid phase SC5b-9. The observations reported herein establish a link between lipid insudation and inflammation in atherosclerotic lesions via the mechanism of complement activation. PMID:2373993

  20. Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration

    PubMed Central

    van der Valk, Fleur M.; van Wijk, Diederik F.; Lobatto, Mark E.; Verberne, Hein J.; Storm, Gert; Willems, Martine C.M.; Legemate, Dink A.; Nederveen, Aart J.; Calcagno, Claudia; Mani, Venkatesh; Ramachandran, Sarayu; Paridaans, Maarten P.M.; Otten, Maarten J.; Dallinga-Thie, Geesje M.; Fayad, Zahi A.; Nieuwdorp, Max; Schulte, Dominik M.; Metselaar, Josbert M.; Mulder, Willem J.M.; Stroes, Erik S.

    2015-01-01

    Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents’ risk–benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP’s liposomal encapsulation improved its pharmacokinetic profile in humans (n = 13) as attested by an increased plasma half-life of 63 h (LN-PLP 1.5 mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n = 14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n = 30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. PMID:25791806

  1. A Proteomic Focus on the Alterations Occurring at the Human Atherosclerotic Coronary Intima*

    PubMed Central

    de la Cuesta, Fernando; Alvarez-Llamas, Gloria; Maroto, Aroa S.; Donado, Alicia; Zubiri, Irene; Posada, Maria; Padial, Luis R.; Pinto, Angel G.; Barderas, Maria G.; Vivanco, Fernando

    2011-01-01

    Coronary atherosclerosis still represents the major cause of mortality in western societies. Initiation of atherosclerosis occurs within the intima, where major histological and molecular changes are produced during pathogenesis. So far, proteomic analysis of the atherome plaque has been mainly tackled by the analysis of the entire tissue, which may be a challenging approach because of the great complexity of this sample in terms of layers and cell type composition. Based on this, we aimed to study the intimal proteome from the human atherosclerotic coronary artery. For this purpose, we analyzed the intimal layer from human atherosclerotic coronaries, which were isolated by laser microdissection, and compared with those from preatherosclerotic coronary and radial arteries, using a two-dimensional Differential-In-Gel-Electrophoresis (DIGE) approach. Results have pointed out 13 proteins to be altered (seven up-regulated and six down-regulated), which are implicated in the migrative capacity of vascular smooth muscle cells, extracellular matrix composition, coagulation, apoptosis, heat shock response, and intraplaque hemorrhage deposition. Among these, three proteins (annexin 4, myosin regulatory light 2, smooth muscle isoform, and ferritin light chain) constitute novel atherosclerotic coronary intima proteins, because they were not previously identified at this human coronary layer. For this reason, these novel proteins were validated by immunohistochemistry, together with hemoglobin and vimentin, in an independent cohort of arteries. PMID:21248247

  2. Laser-induced fluorescence: quantitative analysis of atherosclerotic plaque chemical content in human aorta

    NASA Astrophysics Data System (ADS)

    Dai, Erbin; Wishart, David; Khoury, Samir; Kay, Cyril M.; Jugdutt, Bodh I.; Tulip, John; Lucas, Alexandra

    1996-05-01

    We have been studying laser-induced fluorescence as a technique for identification of selected changes in the chemical composition of atherosclerotic plaque. Formulae for quantification of chemical changes have been developed based upon analysis of fluorescence emission spectra using multiple regression analysis and the principal of least squares. The intima of human aortic necropsy specimens was injected with chemical compounds present in atherosclerotic plaque. Spectra recorded after injection of selected chemical components found in plaque (collagen I, III, IV, elastin and cholesterol) at varying concentrations (0.01 - 1.0 mg) were compared with saline injection. A single fiber system was used for both fluorescence excitation (XeCl excimer laser, 308 nm, 1.5 - 2.0 mJ/ pulse, 5 Hz) and fluorescence emission detection. Average spectra for each chemical have been developed and the wavelengths of peak emission intensity identified. Curve fitting analysis as well as multiple regression analysis were used to develop formulae for assessment of chemical content. Distinctive identifying average curves were established for each chemical. Excellent correlations were identified for collagen I, III, and IV, elastin, and cholesterol (R2 equals 0.92 6- 0.997). Conclusions: (1) Fluorescence spectra of human aortas were significantly altered by collagen I, collagen III, elastin and cholesterol. (2) Fluorescence spectroscopic analysis may allow quantitative assessment of atherosclerotic plaque chemical content in situ.

  3. Ex vivo differential phase contrast and magnetic resonance imaging for characterization of human carotid atherosclerotic plaques.

    PubMed

    Meletta, Romana; Borel, Nicole; Stolzmann, Paul; Astolfo, Alberto; Klohs, Jan; Stampanoni, Marco; Rudin, Markus; Schibli, Roger; Krämer, Stefanie D; Herde, Adrienne Müller

    2015-10-01

    Non-invasive detection of specific atherosclerotic plaque components related to vulnerability is of high clinical relevance to prevent cerebrovascular events. The feasibility of magnetic resonance imaging (MRI) for characterization of plaque components was already demonstrated. We aimed to evaluate the potential of ex vivo differential phase contrast X-ray tomography (DPC) to accurately characterize human carotid plaque components in comparison to high field multicontrast MRI and histopathology. Two human plaque segments, obtained from carotid endarterectomy, classified according to criteria of the American Heart Association as stable and unstable plaque, were examined by ex vivo DPC tomography and multicontrast MRI (T1-, T2-, and proton density-weighted imaging, magnetization transfer contrast, diffusion-weighted imaging). To identify specific plaque components, the plaques were subsequently sectioned and stained for fibrous and cellular components, smooth muscle cells, hemosiderin, and fibrin. Histological data were then matched with DPC and MR images to define signal criteria for atherosclerotic plaque components. Characteristic structures, such as the lipid and necrotic core covered by a fibrous cap, calcification and hemosiderin deposits were delineated by histology and found with excellent sensitivity, resolution and accuracy in both imaging modalities. DPC tomography was superior to MRI regarding resolution and soft tissue contrast. Ex vivo DPC tomography allowed accurate identification of structures and components of atherosclerotic plaques at different lesion stages, in good correlation with histopathological findings.

  4. Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

    PubMed Central

    Johnson, Jason L.; Jenkins, Nicholas P.; Huang, Wei-Chun; Sala-Newby, Graciela B.; Scholtes, Vincent P. W.; Moll, Frans L.; Pasterkamp, Gerard; Newby, Andrew C.

    2014-01-01

    Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi  TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo  TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction. PMID:25301980

  5. The Impact of Macrophage Insulin Resistance on Advanced Atherosclerotic Plaque Progression

    PubMed Central

    Tabas, Ira; Tall, Alan; Accili, Domenico

    2009-01-01

    Atherothrombotic vascular disease is the major cause of death and disability in obese and diabetic subjects with insulin resistance. Although increased systemic risk factors in the setting of insulin resistance contribute to this problem, it is likely exacerbated by direct effects of insulin resistance on the arterial wall cells that participate in atherosclerosis. A critical process in the progression of atherosclerotic lesions to those that cause clinical disease is necrotic breakdown of plaques. Plaque necrosis, which is particularly prominent in the lesions of diabetics, is caused by the combination of macrophage apoptosis and defective clearance, or efferocytosis, of the apoptotic macrophages. One cause of macrophage apoptosis in advanced plaques is activation of a pro-apoptotic branch of the endoplasmic reticulum stress pathway known as the Unfolded Protein Response (UPR). Macrophages have a functional insulin receptor signal transduction pathway, and down regulation of this pathway in the setting insulin resistance enhances UPR-induced apoptosis. Moreover, other aspects of the obesity/insulin-resistance syndrome may adversely affect efferocytosis. These processes may therefore provide an important mechanistic link among insulin resistance, plaque necrosis, and atherothrombotic vascular disease and suggest novel therapeutic approaches to this expanding health problem. PMID:20056946

  6. Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries.

    PubMed

    Castillo-Díaz, Silvia A; Garay-Sevilla, María E; Hernández-González, Martha A; Solís-Martínez, Martha O; Zaina, Silvio

    2010-11-01

    Global DNA hypomethylation potentially leading to pro-atherogenic gene expression occurs in atherosclerotic lesions. However, limited information is available on the genomic location of hypomethylated sequences. We present a microarray-based survey of the methylation status of CpG islands (CGIs) in 45 human atherosclerotic arteries and 16 controls. Data from 10,367 CGIs revealed that a subset (151 or 1.4%) of these was hypermethylated in control arteries. The vast majority (142 or 94%) of this CGI subset was found to be unmethylated or partially methylated in atherosclerotic tissue, while only 17 of the normally unmethylated CGIs were hypermethylated in the diseased tissue. The most common functional classes among annotated genes adjacent to or containing differentially methylated CGIs, were transcription (23%) and signalling factors (16%). The former included HOX members, PROX1, NOTCH1 and FOXP1, which are known to regulate key steps of atherogenesis. Expression analysis revealed differential expression of all CGI-associated genes analysed. Sequence analysis identified novel DNA motifs with regulatory potential, associated with differentially methylated CGIs. This study is the first large-scale analysis of DNA methylation in atherosclerosis. Our data suggest that aberrant DNA methylation in atherosclerosis affects the transcription of critical regulatory genes for the induction of a pro-atherogenic cellular phenotype.

  7. Simulation of human atherosclerotic femoral plaque tissue: the influence of plaque material model on numerical results

    PubMed Central

    2015-01-01

    Background Due to the limited number of experimental studies that mechanically characterise human atherosclerotic plaque tissue from the femoral arteries, a recent trend has emerged in current literature whereby one set of material data based on aortic plaque tissue is employed to numerically represent diseased femoral artery tissue. This study aims to generate novel vessel-appropriate material models for femoral plaque tissue and assess the influence of using material models based on experimental data generated from aortic plaque testing to represent diseased femoral arterial tissue. Methods Novel material models based on experimental data generated from testing of atherosclerotic femoral artery tissue are developed and a computational analysis of the revascularisation of a quarter model idealised diseased femoral artery from a 90% diameter stenosis to a 10% diameter stenosis is performed using these novel material models. The simulation is also performed using material models based on experimental data obtained from aortic plaque testing in order to examine the effect of employing vessel appropriate material models versus those currently employed in literature to represent femoral plaque tissue. Results Simulations that employ material models based on atherosclerotic aortic tissue exhibit much higher maximum principal stresses within the plaque than simulations that employ material models based on atherosclerotic femoral tissue. Specifically, employing a material model based on calcified aortic tissue, instead of one based on heavily calcified femoral tissue, to represent diseased femoral arterial vessels results in a 487 fold increase in maximum principal stress within the plaque at a depth of 0.8 mm from the lumen. Conclusions Large differences are induced on numerical results as a consequence of employing material models based on aortic plaque, in place of material models based on femoral plaque, to represent a diseased femoral vessel. Due to these large

  8. Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

    PubMed Central

    Luoma, J; Hiltunen, T; Särkioja, T; Moestrup, S K; Gliemann, J; Kodama, T; Nikkari, T; Ylä-Herttuala, S

    1994-01-01

    Macrophage- and smooth muscle cell (SMC)-derived foam cells are typical constituents of human atherosclerotic lesions. At least three receptor systems have been characterized that could be involved in the development of foam cells: alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2 MR/LRP), scavenger receptor, and LDL receptor. We studied the expression of these receptors in human atherosclerotic lesions with in situ hybridization and immunocytochemistry. An abundant expression of alpha 2MR/LRP mRNA and protein was found in SMC and macrophages in both early and advanced lesions in human aortas. alpha 2MR/LRP was also present in SMC in normal aortas. Scavenger receptor mRNA and protein were expressed in lesion macrophages but no expression was found in lesion SMC. LDL receptor was absent from the lesion area but was expressed in some aortas in medial SMC located near the adventitial border. The results demonstrate that (a) alpha 2MR/LRP is, so far, the only lipoprotein receptor expressed in lesions SMC in vivo; (b) scavenger receptors are expressed only in lesion macrophages; and (c) both receptors may play important roles in the development of human atherosclerotic lesions. Images PMID:8182133

  9. Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.

    PubMed Central

    Ylä-Herttuala, S; Rosenfeld, M E; Parthasarathy, S; Sigal, E; Särkioja, T; Witztum, J L; Steinberg, D

    1991-01-01

    Oxidatively modified low density lipoprotein (LDL) exhibits several potentially atherogenic properties, and inhibition of LDL oxidation in rabbits decreases the rate of the development of atherosclerotic lesions. In vitro studies have suggested that cellular lipoxygenases may be involved in LDL oxidation, and we have shown previously that 15-lipoxygenase and oxidized LDL are present in rabbit atherosclerotic lesions. We now report that epitopes of oxidized LDL are also found in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions. Using in situ hybridization and immunostaining techniques, we also report that 15-lipoxygenase mRNA and protein colocalize to the same macrophage-rich areas. Moreover, these same lesions express abundant mRNA for the acetyl LDL receptor but no detectable mRNA for the LDL receptor. We suggest that atherogenesis in human arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase, leading to subsequent enhanced macrophage uptake, partly by way of the acetyl LDL receptor. Images PMID:2010531

  10. Differential Inhibition of Human Atherosclerotic Plaque–Induced Platelet Activation by Dimeric GPVI-Fc and Anti-GPVI Antibodies

    PubMed Central

    Jamasbi, Janina; Megens, Remco T.A.; Bianchini, Mariaelvy; Münch, Götz; Ungerer, Martin; Faussner, Alexander; Sherman, Shachar; Walker, Adam; Goyal, Pankaj; Jung, Stephanie; Brandl, Richard; Weber, Christian; Lorenz, Reinhard; Farndale, Richard; Elia, Natalie; Siess, Wolfgang

    2015-01-01

    Background Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this receptor has selective antithrombotic potential. Objectives This study sought to compare compounds interfering with platelet GPVI–atherosclerotic plaque interaction to improve current antiatherothrombotic therapy. Methods Human atherosclerotic plaque–induced platelet aggregation was measured in anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s, and 1,500/s). Inhibition by dimeric GPVI fragment crystallizable region of IgG (Fc) masking GPVI binding sites on collagen was compared with that of 3 anti-GPVI antibodies: BLO8-1, a human domain antibody; 5C4, a fragment antigen-binding (Fab fragment) of monoclonal rat immunoglobulin G; and m-Fab-F, a human recombinant sFab against GPVI dimers. Results GPVI-Fc reduced plaque-triggered platelet aggregation in static blood by 51%, BLO8-1 by 88%, and 5C4 by 93%. Under arterial flow conditions, BLO8-1 and 5C4 almost completely inhibited platelet aggregation while preserving platelet adhesion on plaque. Inhibition by GPVI-Fc, even at high concentrations, was less marked but increased with shear rate. Advanced optical imaging revealed rapid persistent GPVI-Fc binding to collagen under low and high shear flow, upstream and downstream of plaque fragments. At low shear particularly, platelets adhered in plaque flow niches to GPVI-Fc–free segments of collagen fibers and recruited other platelets onto aggregates via ADP and TxA2 release. Conclusions Anti-GPVI antibodies inhibit atherosclerotic plaque-induced platelet aggregation under static and flow conditions more effectively than GPVI-Fc. However, potent platelet inhibition by GPVI-Fc at a higher shear rate (1,500/s) suggests localized antithrombotic efficacy at denuded or fissured stenotic high-risk lesions without systemic bleeding. The compound-specific differences

  11. A computational fluid-structure interaction model for plaque vulnerability assessment in atherosclerotic human coronary arteries

    NASA Astrophysics Data System (ADS)

    Karimi, Alireza; Navidbakhsh, Mahdi; Razaghi, Reza; Haghpanahi, Mohammad

    2014-04-01

    Coronary artery disease is responsible for a third of global deaths worldwide. Computational simulations of blood flow can be used to understand the interactions of artery/plaque and blood in coronary artery disease and to better predict the rupture of atherosclerotic plaques. So far, the mechanical properties of animals' coronary artery have been mostly used for hemodynamic simulation of atherosclerotic arteries. The mechanical properties of animals' coronary arteries are often not accurate enough and can be only used for an approximate estimation and comparative assessment of the cognate parameters in human. In this study, a three-dimensional (3D) computational fluid-structure interactions model with three different plaque types is presented to perform a more accurate plaque vulnerability assessment for human atherosclerotic plaques. The coronary arteries of twenty-two male individuals were removed during autopsy and subjected to uniaxial tensile loading. The hyperelastic material coefficients of coronary arteries were calculated and implemented to the computational model. The fully coupled fluid and structure models were solved using the explicit dynamics finite element code LS-DYNA. The normal and shear stresses induced within the plaques were significantly affected by different plaque types. The highest von Mises (153 KPa) and shear (57 KPa) stresses were observed for hypocellular plaques, while the lowest von Mises (70 KPa) and shear (39 KPa) stresses were observed on the stiffer calcified plaques. The results suggest that the risk of plaque rupture due to blood flow is lower for cellular and hypocellular plaques, while higher for calcified plaques with low fracture stresses.

  12. Serum-Sphingosine-1-Phosphate Concentrations Are Inversely Associated with Atherosclerotic Diseases in Humans

    PubMed Central

    Geissen, Markus; Schwedhelm, Edzard; Winkler, Martin S.; Geffken, Maria; Peine, Sven; Schoen, Gerhard; Debus, E. Sebastian; Larena-Avellaneda, Axel; Daum, Guenter

    2016-01-01

    Background and Objectives Atherosclerotic changes of arteries are the leading cause for deaths in cardiovascular disease and greatly impair patient’s quality of life. Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that regulates potentially pro-as well as anti-atherogenic processes. Here, we investigate whether serum-S1P concentrations are associated with peripheral artery disease (PAD) and carotid stenosis (CS). Methods and Results Serum was sampled from blood donors (controls, N = 174) and from atherosclerotic patients (N = 132) who presented to the hospital with either clinically relevant PAD (N = 102) or CS (N = 30). From all subjects, serum-S1P was measured by mass spectrometry and blood parameters were determined by routine laboratory assays. When compared to controls, atherosclerotic patients before invasive treatment to restore blood flow showed significantly lower serum-S1P levels. This difference cannot be explained by risk factors for atherosclerosis (old age, male gender, hypertension, hypercholesteremia, obesity, diabetes or smoking) or comorbidities (Chronic obstructive pulmonary disease, kidney insufficiency or arrhythmia). Receiver operating characteristic curves suggest that S1P has more power to indicate atherosclerosis (PAD and CS) than high density lipoprotein-cholesterol (HDL-C). In 35 patients, serum-S1P was measured again between one and six months after treatment. In this group, serum-S1P concentrations rose after treatment independent of whether patients had PAD or CS, or whether they underwent open or endovascular surgery. Post-treatment S1P levels were highly associated to platelet numbers measured pre-treatment. Conclusions Our study shows that PAD and CS in humans is associated with decreased serum-S1P concentrations and that S1P may possess higher accuracy to indicate these diseases than HDL-C. PMID:27973607

  13. STAT1 is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress in Vitro and in Advanced Atherosclerotic Lesions in Vivo

    PubMed Central

    Lim, Wah-Seng; Timmins, Jenelle M.; Seimon, Tracie A.; Sadler, Anthony; Kolodgie, Frank D.; Virmani, Renu; Tabas, Ira

    2008-01-01

    Background Macrophage apoptosis is a critical process in the formation of necrotic cores in vulnerable atherosclerotic plaques. In-vitro and in-vivo data suggest that macrophage apoptosis in advanced atheromata may be triggered by a combination of endoplasmic reticulum (ER) stress and engagement of the type A scavenger receptor (SRA), which together induce death through a rise in cytosolic calcium and activation of toll-like receptor-4 (TLR4). Methods and Results Using both primary peritoneal macrophages and studies in advanced atheromata in vivo, we introduce Signal Transducer and Activator of Transcription-1 (STAT1) as a critical and necessary component of ER stress/SRA-induced macrophage apoptosis. We show that STAT1 is serine-phosphorylated in macrophages subjected to SRA ligands and ER stress in a manner requiring cytosolic calcium, calcium/calmodulin-dependent protein kinase II (CaMKII), and TLR4. Remarkably, apoptosis was inhibited by ~80–90% (p < 0.05) by STAT1 deficiency or CaMKII inhibition. In vivo, nuclear Ser-P-STAT1 was found in macrophage-rich regions of advanced murine and human atheromata. Most importantly, macrophage apoptosis was decreased by 61% (p = 0.034) and plaque necrosis by 34% (p = 0.02) in the plaques of fat-fed Ldlr−/− mice transplanted with Stat1−/− bone marrow. Conclusions STAT1 is critical for ER stress/SRA-induced apoptosis in primary tissue macrophages and in macrophage apoptosis in advanced atheromata. These findings suggest a potentially important role for STAT1-mediated macrophage apoptosis in atherosclerotic plaque progression. PMID:18227389

  14. Advances in immune-modulating therapies to treat atherosclerotic cardiovascular diseases.

    PubMed

    Chyu, Kuang-Yuh; Shah, Prediman K

    2014-03-01

    In addition to hypercholesterolemia, innate and adaptive immune mechanisms play a critical role in atherogenesis, thus making immune-modulation therapy a potentially attractive way of managing atherosclerotic cardiovascular disease. These immune-modulation strategies include both active and passive immunization and confer beneficial reduction in atherosclerosis. Preclinical studies have demonstrated promising results and we review current knowledge on the complex role of the immune system and the potential for immunization as an immune-modulation therapy for atherosclerosis.

  15. Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions.

    PubMed Central

    Ylä-Herttuala, S; Lipton, B A; Rosenfeld, M E; Goldberg, I J; Steinberg, D; Witztum, J L

    1991-01-01

    Lipoprotein lipase (LPL; EC 3.1.1.34) may promote atherogenesis by producing remnant lipoproteins on the endothelial surface and by acting on lipoproteins in the artery wall. In vitro, smooth muscle cells and macrophages synthesize LPL, but in human carotid lesions only a few smooth muscle cells were reported to contain LPL protein. Endothelial cells do not synthesize LPL in vitro, but in normal arteries intense immunostaining for LPL is present on the endothelium. We used Northern blot analysis, in situ hybridization, and immunocytochemistry of human and rabbit arteries to determine cellular distribution and the site of the synthesis of LPL in atherosclerotic lesions. Northern blot analysis showed that LPL mRNA was detectable in macrophage-derived foam cells isolated from arterial lesions of "ballooned" cholesterol-fed rabbits. In situ hybridization studies of atherosclerotic lesions with an antisense riboprobe showed a strong hybridization signal for LPL mRNA in some, but not all, lesion macrophages, which were mostly located in the subendothelial and edge areas of the lesions. Also, some smooth muscle cells in lesion areas also expressed LPL mRNA. Immunocytochemistry of frozen sections of rabbit lesions with a monoclonal antibody to human milk LPL showed intense staining for LPL protein in macrophage-rich intimal lesions. The results suggest that lesion macrophages and macrophage-derived foam cells express LPL mRNA and protein. Some smooth muscle cells in the lesion areas also synthesize LPL. These data are consistent with an important role for LPL in atherogenesis. Images PMID:1719546

  16. Human macrophage scavenger receptors: Primary structure, expression, and localization in atherosclerotic lesions

    SciTech Connect

    Matsumoto, Akiyo; Itakura, Hiroshige; Kodama, Tatsuhiko National Inst. of Health and Nutrition, Tokyo ); Naito, Makoto; Takahashi, Kiyoshi ); Ikemoto, Shinji; Asaoka, Hitoshi; Hayakawa, Ikuho ); Kanamori, Hiroshi; Takaku, Fumimaro ); Aburatani, Hiroyuki Massachusetts Inst. of Tech., Cambridge, MA ); Suzuki, Hiroshi; Kobari, Yukage; Miyai, Tatsuya ); Cohen, E.H.; Wydro, R. ); Housman, D.E. )

    1990-12-01

    Two types of cDNAs for human macrophage scavenger receptors were cloned from a cDNA library derived from the phorbol ester-treated human monocytic cell line THP-1. The type I and type II human scavenger receptors encoded by these cDNAs are homologous (73% and 71% amino acid identity) to their previously characterized bovine counterparts and consist of six domains: cytoplasmic (I), membrane-spanning (II), spacer (III), {alpha}-helical coiled-coil (IV), collagen-like (V), and a type-specific C-terminal (VI). The receptor gene is located on human chromosome 8. The human receptors expressed in CHO-K1 cells mediated endocytosis of modified low density lipoproteins. Two mRNAs, 4.0 and 3.2 kilobases, have been detected in human liver, placenta, and brain. Immunohistochemical studies using an anti-peptide antibody which recognizes human scavenger receptors indicated the presence of the scavenger receptors in the macrophages of lipid-rich atherosclerotic lesions, suggesting the involvement of scavenger receptors in atherogenesis.

  17. Localized adhesion of monocytes to human atherosclerotic plaques demonstrated in vitro: implications for atherogenesis.

    PubMed Central

    Poston, R. N.; Johnson-Tidey, R. R.

    1996-01-01

    Blood-derived macrophages in the arterial intima are a characteristic feature of active atherosclerotic plaques. Adherent monocytes on the luminal surface and increased adhesion molecules on the endothelium have suggested that specific molecular mechanisms are involved in monocyte/macrophage traffic into the arterial wall. Adhesion of human monocytes and related cell lines was therefore studied in vitro to histological sections of human plaques. At 37 degrees C, these cells bound selectively to the plaques. Binding to the endothelium occurred and was also present extensively in the diseased intima. Inhibition studies showed that the endothelial and general intimal binding had largely similar molecular properties. Strong inhibition was produced by antibodies to the monocyte-specific adhesion molecule CD14, to beta2 integrins, and to ICAM-1. Likewise, a peptide containing the Arg-Gly-Asp sequence was strongly inhibitory, suggesting that binding of leukocyte integrins to arterial extracellular matrix was synergistic with cell-cell interactions. A P-selectin antibody was exceptional in giving selective inhibition of endothelial adhesion, which correlates with the specific endothelial localization of this adhesion molecule. These results show that monocytes adhere to atherosclerotic plaques through the focal activation of multiple arterial wall adhesion molecules, confirming the adhesion hypothesis. A positive feedback theory for the pathogenesis of atherosclerosis can be suggested, based on the ability of macrophages in the wall to activate the endothelium, induce adhesion molecules, and facilitate additional monocyte entry. The adhesion assay provides a means for the identification of adhesion inhibitors with therapeutic potential. Images Figure 2 PMID:8686764

  18. Regression and stabilization of advanced murine atherosclerotic lesions: a comparison of LDL lowering and HDL raising gene transfer strategies.

    PubMed

    Van Craeyveld, Eline; Gordts, Stephanie C; Nefyodova, Elena; Jacobs, Frank; De Geest, Bart

    2011-06-01

    Both reductions in atherogenic lipoproteins and increases in high-density lipoprotein (HDL) levels may affect atherosclerosis regression. Here, the relative potential of low-density lipoprotein (LDL) lowering and HDL raising gene transfer strategies to induce regression of complex murine atherosclerotic lesions was directly compared. Male C57BL/6 LDL receptor (LDLr)(-/-) mice were fed an atherogenic diet (1.25% cholesterol and 10% coconut oil) to induce advanced atherosclerotic lesions. A baseline group was killed after 6 months and remaining mice were randomized into a control progression (Adnull or saline), an apolipoprotein (apo) A-I (AdA-I), an LDLr (AdLDLr), or a combined apo A-I/LDLr (AdA-I/AdLDLr) adenoviral gene transfer group and followed-up for another 12 weeks with continuation of the atherogenic diet. Gene transfer with AdLDLr decreased non-HDL cholesterol levels persistently by 95% (p < 0.001) compared with baseline. This drastic reduction of non-HDL cholesterol levels induced lesion regression by 28% (p < 0.001) in the aortic root and by 25% (p < 0.05) in the brachiocephalic artery at 12 weeks after transfer. Change in lesion size was accompanied by enhanced plaque stability, as evidenced by increased collagen content, reduced lesional macrophage content, a drastic reduction of necrotic core area, and decreased expression of inflammatory genes. Elevated HDL cholesterol following AdA-I transfer increased collagen content in lesions, but did not induce regression. Apo A-I gene transfer on top of AdLDLr transfer resulted in additive effects, particularly on inflammatory gene expression. In conclusion, drastic lipid lowering induced by a powerful gene transfer strategy leads to pronounced regression and stabilization of advanced murine atherosclerosis.

  19. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling

    PubMed Central

    Chistiakov, Dmitry A.; Sobenin, Igor A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2015-01-01

    A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC “contractile” phenotype to the “synthetic” phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles. PMID:26221589

  20. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.

    PubMed Central

    Ylä-Herttuala, S; Lipton, B A; Rosenfeld, M E; Särkioja, T; Yoshimura, T; Leonard, E J; Witztum, J L; Steinberg, D

    1991-01-01

    The recruitment of monocyte-macrophages into the artery wall is one of the earliest events in the pathogenesis of atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) is a potent monocyte chemoattractant secreted by many cells in vitro, including vascular smooth muscle and endothelial cells. To test whether it is expressed in the artery in vivo, we used Northern blot analysis, in situ hybridization, and immunocytochemistry to study the expression of MCP-1 in normal and atherosclerotic human and rabbit arteries. Northern blot analysis showed that MCP-1 mRNA could be isolated from rabbit atherosclerotic lesions but not from the intima media of normal animals. Furthermore, MCP-1 mRNA was extracted from macrophage-derived foam cells isolated from arterial lesions of ballooned cholesterol-fed rabbits, whereas alveolar macrophages isolated simultaneously from the same rabbits did not express MCP-1 mRNA. MCP-1 mRNA was detected by in situ hybridization in macrophage-rich regions of both human and rabbit atherosclerotic lesions. No MCP-1 mRNA was found in sublesional medial smooth muscle cells or in normal arteries. By using immunocytochemistry, MCP-1 protein was demonstrated in human lesions, again only in macrophage-rich regions. Immunostaining of the serial sections with an antiserum against malondialdehyde-modified low density lipoprotein indicated the presence of oxidized low density lipoprotein indicated the presence of oxidized low density lipoprotein and/or other oxidation-specific lipid-protein adducts in the same areas that contained macrophages and MCP-1. We conclude that (i) MCP-1 is strongly expressed in a small subset of cells in macrophage-rich regions of human and rabbit atherosclerotic lesions and (ii) MCP-1 may, therefore, play an important role in the ongoing recruitment of monocyte-macrophages into developing lesions in vivo. Images PMID:2052604

  1. Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

    PubMed Central

    Belgore, F; Blann, A; Neil, D; Ahmed, A S; Lip, G Y H

    2004-01-01

    Background: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. Methods: The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. Results: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. Conclusion: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications. PMID:14990597

  2. Increased platelet deposition on atherosclerotic coronary arteries.

    PubMed Central

    van Zanten, G H; de Graaf, S; Slootweg, P J; Heijnen, H F; Connolly, T M; de Groot, P G; Sixma, J J

    1994-01-01

    A ruptured atherosclerotic plaque leads to exposure of deeper layers of the plaque to flowing blood and subsequently to thrombus formation. In contrast to the wealth of data on the occurrence of thrombi, little is known about the reasons why an atherosclerotic plaque is thrombogenic. One of the reasons is the relative inaccessibility of the atherosclerotic plaque. We have circumvented this problem by using 6-microns cryostat cross sections of human coronary arteries. These sections were mounted on coverslips that were exposed to flowing blood in a rectangular perfusion chamber. In normal-appearing arteries, platelet deposition was seen on the luminal side of the intima and on the adventitia. In atherosclerotic arteries, strongly increased platelet deposition was seen on the connective tissue of specific parts of the atherosclerotic plaque. The central lipid core of an advanced plaque was not reactive towards platelets. The results indicate that the atherosclerotic plaque by itself is more thrombogenic than the normal vessel wall. To study the cause of the increased thrombus formation on the atherosclerotic plaque, perfusion studies were combined with immunohistochemical studies. Immunohistochemical studies of adhesive proteins showed enrichment of collagen types I, III, V, and VI, vitronectin, fibronectin, fibrinogen/fibrin, and thrombospondin in the atherosclerotic plaque. Laminin and collagen type IV were not enriched. von Willebrand Factor (vWF) was not present in the plaque. The pattern of increased platelet deposition in serial cross sections corresponded best with areas in which collagen types I and III were enriched, but there were also areas in the plaque where both collagens were enriched but no increased reactivity was seen. Inhibition of platelet adhesion with a large range of antibodies or specific inhibitors showed that vWF from plasma and collagen types I and/or III in the plaque were involved. Fibronectin from plasma and fibronectin, fibrinogen

  3. Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans.

    PubMed Central

    Rosenfeld, M. E.; Ylä-Herttuala, S.; Lipton, B. A.; Ord, V. A.; Witztum, J. L.; Steinberg, D.

    1992-01-01

    In this study, the authors demonstrate the expression of mRNA and the presence of protein for macrophage colony-stimulating factor (MCSF) in atherosclerotic lesions from humans and rabbits. In situ hybridization of serial sections of human fatty streaks demonstrated expression of MCSF mRNA by cells dispersed throughout the lesions. Immunocytochemical staining with a panel of MCSF-specific antibodies showed extensive cell-associated staining of all of the cell types in the lesions. Immunocytochemical studies of atherosclerotic lesions from Watanabe heritable hyperlipidemic (WHHL) and cholesterol-fed rabbits demonstrated a similar cell-associated pattern of staining. There was no MCSF-specific staining of aortas from normal rabbits or of cultured aortic smooth muscle cells from either humans or rabbits. Macrophage-derived foam cells (MFC) were isolated from the aortas of ballooned, cholesterol-fed rabbits. A Northern blot demonstrated that RNA isolated from the MFC hybridized with a human cDNA probe for MCSF. RNA from alveolar macrophages isolated simultaneously from the same rabbits did not hybridize with the MCSF probe. Conditioned media from an 18- to 24-hour incubation of the MFC contained colony-stimulating activity as demonstrated in a mouse bone marrow culture assay. Most of this colony-stimulating activity was neutralized by preincubating the conditioned media with an MCSF-specific antibody. Images Figure 2 Figure 1 Figure 1 Figure 3 PMID:1739123

  4. Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques.

    PubMed Central

    O'Brien, K D; Gordon, D; Deeb, S; Ferguson, M; Chait, A

    1992-01-01

    Lipoprotein lipase (LPL), hydrolyzes the core triglycerides of lipoproteins, thereby playing a role in their maturation. LPL may be important in the metabolic pathways that lead to atherosclerosis, since it is secreted in vitro by both of the predominant cell types of the atherosclerotic plaque, i.e., macrophages and smooth muscle cells. Because of uncertainty concerning the primary cellular source of LPL in atherosclerotic lesions, in situ hybridization assays for LPL mRNA were performed on 12 coronary arteries obtained from six cardiac allograft recipients. Macrophages and smooth muscle cells were identified on adjacent sections with cell-specific antibodies and foam cells were identified morphologically. LPL protein was localized using a polyclonal antibody. LPL mRNA was produced by a proportion of plaque macrophages, particularly macrophage-derived foam cells, but was not detected in association with any intimal or medial smooth muscle cells. These findings were confirmed by combined immunocytochemistry and in situ hybridization on the same tissue sections. LPL protein was detected in association with macrophage-derived foam cells, endothelial cells, adventitial adipocytes, and medial smooth muscle cells, and, to a lesser extent, in intimal smooth muscle cells and media underlying well-developed plaque. These results indicate that macrophage-derived foam cells are the primary source of LPL in atherosclerotic plaques and are consistent with a role for LPL in the pathogenesis of atherosclerosis. Images PMID:1569193

  5. 3-D reconstruction of tissue components for atherosclerotic human arteries using ex vivo high-resolution MRI.

    PubMed

    Auer, Martin; Stollberger, Rudolf; Regitnig, Peter; Ebner, Franz; Holzapfel, Gerhard A

    2006-03-01

    Automatic computer-based methods are well suited for the image analysis of the different components in atherosclerotic plaques. Although several groups work on such analysis some of the methods used are oversimplified and require improvements when used within a computational framework for predicting meaningful stress and strain distributions in the heterogeneous arterial wall under various loading conditions. Based on high-resolution magnetic resonance imaging of excised atherosclerotic human arteries and a series of two-dimensional (2-D) contours we present a segmentation tool that permits a three-dimensional (3-D) reconstruction of the most important tissue components of atherosclerotic arteries. The underlying principle of the proposed approach is a model-based snake algorithm for identifying 2-D contours, which uses information about the plaque composition and geometric data of the tissue layers. Validation of the computer-generated tissue boundaries is performed with 100 MR images, which are compared with the results of a manual segmentation performed by four experts. Based on the Hausdorff distance and the average distance for computer-to-expert differences and the interexpert differences for the outer boundary of the adventitia, the adventitia-media, media-intima, intima-lumen and calcification boundaries are less than 1 pixel (0.234 mm). The percentage statistic shows similar results to the modified Williams index in terms of accuracy. Except for the identification of lipid-rich regions the proposed algorithm is automatic. The nonuniform rational B-spline-based computer-generated 3-D models of the individual tissue components provide a basis for clinical and computational analysis.

  6. In vivo MRI-based simulation of fatigue process: a possible trigger for human carotid atherosclerotic plaque rupture

    PubMed Central

    2013-01-01

    Background Atherosclerotic plaque is subjected to a repetitive deformation due to arterial pulsatility during each cardiac cycle and damage may be accumulated over a time period causing fibrous cap (FC) fatigue, which may ultimately lead to rupture. In this study, we investigate the fatigue process in human carotid plaques using in vivo carotid magnetic resonance (MR) imaging. Method Twenty seven patients with atherosclerotic carotid artery disease were included in this study. Multi-sequence, high-resolution MR imaging was performed to depict the plaque structure. Twenty patients were found with ruptured FC or ulceration and 7 without. Modified Paris law was used to govern crack propagation and the propagation direction was perpendicular to the maximum principal stress at the element node located at the vulnerable site. Results The predicted crack initiations from 20 patients with FC defect all matched with the locations of the in vivo observed FC defect. Crack length increased rapidly with numerical steps. The natural logarithm of fatigue life decreased linearly with the local FC thickness (R2 = 0.67). Plaques (n=7) without FC defect had a longer fatigue life compared with those with FC defect (p = 0.03). Conclusion Fatigue process seems to explain the development of cracks in FC, which ultimately lead to plaque rupture. PMID:23617791

  7. Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.

    PubMed

    Feldmann, Radmila; Fischer, Cornelius; Kodelja, Vitam; Behrens, Sarah; Haas, Stefan; Vingron, Martin; Timmermann, Bernd; Geikowski, Anne; Sauer, Sascha

    2013-04-01

    Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

  8. An Experimental Study on the Ultimate Strength of the Adventitia and Media of Human Atherosclerotic Carotid Arteries in Circumferential and Axial Directions

    PubMed Central

    Teng, Zhongzhao; Tang, Dalin; Zheng, Jie; Woodard, Pamela K.; Hoffman, Allen H.

    2009-01-01

    Atherosclerotic plaque may rupture without warning causing heart attack or stroke. Knowledge of the ultimate strength of human atherosclerotic tissues is essential for understanding the rupture mechanism and predicting cardiovascular events. Despite its great importance, experimental data on ultimate strength of human atherosclerotic carotid artery remains very sparse. This study determined the uniaxial tensile strength of human carotid artery sections containing type II and III lesions (AHA classifications). Axial and circumferential oriented adventitia, media and intact specimens (total=73) were prepared from 6 arteries. The ultimate strength in uniaxial tension was taken as the peak stress recorded when the specimen showed the first evidence of failure and the extensibility was taken as the stretch ratio at failure. The mean adventitia strength values calculated using the 1st Piola-Kirchoff stress were 1996±867kPa and 1802±703kPa in the axial and circumferential directions respectively, while the corresponding values for the media sections were 519±270kPa and 1230±533kPa. The intact specimens showed ultimate strengths similar to media in circumferential direction but were twice as strong as the media in the axial direction. Results also indicated that adventitia, media and intact specimens exhibited similar extensibility at failure, in both the axial and circumferential directions (stretch ratio 1.50 +/−0.22). These measurements of the material strength limits for human atherosclerotic carotid arteries could be useful in improving computational models that assess plaque vulnerability. PMID:19665126

  9. Is Cadmium Exposure Associated with the Burden, Vulnerability and Rupture of Human Atherosclerotic Plaques?

    PubMed Central

    Sallsten, Gerd; Lundh, Thomas; Barregard, Lars

    2015-01-01

    The general population is exposed to cadmium from food and smoking. Cadmium is a widely spread toxic pollutant that seems to be associated with cardiovascular diseases, although little is known if it contributes to the occurrence of atherosclerotic plaques and the process whereby plaques become vulnerable and are prone to rupture. We tested the hypotheses that cadmium exposure is associated not only with an increased subclinical burden of atherosclerotic plaques in different vascular territories and early signs of plaque vulnerability, but also with cadmium content and plaque-rupture in the clinical phase of the disease. Ultrasound technique was used to measure plaque prevalence and echogenicity in the carotid and femoral arteries in a population sample of women (n = 599) in whom blood cadmium was measured. In addition cadmium was measured in snap-frozen endarterectomies and whole blood obtained from patients who were referred to surgery because of symptomatic carotid plaques (n = 37). Sixteen endarterectomies were divided into three parts corresponding to different flow conditions and plaque vulnerability. In the population sample blood cadmium was associated with the number of vascular territories with plaques (p = 0.003 after adjustment for potential confounders). The cadmium concentrations in symptomatic plaques were 50-fold higher in plaque tissue than in blood. Cadmium levels in blood and plaque correlated, also after adjustment for smoking and other cardiovascular risk factors (p<0.001). Compared with the other parts of the plaque, the cadmium content was double as high in the part where plaque rupture usually occurs. In conclusion, the results show that cadmium exposure is associated with the burden of subclinical atherosclerosis in middle-aged women with different degrees of glucose tolerance, and that the content of cadmium in symptomatic plaques in patients is related to that in blood, but much higher, and preferentially located in the part of plaque

  10. Lipoprotein(a) Promotes Smooth Muscle Cell Proliferation and Dedifferentiation in Atherosclerotic Lesions of Human Apo(a) Transgenic Rabbits

    PubMed Central

    Ichikawa, Tomonaga; Unoki, Hiroyuki; Sun, Huijun; Shimoyamada, Hiroaki; Marcovina, Santica; Shikama, Hisataka; Watanabe, Teruo; Fan, Jianglin

    2002-01-01

    Elevated plasma lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the mechanism underlying Lp(a) atherogenicity is unclear. Recently, we demonstrated that Lp(a) may potentially be proatherogenic in transgenic rabbits expressing human apolipoprotein(a) [apo(a)]. In this study, we further investigated atherosclerotic lesions of transgenic rabbits by morphometry and immunohistochemistry. On a cholesterol diet, human apo(a) transgenic rabbits had more extensive atherosclerotic lesions of the aorta, carotid artery, iliac artery, and coronary artery than did nontransgenic littermate rabbits as defined by increased intimal lesion area. Enhanced lesion development in transgenic rabbits was characterized by increased accumulation of smooth muscle cells, that was often associated with the Lp(a) deposition. To explore the possibility that Lp(a) may be involved in the smooth-muscle cell phenotypic modulation, we stained the lesions using a panel of monoclonal antibodies against smooth-muscle myosin heavy-chain isoforms (SM1, SM2, and SMemb) and basic transcriptional element binding protein-2 (BTEB2). We found that a large number of smooth muscle cells located in the apo(a)-containing areas of transgenic rabbits were positive for SMemb and BTEB2, suggesting that these smooth muscle cells were either immature or in the state of activation. In addition, transgenic rabbits showed delayed fibrinolytic activity accompanied by increased plasma plasminogen activator inhibitor-1. We conclude that Lp(a) may enhance the lesion development by mediating smooth muscle cell proliferation and dedifferentiation possibly because of impaired fibrinolytic activity. PMID:11786416

  11. Layer-specific damage experiments and modeling of human thoracic and abdominal aortas with non-atherosclerotic intimal thickening.

    PubMed

    Weisbecker, Hannah; Pierce, David M; Regitnig, Peter; Holzapfel, Gerhard A

    2012-08-01

    Many treatments for cardiovascular diseases include an endovascular insertion of stents or stent grafts into arteries, a procedure which may cause high tissue stresses and even damage in the arterial wall. In order to study such problems by using finite element methods, both appropriate constitutive models and experimental data on human tissue samples are required. Layer-specific experimental data for human tissue tested up to the supra-physiological loading range are rare in the literature. In this study, intact and layer-separated experimental data from uniaxial extension tests are presented for human thoracic and abdominal aortas with non-atherosclerotic intimal thickening undergoing supra-physiological loading. A novel pseudo-elastic damage model, proposed to describe discontinuous softening in aortic arterial tissues, is fit to the obtained experimental data. Fitting of the model with and without consideration of damage accumulation in the non-collagenous matrix material reveals that tissue damage is primarily related to the collagen fiber fabric. By employing the fit model, the effect of aortic tissue pre-conditioning on the material parameters from the resulting data fits is evaluated. Histological examination of the collagen fibers under different applied stretches is used to gain more insights into the structural changes of the tissue under supra-physiological loading.

  12. Non-invasive assessment of atherosclerotic plaques effects on the segment-to-segment human carotid visco-elasticity and filtering.

    PubMed

    Bia, D; Pessana, F; Forcada, P; Zócalo, Y; Kotliar, C; Armentano, R L

    2010-01-01

    Although a variety of factors have been proposed as key factors of the atherosclerotic plaque vulnerability, the mechanisms that contribute to this problem are not yet fully characterized. In previous works we demonstrated that changes in arterial wall viscosity and elasticity and/or in the filtering function (FF) could be in the basis of arterial wall alterations. If these properties are altered in arterial wall with atherosclerotic plaques remain to be analyzed. Our aims were to analyze, the arterial wall visco-elasticity and FF of human carotid arteries with atherosclerotic plaques. To this end, instantaneous arterial diameter waveforms were obtained non-invasively (B-Mode Echography), in five sites (S1-S5) on the carotid artery. After that, diameter waveform obtained in S1 (first segment of the common carotid artery) was calibrated using pressure values, and used to quantify the pressure-diameter relationship for each segment. From pressure-diameter relationships, viscosity, elasticity and FF were quantified. Central portions of atherosclerotic plaques showed a reduced FF. At least in theoretical terms, the FF reduction could be related with the plaque vulnerability.

  13. Ultrastructure of the human aortic fibrolipid lesion. Formation of the atherosclerotic lipid-rich core.

    PubMed Central

    Bocan, T. M.; Schifani, T. A.; Guyton, J. R.

    1986-01-01

    The formation of the atherosclerotic lipid-rich core has been elucidated by electron microscopy of the core region in small, raised fibrolipid lesions. The relationship among lipid deposits, extracellular matrix, and cells found in distinct regions of the fibrolipid lesion was examined. Extracellular lipid droplets, verified by osmium-thiocarbohydrazide-osmium staining, made up approximately 40% of the lipid-rich core volume. The lipid droplets were often found distinctly associated with elastin and/or collagen; these associations were dependent upon the location examined within or near the lipid-rich core. Within areas of intense extracellular lipid deposits, crystalline clefts suggesting cholesterol monohydrate were observed. Stereologic analysis of the lipid-rich core components revealed marked reductions in the volume fractions of cells, reticular ground substance, and basement membrane; while the extent of extracellular lipid increased 7-10-fold. Eleven percent or less of lipid in the core region was found within cells, usually smooth muscle cells. Above the core region in the lesion cap, monocyte-macrophage foam cells were prominent. Cellular lipid droplets were much larger (profile diameters sixfold higher) than extracellular droplets. With these data as well as transitional morphologic features at the boundaries of the core region, it is suggested that the abundant extracellular lipid does not derive from cell necrosis, and lipid deposition in association with extracellular matrix constituents is an early event in the development of the lipid-rich core. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:3717297

  14. A Combination of Constitutive Damage Model and Artificial Neural Networks to Characterize the Mechanical Properties of the Healthy and Atherosclerotic Human Coronary Arteries.

    PubMed

    Karimi, Alireza; Rahmati, Seyed Mohammadali; Sera, Toshihiro; Kudo, Susumu; Navidbakhsh, Mahdi

    2017-02-02

    It has been indicated that the content and structure of the elastin and collagen of the arterial wall can subject to a significant alteration due to the atherosclerosis. Consequently, a high tissue stiffness, stress, and even damage/rupture are triggered in the arterial wall. Although many studies so far have been conducted to quantify the mechanical properties of the coronary arteries, none of them consider the role of collagen damage of the healthy and atherosclerotic human coronary arterial walls. Recently, a fiber family-based constitutive equation was proposed to capture the anisotropic mechanical response of the healthy and atherosclerotic human coronary arteries via both the histostructural and uniaxial data. In this study, experimental mechanical measurements along with histological data of the healthy and atherosclerotic arterial walls were employed to determine the constitutive damage parameters and remodeling of the collagen fibers. To do this, the preconditioned arterial tissues were excised from human cadavers within 5-h postmortem, and the mean angle of their collagen fibers was precisely determined. Thereafter, a group of quasistatic axial and circumferential loadings were applied to the arterial walls, and the constrained nonlinear minimization method was employed to identify the arterial parameters according to the axial and circumferential extension data. The remodeling of the collagen fibers during the tensile test was also predicted via Artificial Neural Networks algorithm. Regardless of loading direction, the results presented a noteworthy load-bearing capability and stiffness of the atherosclerotic arteries compared to the healthy ones (P < 0.005). Theoretical fiber angles were found to be consistent with the experimental histological data with less than 2 and 5° difference for the healthy and atherosclerotic arterial walls, respectively. The pseudoelastic damage model data were also compared with that of the experimental data, and

  15. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries.

    PubMed Central

    Riessen, R.; Isner, J. M.; Blessing, E.; Loushin, C.; Nikol, S.; Wight, T. N.

    1994-01-01

    Proteoglycans are important constituents of blood vessels and accumulate in various forms of vascular disease. Little is known concerning the proteoglycan composition of restenotic lesions formed after angioplasty and whether the proteoglycan composition of these lesions differs from that of primary atherosclerosis. Accordingly, we sought to characterize the distribution of two proteoglycans, biglycan and decorin, in primary atherosclerotic and restenotic lesions of human coronary arteries. Restenosis (n = 37) and primary (n = 11) lesions obtained from 48 patients by directional atherectomy of human coronary arteries were stained with antibodies against biglycan and decorin. To further characterize the extracellular matrix of restenotic tissues, we studied the co-distribution of these proteoglycans with collagen types I, III, and IV. The loose fibroproliferative tissue seen predominantly in restenosis lesions consistently stained positively for biglycan in patterns of deposition ranging from disseminated to homogeneous. The density and intensity of biglycan staining was correlated with the density of collagen type I and III fiber networks, both of which were observed to interweave among the loose fibroproliferative tissue. The compact connective tissue of primary atherosclerotic plaque was characterized by strong biglycan staining which co-localized with intense collagen type I and III staining. Only basement membrane-like structures rich in collagen type IV demonstrated negative biglycan staining. In contrast, loose fibroproliferative tissue exhibited no significant staining for decorin. Strong immunostaining for decorin, however, was found in primary atherosclerotic plaque. There are thus regional differences in the distribution of extracellular matrix proteoglycans of restenotic and primary human atherosclerotic lesions; these observations suggest that differences established for the biological roles of biglycan and decorin in other organ systems may extend as

  16. 3D MRI-based anisotropic FSI models with cyclic bending for human coronary atherosclerotic plaque mechanical analysis.

    PubMed

    Tang, Dalin; Yang, Chun; Kobayashi, Shunichi; Zheng, Jie; Woodard, Pamela K; Teng, Zhongzhao; Billiar, Kristen; Bach, Richard; Ku, David N

    2009-06-01

    Heart attack and stroke are often caused by atherosclerotic plaque rupture, which happens without warning most of the time. Magnetic resonance imaging (MRI)-based atherosclerotic plaque models with fluid-structure interactions (FSIs) have been introduced to perform flow and stress/strain analysis and identify possible mechanical and morphological indices for accurate plaque vulnerability assessment. For coronary arteries, cyclic bending associated with heart motion and anisotropy of the vessel walls may have significant influence on flow and stress/strain distributions in the plaque. FSI models with cyclic bending and anisotropic vessel properties for coronary plaques are lacking in the current literature. In this paper, cyclic bending and anisotropic vessel properties were added to 3D FSI coronary plaque models so that the models would be more realistic for more accurate computational flow and stress/strain predictions. Six computational models using one ex vivo MRI human coronary plaque specimen data were constructed to assess the effects of cyclic bending, anisotropic vessel properties, pulsating pressure, plaque structure, and axial stretch on plaque stress/strain distributions. Our results indicate that cyclic bending and anisotropic properties may cause 50-800% increase in maximum principal stress (Stress-P1) values at selected locations. The stress increase varies with location and is higher when bending is coupled with axial stretch, nonsmooth plaque structure, and resonant pressure conditions (zero phase angle shift). Effects of cyclic bending on flow behaviors are more modest (9.8% decrease in maximum velocity, 2.5% decrease in flow rate, 15% increase in maximum flow shear stress). Inclusion of cyclic bending, anisotropic vessel material properties, accurate plaque structure, and axial stretch in computational FSI models should lead to a considerable improvement of accuracy of computational stress/strain predictions for coronary plaque vulnerability

  17. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques.

    PubMed Central

    Giachelli, C M; Bae, N; Almeida, M; Denhardt, D T; Alpers, C E; Schwartz, S M

    1993-01-01

    In an earlier report, we used differential cloning to identify genes that might be critical in controlling arterial neointima formation (Giachelli, C., N. Bae, D. Lombardi, M. Majesky, and S. Schwartz. 1991. Biochem. Biophys. Res. Commun. 177:867-873). In this study, we sequenced the complete cDNA and conclusively identified one of these genes, 2B7, as rat osteopontin. Using immunochemistry and in situ hybridization, we found that medial smooth muscle cells (SMC) in uninjured arteries contained very low levels of osteopontin protein and mRNA. Injury to either the adult rat aorta or carotid artery using a balloon catheter initiated a qualitatively similar time-dependent increase in both osteopontin protein and mRNA in arterial SMC. Expression was transient and highly localized to neointimal SMC during the proliferative and migratory phases of arterial injury, suggesting a possible role for osteopontin in these processes. In vitro, basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and angiotensin II (AII), all proteins implicated in the rat arterial injury response, elevated osteopontin expression in confluent vascular SMC. Finally, we found that osteopontin was a novel component of the human atherosclerotic plaque found most strikingly associated with calcified deposits. These data implicate osteopontin as a potentially important mediator of arterial neointima formation as well as dystrophic calcification that often accompanies this process. Images PMID:8408622

  18. In vitro angioplasty of atherosclerotic human femoral arteries: analysis of the geometrical changes in the individual tissues using MRI and image processing.

    PubMed

    Auer, Martin; Stollberger, Rudolf; Regitnig, Peter; Ebner, Franz; Holzapfel, Gerhard A

    2010-04-01

    Existing atherosclerotic plaque imaging techniques such as intravascular ultrasound, multidetector computed tomography, optical coherence tomography, and high-resolution magnetic resonance imaging (hrMRI) require computerized methods to separate and analyze the plaque morphology. In this work, we perform in vitro balloon angioplasty experiments with 10 human femoral arteries using hrMRI and image processing. The vessel segments contain low-grade to high-grade lesions with very different plaque compositions. The experiments are designed to mimic the in vivo situation. We use a semi-automatic image processing tool to extract the three-dimensional (3D) geometries of the tissue components at four characteristic stages of the angioplasty procedure. The obtained geometries are then used to determine geometrical and mechanical indices in order to characterize, classify, and analyze the atherosclerotic plaques by their specific geometrical changes. During inflation, three vessels ruptured via helical crack propagation. The adventitia, media, and intima did not preserve their area/volume during inflation; the area changes of the lipid pool during inflation were significant. The characterization of changes in individual 3D tissue geometries, together with tissue-specific mechanical properties, may serve as a basis for refined finite element (FE) modeling, which is key to better understand stress evolution in various atherosclerotic plaque configurations.

  19. Phenotypic alterations in human saphenous vein culture induced by tumor necrosis factor-alpha and lipoproteins: a preliminary development of an initial atherosclerotic plaque model

    PubMed Central

    2013-01-01

    Background Atherosclerosis is a chronic progressive inflammatory disease of blood vessels particularly the arteries. The development of atherosclerotic plaques or atherogenesis is a complex process that is influenced by cardiovascular risk factors such as vascular inflammation and dyslipidemia. This study demonstrates the ability of tumor necrosis factor-alpha (TNF-α) and low density lipoproteins (LDL) to induce atherosclerotic plaque in human saphenous vein (HSV) organ culture. Methods Normal HSV segments, from male patients who had coronary bypass graft, were cultured in DMEM containing 5% heat inactivated fetal bovine serum. TNF-α (5 ng/ml) was applied in combination with native LDL (nLDL) or oxidized LDL (oxLDL) at the dose of 50 μg/ml for 14 days. The phenotypic changes of the organ cultures characteristic of initial atherosclerotic plaques were evaluated. The effect of anti-atherogenic agent, 17-β estradiol (E2), was also determined. Results Histologic, histomorphometric, and immunohistochemical examinations revealed that HSV rings stimulated with TNF-α + nLDL or TNF-α + oxLDL can exhibit the essential morphological features of atherogenesis, including fibrous cap formation, cholesterol clefts, evident thickening of the intimal layer, increased proliferation of smooth muscle cells (SMC) and migration to the subendothelial layer, significant SMC foam cell formation, and increased expression of adhesion molecules in the vascular wall. Addition of E2 (50 nM) to the culture significantly modulated the critical changes. Consistently, mRNA profiling of the HSV model revealed that 50 of 84 genes of atherosclerosis were up-regulated. Conclusions Phenotypic changes characteristic of the initial development of atherosclerotic plaques can be induced in HSV organ culture. PMID:24010774

  20. Uptake by mouse peritoneal macrophages of large cholesteryl ester-rich particles isolated from human atherosclerotic lesions.

    PubMed

    Hoff, H F; Clevidence, B A

    1987-06-01

    We have previously shown that a lipoprotein fraction consisting of large cholesteryl ester-rich particles can be isolated from homogenates of human aortic plaques by gel exclusion chromatography. This fraction was recognized by a high-affinity binding site on mouse peritoneal macrophages (MPM) resulting in unregulated uptake, stimulation of cholesterol esterification, and massive accumulation of cholesteryl esters. In this report we have further characterized such a fraction, designated lipid-protein complex (LP), which can be isolated from the void volume fraction of a Bio-Gel A-150m column following chromatography of plaque extracts. LP possessed a mean cholesterol-to-protein ratio of 2.3; it was heterogeneous in size and structure as observed by electron microscopy after negative staining, and it stimulated cholesterol esterification in MPM in a linear fashion over a 48-hr time interval, suggesting that the binding site on MPM recognizing LP was not down-regulated by intracellular cholesterol content. This uptake resulted in the presence of oil red O-positive intracellular droplets and numerous vacuoles containing electron-dense structures, whereas MPM incubated without lipoprotein showed few vacuoles or lipid droplets. Using SDS-PAGE and immunoblot and dot-blot techniques, we found that the major proteins associated with LP were albumin and fibronectin, whereas apoB and apoE were present in lower amounts. These proteins may be responsible for opsonization of LP, making it recognizable to receptors on MPM and facilitating LP uptake by MPM. LP isolated from tissue extracts without homogenization had the same structural and functional characteristics, suggesting that homogenization per se was not responsible for creating a particle that was recognized by MPM. However, homogenization yielded two to three times more LP. MPM uptake of LP derived from lysed foam cells may represent one of the mechanisms by which fatty streak lesions may grow to larger atherosclerotic

  1. Detection of Human Cytomegalovirus and Epstein-Barr Virus in Coronary Atherosclerotic Tissue

    PubMed Central

    Imbronito, Ana Vitória; Marcelino, Silvia Linardi; Grande, Sabrina Rosa; Nunes, Fabio Daumas; Romito, Giuseppe Alexandre

    2010-01-01

    Previous studies indicated that patients with atherosclerosis are predominantly infected by human cytomegalovirus (HCMV), but rarely infected by type 1 Epstein-Barr virus (EBV-1). In this study, atheromas of 30 patients who underwent aortocoronary bypass surgery with coronary endartherectomy were tested for the presence of these two viruses. HCMV occurred in 93.3% of the samples and EBV-1 was present in 50% of them. Concurrent presence of both pathogens was detected in 43.3% of the samples. PMID:24031529

  2. Comparing Raman and fluorescence lifetime spectroscopy from human atherosclerotic lesions using a bimodal probe.

    PubMed

    Dochow, Sebastian; Fatakdawala, Hussain; Phipps, Jennifer E; Ma, Dinglong; Bocklitz, Thomas; Schmitt, Michael; Bishop, John W; Margulies, Kenneth B; Marcu, Laura; Popp, Jürgen

    2016-09-01

    Fluorescence lifetime imaging (FLIm) and Raman spectroscopy are two promising methods to support morphological intravascular imaging techniques with chemical contrast. Both approaches are complementary and may also be used in combination with OCT/IVUS to add chemical specificity to these morphologic intravascular imaging modalities. In this contribution, both modalities were simultaneously acquired from two human coronary specimens using a bimodal probe. A previously trained SVM model was used to interpret the fluorescence lifetime data; integrated band intensities displayed in RGB false color images were used to interpret the Raman data. Both modalities demonstrate unique strengths and weaknesses and these will be discussed in comparison to histologic analyses from the two coronary arteries imaged.

  3. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

    PubMed Central

    Shanahan, C M; Cary, N R; Metcalfe, J C; Weissberg, P L

    1994-01-01

    Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability. Images PMID:8200973

  4. Characterising human atherosclerotic carotid plaque tissue composition and morphology using combined spectroscopic and imaging modalities

    PubMed Central

    2015-01-01

    Calcification is a marked pathological component in carotid artery plaque. Studies have suggested that calcification may induce regions of high stress concentrations therefore increasing the potential for rupture. However, the mechanical behaviour of the plaque under the influence of calcification is not fully understood. A method of accurately characterising the calcification coupled with the associated mechanical plaque properties is needed to better understand the impact of calcification on the mechanical behaviour of the plaque during minimally invasive treatments. This study proposes a comparison of biochemical and structural characterisation methods of the calcification in carotid plaque specimens to identify plaque mechanical behaviour. Biochemical analysis, by Fourier Transform Infrared (FTIR) spectroscopy, was used to identify the key components, including calcification, in each plaque sample. However, FTIR has a finite penetration depth which may limit the accuracy of the calcification measurement. Therefore, this FTIR analysis was coupled with the identification of the calcification inclusions located internally in the plaque specimen using micro x-ray computed tomography (μX-CT) which measures the calcification volume fraction (CVF) to total tissue content. The tissue characterisation processes were then applied to the mechanical material plaque properties acquired from experimental circumferential loading of human carotid plaque specimen for comparison of the methods. FTIR characterised the degree of plaque progression by identifying the functional groups associated with lipid, collagen and calcification in each specimen. This identified a negative relationship between stiffness and 'lipid to collagen' and 'calcification to collagen' ratios. However, μX-CT results suggest that CVF measurements relate to overall mechanical stiffness, while peak circumferential strength values may be dependent on specific calcification geometries. This study

  5. Reduced Necrosis and Content of Apoptotic M1 Macrophages in Advanced Atherosclerotic Plaques of Mice With Macrophage-Specific Loss of Trpc3

    PubMed Central

    Solanki, Sumeet; Dube, Prabhatchandra R.; Birnbaumer, Lutz; Vazquez, Guillermo

    2017-01-01

    In previous work we reported that ApoeKO mice transplanted with bone marrow cells deficient in the Transient Receptor Potential Canonical 3 (TRPC3) channel have reduced necrosis and number of apoptotic macrophages in advanced atherosclerotic plaques. Also, in vitro studies with polarized macrophages derived from mice with macrophage-specific loss of TRPC3 showed that M1, but not M2 macrophages, deficient in Trpc3 are less susceptible to ER stress-induced apoptosis than Trpc3 expressing cells. The questions remained (a) whether the plaque phenotype in transplanted mice resulted from a genuine effect of Trpc3 on macrophages, and (b) whether the reduced necrosis and macrophage apoptosis in plaques of these mice was a manifestation of the selective effect of TRPC3 on apoptosis of M1 macrophages previously observed in vitro. Here, we addressed these questions using Ldlr knockout (Ldlr−/−) mice with macrophage-specific loss of Trpc3 (MacTrpc3−/−/Ldlr−/− → Ldlr−/−). Compared to controls, we observed decreased plaque necrosis and number of apoptotic macrophages in MacTrpc3−/−/Ldlr−/− → Ldlr−/− mice. Immunohistochemical analysis revealed a reduction in apoptotic M1, but not apoptotic M2 macrophages. These findings confirm an effect of TRPC3 on plaque necrosis and support the notion that this is likely a reflection of the reduced susceptibility of Trpc3-deficient M1 macrophages to apoptosis. PMID:28186192

  6. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta.

    PubMed Central

    Bossaller, C; Habib, G B; Yamamoto, H; Williams, C; Wells, S; Henry, P D

    1987-01-01

    The dependence of vascular relaxation on an intact endothelium and the relationship between relaxation and cyclic GMP accumulation were determined in coronary arteries isolated from cardiac transplantation patients with or without coronary atherosclerosis. In nonatherosclerotic arteries, the endothelium-dependent agent acetylcholine produced concentration-related relaxations. In atherosclerotic arteries, endothelium-dependent relaxations were abolished with acetylcholine, partly suppressed with substance P and histamine, and completely preserved with the ionophore A23187. In these arteries, the endothelium-independent agent nitroglycerin remained fully active. Accumulation of cyclic GMP in atherosclerotic strips was suppressed with acetylcholine but unattenuated with A23187 and nitroglycerin. In aortas from rabbits with diet-induced atherosclerosis, there was likewise an impaired cholinergic relaxation and cyclic GMP accumulation in the presence of preserved responses to A23187 and nitroglycerin. The results demonstrate that impaired cholinergic responses in atherosclerotic arteries reflect a muscarinic defect and not an inability of endothelium to release endothelial factor or smooth muscle to respond to it. PMID:2432088

  7. In Vivo/Ex Vivo MRI-Based 3D Non-Newtonian FSI Models for Human Atherosclerotic Plaques Compared with Fluid/Wall-Only Models.

    PubMed

    Yang, Chun; Tang, Dalin; Yuan, Chun; Hatsukami, Thomas S; Zheng, Jie; Woodard, Pamela K

    2007-01-01

    It has been recognized that fluid-structure interactions (FSI) play an important role in cardiovascular disease initiation and development. However, in vivo MRI multi-component FSI models for human carotid atherosclerotic plaques with bifurcation and quantitative comparisons of FSI models with fluid-only or structure-only models are currently lacking in the literature. A 3D non-Newtonian multi-component FSI model based on in vivo/ex vivo MRI images for human atherosclerotic plaques was introduced to investigate flow and plaque stress/strain behaviors which may be related to plaque progression and rupture. Both artery wall and plaque components were assumed to be hyperelastic, isotropic, incompressible and homogeneous. Blood flow was assumed to be laminar, non-Newtonian, viscous and incompressible. In vivo/ex vivo MRI images were acquired using histologically-validated multi-spectral MRI protocols. The 3D FSI models were solved and results were compared with those from a Newtonian FSI model and wall-only/fluid-only models. A 145% difference in maximum principal stresses (Stress-P(1)) between the FSI and wall-only models and 40% difference in flow maximum shear stress (MSS) between the FSI and fluid-only models were found at the throat of the plaque using a severe plaque sample (70% severity by diameter). Flow maximum shear stress (MSS) from the rigid wall model is much higher (20-40% in maximum MSS values, 100-150% in stagnation region) than those from FSI models.

  8. Propionibacterium acnes Recovered from Atherosclerotic Human Carotid Arteries Undergoes Biofilm Dispersion and Releases Lipolytic and Proteolytic Enzymes in Response to Norepinephrine Challenge In Vitro

    PubMed Central

    Lanter, Bernard B.

    2015-01-01

    In the present study, human atherosclerotic carotid arteries were examined following endarterectomy for the presence of the Gram-positive bacterium Propionibacterium acnes and its potential association with biofilm structures within the arterial wall. The P. acnes 16S rRNA gene was detectable in 4 of 15 carotid artery samples, and viable P. acnes was one among 10 different bacterial species recoverable in culture. Fluorescence in situ hybridization analysis of 5 additional atherosclerotic carotid arteries demonstrated biofilm bacteria within all samples, with P. acnes detectable in 4 samples. We also demonstrated that laboratory-grown cultures of P. acnes biofilms were susceptible to induction of a biofilm dispersion response when challenged with physiologically relevant levels of norepinephrine in the presence of iron-bound transferrin or with free iron. The production and release of lipolytic and proteolytic extracellular enzymes by P. acnes were shown to increase in iron-induced dispersed biofilms, and these dispersion-induced P. acnes VP1 biofilms showed increased expression of mRNAs for the triacylglycerol lipases PPA2105 and PPA1796 and the hyaluronate lyase PPA380 compared to that in untreated biofilms. These results demonstrate that P. acnes can infect the carotid arteries of humans with atherosclerosis as a component of multispecies biofilms and that dispersion is inducible for this organism, at least in vitro, with physiologically relevant levels of norepinephrine resulting in the production and release of degradative enzymes. PMID:26216428

  9. The influence of constitutive law choice used to characterise atherosclerotic tissue material properties on computing stress values in human carotid plaques.

    PubMed

    Teng, Zhongzhao; Yuan, Jianmin; Feng, Jiaxuan; Zhang, Yongxue; Brown, Adam J; Wang, Shuo; Lu, Qingsheng; Gillard, Jonathan H

    2015-11-05

    Calculating high stress concentration within carotid atherosclerotic plaques has been shown to be complementary to anatomical features in assessing vulnerability. Reliability of stress calculation may depend on the constitutive laws/strain energy density functions (SEDFs) used to characterize tissue material properties. Different SEDFs, including neo-Hookean, one-/two-term Ogden, Yeoh, 5-parameter Mooney-Rivlin, Demiray and modified Mooney-Rivlin, have been used to describe atherosclerotic tissue behavior. However, the capacity of SEDFs to fit experimental data and the difference in the stress calculation remains unexplored. In this study, seven SEDFs were used to fit the stress-stretch data points of media, fibrous cap, lipid and intraplaque hemorrhage/thrombus obtained from 21 human carotid plaques. Semi-analytic solution, 2D structure-only and 3D fully coupled fluid-structure interaction (FSI) analyses were used to quantify stress using different SEDFs and the related material stability examined. Results show that, except for neo-Hookean, all other six SEDFs fitted the experimental points well, with vessel stress distribution in the circumferential and radial directions being similar. 2D structural-only analysis was successful for all seven SEDFs, but 3D FSI were only possible with neo-Hookean, Demiray and modified Mooney-Rivlin models. Stresses calculated using Demiray and modified Mooney-Rivlin models were nearly identical. Further analyses indicated that the energy contours of one-/two-term Ogden and 5-parameter Mooney-Rivlin models were not strictly convex and the material stability indictors under homogeneous deformations were not always positive. In conclusion, considering the capacity in characterizing material properties and stabilities, Demiray and modified Mooney-Rivlin SEDF appear practical choices for mechanical analyses to predict the critical mechanical conditions within carotid atherosclerotic plaques.

  10. Active macrophage-associated TGF-beta co-localizes with type I procollagen gene expression in atherosclerotic human pulmonary arteries.

    PubMed Central

    Bahadori, L.; Milder, J.; Gold, L.; Botney, M.

    1995-01-01

    Vascular remodeling in adult atherosclerotic pulmonary arteries is characterized by discrete areas of neointimal smooth muscle cell extracellular matrix gene expression in close proximity to non-foamy macrophages, suggesting regulation by local macrophage-associated factors. The purpose of these studies was to begin addressing the role of putative macrophage-associated factors such as transforming growth factor-beta (TGF-beta), by determining the spatial relationship between TGF-beta and neointimal matrix gene expression in human atherosclerotic pulmonary arteries. For example, the participation of TGF-beta in vascular remodeling could be inferred by its colocalization with non-foamy macrophages in areas of active matrix synthesis. In situ hybridization and immunohistochemistry demonstrated focal neointimal procollagen gene expression in close association with non-foamy but not foamy macrophages. Immunohistochemistry with isoform-specific anti-TGF-beta antibodies demonstrated all three isoforms of TGF-beta associated with non-foamy macrophages, but foamy macrophages were not immunoreactive. Neointimal and medial smooth muscle cells stained lightly. In contrast, intense TGF-beta immunoreactivity was also associated with medial smooth muscle cells in normal nonremodeling vessels. Immunohistochemistry with antibodies specific for latent TGF-beta was similar to immunohistochemistry for mature TGF-beta in both remodeling and nonremodeling vessels. Finally, using an antibody specific for active TGF-beta 1, immunoreactivity was only seen in non-foamy neointimal macrophages but not in foamy macrophages or medial smooth muscle cells from hypertensive or normal vessels. These observations suggest non-foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-beta-dependent mechanism. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7747808

  11. The influence of constitutive law choice used to characterise atherosclerotic tissue material properties on computing stress values in human carotid plaques

    PubMed Central

    Teng, Zhongzhao; Yuan, Jianmin; Feng, Jiaxuan; Zhang, Yongxue; Brown, Adam J.; Wang, Shuo; Lu, Qingsheng; Gillard, Jonathan H.

    2015-01-01

    Calculating high stress concentration within carotid atherosclerotic plaques has been shown to be complementary to anatomical features in assessing vulnerability. Reliability of stress calculation may depend on the constitutive laws/strain energy density functions (SEDFs) used to characterize tissue material properties. Different SEDFs, including neo-Hookean, one-/two-term Ogden, Yeoh, 5-parameter Mooney–Rivlin, Demiray and modified Mooney–Rivlin, have been used to describe atherosclerotic tissue behavior. However, the capacity of SEDFs to fit experimental data and the difference in the stress calculation remains unexplored. In this study, seven SEDFs were used to fit the stress–stretch data points of media, fibrous cap, lipid and intraplaque hemorrhage/thrombus obtained from 21 human carotid plaques. Semi-analytic solution, 2D structure-only and 3D fully coupled fluid-structure interaction (FSI) analyses were used to quantify stress using different SEDFs and the related material stability examined. Results show that, except for neo-Hookean, all other six SEDFs fitted the experimental points well, with vessel stress distribution in the circumferential and radial directions being similar. 2D structural-only analysis was successful for all seven SEDFs, but 3D FSI were only possible with neo-Hookean, Demiray and modified Mooney–Rivlin models. Stresses calculated using Demiray and modified Mooney–Rivlin models were nearly identical. Further analyses indicated that the energy contours of one-/two-term Ogden and 5-parameter Mooney–Rivlin models were not strictly convex and the material stability indictors under homogeneous deformations were not always positive. In conclusion, considering the capacity in characterizing material properties and stabilities, Demiray and modified Mooney–Rivlin SEDF appear practical choices for mechanical analyses to predict the critical mechanical conditions within carotid atherosclerotic plaques. PMID:26472305

  12. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.

    PubMed

    Siess, W; Zangl, K J; Essler, M; Bauer, M; Brandl, R; Corrinth, C; Bittman, R; Tigyi, G; Aepfelbacher, M

    1999-06-08

    Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis of atherosclerosis and its thrombotic complications, such as stroke and myocardial infarction. It activates endothelial cells and platelets through mechanisms that are largely unknown. Here, we show that lysophosphatidic acid (LPA) was formed during mild oxidation of LDL and was the active compound in mildly oxidized LDL and minimally modified LDL, initiating platelet activation and stimulating endothelial cell stress-fiber and gap formation. Antagonists of the LPA receptor prevented platelet and endothelial cell activation by mildly oxidized LDL. We also found that LPA accumulated in and was the primary platelet-activating lipid of atherosclerotic plaques. Notably, the amount of LPA within the human carotid atherosclerotic lesion was highest in the lipid-rich core, the region most thrombogenic and most prone to rupture. Given the potent biological activity of LPA on platelets and on cells of the vessel wall, our study identifies LPA as an atherothrombogenic molecule and suggests a possible strategy to prevent and treat atherosclerosis and cardiocerebrovascular diseases.

  13. Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3.

    PubMed Central

    Printseva OYu; Peclo, M. M.; Gown, A. M.

    1992-01-01

    The specificity of monoclonal antibody 10F3, generated to smooth muscle cells isolated from fetal human aorta, has been further explored in a series of biological, biochemical, and immunocytochemical studies. In the first assay, it was found that 10F3 could inhibit aggregation of phytohemagglutinin (PHA)-induced lymphocytes in a manner comparable to that of antibody RR1/1, an anti-intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody. In immunoprecipitation experiments followed by one-dimensional gel electrophoresis, both 10F3 and RR1/1 immunoprecipitated 90 kd proteins, with results suggesting that the two antibodies recognized different epitopes of the same molecule. A series of immunocytochemical studies on human atherosclerotic lesions was performed; using single-labeling techniques, 10F3-positive cells were found in the vessel wall and in lesions of virtually all specimens of fatty streaks and fibrous plaques. Using double-labeling techniques, 10F3-positive macrophages and 10F3-positive smooth muscle cells were found; however, there were also a significant number of non-smooth muscle, nonmacrophage 10F3-positive cells. These studies demonstrate that 10F3 identifies ICAM-1, and that this protein is expressed on a variety of cell types in human atherosclerotic lesions. ICAM-1 may represent a developmentally regulated protein that is expressed in fetal but not adult mesenchymal cells, but can be re-expressed in pathologic processes such as atherosclerosis. Images Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1348606

  14. Atherosclerotic Lesion Progression Changes Lysophosphatidic Acid Homeostasis to Favor its Accumulation

    PubMed Central

    Bot, Martine; Bot, Ilze; Lopez-Vales, Rubén; van de Lest, Chris H.A.; Saulnier-Blache, Jean Sébastien; Helms, J. Bernd; David, Samuel; van Berkel, Theo J.C.; Biessen, Erik A.L.

    2010-01-01

    Lysophosphatidic acid (LPA) accumulates in the central atheroma of human atherosclerotic plaques and is the primary platelet-activating lipid constituent of plaques. Here, we investigated the enzymatic regulation of LPA homeostasis in atherosclerotic lesions at various stages of disease progression. Atherosclerotic lesions were induced in carotid arteries of low-density lipoprotein receptor–deficient mice by semiconstrictive collar placement. At 2-week intervals after collar placement, lipids and RNA were extracted from the vessel segments carrying the plaque. Enzymatic-and liquid chromatography-mass spectrometry–based lipid profiling revealed progressive accumulation of LPA species in atherosclerotic tissue preceded by an increase in lysophosphatidylcholine, a precursor in LPA synthesis. Plaque expression of LPA-generating enzymes cytoplasmic phospholipase A2IVA (cPLA2IVA) and calcium-independent PLA2VIA (iPLA2VIA) was gradually increased, whereas that of the LPA-hydrolyzing enzyme LPA acyltransferase α was quenched. Increased expression of cPLA2IVA and iPLA2VIA in advanced lesions was confirmed by immunohistochemistry. Moreover, LPA receptors 1 and 2 were 50% decreased and sevenfold upregulated, respectively. Therefore, key proteins in LPA homeostasis are increasingly dysregulated in the plaque during atherogenesis, favoring intracellular LPA production. This might at least partly explain the observed progressive accumulation of this thrombogenic proinflammatory lipid in human and mouse plaques. Thus, intervention in the enzymatic LPA production may be an attractive measure to lower intraplaque LPA content, thereby reducing plaque progression and thrombogenicity. PMID:20431029

  15. A method to compensate for the underestimation of collagen with polarized picrosirius red imaging in human artery atherosclerotic plaques

    NASA Astrophysics Data System (ADS)

    Greiner, C. A.; Grainger, S. J.; Su, J. L.; Madden, S. P.; Muller, J. E.

    2016-04-01

    Although picrosirius red (PSR) is known to be in quantifying collagen under polarized light (PL), commonly used linearly PL can result in an underestimation of collagen, as some of the fibers may appear dark if aligned with the transmission axis of the polarizers. To address this, a sample may be imaged with circularly polarized light at the expense of higher background intensity. However, the quality and alignment of the microscope illumination optics, polarizers and waveplates can still produce imaging variability with circular polarization. A simpler technique was tested that minimized variability and background intensity with linear polarization by acquiring images at multiple angles of histology slide rotation to create a composite co-registered image, permitting the optimal semi-quantitative visualization of collagen. Linear polarization imaging was performed on PSR stained artery sections. By rotating the slide at 60° intervals while maintaining illumination, polarization and exposure parameters, 6 images were acquired for each section. A composite image was created from the 6 co-registered images, and comprised of the maximum pixel intensity at each point. Images from any of the 6 rotation positions consistently showed variation in PSR signal. A composite image compensates for this variability, without loss of spatial resolution. Additionally, grayscale analysis showed an increased intensity range of 15 - 50% with a linearly polarized composite image over a circularly polarized image after background correction, indicating better SNR. This proposed technique will be applied in the development of a near infrared spectroscopy algorithm to detect vulnerable atherosclerotic plaques in vivo.

  16. Influence of non-Newtonian Properties of Blood on the Wall Shear Stress in Human Atherosclerotic Right Coronary Arteries

    PubMed Central

    Liu, Biyue; Tang, Dalin

    2011-01-01

    The objective of this work is to investigate the effect of non-Newtonian properties of blood on the wall shear stress (WSS) in atherosclerotic coronary arteries using both Newtonian and non-Newtonian models. Numerical simulations were performed to examine how the spatial and temporal WSS distributions are influenced by the stenosis size, blood viscosity, and flow rate. The computational results demonstrated that blood viscosity properties had considerable effect on the magnitude of the WSS, especially where disturbed flow was observed. The WSS distribution is highly non-uniform both temporally and spatially, especially in the stenotic region. The maximum WSS occurred at the proximal side of the stenosis, near the outer wall in the curved artery with no stenosis. The lumen area near the inner wall distal to the stenosis region experienced a lower WSS during the entire cardiac cycle. Among the factors of stenosis size, blood viscosity, and flow rate, the size of the stenosis has the most significant effect on the spatial and temporal WSS distributions qualitatively and quantitatively. PMID:21379375

  17. Introduction. Teaching Advanced Placement Human Geography.

    ERIC Educational Resources Information Center

    Murphy, Alexander B.

    2000-01-01

    Introduces this special issue of "Journal of Geography" focusing on the teaching of Advanced Placement (AP) human geography. States that essays were developed by members of the AP Human Geography Development Committee focusing on areas in the human geography course outline which are included in the appendix. (CMK)

  18. A framework for the co-registration of hemodynamic forces and atherosclerotic plaque components

    PubMed Central

    Chiu, Bernard; Chen, Huijun; Chen, Yimin; Hatsukami, Thomas S.; Kerwin, William S.; Yuan, Chun

    2013-01-01

    Local hemodynamic forces, such as wall shear stress, are thought to trigger cellular and molecular mechanisms that determine atherosclerotic plaque vulnerability to rupture. Magnetic resonance imaging (MRI) has emerged as a powerful tool to characterize human carotid atherosclerotic plaque composition and morphology, and to identify plaque features shown to be key determinants of plaque vulnerability. Image-based computational fluid dynamics (CFD) has allowed researchers to obtain time-resolved wall shear stress (WSS) information of atherosclerotic carotid arteries. A deeper understanding of the mechanisms of initiation and progression of atherosclerosis can be obtained through the comparison of WSS and plaque composition and morphology. To date, however, advance in knowledge has been limited greatly due to the lack of a reliable infrastructure to perform such analysis. The aim of this study is to establish a framework that will allow for the co-registration and analysis of the three-dimensional (3D) distribution ofWSS and plaque components and morphology. The use of this framework will lead to future studies targeted to determining the role of WSS in atherosclerotic plaque progression and vulnerability. PMID:23945133

  19. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.

    PubMed

    Tang, Jun; Lobatto, Mark E; Hassing, Laurien; van der Staay, Susanne; van Rijs, Sarian M; Calcagno, Claudia; Braza, Mounia S; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L; Duivenvoorden, Raphaël; Sager, Hendrik; Astudillo, Yaritzy M; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P; Strijkers, Gustav J; Stroes, Erik S G; Swirski, Filip K; Nahrendorf, Matthias; Fisher, Edward A; Fayad, Zahi A; Mulder, Willem J M

    2015-04-01

    Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice (Apoe(-/-) ) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

  20. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

    PubMed Central

    Tang, Jun; Lobatto, Mark E.; Hassing, Laurien; van der Staay, Susanne; van Rijs, Sarian M.; Calcagno, Claudia; Braza, Mounia S.; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L.; Duivenvoorden, Raphaël; Sager, Hendrik B.; Astudillo, Yaritzy M.; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P.; Strijkers, Gustav J.; Stroes, Erik S. G.; Swirski, Filip K.; Nahrendorf, Matthias; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

    2015-01-01

    Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis. PMID:26295063

  1. The lipid-rich core region of human atherosclerotic fibrous plaques. Prevalence of small lipid droplets and vesicles by electron microscopy.

    PubMed Central

    Guyton, J. R.; Klemp, K. F.

    1989-01-01

    Abundant extracellular lipid deposits are associated with cell necrosis and tissue weakening in the core region of human atherosclerotic fibrous plaques. The ultrastructural morphology of the core region, previously undefined because of lipid extraction artifacts, was studied with the aid of new osmium-thiocarbohydrazide-osmium and osmium-tannic acid-paraphenylenediamine sequences for tissue processing. Small droplets of neutral lipid (30 to 400 nm profile diameter) and lipid vesicles with aqueous centers accounted for more than 90% of the area occupied by lipid-rich structures in the core region. No foam cells were present. Cholesterol crystals, lipid droplets of a size similar to those in foam cells (0.4 to 6 mu), and larger neutral lipid deposits (greater than 6 mu) together occupied less than 10% of the total area of lipid structures. Abundant lipid vesicles were associated with the nearby presence of cholesterol crystals, whereas small lipid droplets were predominant in areas without crystals. Many droplets had surface defects in the form of pits and vesicular blebs. These morphologic findings are explained most concisely by postulating direct accumulation of extracellular lipid from interstitial lipoproteins as a major process in core region formation. Moreover, a dynamic state of ongoing physical/metabolic transformation of extracellular lipid deposits is suggested. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 Figure 8 Figure 9 PMID:2646938

  2. Advances in gene technology: Human genetic disorders

    SciTech Connect

    Scott, W.A.; Ahmad, F.; Black, S.; Schultz, J.; Whelan, W.J.

    1984-01-01

    This book discusses the papers presented at the conference on the subject of ''advances in Gene technology: Human genetic disorders''. Molecular biology of various carcinomas and inheritance of metabolic diseases is discussed and technology advancement in diagnosis of hereditary diseases is described. Some of the titles discussed are-Immunoglobulin genes translocation and diagnosis; hemophilia; oncogenes; oncogenic transformations; experimental data on mice, hamsters, birds carcinomas and sarcomas.

  3. Human factors challenges for advanced process control

    SciTech Connect

    Stubler, W.F.; O`Hara, J..M.

    1996-08-01

    New human-system interface technologies provide opportunities for improving operator and plant performance. However, if these technologies are not properly implemented, they may introduce new challenges to performance and safety. This paper reports the results from a survey of human factors considerations that arise in the implementation of advanced human-system interface technologies in process control and other complex systems. General trends were identified for several areas based on a review of technical literature and a combination of interviews and site visits with process control organizations. Human factors considerations are discussed for two of these areas, automation and controls.

  4. Technological advances for studying human behavior

    NASA Technical Reports Server (NTRS)

    Roske-Hofstrand, Renate J.

    1990-01-01

    Technological advances for studying human behavior are noted in viewgraph form. It is asserted that performance-aiding systems are proliferating without a fundamental understanding of how they would interact with the humans who must control them. Two views of automation research, the hardware view and the human-centered view, are listed. Other viewgraphs give information on vital elements for human-centered research, a continuum of the research process, available technologies, new technologies for persistent problems, a sample research infrastructure, the need for metrics, and examples of data-link technology.

  5. Modern Agriculture in Advanced Placement Human Geography.

    ERIC Educational Resources Information Center

    Lanegran, David A.

    2000-01-01

    Discusses the four sections of the Advanced Placement (AP) human geography course focusing on agriculture: (1) development and diffusion of agriculture; (2) major agricultural production regions; (3) rural land use and change; and (4) impacts of modern agricultural change. Includes references and a resource list. (CMK)

  6. Human carotid atherosclerotic plaque protein(s) change HDL protein(s) composition and impair HDL anti-oxidant activity.

    PubMed

    Cohen, Elad; Aviram, Michael; Khatib, Soliman; Volkova, Nina; Vaya, Jacob

    2016-01-01

    High density lipoprotein (HDL) anti-atherogenic functions are closely associated with cardiovascular disease risk factor, and are dictated by its composition, which is often affected by environmental factors. The present study investigates the effects of the human carotid plaque constituents on HDL composition and biological functions. To this end, human carotid plaques were homogenized and incubated with HDL. Results showed that after incubation, most of the apolipoprotein A1 (Apo A1) protein was released from the HDL, and HDL diameter increased by an average of approximately 2 nm. In parallel, HDL antioxidant activity was impaired. In response to homogenate treatment HDL could not prevent the accelerated oxidation of LDL caused by the homogenate. Boiling of the homogenate prior to its incubation with HDL abolished its effects on HDL composition changes. Moreover, tryptophan fluorescence quenching assay revealed an interaction between plaque component(s) and HDL, an interaction that was reduced by 50% upon using pre-boiled homogenate. These results led to hypothesize that plaque protein(s) interacted with HDL-associated Apo A1 and altered the HDL composition. Immuno-precipitation of Apo A1 that was released from the HDL after its incubation with the homogenate revealed a co-precipitation of three isomers of actin. However, beta-actin alone did not significantly affect the HDL composition, and yet the active protein within the plaque was elusive. In conclusion then, protein(s) in the homogenate interact with HDL protein(s), leading to release of Apo A1 from the HDL particle, a process that was associated with an increase in HDL diameter and with impaired HDL anti-oxidant activity.

  7. The Advancement of Humans in Space

    NASA Technical Reports Server (NTRS)

    Graves, John A.

    2014-01-01

    The advancement of humans into space and potentially beyond started slow but has greatly increased in speed over the past 2 generations. NASA has been at the forefront of this development and coontinues to lead the way into space exploration. This presentation provides a brief historical overview of NASA's space exploration efforts and touches on the abilityof each new generation to greatly expand our presence in space.

  8. Application of IR and NIR fiber optic imaging in thermographic and spectroscopic diagnosis of atherosclerotic vulnerable plaques: preliminary experience

    NASA Astrophysics Data System (ADS)

    Naghavi, Morteza; Khan, Tania; Gu, Bujin; Soller, Babs R.; Melling, Peter; Asif, Mohammed; Gul, Khawar; Madjid, Mohammad; Casscells, S. W.; Willerson, James T.

    2000-12-01

    Despite major advances in cardiovascular science and technology during the past three decades, approximately half of all myocardial infarctions and sudden deaths occur unexpectedly. It is widely accepted that coronary atherosclerotic plaques and thrombotic complications resulting from their rupture or erosion are the underlying causes of this major health problem. The majority of these vulnerable plaques exhibit active inflammation, a large necrotic lipid core, a thin fibrous cap, and confer a stenosis of less than 70%. These lesions are not detectable by stress testing or coronary angiography. Our group is exploring the possibility of a functional classification based on physiological variables such as plaque temperature, pH, oxygen consumption, lactate production etc. We have shown that heat accurately locates the inflamed plaques. We also demonstrated human atherosclerotic plaques are heterogeneous with regard to pH and hot plaques and are more likely to be acidic. To develop a nonsurgical method for locating the inflamed plaques, we are developing both IR fiber optic imaging and NIR spectroscopic systems in our laboratory to detect hot and acidic plaque in atherosclerotic arterial walls. Our findings introduce the possibility of an isolated/combined IR and NIR fiber optic catheter that can bring new insight into functional assessment of atherosclerotic plaque and thereby detection of active and inflamed lesions responsible for heart attacks and strokes.

  9. Caspase-3 Deletion Promotes Necrosis in Atherosclerotic Plaques of ApoE Knockout Mice

    PubMed Central

    Schrijvers, Dorien M.; Hermans, Marthe; Van Hoof, Viviane O.; De Meyer, Guido R. Y.

    2016-01-01

    Apoptosis of macrophages and vascular smooth muscle cells (VSMCs) in advanced atherosclerotic plaques contributes to plaque progression and instability. Caspase-3, a key executioner protease in the apoptotic pathway, has been identified in human and mouse atherosclerotic plaques but its role in atherogenesis is not fully explored. We therefore investigated the impact of caspase-3 deletion on atherosclerosis by crossbreeding caspase-3 knockout (Casp3−/−) mice with apolipoprotein E knockout (ApoE−/−) mice. Bone marrow-derived macrophages and VSMCs isolated from Casp3−/−ApoE−/− mice were resistant to apoptosis but showed increased susceptibility to necrosis. However, caspase-3 deficiency did not sensitize cells to undergo RIP1-dependent necroptosis. To study the effect on atherosclerotic plaque development, Casp3+/+ApoE−/− and Casp3−/−ApoE−/− mice were fed a western-type diet for 16 weeks. Though total plasma cholesterol, triglycerides, and LDL cholesterol levels were not altered, both the plaque size and percentage necrosis were significantly increased in the aortic root of Casp3−/−ApoE−/− mice as compared to Casp3+/+ApoE−/− mice. Macrophage content was significantly decreased in plaques of Casp3−/−ApoE−/− mice as compared to controls, while collagen content and VSMC content were not changed. To conclude, deletion of caspase-3 promotes plaque growth and plaque necrosis in ApoE−/− mice, indicating that this antiapoptotic strategy is unfavorable to improve atherosclerotic plaque stability. PMID:27847551

  10. Plaque and arterial vulnerability investigation in a three-layer atherosclerotic human coronary artery using computational fluid-structure interaction method

    NASA Astrophysics Data System (ADS)

    Karimi, Alireza; Navidbakhsh, Mahdi; Razaghi, Reza

    2014-08-01

    Coronary artery disease is the common form of cardiovascular diseases and known to be the main reason of deaths in the world. Fluid-Structure Interaction (FSI) simulations can be employed to assess the interactions of artery/plaque and blood to provide a more precise anticipation for rupture of arterial tissue layers and plaque tissues inside an atherosclerotic artery. To date, the arterial tissue in computational FSI simulations has been considered as a one-layer structure. However, a single layer assumption might have deeply bounded the results and, consequently, more computational simulation is needed by considering the arterial tissue as a three-layer structure. In this study, a three-dimensional computational FSI model of an atherosclerotic artery with a three-layer structure and different plaque types was established to perform a more accurate arterial wall/plaque tissue vulnerability assessment. The hyperelastic material coefficients of arterial layers were calculated and implemented in the computational model. The fully coupled fluid and structure models were solved using the explicit dynamics finite element code LS-DYNA. The results revealed the significant role of plaque types in the normal and shear stresses induced within the arterial tissue layers. The highest von Mises and shear stresses were observed on the stiffest calcified plaque with 3.59 and 3.27 MPa, while the lowest von Mises and shear stresses were seen on the hypocellular plaque with 1.15 and 0.63 MPa, respectively. Regardless of plaque types, the media and adventitia layers were played protective roles by displaying less stress on their wall, whilst the intima layer was at a high risk of rupture. The findings of this study have implications not only for determining the most vulnerable arterial layer/plaque tissue inside an atherosclerotic coronary artery but also for balloon-angioplasty, stenting, and bypass surgeries.

  11. Recent advances in human viruses imaging studies.

    PubMed

    Florian, Paula Ecaterina; Rouillé, Yves; Ruta, Simona; Nichita, Norica; Roseanu, Anca

    2016-06-01

    Microscopy techniques are often exploited by virologists to investigate molecular details of critical steps in viruses' life cycles such as host cell recognition and entry, genome replication, intracellular trafficking, and release of mature virions. Fluorescence microscopy is the most attractive tool employed to detect intracellular localizations of various stages of the viral infection and monitor the pathogen-host interactions associated with them. Super-resolution microscopy techniques have overcome the technical limitations of conventional microscopy and offered new exciting insights into the formation and trafficking of human viruses. In addition, the development of state-of-the art electron microscopy techniques has become particularly important in studying virus morphogenesis by revealing ground-braking ultrastructural details of this process. This review provides recent advances in human viruses imaging in both, in vitro cell culture systems and in vivo, in the animal models recently developed. The newly available imaging technologies bring a major contribution to our understanding of virus pathogenesis and will become an important tool in early diagnosis of viral infection and the development of novel therapeutics to combat the disease.

  12. Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions

    PubMed Central

    Hoeksema, Marten A; Gijbels, Marion JJ; Van den Bossche, Jan; van der Velden, Saskia; Sijm, Ayestha; Neele, Annette E; Seijkens, Tom; Stöger, J Lauran; Meiler, Svenja; Boshuizen, Marieke CS; Dallinga-Thie, Geesje M; Levels, Johannes HM; Boon, Louis; Mullican, Shannon E; Spann, Nathanael J; Cleutjens, Jack P; Glass, Chris K; Lazar, Mitchell A; de Vries, Carlie JM; Biessen, Erik AL; Daemen, Mat JAP; Lutgens, Esther; de Winther, Menno PJ

    2014-01-01

    Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease. PMID:25007801

  13. Atherosclerotic plaque behind the stent changes after bare-metal and drug-eluting stent implantation in humans: implications for late stent failure?

    PubMed Central

    Andreou, Ioannis; Takahashi, Saeko; Tsuda, Masaya; Shishido, Koki; Antoniadis, Antonios P.; Papafaklis, Michail I.; Mizuno, Shingo; Coskun, Ahmet U.; Saito, Shigeru; Feldman, Charles L.; Edelman, Elazer R.; Stone, Peter H.

    2016-01-01

    Background and aims The natural history and the role of atherosclerotic plaque located behind the stent (PBS) are still poorly understood. We evaluated the serial changes in PBS following bare-metal (BMS) compared to first-generation drug-eluting stent (DES) implantation and the impact of these changes on in-stent neointimal hyperplasia (NIH). Methods Three-dimensional coronary reconstruction by angiography and intravascular ultrasound was performed after intervention and at 6–10-month follow-up in 157 patients with 188 lesions treated with BMS (n=89) and DES (n=99). Results There was a significant decrease in PBS area (−7.2%; p<0.001) and vessel area (−1.7%; p<0.001) after BMS and a respective increase in both areas after DES implantation (6.1%; p<0.001 and 4.1%; p<0.001, respectively). The decrease in PBS area significantly predicted neointimal area at follow-up after BMS (β: 0.15; 95% confidence interval [CI]: 0.10–0.20, p<0.001) and DES (β: 0.09; 95% CI: 0.07–0.11; p<0.001) implantation. The decrease in PBS area was the most powerful predictor of significant NIH after BMS implantation (odds ratio: 1.13; 95% CI: 1.02–1.26; p=0.02). Conclusions The decrease in PBS area after stent implantation is significantly associated with the magnitude of NIH development at follow-up. This finding raises the possibility of a communication between the lesion within the stent and the underlying native atherosclerotic plaque, and may have important implications regarding the pathobiology of in-stent restenosis and late/very late stent thrombosis. PMID:27494445

  14. Advancing swine models for human health and diseases.

    PubMed

    Walters, Eric M; Prather, Randall S

    2013-01-01

    Swine models are relatively new kids on the block for modeling human health and diseases when compared to rodents and dogs. Because of the similarity to humans in size, physiology, and genetics, the pig has made significant strides in advancing the understanding of the human condition, and is thus an excellent choice for an animal model. Recent technological advances to genetic engineering of the swine genome enhance the utility of swine as models of human genetic diseases.

  15. Nuclear Molecular Imaging for Vulnerable Atherosclerotic Plaques

    PubMed Central

    Lee, Soo Jin

    2015-01-01

    Atherosclerosis is an inflammatory disease as well as a lipid disorder. Atherosclerotic plaque formed in vessel walls may cause ischemia, and the rupture of vulnerable plaque may result in fatal events, like myocardial infarction or stroke. Because morphological imaging has limitations in diagnosing vulnerable plaque, molecular imaging has been developed, in particular, the use of nuclear imaging probes. Molecular imaging targets various aspects of vulnerable plaque, such as inflammatory cell accumulation, endothelial activation, proteolysis, neoangiogenesis, hypoxia, apoptosis, and calcification. Many preclinical and clinical studies have been conducted with various imaging probes and some of them have exhibited promising results. Despite some limitations in imaging technology, molecular imaging is expected to be used both in the research and clinical fields as imaging instruments become more advanced. PMID:26357491

  16. Fluorescence lifetime imaging microscopy for the characterization of atherosclerotic plaques

    NASA Astrophysics Data System (ADS)

    Phipps, Jennifer; Sun, Yinghua; Saroufeem, Ramez; Hatami, Nisa; Marcu, Laura

    2009-02-01

    Atherosclerotic plaque composition has been associated with plaque instability and rupture. This study investigates the use of fluorescence lifetime imaging microscopy (FLIM) for mapping plaque composition and assessing features of vulnerability. Measurements were conducted in atherosclerotic human aortic samples using an endoscopic FLIM system (spatial resolution of 35 µm temporal resolution 200 ps) developed in our lab which allows mapping in one measurement the composition within a volume of 4 mm diameter x 250 µm depth. Each pixel in the image represents a corresponding fluorescence lifetime value; images are formed through a flexible 0.6 mm side-viewing imaging bundle which allows for further intravascular applications. Based on previously recorded spectra of human atherosclerotic plaque, fluorescence emission was collected through two filters: f1: 377/50 and f2: 460/60 (center wavelength/bandwidth), which together provides the greatest discrimination between intrinsic fluorophores related to plaque vulnerability. We have imaged nine aortas and lifetime images were retrieved using a Laguerre expansion deconvolution technique and correlated with histopathology. Early results demonstrate discrimination using fluorescence lifetime between early, lipid-rich, and collagen-rich lesions which are consistent with previously reported time-resolved atherosclerotic plaque measurements.

  17. Morpheus: Advancing Technologies for Human Exploration

    NASA Technical Reports Server (NTRS)

    Olansen, Jon B.; Munday, Stephen R.; Mitchell, Jennifer D.; Baine, Michael

    2012-01-01

    NASA's Morpheus Project has developed and tested a prototype planetary lander capable of vertical takeoff and landing. Designed to serve as a vertical testbed (VTB) for advanced spacecraft technologies, the vehicle provides a platform for bringing technologies from the laboratory into an integrated flight system at relatively low cost. This allows individual technologies to mature into capabilities that can be incorporated into human exploration missions. The Morpheus vehicle is propelled by a LOX/Methane engine and sized to carry a payload of 1100 lb to the lunar surface. In addition to VTB vehicles, the Project s major elements include ground support systems and an operations facility. Initial testing will demonstrate technologies used to perform autonomous hazard avoidance and precision landing on a lunar or other planetary surface. The Morpheus vehicle successfully performed a set of integrated vehicle test flights including hot-fire and tethered hover tests, leading up to un-tethered free-flights. The initial phase of this development and testing campaign is being conducted on-site at the Johnson Space Center (JSC), with the first fully integrated vehicle firing its engine less than one year after project initiation. Designed, developed, manufactured and operated in-house by engineers at JSC, the Morpheus Project represents an unprecedented departure from recent NASA programs that traditionally require longer, more expensive development lifecycles and testing at remote, dedicated testing facilities. Morpheus testing includes three major types of integrated tests. A hot-fire (HF) is a static vehicle test of the LOX/Methane propulsion system. Tether tests (TT) have the vehicle suspended above the ground using a crane, which allows testing of the propulsion and integrated Guidance, Navigation, and Control (GN&C) in hovering flight without the risk of a vehicle departure or crash. Morpheus free-flights (FF) test the complete Morpheus system without the additional

  18. Advanced Human Factors Engineering Tool Technologies.

    DTIC Science & Technology

    1987-03-20

    identified the types of tools they would like to see V developed to fill the existing technology gaps. The advanced tools were catego- rized using an...the prototype phase of development were considered candidates for inclusion. The advanced tools were next categorized using an eight point...role, application, status and cost. Decision criteria were then developed as the basis for the tradeoff process to aid in tool selection. To

  19. Advancing Humanities Studies at Community, Technical, and Junior Colleges.

    ERIC Educational Resources Information Center

    Eisenberg, Diane U.; And Others

    The American Association of Community and Junior Colleges' (AACJC's) two-year Advancing the Humanities Project (AHP) has assisted selected community colleges in promoting the humanities on their campuses. Parts I and II of this report on the AHP present statements by Dale Parnell and Judith Jeffrey Howard about the AACJC's humanities initiatives…

  20. Human factors survey of advanced instrumentation and controls

    SciTech Connect

    Carter, R.J.

    1989-01-01

    A survey oriented towards identifying the human factors issues in regard to the use of advanced instrumentation and controls (I C) in the nuclear industry was conducted. A number of United States (US) and Canadian nuclear vendors and utilities were participants in the survey. Human factors items, subsumed under the categories of computer-generated displays (CGD), controls, organizational support, training, and related topics, were discussed. The survey found the industry to be concerned about the human factors issues related to the implementation of advanced I C. Fifteen potential human factors problems were identified. They include: the need for an advanced I C guideline equivalent to NUREG-0700; a role change in the control room from operator to supervisor; information overload; adequacy of existing training technology for advanced I C; and operator acceptance and trust. 11 refs., 1 tab.

  1. Advancing Usability Evaluation through Human Reliability Analysis

    SciTech Connect

    Ronald L. Boring; David I. Gertman

    2005-07-01

    This paper introduces a novel augmentation to the current heuristic usability evaluation methodology. The SPAR-H human reliability analysis method was developed for categorizing human performance in nuclear power plants. Despite the specialized use of SPAR-H for safety critical scenarios, the method also holds promise for use in commercial off-the-shelf software usability evaluations. The SPAR-H method shares task analysis underpinnings with human-computer interaction, and it can be easily adapted to incorporate usability heuristics as performance shaping factors. By assigning probabilistic modifiers to heuristics, it is possible to arrive at the usability error probability (UEP). This UEP is not a literal probability of error but nonetheless provides a quantitative basis to heuristic evaluation. When combined with a consequence matrix for usability errors, this method affords ready prioritization of usability issues.

  2. Advanced Human Factors Engineering Tool Technologies.

    DTIC Science & Technology

    1988-03-01

    representing the government, the military, academe, and private industry were surveyed to identify those tools that are most frequently used or viewed...tools by HFE researchers and practitioners within the academic, industrial , and military settings. % .. J. &@ossion For XTIS GR&&I DTIC TAS 0...267 E. Human Factors Engineering Tools Questionnaire .. ......... . 279 F. Listing of Industry , Government, and Academe

  3. Human factors aspects of advanced instrumentation in the nuclear industry

    SciTech Connect

    Carter, R.J.

    1989-01-01

    An important consideration in regards to the use of advanced instrumentation in the nuclear industry is the interface between the instrumentation system and the human. A survey, oriented towards identifying the human factors aspects of digital instrumentation, was conducted at a number of United States (US) and Canadian nuclear vendors and utilities. Human factors issues, subsumed under the categories of computer-generated displays, controls, organizational support, training, and related topics were identified. 20 refs., 2 tabs.

  4. Advanced Solid State Lighting for Human Evaluation Project

    NASA Technical Reports Server (NTRS)

    Zeitlin, Nancy; Holbert, Eirik

    2015-01-01

    Lighting intensity and color have a significant impact on human circadian rhythms. Advanced solid state lighting was developed for the Advanced Exploration System (AES) Deep Space Habitat(DSH) concept demonstrator. The latest generation of assemblies using the latest commercially available LED lights were designed for use in the Bigelow Aerospace Environmental Control and Life Support System (ECLSS) simulator and the University of Hawaii's Hawaii Space Exploration Analog and Simulation (Hi-SEAS) habitat. Agreements with both these organizations will allow the government to receive feedback on the lights and lighting algorithms from long term human interaction.

  5. Automatic classification of atherosclerotic plaques imaged with intravascular OCT

    PubMed Central

    Rico-Jimenez, Jose J.; Campos-Delgado, Daniel U.; Villiger, Martin; Otsuka, Kenichiro; Bouma, Brett E.; Jo, Javier A.

    2016-01-01

    Intravascular optical coherence tomography (IV-OCT) allows evaluation of atherosclerotic plaques; however, plaque characterization is performed by visual assessment and requires a trained expert for interpretation of the large data sets. Here, we present a novel computational method for automated IV-OCT plaque characterization. This method is based on the modeling of each A-line of an IV-OCT data set as a linear combination of a number of depth profiles. After estimating these depth profiles by means of an alternating least square optimization strategy, they are automatically classified to predefined tissue types based on their morphological characteristics. The performance of our proposed method was evaluated with IV-OCT scans of cadaveric human coronary arteries and corresponding tissue histopathology. Our results suggest that this methodology allows automated identification of fibrotic and lipid-containing plaques. Moreover, this novel computational method has the potential to enable high throughput atherosclerotic plaque characterization. PMID:27867716

  6. Approach to atherosclerotic renovascular disease: 2016

    PubMed Central

    Daloul, Reem; Morrison, Aubrey R.

    2016-01-01

    The management of atherosclerotic renal artery stenosis in patients with hypertension or impaired renal function remains a clinical dilemma. The current general consensus, supported by the results of the Angioplasty and Stenting for Renal Atherosclerotic Lesions and Cardiovascular Outcomes for Renal Artery Lesions trials, argues strongly against endovascular intervention in favor of optimal medical management. We discuss the limitations and implications of the contemporary clinical trials and present our approach and formulate clear recommendations to help with the management of patients with atherosclerotic narrowing of the renal artery. PMID:27679718

  7. Endovascular Treatment of Symptomatic Intracranial Atherosclerotic Disease

    PubMed Central

    Short, Jody L.; Majid, Arshad; Hussain, Syed I.

    2011-01-01

    Symptomatic intracranial atherosclerotic disease (ICAD) is responsible for approximately 10% of all ischemic strokes in the United States. The risk of recurrent stroke may be as high as 35% in patient with critical stenosis >70% in diameter narrowing. Recent advances in medical and endovascular therapy have placed ICAD at the forefront of clinical stroke research to optimize the best medical and endovascular approach to treat this important underlying stroke etiology. Analysis of symptomatic ICAD studies lead to the question that whether angioplasty and/or stenting is a safe, suitable, and efficacious therapeutic strategy in patients with critical stenoses that are deemed refractory to medical management. Most of the currently available data in support of angioplasty and/or stenting in high risk patients with severe symptomatic ICAD is in the form of case series and randomized trial results of endovascular therapy versus medical treatment are awaited. This is a comprehensive review of the state of the art in the endovascular approach with angioplasty and/or stenting of symptomatic ICAD. PMID:21359195

  8. Primary Stenting of Intracranial Atherosclerotic Stenoses

    SciTech Connect

    Straube, T. Stingele, Robert; Jansen, Olav

    2005-04-15

    Purpose: To determine the feasibility and safety of stenting intracranial atherosclerotic stenoses.Methods: In 12 patients the results of primary intracranial stenting were evaluated retrospectively. Patient ages ranged from 49 to 79 years (mean 64 years). Six patients presented with stenoses in the anterior circulation, and six had stenosis in the posterior circulation. One patient presented with extra- and intracranial tandem stenosis of the left internal carotid artery. Three patients presented with acute basilar thrombosis, caused by high-grade basilar stenoses.Results: Intracranial stenoses were successfully stented in 11 of 12 patients. In one patient the stent could not be advanced over the carotid siphon to reach the stenosis of the ophthalmic internal carotid artery. Follow-up digital subtraction angiographic studies were obtained in two patients who had presented with new neurologic signs or symptoms. In both cases the angiogram did not show any relevant stenotic endothelial hyperplasia. In one patient, after local thrombolysis the stenosis turned out to be so narrow that balloon angioplasty had to be performed before stent deployment. All three patients treated for stenosis-related basilar thrombosis died due to brainstem infarction that had ensued before the intervention.Conclusions: Prophylactic primary stenting of intracranial stenoses of the anterior or posterior cerebral circulation can be performed with a low complication rate; technical problems such as stent flexibility must still be solved. Local thrombolysis followed by stenting in stenosis-related thrombotic occlusion is technically possible.

  9. Advanced Placement Human Geography: The First Five Years

    ERIC Educational Resources Information Center

    Gray, Paul T., Jr.; Hidlebrant, Barbara S.; Strauss, Tim R.

    2006-01-01

    Advanced Placement Human Geography (APHG) has grown steadily from 3,272 tests at the first test administration in 2001 to 14,139 tests in 2005. This paper examines the dynamics of growth throughout the United States through numbers of students and numbers of high schools involved in the program. APHG is discussed relative to the establishment of…

  10. Cities and Urban Land Use in Advanced Placement Human Geography.

    ERIC Educational Resources Information Center

    Ford, Larry R.

    2000-01-01

    Discusses the cities and urban land use section of the Advanced Placement (AP) human geography course, focusing on the: (1) definitions of urbanism; (2) origin and evolution of cities; (3) functional character of contemporary cities; (4) built environment and social space; and (5) responses to urban growth. (CMK)

  11. Imagining STEM Higher Education Futures: Advancing Human Well-Being

    ERIC Educational Resources Information Center

    Walker, Melanie

    2015-01-01

    The paper explores a conceptual approach to the question of what it means to provide a university education that addresses equity, and encourages the formation of STEM graduates oriented to public-good values and with commitments to making professional contributions to society which will advance human well-being. It considers and rejects…

  12. Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance.

    PubMed

    Park, Arick C; Huang, Guorui; Jankowska-Gan, Ewa; Massoudi, Dawiyat; Kernien, John F; Vignali, Dario A; Sullivan, Jeremy A; Wilkes, David S; Burlingham, William J; Greenspan, Daniel S

    2016-02-12

    We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.

  13. Human life support for advanced space exploration

    NASA Technical Reports Server (NTRS)

    Schwartzkopf, S. H.

    1997-01-01

    The requirements for a human life support system for long-duration space missions are reviewed. The system design of a controlled ecological life support system is briefly described, followed by a more detailed account of the study of the conceptual design of a Lunar Based CELSS. The latter is to provide a safe, reliable, recycling lunar base life support system based on a hybrid physicochemical/biological representative technology. The most important conclusion reached by this study is that implementation of a completely recycling CELSS approach for a lunar base is not only feasible, but eminently practical. On a cumulative launch mass basis, a 4-person Lunar Base CELSS would pay for itself in approximately 2.6 years relative to a physicochemical air/water recycling system with resupply of food from the Earth. For crew sizes of 30 and 100, the breakeven point would come even sooner, after 2.1 and 1.7 years, respectively, due to the increased mass savings that can be realized with the larger plant growth units. Two other conclusions are particularly important with regard to the orientation of future research and technology development. First, the mass estimates of the Lunar Base CELSS indicate that a primary design objective in implementing this kind of system must be to minimized the mass and power requirement of the food production plant growth units, which greatly surpass those of the other air and water recycling systems. Consequently, substantial research must be directed at identifying ways to produce food more efficiently. On the other hand, detailed studies to identify the best technology options for the other subsystems should not be expected to produce dramatic reductions in either mass or power requirement of a Lunar Base CELSS. The most crucial evaluation criterion must, therefore, be the capability for functional integration of these technologies into the ultimate design of the system. Secondly, this study illustrates that existing or near

  14. Human life support for advanced space exploration.

    PubMed

    Schwartzkopf, S H

    1997-01-01

    The requirements for a human life support system for long-duration space missions are reviewed. The system design of a controlled ecological life support system is briefly described, followed by a more detailed account of the study of the conceptual design of a Lunar Based CELSS. The latter is to provide a safe, reliable, recycling lunar base life support system based on a hybrid physicochemical/biological representative technology. The most important conclusion reached by this study is that implementation of a completely recycling CELSS approach for a lunar base is not only feasible, but eminently practical. On a cumulative launch mass basis, a 4-person Lunar Base CELSS would pay for itself in approximately 2.6 years relative to a physicochemical air/water recycling system with resupply of food from the Earth. For crew sizes of 30 and 100, the breakeven point would come even sooner, after 2.1 and 1.7 years, respectively, due to the increased mass savings that can be realized with the larger plant growth units. Two other conclusions are particularly important with regard to the orientation of future research and technology development. First, the mass estimates of the Lunar Base CELSS indicate that a primary design objective in implementing this kind of system must be to minimized the mass and power requirement of the food production plant growth units, which greatly surpass those of the other air and water recycling systems. Consequently, substantial research must be directed at identifying ways to produce food more efficiently. On the other hand, detailed studies to identify the best technology options for the other subsystems should not be expected to produce dramatic reductions in either mass or power requirement of a Lunar Base CELSS. The most crucial evaluation criterion must, therefore, be the capability for functional integration of these technologies into the ultimate design of the system. Secondly, this study illustrates that existing or near

  15. Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Liu, Cheng-hui; Boydston-White, Susie; Weisberg, Arel; Wang, Wubao; Sordillo, Laura A.; Perotte, Adler; Tomaselli, Vincent P.; Sordillo, Peter P.; Pei, Zhe; Shi, Lingyan; Alfano, Robert R.

    2016-12-01

    A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66 μm, very close to the 65-μm empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP.

  16. High speed intravascular photoacoustic imaging of atherosclerotic arteries (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Piao, Zhonglie; Ma, Teng; Qu, Yueqiao; Li, Jiawen; Yu, Mingyue; He, Youmin; Shung, K. Kirk; Zhou, Qifa; Kim, Chang-Seok; Chen, Zhongping

    2016-02-01

    Cardiovascular disease is the leading cause of death in the industrialized nations. Accurate quantification of both the morphology and composition of lipid-rich vulnerable atherosclerotic plaque are essential for early detection and optimal treatment in clinics. In previous works, intravascular photoacoustic (IVPA) imaging for detection of lipid-rich plaque within coronary artery walls has been demonstrated in ex vivo, but the imaging speed is still limited. In order to increase the imaging speed, a high repetition rate laser is needed. In this work, we present a high speed integrated IVPA/US imaging system with a 500 Hz optical parametric oscillator laser at 1725 nm. A miniature catheter with 1.0 mm outer diameter was designed with a 200 μm multimode fiber and an ultrasound transducer with 45 MHz center frequency. The fiber was polished at 38 degree and enclosed in a glass capillary for total internal reflection. An optical/electrical rotary junction and pull-back mechanism was applied for rotating and linearly scanning the catheter to obtain three-dimensional imaging. Atherosclerotic rabbit abdominal aorta was imaged as two frame/second at 1725 nm. Furthermore, by wide tuning range of the laser wavelength from 1680 nm to 1770 nm, spectroscopic photoacoustic analysis of lipid-mimicking phantom and an human atherosclerotic artery was performed ex vivo. The results demonstrated that the developed IVPA/US imaging system is capable for high speed intravascular imaging for plaque detection.

  17. Human carotid atherosclerotic lesion protein components decrease cholesterol biosynthesis rate in macrophages through 3-hydroxy-3-methylglutaryl-CoA reductase regulation.

    PubMed

    Cohen, Elad; Aviram, Michael; Khatib, Soliman; Rosenblat, Mira; Vaya, Jacob

    2015-01-01

    Atherosclerosis is characterized by the formation of cholesterol-loaded macrophages, which are turned into foam cells, the hallmark of early atherogenesis. As part of ongoing research on the interactions among human carotid lesion components and blood elements, the effect of plaque homogenate on macrophage cholesterol biosynthesis rate was examined. Human carotid plaques were ground, extracted with phosphate-buffered saline (homogenate), and then added to the macrophage medium. This extract decreased macrophage cholesterol biosynthesis rate up to 50% in a dose-dependent manner. Cholesterol or lipoproteins were separated from the homogenate and added to the MQ medium. Unlike the homogenate, neither free cholesterol nor the lipoproteins were able to inhibit cholesterol biosynthesis rate under the above experimental concentration, suggesting that the homogenate-induced cholesterol biosynthesis inhibition in our experimental system was not owing to the feedback inhibition of cholesterol. Furthermore, the homogenate remaining after lipoprotein removal (lipoprotein-deficient homogenate) also decreased cholesterol biosynthesis rate, whereas boiled homogenate or phospholipids extracted from the homogenate decreased macrophage cholesterol biosynthesis rate only partially. Finally, cholesterol biosynthesis inhibition was achieved only upon using the precursor [(3)H]acetate, but not [(14)C]mevalonate, suggesting that 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA Reductase), the rate-limiting enzyme in the cholesterol biosynthesis pathway, is involved in the above antiatherogenic effect of the homogenate, whereas the treatment with homogenate decreased HMGCoA Reductase mRNA. Proteins and phospholipids from human carotid lesion homogenate decrease cholesterol biosynthesis rate in macrophages secondary to HMGCoA Reductase feedback regulation. Such an effect may delay foam cell formation and atherosclerosis progression.

  18. Advanced Video Analysis Needs for Human Performance Evaluation

    NASA Technical Reports Server (NTRS)

    Campbell, Paul D.

    1994-01-01

    Evaluators of human task performance in space missions make use of video as a primary source of data. Extraction of relevant human performance information from video is often a labor-intensive process requiring a large amount of time on the part of the evaluator. Based on the experiences of several human performance evaluators, needs were defined for advanced tools which could aid in the analysis of video data from space missions. Such tools should increase the efficiency with which useful information is retrieved from large quantities of raw video. They should also provide the evaluator with new analytical functions which are not present in currently used methods. Video analysis tools based on the needs defined by this study would also have uses in U.S. industry and education. Evaluation of human performance from video data can be a valuable technique in many industrial and institutional settings where humans are involved in operational systems and processes.

  19. LOX-1 in atherosclerotic disease.

    PubMed

    Sawamura, Tatsuya; Wakabayashi, Ichiro; Okamura, Tomonori

    2015-02-02

    Oxidized low-density lipoprotein (LDL) exhibits various biological activities and accumulates in atheromas. LOX-1 (lectin-like oxidized LDL receptor) is the receptor that mediates oxidized LDL activity in vascular endothelial cells. Activation of LOX-1 results in oxidized LDL-induced endothelial dysfunction and hyperlipidemia-induced vascular lipid deposition. We hypothesized that LOX-1 is a candidate risk factor beyond LDL cholesterol (LDLC) and developed a novel assay to quantify LOX-1 ligand containing apoB (LAB). In men from the United States, serum LAB showed a significant positive association with carotid intima-media thickness, independent of LDLC. LAB and the LOX index (obtained by multiplying LAB by sLOX-1) were significantly associated with the incidence of coronary artery disease and ischemic stroke after adjusting for confounding factors, including non-HDL cholesterol. sLOX-1 is thought to be a better biomarker for early diagnosis of acute coronary syndrome than traditional biomarkers, including troponin T. LAB was associated with various atherosclerotic risk factors such as smoking, obesity, diabetes, diastolic hypertension, hypertriglyceridemia, and metabolic syndrome. Measurement of the soluble form of LOX-1 (sLOX-1) and LAB seems to be useful for evaluating the state and risk of atherosclerosis and atherosclerosis-related diseases. Further prospective studies using large populations and randomized clinical trials on sLOX-1, LAB, and the LOX index are needed.

  20. Advanced automated glass cockpit certification: Being wary of human factors

    NASA Technical Reports Server (NTRS)

    Amalberti, Rene; Wilbaux, Florence

    1994-01-01

    This paper presents some facets of the French experience with human factors in the process of certification of advanced automated cockpits. Three types of difficulties are described: first, the difficulties concerning the hotly debated concept of human error and its non-linear relationship to risk of accident; a typology of errors to be taken into account in the certification process is put forward to respond to this issue. Next, the difficulties connected to the basically gradual and evolving nature of pilot expertise on a given type of aircraft, which contrasts with the immediate and definitive style of certifying systems. The last difficulties to be considered are those related to the goals of certification itself on these new aircraft and the status of findings from human factor analyses (in particular, what should be done with disappointing results, how much can the changes induced by human factors investigation economically affect aircraft design, how many errors do we need to accumulate before we revise the system, what should be remedied when human factor problems are discovered at the certification stage: the machine? pilot training? the rules? or everything?). The growth of advanced-automated glass cockpits has forced the international aeronautical community to pay more attention to human factors during the design phase, the certification phase and pilot training. The recent creation of a human factor desk at the DGAC-SFACT (Official French services) is a direct consequence of this. The paper is divided into three parts. Part one debates human error and its relationship with system design and accident risk. Part two describes difficulties connected to the basically gradual and evolving nature of pilot expertise on a given type of aircraft, which contrasts with the immediate and definitive style of certifying systems. Part three focuses on concrete outcomes of human factors for certification purposes.

  1. Recent Advances in Human Protozoan Parasites of Gastrointestinal Tract

    DTIC Science & Technology

    1987-02-01

    frequency of oral-anal sexual contacts. No relation was seen between the presence or chance of gastrointestinal symptoms and infection with E...Lancet May 14: 1103. SPENCER MJ., CHAPIN M.R. & GARCIA L.S. 1962. Dientamoeba fragilis: A gastrointestinal protozoan infection in adults. American...ULIC EIL& p .( RECENT ADVANCES IN HUMAN PROTOZOAN PARASITES OF GASTROINTESTINAL TRACT J.H. Cross REPORT NO. CS -142 AD-A 182 878 ,ji.. ELECTE JULS j

  2. Multiscale investigation of USPIO nanoparticles in atherosclerotic plaques and their catabolism and storage in vivo.

    PubMed

    Maraloiu, Valentin-Adrian; Appaix, Florence; Broisat, Alexis; Le Guellec, Dominique; Teodorescu, Valentin Serban; Ghezzi, Catherine; van der Sanden, Boudewijn; Blanchin, Marie-Genevieve

    2016-01-01

    The storage and catabolism of Ultrasmall SuperParamagnetic Iron Oxide (USPIO) nanoparticles were analyzed through a multiscale approach combining Two Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM) at different times after intravenous injection in an atherosclerotic ApoE(-/-) mouse model. The atherosclerotic plaque features and the USPIO heterogeneous biodistribution were revealed down from organ's scale to subcellular level. The biotransformation of the nanoparticle iron oxide (maghemite) core into ferritin, the non-toxic form of iron storage, was demonstrated for the first time ex vivo in atherosclerotic plaques as well as in spleen, the iron storage organ. These results rely on an innovative spatial and structural investigation of USPIO's catabolism in cellular phagolysosomes. This study showed that these nanoparticles were stored as non-toxic iron compounds: maghemite oxide or ferritin, which is promising for MRI detection of atherosclerotic plaques in clinics using these USPIOs. From the Clinical Editor: Advance in nanotechnology has brought new contrast agents for clinical imaging. In this article, the authors investigated the use and biotransformation of Ultrasmall Super-paramagnetic Iron Oxide (USPIO) nanoparticles for analysis of atherosclerotic plagues in Two Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM). The biophysical data generated from this study could enable the possible use of these nanoparticles for the benefits of clinical patients.

  3. Advanced haptic sensor for measuring human skin conditions

    NASA Astrophysics Data System (ADS)

    Tsuchimi, Daisuke; Okuyama, Takeshi; Tanaka, Mami

    2009-12-01

    This paper is concerned with the development of a tactile sensor using PVDF (Polyvinylidene Fluoride) film as a sensory receptor of the sensor to evaluate softness, smoothness, and stickiness of human skin. Tactile sense is the most important sense in the sensation receptor of the human body along with eyesight, and we can examine skin condition quickly using these sense. But, its subjectivity and ambiguity make it difficult to quantify skin conditions. Therefore, development of measurement device which can evaluate skin conditions easily and objectively is demanded by dermatologists, cosmetic industries, and so on. In this paper, an advanced haptic sensor system that can measure multiple information of skin condition in various parts of human body is developed. The applications of the sensor system to evaluate softness, smoothness, and stickiness of skin are investigated through two experiments.

  4. Advanced haptic sensor for measuring human skin conditions

    NASA Astrophysics Data System (ADS)

    Tsuchimi, Daisuke; Okuyama, Takeshi; Tanaka, Mami

    2010-01-01

    This paper is concerned with the development of a tactile sensor using PVDF (Polyvinylidene Fluoride) film as a sensory receptor of the sensor to evaluate softness, smoothness, and stickiness of human skin. Tactile sense is the most important sense in the sensation receptor of the human body along with eyesight, and we can examine skin condition quickly using these sense. But, its subjectivity and ambiguity make it difficult to quantify skin conditions. Therefore, development of measurement device which can evaluate skin conditions easily and objectively is demanded by dermatologists, cosmetic industries, and so on. In this paper, an advanced haptic sensor system that can measure multiple information of skin condition in various parts of human body is developed. The applications of the sensor system to evaluate softness, smoothness, and stickiness of skin are investigated through two experiments.

  5. [Is regression of atherosclerotic plaque possible?

    PubMed

    Páramo, José A; Civeira, Fernando

    As it is well-known, a thrombus evolving into a disrupted/eroded atherosclerotic plaque causes most acute coronary syndromes. Plaque stabilization via reduction of the lipid core and/or thickening of the fibrous cap is one of the possible mechanisms accounted for the clinical benefits displayed by different anti-atherosclerotic strategies. The concept of plaque stabilization was developed to explain how lipid-lowering agents could decrease adverse coronary events without substantial modifications of the atherosclerotic lesion ('angiographic paradox'). A number of imaging modalities (vascular ultrasound and virtual histology, MRI, optical coherence tomography, positron tomography, etc.) are used for non-invasive assessment of atherosclerosis; most of them can identify plaque volume and composition beyond lumen stenosis. An 'aggressive' lipid-lowering strategy is able to reduce the plaque burden and the incidence of cardiovascular events; this may be attributable, at least in part, to plaque-stabilizing effects.

  6. Leukocyte trafficking-associated vascular adhesion protein 1 is expressed and functionally active in atherosclerotic plaques

    PubMed Central

    Silvola, Johanna M. U.; Virtanen, Helena; Siitonen, Riikka; Hellberg, Sanna; Liljenbäck, Heidi; Metsälä, Olli; Ståhle, Mia; Saanijoki, Tiina; Käkelä, Meeri; Hakovirta, Harri; Ylä-Herttuala, Seppo; Saukko, Pekka; Jauhiainen, Matti; Veres, Tibor Z.; Jalkanen, Sirpa; Knuuti, Juhani; Saraste, Antti; Roivainen, Anne

    2016-01-01

    Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR−/−ApoB100/100), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer [68Ga]DOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis. PMID:27731409

  7. A new murine model of stress-induced complex atherosclerotic lesions

    PubMed Central

    Najafi, Amir H.; Aghili, Nima; Tilan, Justin U.; Andrews, James A.; Peng, XinZhi; Lassance-Soares, Roberta M.; Sood, Subeena; Alderman, Lee O.; Abe, Ken; Li, Lijun; Kolodgie, Frank D.; Virmani, Renu; Zukowska, Zofia; Epstein, Stephen E.; Burnett, Mary Susan

    2013-01-01

    SUMMARY The primary purpose of this investigation was to determine whether ApoE−/− mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE−/− mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability. PMID:23324329

  8. Specific imaging of atherosclerotic plaque lipids with two-wavelength intravascular photoacoustics

    PubMed Central

    Wu, Min; Jansen, Krista; van der Steen, Antonius F. W.; van Soest, Gijs

    2015-01-01

    The lipid content in plaques is an important marker for identifying atherosclerotic lesions and disease states. Intravascular photoacoustic (IVPA) imaging can be used to visualize lipids in the artery. In this study, we further investigated lipid detection in the 1.7-µm spectral range. By exploiting the relative difference between the IVPA signal strengths at 1718 and 1734 nm, we could successfully detect and differentiate between the plaque lipids and peri-adventitial fat in human coronary arteries ex vivo. Our study demonstrates that IVPA imaging can positively identify atherosclerotic plaques using only two wavelengths, which could enable rapid data acquisition in vivo. PMID:26417500

  9. Recent advances in research on climate and human conflict

    NASA Astrophysics Data System (ADS)

    Hsiang, S. M.

    2014-12-01

    A rapidly growing body of empirical, quantitative research examines whether rates of human conflict can be systematically altered by climatic changes. We discuss recent advances in this field, including Bayesian meta-analyses of the effect of temperature and rainfall on current and future large-scale conflicts, the impact of climate variables on gang violence and suicides in Mexico, and probabilistic projections of personal violence and property crime in the United States under RCP scenarios. Criticisms of this research field will also be explained and addressed.

  10. Genesis and growth of extracellular vesicle-derived microcalcification in atherosclerotic plaques

    PubMed Central

    Hutcheson, Joshua D.; Goettsch, Claudia; Bertazzo, Sergio; Maldonado, Natalia; Ruiz, Jessica L.; Goh, Wilson; Yabusaki, Katsumi; Faits, Tyler; Bouten, Carlijn; Franck, Gregory; Quillard, Thibaut; Libby, Peter; Aikawa, Masanori; Weinbaum, Sheldon; Aikawa, Elena

    2015-01-01

    Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability - are interlinked. PMID:26752654

  11. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques

    NASA Astrophysics Data System (ADS)

    Hutcheson, Joshua D.; Goettsch, Claudia; Bertazzo, Sergio; Maldonado, Natalia; Ruiz, Jessica L.; Goh, Wilson; Yabusaki, Katsumi; Faits, Tyler; Bouten, Carlijn; Franck, Gregory; Quillard, Thibaut; Libby, Peter; Aikawa, Masanori; Weinbaum, Sheldon; Aikawa, Elena

    2016-03-01

    Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque’s collagen content--two determinants of atherosclerotic plaque stability--are interlinked.

  12. Ultrasound imaging versus morphopathology in cardiovascular diseases. Coronary collateral circulation and atherosclerotic plaque

    PubMed Central

    Baroldi, Giorgio; Bigi, Riccardo; Cortigiani, Lauro

    2005-01-01

    This review article is aimed at comparing the results of histopathological and clinical imaging studies to assess coronary collateral circulation in humans. The role of collaterals, as emerging from morphological studies in both normal and atherosclerotic coronary vessels, is described; in addition, present role and future perpectives of echocardiographic techniques in assessing collateral circulation are briefly summarized. PMID:15740620

  13. NASA's Advanced Life Support Systems Human-Rated Test Facility.

    PubMed

    Henninger, D L; Tri, T O; Packham, N J

    1996-01-01

    Future NASA missions to explore the solar system will be long-duration missions, requiring human life support systems which must operate with very high reliability over long periods of time. Such systems must be highly regenerative, requiring minimum resupply, to enable the crews to be largely self-sufficient. These regenerative life support systems will use a combination of higher plants, microorganisms, and physicochemical processes to recycle air and water, produce food, and process wastes. A key step in the development of these systems is establishment of a human-rated test facility specifically tailored to evaluation of closed, regenerative life supports systems--one in which long-duration, large-scale testing involving human test crews can be performed. Construction of such a facility, the Advanced Life Support Program's (ALS) Human-Rated Test Facility (HRTF), has begun at NASA's Johnson Space Center, and definition of systems and development of initial outfitting concepts for the facility are underway. This paper will provide an overview of the HRTF project plan, an explanation of baseline configurations, and descriptive illustrations of facility outfitting concepts.

  14. Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions

    PubMed Central

    Su, Helen

    2017-01-01

    Immunodeficiencies reveal the crucial role of the immune system in defending the body against microbial pathogens. Given advances in genomics and other technologies, this is currently best studied in humans who have inherited monogenic diseases. Such investigations have provided insights into how gene products normally function in the natural environment and have opened the door to new, exciting treatments for these diseases.

  15. Using in vivo Cine and 3D multi-contrast MRI to determine human atherosclerotic carotid artery material properties and circumferential shrinkage rate and their impact on stress/strain predictions.

    PubMed

    Liu, Haofei; Canton, Gador; Yuan, Chun; Yang, Chun; Billiar, Kristen; Teng, Zhongzhao; Hoffman, Allen H; Tang, Dalin

    2012-01-01

    In vivo magnetic resonance image (MRI)-based computational models have been introduced to calculate atherosclerotic plaque stress and strain conditions for possible rupture predictions. However, patient-specific vessel material properties are lacking in those models, which affects the accuracy of their stress/strain predictions. A noninvasive approach of combining in vivo Cine MRI, multicontrast 3D MRI, and computational modeling was introduced to quantify patient-specific carotid artery material properties and the circumferential shrinkage rate between vessel in vivo and zero-pressure geometries. In vivo Cine and 3D multicontrast MRI carotid plaque data were acquired from 12 patients after informed consent. For each patient, one nearly-circular slice and an iterative procedure were used to quantify parameter values in the modified Mooney-Rivlin model for the vessel and the vessel circumferential shrinkage rate. A sample artery slice with and without a lipid core and three material parameter sets representing stiff, median, and soft materials from our patient data were used to demonstrate the effect of material stiffness and circumferential shrinkage process on stress/strain predictions. Parameter values of the Mooney-Rivlin models for the 12 patients were quantified. The effective Young's modulus (YM, unit: kPa) values varied from 137 (soft), 431 (median), to 1435 (stiff), and corresponding circumferential shrinkages were 32%, 12.6%, and 6%, respectively. Using the sample slice without the lipid core, the maximum plaque stress values (unit: kPa) from the soft and median materials were 153.3 and 96.2, which are 67.7% and 5% higher than that (91.4) from the stiff material, while the maximum plaque strain values from the soft and median materials were 0.71 and 0.293, which are about 700% and 230% higher than that (0.089) from the stiff material, respectively. Without circumferential shrinkages, the maximum plaque stress values (unit: kPa) from the soft, median, and

  16. Using In Vivo Cine and 3D Multi-Contrast MRI to Determine Human Atherosclerotic Carotid Artery Material Properties and Circumferential Shrinkage Rate and Their Impact on Stress/Strain Predictions

    PubMed Central

    Liu, Haofei; Canton, Gador; Yuan, Chun; Yang, Chun; Billiar, Kristen; Teng, Zhongzhao; Hoffman, Allen H.; Tang, Dalin

    2012-01-01

    Background In vivo magnetic resonance image (MRI)-based computational models have been introduced to calculate atherosclerotic plaque stress and strain conditions for possible rupture predictions. However, patient-specific vessel material properties are lacking in those models which affect the accuracy of their stress/strain predictions. A non-invasive approach of combining in vivo Cine MRI, multi-contrast 3D MRI and computational modeling was introduced to quantify patient-specific carotid artery material properties and circumferential shrinkage rate between vessel in vivo and zero-pressure geometries. Method In vivo Cine and 3D multicontrast MRI carotid plaque data were acquired from 12 patients after informed consent. For each patient, one nearly-circular slice and an iterative procedure were used to quantify parameter values in the modified Mooney-Rivlin model for the vessel and the vessel circumferential shrinkage rate. A sample artery slice with and without a lipid core and three material parameter sets representing stiff, median and soft materials from our patient data were used to demonstrate the effect of material stiffness and circumferential shrinkage process on stress/strain predictions. Results Parameter values of the Mooney-Rivlin models for the 12 patients were quantified. Effective Young's Modulus (YM, unit: kPa) values varied from 137 (soft), 431 (median) to 1435 (stiff), and corresponding circumferential shrinkages were 32%, 12.6% to 6%, respectively. Using the sample slice without the lipid core, the maximum plaque stress values (unit: kPa) from the soft and median materials were 153.3 and 96.2, 67.7% and 5% higher than that (91.4) from the stiff material, while the maximum plaque strain values from the soft and median materials were 0.71 and 0.293, about 700% and 230% higher than that (0.089) from the stiff material, respectively. Without circumferential shrinkages, the maximum plaque stress values (unit: kPa) from the soft, median and stiff

  17. Does human cognition allow Human Factors (HF) certification of advanced aircrew systems?

    NASA Technical Reports Server (NTRS)

    Macleod, Iain S.; Taylor, Robert M.

    1994-01-01

    This paper has examined the requirements of HF specification and certification within advanced or complex aircrew systems. It suggests reasons for current inadequacies in the use of HF in the design process, giving some examples in support, and suggesting an avenue towards the improvement of the HF certification process. The importance of human cognition to the operation and performance of advanced aircrew systems has been stressed. Many of the shortfalls of advanced aircrew systems must be attributed to over automated designs that show little consideration on either the mental limits or the cognitive capabilities of the human system component. Traditional approaches to system design and HF certification are set within an over physicalistic foundation. Also, traditionally it was assumed that physicalistic system functions could be attributed to either the human or the machine on a one to one basis. Moreover, any problems associated with the parallel needs, or promoting human understanding alongside system operation and direction, were generally equated in reality by the natural flexibility and adaptability of human skills. The consideration of the human component of a complex system is seen as being primarily based on manifestations of human behavior to the almost total exclusion of any appreciation of unobservable human mental and cognitive processes. The argument of this paper is that the considered functionality of any complex human-machine system must contain functions that are purely human and purely cognitive. Human-machine system reliability ultimately depends on human reliability and dependability and, therefore, on the form and frequency of cognitive processes that have to be conducted to support system performance. The greater the demand placed by an advanced aircraft system on the human component's basic knowledge processes or cognition, rather than on skill, the more insiduous the effects the human may have on that system. This paper discusses one

  18. Advancing biomaterials of human origin for tissue engineering

    PubMed Central

    Chen, Fa-Ming; Liu, Xiaohua

    2015-01-01

    Biomaterials have played an increasingly prominent role in the success of biomedical devices and in the development of tissue engineering, which seeks to unlock the regenerative potential innate to human tissues/organs in a state of deterioration and to restore or reestablish normal bodily function. Advances in our understanding of regenerative biomaterials and their roles in new tissue formation can potentially open a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multi-component construction of native extracellular matrices (ECMs) for cell accommodation, the synthetic biomaterials produced today routinely incorporate biologically active components to define an artificial in vivo milieu with complex and dynamic interactions that foster and regulate stem cells, similar to the events occurring in a natural cellular microenvironment. The range and degree of biomaterial sophistication have also dramatically increased as more knowledge has accumulated through materials science, matrix biology and tissue engineering. However, achieving clinical translation and commercial success requires regenerative biomaterials to be not only efficacious and safe but also cost-effective and convenient for use and production. Utilizing biomaterials of human origin as building blocks for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural tissue with regard to its physical and chemical properties for the orchestration of wound healing and tissue regeneration. In addition to directly using tissue transfers and transplants for repair, new applications of human-derived biomaterials are now focusing on the use of naturally occurring biomacromolecules, decellularized ECM scaffolds and autologous preparations rich in growth factors/non-expanded stem cells to either target acceleration/magnification of the body's own repair capacity or use nature's paradigms to create new tissues for

  19. Bacterial Communities Associated with Atherosclerotic Plaques from Russian Individuals with Atherosclerosis

    PubMed Central

    Ziganshina, Elvira E.; Sharifullina, Dilyara M.; Lozhkin, Andrey P.; Khayrullin, Rustem N.; Ignatyev, Igor M.; Ziganshin, Ayrat M.

    2016-01-01

    Atherosclerosis is considered a chronic disease of the arterial wall and is the major cause of severe disease and death among individuals all over the world. Some recent studies have established the presence of bacteria in atherosclerotic plaque samples and suggested their possible contribution to the development of cardiovascular disease. The main objective of this preliminary pilot study was to better understand the bacterial diversity and abundance in human atherosclerotic plaques derived from common carotid arteries of individuals with atherosclerosis (Russian nationwide group) and contribute towards the further identification of a main group of atherosclerotic plaque bacteria by 454 pyrosequencing their 16S ribosomal RNA (16S rRNA) genes. The applied approach enabled the detection of bacterial DNA in all atherosclerotic plaques. We found that distinct members of the order Burkholderiales were present at high levels in all atherosclerotic plaques obtained from patients with atherosclerosis with the genus Curvibacter being predominant in all plaque samples. Moreover, unclassified Burkholderiales as well as members of the genera Propionibacterium and Ralstonia were typically the most significant taxa for all atherosclerotic plaques. Other genera such as Burkholderia, Corynebacterium and Sediminibacterium as well as unclassified Comamonadaceae, Oxalobacteraceae, Rhodospirillaceae, Bradyrhizobiaceae and Burkholderiaceae were always found but at low relative abundances of the total 16S rRNA gene population derived from all samples. Also, we found that some bacteria found in plaque samples correlated with some clinical parameters, including total cholesterol, alanine aminotransferase and fibrinogen levels. Finally, our study indicates that some bacterial agents at least partially may be involved in affecting the development of cardiovascular disease through different mechanisms. PMID:27736997

  20. Bacterial Communities Associated with Atherosclerotic Plaques from Russian Individuals with Atherosclerosis.

    PubMed

    Ziganshina, Elvira E; Sharifullina, Dilyara M; Lozhkin, Andrey P; Khayrullin, Rustem N; Ignatyev, Igor M; Ziganshin, Ayrat M

    2016-01-01

    Atherosclerosis is considered a chronic disease of the arterial wall and is the major cause of severe disease and death among individuals all over the world. Some recent studies have established the presence of bacteria in atherosclerotic plaque samples and suggested their possible contribution to the development of cardiovascular disease. The main objective of this preliminary pilot study was to better understand the bacterial diversity and abundance in human atherosclerotic plaques derived from common carotid arteries of individuals with atherosclerosis (Russian nationwide group) and contribute towards the further identification of a main group of atherosclerotic plaque bacteria by 454 pyrosequencing their 16S ribosomal RNA (16S rRNA) genes. The applied approach enabled the detection of bacterial DNA in all atherosclerotic plaques. We found that distinct members of the order Burkholderiales were present at high levels in all atherosclerotic plaques obtained from patients with atherosclerosis with the genus Curvibacter being predominant in all plaque samples. Moreover, unclassified Burkholderiales as well as members of the genera Propionibacterium and Ralstonia were typically the most significant taxa for all atherosclerotic plaques. Other genera such as Burkholderia, Corynebacterium and Sediminibacterium as well as unclassified Comamonadaceae, Oxalobacteraceae, Rhodospirillaceae, Bradyrhizobiaceae and Burkholderiaceae were always found but at low relative abundances of the total 16S rRNA gene population derived from all samples. Also, we found that some bacteria found in plaque samples correlated with some clinical parameters, including total cholesterol, alanine aminotransferase and fibrinogen levels. Finally, our study indicates that some bacterial agents at least partially may be involved in affecting the development of cardiovascular disease through different mechanisms.

  1. Consciousness in humans and non-human animals: recent advances and future directions

    PubMed Central

    Boly, Melanie; Seth, Anil K.; Wilke, Melanie; Ingmundson, Paul; Baars, Bernard; Laureys, Steven; Edelman, David B.; Tsuchiya, Naotsugu

    2013-01-01

    This joint article reflects the authors' personal views regarding noteworthy advances in the neuroscience of consciousness in the last 10 years, and suggests what we feel may be promising future directions. It is based on a small conference at the Samoset Resort in Rockport, Maine, USA, in July of 2012, organized by the Mind Science Foundation of San Antonio, Texas. Here, we summarize recent advances in our understanding of subjectivity in humans and other animals, including empirical, applied, technical, and conceptual insights. These include the evidence for the importance of fronto-parietal connectivity and of “top-down” processes, both of which enable information to travel across distant cortical areas effectively, as well as numerous dissociations between consciousness and cognitive functions, such as attention, in humans. In addition, we describe the development of mental imagery paradigms, which made it possible to identify covert awareness in non-responsive subjects. Non-human animal consciousness research has also witnessed substantial advances on the specific role of cortical areas and higher order thalamus for consciousness, thanks to important technological enhancements. In addition, much progress has been made in the understanding of non-vertebrate cognition relevant to possible conscious states. Finally, major advances have been made in theories of consciousness, and also in their comparison with the available evidence. Along with reviewing these findings, each author suggests future avenues for research in their field of investigation. PMID:24198791

  2. The prevention and regression of atherosclerotic plaques: emerging treatments

    PubMed Central

    Kalanuria, Atul Ashok; Nyquist, Paul; Ling, Geoffrey

    2012-01-01

    Occlusive vascular diseases, such as sudden coronary syndromes, stroke, and peripheral arterial disease, are a huge burden on the health care systems of developed and developing countries. Tremendous advances have been made over the last few decades in the diagnosis and treatment of atherosclerotic diseases. Intravascular ultrasound has been able to provide detailed information of plaque anatomy and has been used in several studies to assess outcomes. The presence of atherosclerosis disrupts the normal protective mechanism provided by the endothelium and this mechanism has been implicated in the pathophysiology of coronary artery disease and stroke. Efforts are being put into the prevention of atherosclerosis, which has been shown to begin in childhood. This paper reviews the pathophysiology of atherosclerosis and discusses the current options available for the prevention and reversal of plaque formation. PMID:23049260

  3. Human umbilical cord blood cells and diabetes mellitus: recent advances.

    PubMed

    Reddi, Alluru S; Kothari, Neil; Kuppasani, Kishore; Ende, Norman

    2015-01-01

    Stem cell therapy for patients with diabetes is an area of great interest to both scientists and clinicians. Human umbilical cord blood cells (HUCBCs) are being increasingly used as a source of stem cells for cell-based therapy for diabetes because these cells can differentiate into pancreatic islet β-cells. Administration of HUCBCs has been shown to lower blood glucose levels in diabetic animal models. The use of autologous HUCBC transfusion in type 1 diabetic children has not shown any benefit. However, "Stem Cell Educator" therapy has shown promise in long term lowering of blood glucose levels in both type 1 and type 2 diabetic patients. In this review, we will briefly discuss recent advances in HUCBC therapy in the treatment of diabetes and some of its complications.

  4. Advanced Plasma Propulsion for Human Missions to Jupiter

    NASA Technical Reports Server (NTRS)

    Donahue, Benjamin B.; Pearson, J. Boise

    1999-01-01

    This paper will briefly identify a promising fusion plasma power source, which when coupled with a promising electric thruster technology would provide for an efficient interplanetary transfer craft suitable to a 4 year round trip mission to the Jovian system. An advanced, nearly radiation free Inertial Electrostatic Confinement scheme for containing fusion plasma was judged as offering potential for delivering the performance and operational benefits needed for such high energy human expedition missions, without requiring heavy superconducting magnets for containment of the fusion plasma. Once the Jovian transfer stage has matched the heliocentric velocity of Jupiter, the energy requirements for excursions to its outer satellites (Callisto, Ganymede and Europa) by smaller excursion craft are not prohibitive. The overall propulsion, power and thruster system is briefly described and a preliminary vehicle mass statement is presented.

  5. Advanced plasma propulsion for human missions to Jupiter

    NASA Astrophysics Data System (ADS)

    Donahue, Benjamin B.; Pearson, J. Boise

    2000-01-01

    This paper will briefly identify a promising fusion plasma power source, which when coupled with a promising electric thruster technology would provide for an efficient interplanetary transfer craft suitable to a 4 year round trip mission to the Jovian system. An advanced, nearly radiation free Inertial Electrostatic Confinement scheme for containing fusion plasma was judged as offering potential for delivering the performance and operational benefits needed for such high energy human expedition missions, without requiring heavy superconducting magnets for containment of the fusion plasma. Once the Jovian transfer stage has matched the heliocentric velocity of Jupiter, the energy requirements for excursions to its outer satellites (Callisto, Ganymede and Europa) by smaller excursion craft are not prohibitive. The overall propulsion, power and thruster system is briefly described and a preliminary vehicle mass statement is presented. .

  6. Advancing our understanding of the human microbiome using QIIME

    PubMed Central

    Navas-Molina, José A.; Peralta-Sánchez, Juan M.; González, Antonio; McMurdie, Paul J.; Vázquez-Baeza, Yoshiki; Xu, Zhenjiang; Ursell, Luke K.; Lauber, Christian; Zhou, Hongwei; Song, Se Jin; Huntley, James; Ackermann, Gail L.; Berg-Lyons, Donna; Holmes, Susan; Caporaso, J. Gregory; Knight, Rob

    2014-01-01

    High-throughput DNA sequencing technologies, coupled with advanced bioinformatics tools, have enabled rapid advances in microbial ecology and our understanding of the human microbiome. QIIME (Quantitative Insights Into Microbial Ecology) is an open-source bioinformatics software package designed for microbial community analysis based on DNA sequence data, which provides a single analysis framework for analysis of raw sequence data through publication quality statistical analyses and interactive visualizations. In this paper, we demonstrate the use of the QIIME pipeline to analyze microbial communities obtained from several sites on the bodies of transgenic and wild-type mice, as assessed using 16S rRNA gene sequences generated on the Illumina MiSeq platform. We present our recommended pipeline for performing microbial community analysis, and provide guidelines for making critical choices in the process. We present examples of some of the types of analyses that are enabled by QIIME, and discuss how other tools, such as phyloseq and R, can be applied to expand upon these analyses. PMID:24060131

  7. Zebrafish Models of Human Leukemia: Technological Advances and Mechanistic Insights

    PubMed Central

    Harrison, Nicholas R.; Laroche, Fabrice J.F.; Gutierrez, Alejandro

    2016-01-01

    Insights concerning leukemic pathophysiology have been acquired in various animal models and further efforts to understand the mechanisms underlying leukemic treatment resistance and disease relapse promise to improve therapeutic strategies. The zebrafish (Danio rerio) is a vertebrate organism with a conserved hematopoietic program and unique experimental strengths suiting it for the investigation of human leukemia. Recent technological advances in zebrafish research including efficient transgenesis, precise genome editing, and straightforward transplantation techniques have led to the generation of a number of leukemia models. The transparency of the zebrafish when coupled with improved lineage-tracing and imaging techniques has revealed exquisite details of leukemic initiation, progression, and regression. With these advantages, the zebrafish represents a unique experimental system for leukemic research and additionally, advances in zebrafish-based high-throughput drug screening promise to hasten the discovery of novel leukemia therapeutics. To date, investigators have accumulated knowledge of the genetic underpinnings critical to leukemic transformation and treatment resistance and without doubt, zebrafish are rapidly expanding our understanding of disease mechanisms and helping to shape therapeutic strategies for improved outcomes in leukemic patients. PMID:27165361

  8. Developing Advanced Human Support Technologies for Planetary Exploration Missions

    NASA Technical Reports Server (NTRS)

    Berdich, Debra P.; Campbell, Paul D.; Jernigan, J. Mark

    2004-01-01

    The United States Vision for Space Exploration calls for sending robots and humans to explore the Earth's moon, the planet Mars, and beyond. The National Aeronautics and Space Administration (NASA) is developing a set of design reference missions that will provide further detail to these plans. Lunar missions are expected to provide a stepping stone, through operational research and evaluation, in developing the knowledge base necessary to send crews on long duration missions to Mars and other distant destinations. The NASA Exploration Systems Directorate (ExSD), in its program of bioastronautics research, manages the development of technologies that maintain human life, health, and performance in space. Using a system engineering process and risk management methods, ExSD's Human Support Systems (HSS) Program selects and performs research and technology development in several critical areas and transfers the results of its efforts to NASA exploration mission/systems development programs in the form of developed technologies and new knowledge about the capabilities and constraints of systems required to support human existence beyond Low Earth Orbit. HSS efforts include the areas of advanced environmental monitoring and control, extravehicular activity, food technologies, life support systems, space human factors engineering, and systems integration of all these elements. The HSS Program provides a structured set of deliverable products to meet the needs of exploration programs. These products reduce the gaps that exist in our knowledge of and capabilities for human support for long duration, remote space missions. They also reduce the performance gap between the efficiency of current space systems and the greater efficiency that must be achieved to make human planetary exploration missions economically and logistically feasible. In conducting this research and technology development program, it is necessary for HSS technologists and program managers to develop a

  9. Human Exploration Spacecraft Testbed for Integration and Advancement (HESTIA)

    NASA Technical Reports Server (NTRS)

    Banker, Brian F.; Robinson, Travis

    2016-01-01

    The proposed paper will cover ongoing effort named HESTIA (Human Exploration Spacecraft Testbed for Integration and Advancement), led at the National Aeronautics and Space Administration (NASA) Johnson Space Center (JSC) to promote a cross-subsystem approach to developing Mars-enabling technologies with the ultimate goal of integrated system optimization. HESTIA also aims to develop the infrastructure required to rapidly test these highly integrated systems at a low cost. The initial focus is on the common fluids architecture required to enable human exploration of mars, specifically between life support and in-situ resource utilization (ISRU) subsystems. An overview of the advancements in both integrated technologies, in infrastructure, in simulation, and in modeling capabilities will be presented, as well as the results and findings of integrated testing,. Due to the enormous mass gear-ratio required for human exploration beyond low-earth orbit, (for every 1 kg of payload landed on Mars, 226 kg will be required on Earth), minimization of surface hardware and commodities is paramount. Hardware requirements can be minimized by reduction of equipment performing similar functions though for different subsystems. If hardware could be developed which meets the requirements of both life support and ISRU it could result in the reduction of primary hardware and/or reduction in spares. Minimization of commodities to the surface of mars can be achieved through the creation of higher efficiency systems producing little to no undesired waste, such as a closed-loop life support subsystem. Where complete efficiency is impossible or impractical, makeup commodities could be manufactured via ISRU. Although, utilization of ISRU products (oxygen and water) for crew consumption holds great promise of reducing demands on life support hardware, there exist concerns as to the purity and transportation of commodities. To date, ISRU has been focused on production rates and purities for

  10. Image segmentation applied to atherosclerotic lesion

    NASA Astrophysics Data System (ADS)

    Morales, R. Rodríguez; Martínez, T. E. Alarcón; Cuello, L. Sánchez; Fernández-Britto, J. E.; Taylor, Charles

    2000-10-01

    The results obtained using two techniques: a supervised method and other unsupervised for image segmentation of atherosclerotic lesions of the thoracic aorta, are presented. Segmentation was used both with and without pre-processing. In this paper, the advantages of pre-processing prior to are shown for discriminating among the different atherosclerotic lesions (fatty streaks, fibrous plaque, complicated plaques and calcified plaques) and identifying them. The results using a supervised method were poor when searching vector consisted of two components, the mean and the variance. This digital image processing was done in order to use the automated atherometric system. This methodology has been considered to be suitable for the characterization of the atherosclerotic lesions in any artery and its organ-related damage in any vascular sector or group of patients. Final results were compared with manual segmentation realized by an expert, where difference errors less than 3% were observed. It is demonstrated by extensive experimentation, using real image data, that proposed strategy is fast and robust in the environment of a personal computer.

  11. Morphology of atherosclerotic coronary arteries

    NASA Astrophysics Data System (ADS)

    Holme, Margaret N.; Schulz, Georg; Deyhle, Hans; Hieber, Simone Elke; Weitkamp, Timm; Beckmann, Felix; Herzen, Julia; Lobrinus, Johannes A.; Montecucco, Fabrizio; Mach, François; Zumbuehl, Andreas; Saxer, Till; Müller, Bert

    2012-10-01

    Atherosclerosis, the narrowing of vessel diameter and build-up of plaques in coronary arteries, leads to an increase in the shear stresses present, which can be used as a physics-based trigger for targeted drug delivery. In order to develop appropriate nanometer-size containers, one has to know the morphology of the critical stenoses with isotropic micrometer resolution. Micro computed tomography in absorption and phase contrast mode provides the necessary spatial resolution and contrast. The present communication describes the pros and cons of the conventional and synchrotron radiation-based approaches in the visualization of diseased human and murine arteries. Using registered datasets, it also demonstrates that multi-modal imaging, including established histology, is even more powerful. The tomography data were evaluated with respect to cross-section, vessel radius and maximal constriction. The average cross-section of the diseased human artery (2.31 mm2) was almost an order of magnitude larger than the murine one (0.27 mm2), whereas the minimal radius differs only by a factor of two (0.51 mm versus 0.24 mm). The maximal constriction, however, was much larger for the human specimen (85% versus 49%). We could also show that a plastic model used for recent experiments in targeted drug delivery represents a very similar morphology, which is, for example, characterized by a maximal constriction of 82%. The tomography data build a sound basis for flow simulations, which allows for conclusions on shear stress distributions in stenosed blood vessels.

  12. Indium-111-labeled LDL: A potential agent for imaging atherosclerotic disease and lipoprotein biodistribution

    SciTech Connect

    Rosen, J.M.; Butler, S.P.; Meinken, G.E.; Wang, T.S.; Ramakrishnan, R.; Srivastava, S.C.; Alderson, P.O.; Ginsberg, H.N. )

    1990-03-01

    Radiolabeling of low-density lipoprotein (LDL) and external imaging with a gamma camera would offer a means of taking advantage of the metabolic activity of developing atherosclerotic lesions in order to noninvasively detect and determine the extent of atherosclerotic cardiovascular disease. Indium-111-({sup 111}In) labeled LDL was prepared and its purity demonstrated by agarose electrophoresis and ultracentrifugation. In vitro studies with cultured human fibroblasts demonstrated significant inhibition of iodine-125-({sup 125}I) LDL binding to LDL receptors by {sup 111}In-LDL, although this was less than the inhibition produced by unlabeled LDL. Adrenal gland uptake of {sup 111}In-LDL by hypercholesterolemic rabbits was reduced by 86% compared to the level of uptake observed in normal rabbits. These results were compatible with downregulation of adrenal LDL receptors in the hypercholesterolemic rabbits. Uptake of {sup 111}In-LDL in the atherosclerotic proximal aorta of hypercholesterolemic rabbits was 2.5 times higher than in normal rabbits. These results suggest that {sup 111}In-LDL has the potential to be a useful agent for external imaging of atherosclerotic lesions and lipoprotein biodistribution.

  13. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

    PubMed Central

    Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D.; Kuriakose, George; Colas, Romain A.; Dorweiler, Bernhard; Connolly, E. Sander; Solomon, Robert; Jones, David M.; Heyer, Eric J.; Spite, Matthew; Tabas, Ira

    2016-01-01

    Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB4), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr−/− mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB4 ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability. PMID:27659679

  14. Opening plenary speaker: Human genomics, precision medicine, and advancing human health.

    PubMed

    Green, Eric D

    2016-08-01

    Starting with the launch of the Human Genome Project in 1990, the past quarter-century has brought spectacular achievements in genomics that dramatically empower the study of human biology and disease. The human genomics enterprise is now in the midst of an important transition, as the growing foundation of genomic knowledge is being used by researchers and clinicians to tackle increasingly complex problems in biomedicine. Of particular prominence is the use of revolutionary new DNA sequencing technologies for generating prodigious amounts of DNA sequence data to elucidate the complexities of genome structure, function, and evolution, as well as to unravel the genomic bases of rare and common diseases. Together, these developments are ushering in the era of genomic medicine. Augmenting the advances in human genomics have been innovations in technologies for measuring environmental and lifestyle information, electronic health records, and data science; together, these provide opportunities of unprecedented scale and scope for investigating the underpinnings of health and disease. To capitalize on these opportunities, U.S. President Barack Obama recently announced a major new research endeavor - the U.S. Precision Medicine Initiative. This bold effort will be framed around several key aims, which include accelerating the use of genomically informed approaches to cancer care, making important policy and regulatory changes, and establishing a large research cohort of >1 million volunteers to facilitate precision medicine research. The latter will include making the partnership with all participants a centerpiece feature in the cohort's design and development. The Precision Medicine Initiative represents a broad-based research program that will allow new approaches for individualized medical care to be rigorously tested, so as to establish a new evidence base for advancing clinical practice and, eventually, human health.

  15. Xyloketal B Attenuates Atherosclerotic Plaque Formation and Endothelial Dysfunction in Apolipoprotein E Deficient Mice

    PubMed Central

    Zhao, Li-Yan; Li, Jie; Yuan, Feng; Li, Mei; Zhang, Quan; Huang, Yun-Ying; Pang, Ji-Yan; Zhang, Bin; Sun, Fang-Yun; Sun, Hong-Shuo; Li, Qian; Cao, Lu; Xie, Yu; Lin, Yong-Cheng; Liu, Jie; Tan, Hong-Mei; Wang, Guan-Lei

    2015-01-01

    Our previous studies demonstrated that xyloketal B, a novel marine compound with a unique chemical structure, has strong antioxidant actions and can protect against endothelial injury in different cell types cultured in vitro and model organisms in vivo. The oxidative endothelial dysfunction and decrease in nitric oxide (NO) bioavailability are critical for the development of atherosclerotic lesion. We thus examined whether xyloketal B had an influence on the atherosclerotic plaque area in apolipoprotein E-deficient (apoE−/−) mice fed a high-fat diet and investigated the underlying mechanisms. We found in our present study that the administration of xyloketal B dose-dependently decreased the atherosclerotic plaque area both in the aortic sinus and throughout the aorta in apoE−/− mice fed a high-fat diet. In addition, xyloketal B markedly reduced the levels of vascular oxidative stress, as well as improving the impaired endothelium integrity and NO-dependent aortic vasorelaxation in atherosclerotic mice. Moreover, xyloketal B significantly changed the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt without altering the expression of total eNOS and Akt in cultured human umbilical vein endothelial cells (HUVECs). Here, it increased eNOS phosphorylation at the positive regulatory site of Ser-1177, while inhibiting phosphorylation at the negative regulatory site of Thr-495. Taken together, these findings indicate that xyloketal B has dramatic anti-atherosclerotic effects in vivo, which is partly due to its antioxidant features and/or improvement of endothelial function. PMID:25874925

  16. Pulsatile Flow Studies in Atherosclerotic Carotid Bifurcations

    NASA Astrophysics Data System (ADS)

    Bale-Glickman, Jocelyn; Selby, Kathy; Saloner, David; Savas, Omer

    2001-11-01

    Particle image velocimetry and flow visualization techniques are used to study flows in models of atherosclerotic carotid bifurcations. The flow models exactly replicate the interior geometry of plaque excised from patients. The input flows are physiological wave forms derived from Doppler Ultrasound scans done on patients before surgery. The systolic and diastolic Reynolds numbers are 300 and 900. The complex internal geometry of the diseased artery combined with the pulsatile input flow results in exceedingly complex flow patterns. These flow patterns include internal jets, three-dimensional shear layers, stagnation lines, and multiple recirculation and separation regions. The physiological input flows are compared to flows when the wave form is sinusoidal.

  17. Endovascular revascularization for aortoiliac atherosclerotic disease

    PubMed Central

    Aggarwal, Vikas; Waldo, Stephen W; Armstrong, Ehrin J

    2016-01-01

    Atherosclerotic iliac artery disease is increasingly being treated with endovascular techniques. A number of new stent technologies can be utilized with high long-term patency, including self-expanding stents, balloon-expandable stents, and covered stents, but comparative data on these stent types and in more complex lesions are lacking. This article provides a review of currently available iliac stent technologies, as well as complex procedural aspects of iliac artery interventions, including approaches to the treatment of iliac bifurcation disease, long segment occlusions, choice of stent type, and treatment of iliac artery in-stent restenosis. PMID:27099509

  18. Atherosclerotic renal artery stenosis: Current status

    PubMed Central

    Kwon, Soon Hyo; Lerman, Lilach O.

    2014-01-01

    Atherosclerotic renal artery stenosis (ARAS) remains a major cause of secondary hypertension and renal failure. Randomized, prospective trials show that medical treatment should constitute the main therapeutic approach in ARAS. Regardless of intensive treatment and adequate blood pressure control, however, renal and extra-renal complications are not uncommon. Yet, the precise mechanisms, accurate detection, and optimal treatment in ARAS remain elusive. Strategies oriented to early detection and targeting these pathogenic pathways might prevent development of clinical endpoints. Here, we review the results of recent clinical trials, current understanding of the pathogenic mechanisms, novel imaging techniques to assess renal damage in ARAS, and treatment options. PMID:25908472

  19. Technical Advancement and Human Progress and The Problems of Education.

    ERIC Educational Resources Information Center

    Bixby, Louis W.

    1980-01-01

    Projects and discusses possible future developments resulting from electrochemical technological advancements. Educational implications are explored, and examples of integrated learning in diverse interest areas are given. (CS)

  20. Quercetin modulates toll-like receptor-mediated protein kinase signaling pathways in oxLDL-challenged human PBMCs and regulates TLR-activated atherosclerotic inflammation in hypercholesterolemic rats.

    PubMed

    Bhaskar, Shobha; Helen, A

    2016-12-01

    Toll-like receptors (TLRs) are pattern recognition receptors that have a unique and essential function in innate immunity. The effect of quercetin on TLR-mediated downstream signaling mechanism and its effect on TLR-mediated MAP kinase and Akt pathways were studied in oxLDL-stimulated hPBMCs using specific inhibitors. The pretreatment of hPBMCs with specific TLR inhibitor, CLI-095, decreased the NF-κB nuclear translocation and TNF-α release by oxLDL. When the cells treated with inhibitor and quercetin together, the inhibition was more effective. The specific inhibitor for p38 MAPK, SB203580, reduced the phosphorylated p38 level and decreased the NF-κB activation and TNF-α release by oxLDL-challenged hPBMCs. This inhibitor showed enhanced inhibition when treated with quercetin together. The inhibitors for ERK1/2, PD98059, and for JNK, SP606125, also showed inhibitory effect on NF-κB activation and TNF-α release by oxLDL-simulated hPBMCs. Quercetin supplementation enhanced the inhibition of nuclear translocation of NF-κB and the release of cytokines. TLR4 inhibition study confirmed the downstream signaling mechanism mediated by NF-κB which is involved in the oxLDL-induced inflammatory response, and quercetin suppresses the cytokine, TNF-α release by modulating TLR-NF-κB signaling pathway. In addition to NF-κB signaling pathway, inflammation induced by oxLDL was also related to the activation of p38MAPK, ERK1/2 and JNK, and Akt pathways, and the protective effect of quercetin may be also related to the inhibition of activation of these pathways. Quercetin significantly downregulated the elevated mRNA expression of TLRs and cytokine TNF-α in HCD-fed atherosclerotic rats in vivo. As quercetin possesses inhibition on both TLR-NF-κB signaling pathway and TLR-mediated MAPK pathway, it is evident that it can be used as a therapeutic agent to ameliorate atherosclerotic inflammation. Since quercetin is the major flavonoid and forms the backbone of many other

  1. Short rendezvous missions for advanced Russian human spacecraft

    NASA Astrophysics Data System (ADS)

    Murtazin, Rafail F.; Budylov, Sergey G.

    2010-10-01

    The two-day stay of crew in a limited inhabited volume of the Soyuz-TMA spacecraft till docking to ISS is one of the most stressful parts of space flight. In this paper a number of possible ways to reduce the duration of the free flight phase are considered. The duration is defined by phasing strategy that is necessary for reduction of the phase angle between the chaser and target spacecraft. Some short phasing strategies could be developed. The use of such strategies creates more comfortable flight conditions for crew thanks to short duration and additionally it allows saving spacecraft's life support resources. The transition from the methods of direct spacecraft rendezvous using one orbit phasing (first flights of " Vostok" and " Soyuz" vehicles) to the currently used methods of two-day rendezvous mission can be observed in the history of Soviet manned space program. For an advanced Russian human rated spacecraft the short phasing strategy is recommended, which can be considered as a combination between the direct and two-day rendezvous missions. The following state of the art technologies are assumed available: onboard accurate navigation; onboard computations of phasing maneuvers; launch vehicle with high accuracy injection orbit, etc. Some operational requirements and constraints for the strategies are briefly discussed. In order to provide acceptable phase angles for possible launch dates the experience of the ISS altitude profile control can be used. As examples of the short phasing strategies, the following rendezvous missions are considered: direct ascent, short mission with the phasing during 3-7 orbits depending on the launch date (nominal or backup). For each option statistical modeling of the rendezvous mission is fulfilled, as well as an admissible phase angle range, accuracy of target state vector and addition fuel consumption coming out of emergency is defined. In this paper an estimation of pros and cons of all options is conducted.

  2. Dengue human infection models to advance dengue vaccine development.

    PubMed

    Larsen, Christian P; Whitehead, Stephen S; Durbin, Anna P

    2015-12-10

    Dengue viruses (DENV) currently infect approximately 400 million people each year causing millions to seek care and overwhelming the health care infrastructure in endemic areas. Vaccines to prevent dengue and therapeutics to treat dengue are not currently available. The efficacy of the most advanced candidate vaccine against symptomatic dengue in general and DENV-2 in particular was much lower than expected, despite the ability of the vaccine to induce neutralizing antibody against all four DENV serotypes. Because seroconversion to the DENV serotypes following vaccination was thought to be indicative of induced protection, these results have made it more difficult to assess which candidate vaccines should or should not be evaluated in large studies in endemic areas. A dengue human infection model (DHIM) could be extremely valuable to down-select candidate vaccines or therapeutics prior to engaging in efficacy trials in endemic areas. Two DHIM have been developed to assess the efficacy of live attenuated tetravalent (LATV) dengue vaccines. The first model, developed by the Laboratory of Infectious Diseases at the U. S. National Institutes of Health, utilizes a modified DENV-2 strain DEN2Δ30. This virus was derived from the DENV-2 Tonga/74 that caused only very mild clinical infection during the outbreak from which it was recovered. DEN2Δ30 induced viremia in 100%, rash in 80%, and neutropenia in 27% of the 30 subjects to whom it was given. The Walter Reed Army Institute of Research (WRAIR) is developing a DHIM the goal of which is to identify DENV that cause symptomatic dengue fever. WRAIR has evaluated seven viruses and has identified two that meet dengue fever criteria. Both of these models may be very useful in the evaluation and down-selection of candidate dengue vaccines and therapeutics.

  3. Fiber-Optic System for Dual-Modality Imaging of Glucose Probes 18F-FDG and 6-NBDG in Atherosclerotic Plaques

    PubMed Central

    Zaman, Raiyan T.; Kosuge, Hisanori; Pratx, Guillem; Carpenter, Colin; Xing, Lei; McConnell, Michael V.

    2014-01-01

    Background Atherosclerosis is a progressive inflammatory condition that underlies coronary artery disease (CAD)–the leading cause of death in the United States. Thus, the ultimate goal of this research is to advance our understanding of human CAD by improving the characterization of metabolically active vulnerable plaques within the coronary arteries using a novel catheter-based imaging system. The aims of this study include (1) developing a novel fiber-optic imaging system with a scintillator to detect both 18F and fluorescent glucose probes, and (2) validating the system on ex vivo murine plaques. Methods A novel design implements a flexible fiber-optic catheter consisting of both a radio-luminescence and a fluorescence imaging system to detect radionuclide 18F-fluorodeoxyglucose (18F-FDG) and the fluorescent analog 6-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-Deoxyglucose (6-NBDG), respectively. Murine macrophage-rich atherosclerotic carotid plaques were imaged ex vivo after intravenous delivery of 18F-FDG or 6-NBDG. Confirmatory optical imaging by IVIS-200 and autoradiography were also performed. Results Our fiber-optic imaging system successfully visualized both 18F-FDG and 6-NBDG probes in atherosclerotic plaques. For 18F-FDG, the ligated left carotid arteries (LCs) exhibited 4.9-fold higher radioluminescence signal intensity compared to the non-ligated right carotid arteries (RCs) (2.6×104±1.4×103 vs. 5.4×103±1.3×103 A.U., P = 0.008). Similarly, for 6-NBDG, the ligated LCs emitted 4.3-fold brighter fluorescent signals than the control RCs (1.6×102±2.7×101 vs. 3.8×101±5.9 A.U., P = 0.002). The higher uptake of both 18F-FDG and 6-NBDG in ligated LCs were confirmed with the IVIS-200 system. Autoradiography further verified the higher uptake of 18F-FDG by the LCs. Conclusions This novel fiber-optic imaging system was sensitive to both radionuclide and fluorescent glucose probes taken up by murine atherosclerotic plaques. In addition, 6

  4. Human factors of advanced technology (glass cockpit) transport aircraft

    NASA Technical Reports Server (NTRS)

    Wiener, Earl L.

    1989-01-01

    A three-year study of airline crews at two U.S. airlines who were flying an advanced technology aircraft, the Boeing 757 is discussed. The opinions and experiences of these pilots as they view the advanced, automated features of this aircraft, and contrast them with previous models they have flown are discussed. Training for advanced automation; (2) cockpit errors and error reduction; (3) management of cockpit workload; and (4) general attitudes toward cockpit automation are emphasized. The limitations of the air traffic control (ATC) system on the ability to utilize the advanced features of the new aircraft are discussed. In general the pilots are enthusiastic about flying an advanced technology aircraft, but they express mixed feelings about the impact of automation on workload, crew errors, and ability to manage the flight.

  5. Thermal compression and molding of atherosclerotic vascular tissue with use of radiofrequency energy: implications for radiofrequency balloon angioplasty

    SciTech Connect

    Lee, B.I.; Becker, G.J.; Waller, B.F.; Barry, K.J.; Connolly, R.J.; Kaplan, J.; Shapiro, A.R.; Nardella, P.C.

    1989-04-01

    The combined delivery of pressure and thermal energy may effectively remodel intraluminal atherosclerotic plaque and fuse intimal tears. To test these hypotheses with use of a non-laser thermal energy source, radiofrequency energy was delivered to postmortem human atherosclerotic vessels from a metal hot-tip catheter, block-mounted bipolar electrodes and from a prototype radiofrequency balloon catheter. Sixty-two radiofrequency doses delivered from a metal electrode tip produced dose-dependent ablation of atherosclerotic plaque, ranging from clean and shallow craters with histologic evidence of thermal compression at doses less than 40 J to tissue charring and vaporization at higher (greater than 80 J) doses. Lesion dimensions ranged between 3.14 and 3.79 mm in diameter and 0.20 and 0.47 mm in depth. Tissue perforation was not observed. To test the potential for radiofrequency fusion of intimal tears, 5 atm of pressure and 200 J radiofrequency energy were delivered from block-mounted bipolar electrodes to 48 segments of human atherosclerotic aorta, which had been manually separated into intima-media and media-adventitial layers. Significantly stronger tissue fusion resulted (28.5 +/- 3.3 g) with radiofrequency compared with that with pressure alone (4.8 +/- 0.26 g; p less than 0.0001). A prototype radiofrequency balloon catheter was used to deliver 3 atm of balloon pressure with or without 200 J radiofrequency energy to 20 postmortem human atherosclerotic arterial segments. In 10 of 10 radiofrequency-treated vessels, thermal molding of both normal and atherosclerotic vessel wall segments resulted with increased luminal diameter and histologic evidence of medial myocyte damage.

  6. The vulnerable and unstable atherosclerotic plaque.

    PubMed

    Fishbein, Michael C

    2010-01-01

    The lesion responsible for the overwhelming majority of acute coronary events is plaque disruption or erosion with superimposed thrombosis. The term "vulnerable plaque" has been used to describe those atherosclerotic plaques that are particularly susceptible to disruption. Vulnerable plaques are generally characterized as those having a thin inflamed fibrous cap over a very large lipid core. However, only a small percentage of such plaques rupture, and plaques with different characteristics may also rupture and thrombose. Most autopsy, intravascular ultrasound, and recent computed tomography angiographic studies of coronary arteries reveal large plaques at sites of rupture. While angiographic data are said to show less severe narrowing at sites of plaque rupture, actual review of data indicates that, even angiographically, more than 50% of plaques have greater than 75% cross-sectional area stenosis at sites of plaque rupture. If plaque rupture is more common at the shoulder region of a plaque, one could envision that this would be at a peripheral site of the plaque where the plaque may not be as large or occlusive. New knowledge about vulnerable plaques is emerging through the evolution of novel techniques used to study plaques in vivo. These methods combine sophisticated imaging techniques, often in conjunction with molecular biomarkers, that provide new insights into plaque biology. Since atherosclerotic coronary artery disease is such a widespread and fatal disease, it is important that we continue to strive for a greater understanding of the nature of the vulnerable plaque. Only then can rational interventions for this disorder be developed and implemented.

  7. The development and evaluation of human factors guidelines for the review of advanced human-system interfaces

    SciTech Connect

    O`Hara, J.M.

    1992-09-01

    Advanced control rooms for future nuclear power plants are being designed utilizing computer-based technologies. The US Nuclear Regulatory Commission reviews the human engineering of such control rooms to ensure that they are designed to good human factors engineering principles and that operator performance and reliability are approximately supported in order to protect public health and safety. This paper describes the rationale, general approach, and initial development of an NRC Advanced Control Room Design Review Guideline.

  8. Cell proliferation in human coronary arteries.

    PubMed Central

    Gordon, D; Reidy, M A; Benditt, E P; Schwartz, S M

    1990-01-01

    Despite the lack of direct evidence for cell multiplication, proliferation of smooth muscle cells in human atherosclerotic lesions has been assumed to play a central role in ontogeny of the plaque. We used antibodies to cell cycle-related proteins on tissue sections of human arteries and coronary atherosclerotic plaques. Specific cell types were identified by immunochemical reagents for smooth muscle, monocyte-macrophages, and other blood cells. Low rates of smooth muscle cell proliferation were observed. Macrophages were also observed with rates of proliferation comparable to that of the smooth muscle. Additional replicating cells could not be defined as belonging to specific cell types with the reagents used in this study. These findings imply that smooth muscle replication in advanced plaques is indolent and raise the possibility of a role for proliferating leukocytes. Images PMID:1972277

  9. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

    NASA Astrophysics Data System (ADS)

    Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

    2014-01-01

    Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

  10. A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation

    PubMed Central

    Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S.G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J.M.

    2014-01-01

    Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation. PMID:24445279

  11. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation.

    PubMed

    Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P; Mieszawska, Aneta J; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J; Zaidi, Neeha; Lobatto, Mark E; van Rijs, Sarian M; Priem, Bram; Kuan, Emma L; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J; Stroes, Erik S G; Fuster, Valentin; Fisher, Edward A; Fayad, Zahi A; Mulder, Willem J M

    2014-01-01

    Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

  12. Positron emission tomography of the vulnerable atherosclerotic plaque in man – a contemporary review

    PubMed Central

    Pedersen, Sune F; Hag, Anne Mette F; Klausen, Thomas L; Ripa, Rasmus S; Bodholdt, Rasmus P; Kjær, Andreas

    2014-01-01

    Atherosclerosis is the primary underlying cause of cardiovascular disease (CVD). It is the leading cause of morbidity and mortality in the Western world today and is set to become the prevailing disease and major cause of death worldwide by 2020. In the 1950s surgical intervention was introduced to treat symptomatic patients with high-grade carotid artery stenosis due to atherosclerosis – a procedure known as carotid endarterectomy (CEA). By removing the atherosclerotic plaque from the affected carotid artery of these patients, CEA is beneficial by preventing subsequent ipsilateral ischemic stroke. However, it is known that patients with low to intermediate artery stenosis may still experience ischemic events, leading clinicians to consider plaque composition as an important feature of atherosclerosis. Today molecular imaging can be used for characterization, visualization and quantification of cellular and subcellular physiological processes as they take place in vivo; using this technology we can obtain valuable information on atherosclerostic plaque composition. Applying molecular imaging clinically to atherosclerotic disease therefore has the potential to identify atherosclerotic plaques vulnerable to rupture. This could prove to be an important tool for the selection of patients for CEA surgery in a health system increasingly focused on individualized treatment. This review focuses on current advances and future developments of in vivo atherosclerosis PET imaging in man. PMID:24289282

  13. Selepressin and Arginine Vasopressin Do Not Display Cardiovascular Risk in Atherosclerotic Rabbit

    PubMed Central

    Boucheix, Olivier; Blakytny, Robert; Haroutunian, Gerard; Henriksson, Marie; Laporte, Regent; Milano, Stephane; Reinheimer, Torsten M.

    2016-01-01

    Background Septic shock remains associated with significant mortality rates. Arginine vasopressin (AVP) and analogs with V1A receptor agonist activity are increasingly used to treat fluid-resistant vasodilatory hypotension, including catecholamine-refractory septic shock. Clinical studies have been restricted to healthy volunteers and catecholamine-refractory septic shock patients excluding subjects with cardiac co-morbidities because of presumed safety issues. The novel selective V1A receptor agonist selepressin, with short half-life, has been designed to avoid V2 receptor-related complications and long-term V1A receptor activation. Cardiovascular safety of selepressin, AVP, and the septic shock standard of care norepinephrine was investigated in a rabbit model of early-stage atherosclerosis. Methods Atherosclerosis was established in New Zealand White rabbits using a 1% cholesterol-containing diet. Selepressin, AVP, or norepinephrine was administered as cumulative intravenous infusion rates to atherosclerotic and non-atherosclerotic animals. Results Selepressin and AVP induced a slight dose-dependent increase in arterial pressure (AP) associated with a moderate decrease in heart rate, no change in stroke volume, and a moderate decrease in aortic blood flow (ABF). In contrast, norepinephrine induced a marked dose-dependent increase in AP associated with a lesser decrease in the heart rate, an increase in stroke volume, and a moderate increase in ABF. For all three vasopressors, there was no difference in responses between atherosclerotic and non-atherosclerotic animals. Conclusion Further studies should be considered using more advanced atherosclerosis models, including with septic shock, before considering septic shock clinical trials of patients with comorbidities. Here, selepressin and AVP treatments did not display relevant cardiovascular risk in early-stage rabbit atherosclerosis. PMID:27788216

  14. Atherosclerotic plaque regression: fact or fiction?

    PubMed

    Shanmugam, Nesan; Román-Rego, Ana; Ong, Peter; Kaski, Juan Carlos

    2010-08-01

    Coronary artery disease is the major cause of death in the western world. The formation and rapid progression of atheromatous plaques can lead to serious cardiovascular events in patients with atherosclerosis. The better understanding, in recent years, of the mechanisms leading to atheromatous plaque growth and disruption and the availability of powerful HMG CoA-reductase inhibitors (statins) has permitted the consideration of plaque regression as a realistic therapeutic goal. This article reviews the existing evidence underpinning current therapeutic strategies aimed at achieving atherosclerotic plaque regression. In this review we also discuss imaging modalities for the assessment of plaque regression, predictors of regression and whether plaque regression is associated with a survival benefit.

  15. Pulsatile Flow Studies in Atherosclerotic Carotid Bifurcation

    NASA Astrophysics Data System (ADS)

    Bale-Glickman, Jocelyn; Selby, Kathy; Saloner, David; Savas, Omer

    2002-11-01

    Particle image velocimetry and flow visualization techniques are used to study flow in models of atherosclerotic carotid bifurcations. The models exactly replicate the interior geometry of plaque excised from patients. The input flow is a physiological waveform derived from Doppler Ultrasound scans done on the patients before surgery. The systolic and diastolic Reynolds numbers are 200 and 900 respectively. The complex internal geometry of the diseased artery combined with the pulsatile input flows give exceedingly complex flow patterns. These flow patterns include internal jets, three-dimensional shear layers, stagnation lines, and multiple recirculation and separation regions. Ensemble averaged and instantaneous flow fields are compared. Wall shear stresses at the stenoses are estimated to be on the order of 10 PA. The physiological input flows are also compared to flows when the waveform is sinusoidal.

  16. Potential Anti-Atherosclerotic Properties of Astaxanthin

    PubMed Central

    Kishimoto, Yoshimi; Yoshida, Hiroshi; Kondo, Kazuo

    2016-01-01

    Astaxanthin is a naturally occurring red carotenoid pigment classified as a xanthophyll, found in microalgae and seafood such as salmon, trout, and shrimp. This review focuses on astaxanthin as a bioactive compound and outlines the evidence associated with its potential role in the prevention of atherosclerosis. Astaxanthin has a unique molecular structure that is responsible for its powerful antioxidant activities by quenching singlet oxygen and scavenging free radicals. Astaxanthin has been reported to inhibit low-density lipoprotein (LDL) oxidation and to increase high-density lipoprotein (HDL)-cholesterol and adiponectin levels in clinical studies. Accumulating evidence suggests that astaxanthin could exert preventive actions against atherosclerotic cardiovascular disease (CVD) via its potential to improve oxidative stress, inflammation, lipid metabolism, and glucose metabolism. In addition to identifying mechanisms of astaxanthin bioactivity by basic research, much more epidemiological and clinical evidence linking reduced CVD risk with dietary astaxanthin intake is needed. PMID:26861359

  17. Ophthalmic masquerades of the atherosclerotic carotids

    PubMed Central

    Arthur, Anupriya; Alexander, Anika; Bal, Simerpreet; Sivadasan, Ajith; Aaron, Sanjith

    2014-01-01

    Patients with carotid atherosclerosis can present with ophthalmic symptoms. These symptoms and signs can be due to retinal emboli, hypoperfusion of the retina and choroid, opening up of collateral channels, or chronic hypoperfusion of the globe (ocular ischemic syndrome). These pathological mechanisms can produce many interesting signs and a careful history can bring out important past symptoms pointing toward the carotid as the source of the patient's presenting symptom. Such patients are at high risk for an ischemic stroke, especially in the subsequent few days following their first acute symptom. It is important for clinicians to be familiar with these ophthalmic symptoms and signs caused by carotid atherosclerosis for making an early diagnosis and to take appropriate measures to prevent a stroke. This review elaborates the clinical features, importance, and implications of various ophthalmic symptoms and signs resulting from atherosclerotic carotid artery disease. PMID:24817748

  18. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses

    PubMed Central

    Lanvin, Thomas; Conkey, Donald B.; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-01-01

    We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal. PMID:26203381

  19. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses.

    PubMed

    Lanvin, Thomas; Conkey, Donald B; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-07-01

    We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal.

  20. [Advances on research of human exposure to triclosan].

    PubMed

    Jin, Chenye; Chen, Yiming; Zhang, Peiqi; Xiong, Zhezhen; Wang, Caifeng; Tian, Ying

    2016-03-01

    Triclosan, a broad-spectrum antimicrobial agent, was reported to have been widely detected in various human biological samples such as urine, blood and human milk among foreign populations. In China, limited reports have been found on human exposure to triclosan, and the reported urinary triclosan concentrations were significantly lower than that of American populations. Besides, the potential influencing factors still remain unclear regarding human exposure to triclosan, but evidences suggest that those in middle age and with higher household income and higher social class tend to have higher urinary triclosan concentrations. Furthermore, triclosan exposure tend to differ by sex, geography, heredity, metabolism and life style.

  1. Human Intelligence: An Introduction to Advances in Theory and Research.

    ERIC Educational Resources Information Center

    Lohman, David F.

    1989-01-01

    Recent advances in three research traditions are summarized: trait theories of intelligence, information-processing theories of intelligence, and general theories of thinking. Work on fluid and crystallized abilities by J. Horn and R. Snow, mental speed, spatial visualization, cognitive psychology, artificial intelligence, and the construct of…

  2. Planetary protection issues in advance of human exploration of Mars

    NASA Technical Reports Server (NTRS)

    Mckay, Christopher P.; Davis, Wanda L.

    1989-01-01

    The major planetary quarantine issues associated with human exploration of Mars, which is viewed as being more likely to harbor indigenous life than is the moon, are discussed. Special attention is given to the environmental impact of human missions to Mars due to contamination and mechanical disturbances of the local environment, the contamination issues associated with the return of humans, and the planetary quarantine strategy for a human base. It is emphasized that, in addition to the question of indigenous life, there may be some concern of returning to earth the earth microorganisms that have spent some time in the Martian environment. It is suggested that, due to the fact that a robot system can be subjected to more stringent controls and protective treatments than a mission involving humans, a robotic sample return mission can help to eliminate many planetary-quarantine concerns about returning samples.

  3. Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

    PubMed Central

    Wei, Shu-jian; Zhang, Ming-xiang; Wang, Xu-ping; Yuan, Qiu-huan; Xue, Li; Wang, Jia-li; Cui, Zhao-qiang; Zhang, Yun; Xu, Feng; Chen, Yu-guo

    2016-01-01

    Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE−/− mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE−/− mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways. PMID:27191745

  4. The effects of human interest framing in television news coverage of medical advances.

    PubMed

    Hong, Hyehyun

    2013-01-01

    The last few decades have witnessed the increasing dissemination of information on medical advances such as new medical treatments and prevention/diagnosis technologies through television news. To engage lay audiences with complex information, medical journalists often personalize news stories about medical advances by exemplifying individual patients and their personal experiences. This study investigates the effects of this journalistic technique, which is referred to as human interest framing, on audiences. The results of an experiment provide empirical evidence that the human interest framing of medical news stories can increase audiences' involvement in those stories and facilitate their positive perception of medical advances.

  5. How to manage hypertension with atherosclerotic renal artery stenosis?

    PubMed

    Ricco, Jean-Baptiste; Belmonte, Romain; Illuminati, Guilio; Barral, Xavier; Schneider, Fabrice; Chavent, Bertrand

    2017-04-01

    The management of atherosclerotic renal artery stenosis (ARAS) in patients with hypertension has been the topic of great controversy. Major contemporary clinical trials such as the Cardiovascular Outcomes for Renal Artery lesions (CORAL) and Angioplasty and Stenting for Renal Atherosclerotic lesions (ASTRAL) have failed to show significant benefit of revascularization over medical management in controlling blood pressure and preserving renal function. We present here the implications and limitations of these trials and formulate recommendations for management of ARAS.

  6. High-Density Lipoprotein Mimetics: a Therapeutic Tool for Atherosclerotic Diseases.

    PubMed

    Ikenaga, Masahiro; Higaki, Yasuki; Saku, Keijiro; Uehara, Yoshinari

    2016-01-01

    Clinical trials and epidemiological studies have revealed a negative correlation between serum high-density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular events. Currently, statin treatment is the standard therapy for cardiovascular diseases, reducing plasma low-density lipoprotein (LDL) cholesterol levels. However, more than half of the patients have not been able to receive the beneficial effects of this treatment.The reverse cholesterol transport pathway has several potential anti-atherogenic properties. An important approach to HDL-targeted therapy is the optimization of HDL cholesterol levels and function in the blood to enhance the removal of circulating cholesterol and to prevent or mitigate inflammation that causes atherosclerosis. Cholesteryl ester transfer protein inhibitors increase HDL cholesterol levels in humans, but whether they reduce the risk of atherosclerotic diseases is unknown. HDL therapies using HDL mimetics, including reconstituted HDL, apolipoprotein (Apo) A-IMilano, ApoA-I mimetic peptides, or full-length ApoA-I, are highly effective in animal models. In particular, the Fukuoka University ApoA-I-mimetic peptide (FAMP) effectively removes cholesterol via the ABCA1 transporter and acts as an anti-atherosclerotic agent by enhancing the biological functions of HDL without elevating HDL cholesterol levels.Our literature review suggests that HDL mimetics have significant atheroprotective potential and are a therapeutic tool for atherosclerotic diseases.

  7. Modeling of Mechanical Stress Exerted by Cholesterol Crystallization on Atherosclerotic Plaques

    PubMed Central

    Cui, Dongyao; Yu, Xiaojun; Chen, Si; Liu, Xinyu; Tang, Hongying; Wang, Xianghong; Liu, Linbo

    2016-01-01

    Plaque rupture is the critical cause of cardiovascular thrombosis, but the detailed mechanisms are not fully understood. Recent studies have found abundant cholesterol crystals in ruptured plaques, and it has been proposed that the rapid expansion of cholesterol crystals in a limited space during crystallization may contribute to plaque rupture. To evaluate the effect of cholesterol crystal growth on atherosclerotic plaques, we modeled the expansion of cholesterol crystals during the crystallization process in the necrotic core and estimated the stress on the thin cap with different arrangements of cholesterol crystals. We developed a two-dimensional finite element method model of atherosclerotic plaques containing expanding cholesterol crystals and investigated the effect of the magnitude and distribution of crystallization on the peak circumferential stress born by the cap. Using micro-optical coherence tomography (μOCT), we extracted the cross-sectional geometric information of cholesterol crystals in human atherosclerotic aorta tissue ex vivo and applied the information to the model. The results demonstrate that (1) the peak circumference stress is proportionally dependent on the cholesterol crystal growth; (2) cholesterol crystals at the cap shoulder impose the highest peak circumference stress; and (3) spatial distributions of cholesterol crystals have a significant impact on the peak circumference stress: evenly distributed cholesterol crystals exert less peak circumferential stress on the cap than concentrated crystals. PMID:27149381

  8. Advanced human-system interface design review guideline. Evaluation procedures and guidelines for human factors engineering reviews

    SciTech Connect

    O`Hara, J.M.; Brown, W.S.; Baker, C.C.; Welch, D.L.; Granda, T.M.; Vingelis, P.J.

    1994-07-01

    Advanced control rooms will use advanced human-system interface (HSI) technologies that may have significant implications for plant safety in that they will affect the operator`s overall role in the system, the method of information presentation, and the ways in which operators interact with the system. The U.S. Nuclear Regulatory Commission (NRC) reviews the HSI aspects of control rooms to ensure that they are designed to good human factors engineering principles and that operator performance and reliability are appropriately supported to protect public health and safety. The principal guidance available to the NRC, however, was developed more than ten years ago, well before these technological changes. Accordingly, the human factors guidance needs to be updated to serve as the basis for NRC review of these advanced designs. The purpose of this project was to develop a general approach to advanced HSI review and the human factors guidelines to support. NRC safety reviews of advanced systems. This two-volume report provides the results of the project. Volume I describes the development of the Advanced HSI Design Review Guideline (DRG) including (1) its theoretical and technical foundation, (2) a general model for the review of advanced HSIs, (3) guideline development in both hard-copy and computer-based versions, and (4) the tests and evaluations performed to develop and validate the DRG. Volume I also includes a discussion of the gaps in available guidance and a methodology for addressing them. Volume 2 provides the guidelines to be used for advanced HSI review and the procedures for their use.

  9. Advanced control rooms and crew performance issues: Implications for human reliability

    SciTech Connect

    O'Hara, J.M.; Hall, R.E.

    1991-01-01

    Recent trends in advanced control room (ACR) design are considered with respect to their impact on human performance. It is concluded that potentially negative influences exist, however, a variety of factors make it difficult to model, analyze, and quantify these effects for human reliability analyses (HRAs).

  10. Advanced control rooms and crew performance issues: Implications for human reliability

    SciTech Connect

    O`Hara, J.M.; Hall, R.E.

    1991-12-31

    Recent trends in advanced control room (ACR) design are considered with respect to their impact on human performance. It is concluded that potentially negative influences exist, however, a variety of factors make it difficult to model, analyze, and quantify these effects for human reliability analyses (HRAs).

  11. Advance techniques for monitoring human tolerance to positive Gz accelerations

    NASA Technical Reports Server (NTRS)

    Pelligra, R.; Sandler, H.; Rositano, S.; Skrettingland, K.; Mancini, R.

    1973-01-01

    Tolerance to positive g accelerations was measured in ten normal male subjects using both standard and advanced techniques. In addition to routine electrocardiogram, heart rate, respiratory rate, and infrared television, monitoring techniques during acceleration exposure included measurement of peripheral vision loss, noninvasive temporal, brachial, and/or radial arterial blood flow, and automatic measurement of indirect systolic and diastolic blood pressure at 60-sec intervals. Although brachial and radial arterial flow measurements reflected significant cardiovascular changes during and after acceleration, they were inconsistent indices of the onset of grayout or blackout. Temporal arterial blood flow, however, showed a high correlation with subjective peripheral light loss.

  12. Human rights advances in women's reproductive health in Africa.

    PubMed

    Ngwena, Charles G; Brookman-Amissah, Eunice; Skuster, Patty

    2015-05-01

    The African Commission on Human and Peoples' Rights recently adopted General Comment No 2 to interpret provisions of Article 14 of the Protocol to the African Charter on the Rights Women. The provisions relate to women's rights to fertility control, contraception, family planning, information and education, and abortion. The present article highlights the General Comment's potential to promote women's sexual and reproductive rights in multiple ways. The General Comment's human rights value goes beyond providing states with guidance for framing their domestic laws, practices, and policies to comply with treaty obligations. General Comment No 2 is invaluable in educating all stakeholders-including healthcare providers, lawyers, policymakers, and judicial officers at the domestic level-about pertinent jurisprudence. Civil society and human rights advocates can use the General Comment to render the state accountable for failure to implement its treaty obligations.

  13. Generating human serotonergic neurons in vitro: Methodological advances.

    PubMed

    Vadodaria, Krishna C; Marchetto, Maria C; Mertens, Jerome; Gage, Fred H

    2016-11-01

    Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this mini-review, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling. Also see the video abstract here.

  14. Human Factors Evaluation of Advanced Electric Power Grid Visualization Tools

    SciTech Connect

    Greitzer, Frank L.; Dauenhauer, Peter M.; Wierks, Tamara G.; Podmore, Robin

    2009-04-01

    This report describes initial human factors evaluation of four visualization tools (Graphical Contingency Analysis, Force Directed Graphs, Phasor State Estimator and Mode Meter/ Mode Shapes) developed by PNNL, and proposed test plans that may be implemented to evaluate their utility in scenario-based experiments.

  15. Advanced Research Training in Human Geography: The Scottish Experience

    ERIC Educational Resources Information Center

    Gwanzura-Ottemoeller, Fungisai; Hopkins, Peter; Lorimer, Hayden; Philip, Lorna J.

    2005-01-01

    Formal research training is integral to research degrees in human geography completed in UK higher education institutions today. The Economic and Social Research Council (ESRC) has been the driving force behind the formalization of research training. Arguably less well known among the ESRC research training recommendations is the stipulation that…

  16. Heat Shock Proteins: Mediators of Atherosclerotic Development.

    PubMed

    Deniset, Justin F; Pierce, Grant N

    2015-01-01

    Heat shock proteins play important housekeeping roles in a variety of cells within the body during normal control conditions. The many different functions for heat shock proteins in the cell depend upon the specific heat shock protein involved. Each protein is nominally differentiated based upon its molecular size. However, in addition to their role in normal cell function, heat shock proteins may play an even more important role as pro-survival proteins conserved through evolution to protect the cell from a variety of stresses. The ability of a cell to withstand these environmental stresses is critical to its capacity to adapt and remain viable. Loss of this ability may lead to pathological states. Abnormal localization, structure or function of the heat shock proteins has been associated with many pathologies, including those involving heart disease. Heat shock proteins like HSP60 and HSP70 in particular have been identified as playing important roles in inflammation and immune reactions. Inflammation has been identified recently as an important pathological risk factor for heart disease. It is perhaps not surprising therefore, that heat shock protein family has been increasingly identified as an important intracellular pathway associated with inflammatory-mediated heart conditions including atherosclerosis. This paper reviews the evidence in support of a role for heat shock proteins in cardiovascular disease and the potential to target these proteins to alter the progression of atherosclerotic disease.

  17. Oncolytic virotherapy for human malignant mesothelioma: recent advances.

    PubMed

    Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François

    2015-01-01

    Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM.

  18. Oncolytic virotherapy for human malignant mesothelioma: recent advances

    PubMed Central

    Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François

    2015-01-01

    Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM. PMID:27512676

  19. Human toxocariasis: current advances in diagnostics, treatment, and interventions.

    PubMed

    Moreira, Gustavo Marçal Schmidt Garcia; Telmo, Paula de Lima; Mendonça, Marcelo; Moreira, Angela Nunes; McBride, Alan John Alexander; Scaini, Carlos James; Conceição, Fabricio Rochedo

    2014-09-01

    Toxocariasis is a neglected zoonosis caused by the nematodes Toxocara canis and Toxocara cati. This disease is widespread in many countries, reaching high prevalence independently of the economic conditions. However, the true number of cases of toxocariasis is likely to be underestimated owing to the lack of adequate surveillance programs. Although some diagnostic tests are available, their sensitivity and specificity need to be improved. In addition, treatment options for toxocariasis are limited and are non-specific. Toxocariasis is listed as one of the five most important neglected diseases by the CDC. This review presents recent advances related to the control of toxocariasis, including new immunodiagnostics, therapies, and drug formulations, as well as novel interventions using DNA vaccines, immunomodulators, and probiotics.

  20. Recent advances in computational mechanics of the human knee joint.

    PubMed

    Kazemi, M; Dabiri, Y; Li, L P

    2013-01-01

    Computational mechanics has been advanced in every area of orthopedic biomechanics. The objective of this paper is to provide a general review of the computational models used in the analysis of the mechanical function of the knee joint in different loading and pathological conditions. Major review articles published in related areas are summarized first. The constitutive models for soft tissues of the knee are briefly discussed to facilitate understanding the joint modeling. A detailed review of the tibiofemoral joint models is presented thereafter. The geometry reconstruction procedures as well as some critical issues in finite element modeling are also discussed. Computational modeling can be a reliable and effective method for the study of mechanical behavior of the knee joint, if the model is constructed correctly. Single-phase material models have been used to predict the instantaneous load response for the healthy knees and repaired joints, such as total and partial meniscectomies, ACL and PCL reconstructions, and joint replacements. Recently, poromechanical models accounting for fluid pressurization in soft tissues have been proposed to study the viscoelastic response of the healthy and impaired knee joints. While the constitutive modeling has been considerably advanced at the tissue level, many challenges still exist in applying a good material model to three-dimensional joint simulations. A complete model validation at the joint level seems impossible presently, because only simple data can be obtained experimentally. Therefore, model validation may be concentrated on the constitutive laws using multiple mechanical tests of the tissues. Extensive model verifications at the joint level are still crucial for the accuracy of the modeling.

  1. Recent Advances in Computational Mechanics of the Human Knee Joint

    PubMed Central

    Kazemi, M.; Dabiri, Y.; Li, L. P.

    2013-01-01

    Computational mechanics has been advanced in every area of orthopedic biomechanics. The objective of this paper is to provide a general review of the computational models used in the analysis of the mechanical function of the knee joint in different loading and pathological conditions. Major review articles published in related areas are summarized first. The constitutive models for soft tissues of the knee are briefly discussed to facilitate understanding the joint modeling. A detailed review of the tibiofemoral joint models is presented thereafter. The geometry reconstruction procedures as well as some critical issues in finite element modeling are also discussed. Computational modeling can be a reliable and effective method for the study of mechanical behavior of the knee joint, if the model is constructed correctly. Single-phase material models have been used to predict the instantaneous load response for the healthy knees and repaired joints, such as total and partial meniscectomies, ACL and PCL reconstructions, and joint replacements. Recently, poromechanical models accounting for fluid pressurization in soft tissues have been proposed to study the viscoelastic response of the healthy and impaired knee joints. While the constitutive modeling has been considerably advanced at the tissue level, many challenges still exist in applying a good material model to three-dimensional joint simulations. A complete model validation at the joint level seems impossible presently, because only simple data can be obtained experimentally. Therefore, model validation may be concentrated on the constitutive laws using multiple mechanical tests of the tissues. Extensive model verifications at the joint level are still crucial for the accuracy of the modeling. PMID:23509602

  2. Human Factors Engineering Review Model for advanced nuclear power reactors

    SciTech Connect

    O'Hara, J.; Higgins, J. ); Goodman, C.; Galletti, G.: Eckenrode, R. )

    1993-01-01

    One of the major issues to emerge from the initial design reviews under the certification process was that detailed human-systems interface (HSI) design information was not available for staff review. To address the lack of design detail issue. The Nuclear Regulatory Commission (NRC) is performing the design certification reviews based on a design process plan which describes the human factors engineering (HFE) program elements that are necessary and sufficient to develop an acceptable detailed design specification. Since the review of a design process is unprecedented in the nuclear industry. The criteria for review are not addressed by current regulations or guidance documents and. therefore, had to be developed. Thus, an HFE Program Review Model was developed. This paper will describe the model's rationale, scope, objectives, development, general characteristics. and application.

  3. Human Factors Engineering Review Model for advanced nuclear power reactors

    SciTech Connect

    O`Hara, J.; Higgins, J.; Goodman, C.; Galletti, G.: Eckenrode, R.

    1993-05-01

    One of the major issues to emerge from the initial design reviews under the certification process was that detailed human-systems interface (HSI) design information was not available for staff review. To address the lack of design detail issue. The Nuclear Regulatory Commission (NRC) is performing the design certification reviews based on a design process plan which describes the human factors engineering (HFE) program elements that are necessary and sufficient to develop an acceptable detailed design specification. Since the review of a design process is unprecedented in the nuclear industry. The criteria for review are not addressed by current regulations or guidance documents and. therefore, had to be developed. Thus, an HFE Program Review Model was developed. This paper will describe the model`s rationale, scope, objectives, development, general characteristics. and application.

  4. Advances in Analysis of Human Milk Oligosaccharides123

    PubMed Central

    Ruhaak, L. Renee; Lebrilla, Carlito B.

    2012-01-01

    Oligosaccharides in human milk strongly influence the composition of the gut microflora of neonates. Because it is now clear that the microflora play important roles in the development of the infant immune system, human milk oligosaccharides (HMO) are studied frequently. Milk samples contain complex mixtures of HMO, usually comprising several isomeric structures that can be either linear or branched. Traditionally, HMO profiling was performed using HPLC with fluorescence or UV detection. By using porous graphitic carbon liquid chromatography MS, it is now possible to separate and identify most of the isomers, facilitating linkage-specific analysis. Matrix-assisted laser desorption ionization time-of-flight analysis allows fast profiling, but does not allow isomer separation. Novel MS fragmentation techniques have facilitated structural characterization of HMO that are present at lower concentrations. These techniques now facilitate more accurate studies of HMO consumption as well as Lewis blood group determinations. PMID:22585919

  5. Advance techniques for monitoring human tolerance to +Gz accelerations.

    NASA Technical Reports Server (NTRS)

    Pelligra, R.; Sandler, H.; Rositano, S.; Skrettingland, K.; Mancini, R.

    1972-01-01

    Standard techniques for monitoring the acceleration-stressed human subject have been augmented by measuring (1) temporal, brachial and/or radial arterial blood flow, and (2) indirect systolic and diastolic blood pressure at 60-sec intervals. Results show that the response of blood pressure to positive accelerations is complex and dependent on an interplay of hydrostatic forces, diminishing venous return, redistribution of blood, and other poorly defined compensatory reflexes.

  6. Advanced human-system interface design review guideline. General evaluation model, technical development, and guideline description

    SciTech Connect

    O`Hara, J.M.

    1994-07-01

    Advanced control rooms will use advanced human-system interface (HSI) technologies that may have significant implications for plant safety in that they will affect the operator`s overall role in the system, the method of information presentation, and the ways in which operators interact with the system. The U.S. Nuclear Regulatory Commission (NRC) reviews the HSI aspects of control rooms to ensure that they are designed to good human factors engineering principles and that operator performance and reliability are appropriately supported to protect public health and safety. The principal guidance available to the NRC, however, was developed more than ten years ago, well before these technological changes. Accordingly, the human factors guidance needs to be updated to serve as the basis for NRC review of these advanced designs. The purpose of this project was to develop a general approach to advanced HSI review and the human factors guidelines to support NRC safety reviews of advanced systems. This two-volume report provides the results of the project. Volume I describes the development of the Advanced HSI Design Review Guideline (DRG) including (1) its theoretical and technical foundation, (2) a general model for the review of advanced HSIs, (3) guideline development in both hard-copy and computer-based versions, and (4) the tests and evaluations performed to develop and validate the DRG. Volume I also includes a discussion of the gaps in available guidance and a methodology for addressing them. Volume 2 provides the guidelines to be used for advanced HSI review and the procedures for their use.

  7. The Myth of “The Vulnerable Plaque”: Transitioning from a Focus on Individual Lesions to Atherosclerotic Disease Burden for Coronary Artery Disease Risk Assessment

    PubMed Central

    Arbab-Zadeh, Armin; Fuster, Valentin

    2014-01-01

    The cardiovascular science community has pursued the quest to identify vulnerable atherosclerotic plaque in patients for decades, hoping to prevent acute coronary events. However, despite major advancements in imaging technology that allow visualization of rupture-prone plaques, clinical studies have not demonstrated improved risk prediction compared to traditional approaches. Considering the complex relationship between plaque rupture and acute coronary event risk suggested by pathology studies and confirmed by clinical investigations, these results are not surprising. This review summarizes the evidence supporting a multifaceted hypothesis of the natural history of atherosclerotic plaque rupture. Managing patients at risk of suffering acute coronary events mandates a greater focus on the atherosclerotic disease burden, rather than on features of individual plaques. PMID:25601032

  8. Human body composition: advances in models and methods.

    PubMed

    Heymsfield, S B; Wang, Z; Baumgartner, R N; Ross, R

    1997-01-01

    The field of human body composition research is reaching a mature stage in its development: The three interconnected areas that define body composition research--models and their rules, methodology, and biological effects--are well-defined and are actively investigated by scientists in diverse disciplines from many different nations; and methods are available for measuring all major atomic, molecular, cellular, and tissue-system level body composition components in research, clinical, and epidemiological settings. This review summarizes main body composition research concepts, examines new component-measurement methodologies, and identifies potential areas of future research.

  9. Nuclear microscopy of atherosclerotic tissue: A review

    NASA Astrophysics Data System (ADS)

    Watt, Frank; Ren, M. Q.; Xie, J. P.; Tan, B. K. H.; Halliwell, B.

    2001-07-01

    This paper reviews the work carried out in the Research Centre for Nuclear Microscopy, NUS on the role of iron in coronary heart disease, using the technique of nuclear microscopy to determine the levels of iron and other trace elements in the artery wall and lesions. These investigations have indicated that iron may play a significant role in the development of atherosclerosis, probably through the promotion of cytotoxic free radicals leading to the oxidation of low-density lipoprotein (LDL). Using a rabbit model we have observed that early atherosclerotic lesions, induced by feeding the animals on a 1% cholesterol diet, contain increased levels of iron (up to 8 times) compared with the adjacent healthy artery wall. In a follow-up time sequence study, we have shown that iron accumulation occurs at the onset of lesion formation, which takes place around 4-6 weeks after exposure to the 1% cholesterol diet. As the lesions mature, they enlarge to occupy a significant fraction of the artery wall, and at about 16 weeks the lesions begin to show signs of calcification. In an additional experiment, where the cholesterol fed rabbits were kept anaemic through weekly bleeding, the iron content of the artery wall was reduced and the onset of atherogenesis was delayed. In a further investigation, rabbits were fed on a 1% cholesterol diet and after 6 weeks (corresponding to the period of early lesion formation) a test group was subjected to treatment using the iron chelator desferal. Preliminary results indicate that during the treatment with desferal, lesion development was slowed down.

  10. Application of infrared fiber optic imaging in atherosclerotic plaques

    NASA Astrophysics Data System (ADS)

    Guo, Bujin; Casscells, S. W.; Bearman, Gregory H.; McNatt, Janice; Naghevi, Morteza; Malik, Basit A.; Gul, Khawar; Willerson, James T.

    1999-07-01

    Rupture of atherosclerotic plaques - the main cause of heart attach and stokes - is not predictable. Hence even treadmill stress tests fail to detect many persons at risk. Fatal plaques are found at autopsies to be associated with active inflammatory cells. Classically, inflammation is detected by its swelling, red color, pain and heat. We have found that heat accurately locates the dangerous plaques that are significantly warmer then atherosclerotic plaques without the same inflammation. In order to develop a non-surgical method of locating these plaques, an IR fiber optic imaging system has been developed in our laboratory to evalute the causes and effect of heat in atherosclerotic plaques. The fiber optical imagin bundle consists of 900 individual As2S3 chalcogenide glass fibers which transmit IR radiation from 0.7 micrometers 7 micrometers with little energy loss. By combining that with a highly sensitive Indium Antimonide IR focal plane array detector, we are able to obtain thermal graphic images in situ. The temperature heterogeneity of atherosclerotic plaques developed in the arteral of the experimental animal models is under study with the new device. The preliminary experimental results from the animal model are encouraging. The potential of using this new technology in diagnostic evaluation of the vulnerable atherosclerotic plaques is considerable.

  11. Ultrafast laser ablation for targeted atherosclerotic plaque removal

    NASA Astrophysics Data System (ADS)

    Lanvin, Thomas; Conkey, Donald B.; Descloux, Laurent; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-07-01

    Coronary artery disease, the main cause of heart disease, develops as immune cells and lipids accumulate into plaques within the coronary arterial wall. As a plaque grows, the tissue layer (fibrous cap) separating it from the blood flow becomes thinner and increasingly susceptible to rupturing and causing a potentially lethal thrombosis. The stabilization and/or treatment of atherosclerotic plaque is required to prevent rupturing and remains an unsolved medical problem. Here we show for the first time targeted, subsurface ablation of atherosclerotic plaque using ultrafast laser pulses. Excised atherosclerotic mouse aortas were ablated with ultrafast near-infrared (NIR) laser pulses. The physical damage was characterized with histological sections of the ablated atherosclerotic arteries from six different mice. The ultrafast ablation system was integrated with optical coherence tomography (OCT) imaging for plaque-specific targeting and monitoring of the resulting ablation volume. We find that ultrafast ablation of plaque just below the surface is possible without causing damage to the fibrous cap, which indicates the potential use of ultrafast ablation for subsurface atherosclerotic plaque removal. We further demonstrate ex vivo subsurface ablation of a plaque volume through a catheter device with the high-energy ultrafast pulse delivered via hollow-core photonic crystal fiber.

  12. CD44 Targeting Magnetic Glyconanoparticles for Atherosclerotic Plaque Imaging

    PubMed Central

    El-Dakdouki, Mohammad H.; El-Boubbou, Kheireddine; Kamat, Medha; Huang, Ruiping; Abela, George S.; Kiupel, Matti; Zhu, David C.; Huang, Xuefei

    2013-01-01

    Purpose The cell surface adhesion molecule CD44 plays important roles in the initiation and development of atherosclerotic plaques. We aim to develop nanoparticles that can selectively target CD44 for the non-invasive detection of atherosclerotic plaques by magnetic resonance imaging. Methods Magnetic glyco-nanoparticles with hyaluronan immobilized on the surface have been prepared. The binding of these nanoparticles with CD44 in vitro was evaluated by enzyme linked immunosorbent assay, flow cytometry and confocal microscopy. In vivo magnetic resonance imaging of plaques was performed on an atherosclerotic rabbit model. Results The magnetic glyconanoparticles can selectively bind CD44. In T2* weighted magnetic resonance images acquired in vivo, significant contrast changes in aorta walls were observed with a very low dose of the magnetic nanoparticles, allowing the detection of atherosclerotic plaques. Furthermore, imaging could be performed without significant delay after probe administration. The selectivity of hyaluronan nanoparticles in plaque imaging was established by several control experiments. Conclusions Magnetic nanoparticles bearing surface hyaluronan enabled the imaging of atherosclerotic plaques in vivo by magnetic resonance imaging. The low dose of nanoparticles required, the possibility to image without much delay and the high biocompatibility are the advantages of these nanoparticles as contrast agents for plaque imaging. PMID:23568520

  13. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.

    PubMed Central

    Hayek, T; Masucci-Magoulas, L; Jiang, X; Walsh, A; Rubin, E; Breslow, J L; Tall, A R

    1995-01-01

    The human cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins. The activity of CETP results in a reduction in HDL cholesterol levels, but CETP may also promote reverse cholesterol transport. Thus, the net impact of CETP expression on atherogenesis is uncertain. The influence of hypertriglyceridemia and CETP on the development of atherosclerotic lesions in the proximal aorta was assessed by feeding transgenic mice a high cholesterol diet for 16 wk. 13 out of 14 (93%) hypertriglyceridemic human apo CIII (HuCIII) transgenic (Tg) mice developed atherosclerotic lesions, compared to 18 out of 29 (62%) controls. In HuCIII/CETPTg, human apo AI/CIIITg and HuAI/CIII/CETPTg mice, 7 of 13 (54%), 5 of 10 (50%), and 5 of 13 (38%), respectively, developed lesions in the proximal aorta (P < .05 compared to HuCIIITg). The average number of aortic lesions per mouse in HuCIIITg and controls was 3.4 +/- 0.8 and 2.7 +/- 0.6, respectively in HuCIII/CETPTg, HuAI/CIIIg, and HuAI/CIII/CETPTg mice the number of lesions was significantly lower than in HuCIIITg and control mice: 0.9 +/- 0.4, 1.5 +/- 0.5, and 0.9 +/- 0.4, respectively. There were parallel reductions in mean lesion area. In a separate study, we found an increased susceptibility to dietary atherosclerosis in nonhypertriglyceridemic CETP transgenic mice compared to controls. We conclude that CETP expression inhibits the development of early atherosclerotic lesions but only in hypertriglyceridemic mice. PMID:7560101

  14. Advanced UV Absorbers for the Protection of Human Skin.

    PubMed

    Hüglin, Dietmar

    The increasing awareness of the damaging effects of UV radiation to human skin triggered the market introduction of new cosmetic UV absorbers. This article summarizes the outcome of a multi-year research program, in which the author contributed to the development of different new UV filters. First of all, the molecular design and the basic properties of bis-ethylhexyloxyphenol methoxyphenyl triazine (BEMT) will be presented. This oil-soluble filter, which today is widely used in both beach products and skin care products, exhibits inherent photostability and strong broad-spectrum UV-A+B absorbance. Based on the concept of micronized organic UV absorbers, the UV-B filter tris biphenyl triazine (TBPT) will be introduced. At present TBPT exhibits the highest efficacy of all cosmetic UV absorbers in the market (measured by area under the UV spectrum). Finally, the concept of liposomogenic UV absorbers will be featured. This approach was developed to create water-resistant UV filters, as liposomogenic structures are thought to integrate into the lipids of the horny layer. Due to prohibitively high costs, this technology did not result in a commercial product so far.

  15. Advanced Nuclear Power Concepts for Human Exploration Missions

    SciTech Connect

    Robert L. Cataldo; Lee S. Mason

    2000-06-04

    The design reference mission for the National Aeronautics and Space Administration's (NASA's) human mission to Mars supports a philosophy of living off the land in order to reduce crew risk, launch mass, and life-cycle costs associated with logistics resupply to a Mars base. Life-support materials, oxygen, water, and buffer gases, and the crew's ascent-stage propellant would not be brought from Earth but rather manufactured from the Mars atmosphere. The propellants would be made over {approx}2 yr, the time between Mars mission launch window opportunities. The production of propellants is very power intensive and depends on type, amount, and time to produce the propellants. Closed-loop life support and food production are also power intensive. With the base having several habitats, a greenhouse, and propellant production capability, total power levels reach well over 125 kW(electric). The most mass-efficient means of satisfying these requirements is through the use of nuclear power. Studies have been performed to identify a potential system concept, described in this paper, using a mobile cart to transport the power system away from the Mars lander and provide adequate separation between the reactor and crew. The studies included an assessment of reactor and power conversion technology options, selection of system and component redundancy, determination of optimum separation distance, and system performance sensitivity to some key operating parameters.

  16. Advanced Analysis of Pharmaco-Sleep Data in Humans.

    PubMed

    Anderer, Peter

    2015-01-01

    Pharmaco-sleep studies in humans aim at the description of the effects of drugs, most frequently substances that act on the central nervous system, by means of quantitative analysis of biosignals recorded in subjects during sleep. Up to 2007, the only standard for the classification of sleep macrostructure that found worldwide acceptance were the rules published in 1968 by Rechtschaffen and Kales. In May 2007, the AASM Manual for the Scoring of Sleep and Associated Events was published by the American Academy of Sleep Medicine, and concerning the classification of sleep stages, these new rules are supposed to replace those developed by Rechtschaffen and Kales. As compared to the rather low interrater reliability of manual sleep scoring, semiautomated approaches may achieve a reliability close to 1 (Cohen's kappa 0.99 for 2 semiautomated scorings as compared to 0.76 for 2 manual scorings) without any decline in validity. Depending on the aim of the pharmaco-sleep study, additional analyses concerning sleep fragmentation, sleep microstructure, sleep depth, sleep processes and local aspects of sleep should be considered. For some of these additional features, rules for visual scoring have been established, while for others automatic analysis is obligatory. Generally, for reasons of cost-effectiveness but also reliability, automatic analysis is preferable to visual analysis. However, the validity of the automatic method applied has to be proven.

  17. A Distributed Simulation Facility to Support Human Factors Research in Advanced Air Transportation Technology

    NASA Technical Reports Server (NTRS)

    Amonlirdviman, Keith; Farley, Todd C.; Hansman, R. John, Jr.; Ladik, John F.; Sherer, Dana Z.

    1998-01-01

    A distributed real-time simulation of the civil air traffic environment developed to support human factors research in advanced air transportation technology is presented. The distributed environment is based on a custom simulation architecture designed for simplicity and flexibility in human experiments. Standard Internet protocols are used to create the distributed environment, linking all advanced cockpit simulator, all Air Traffic Control simulator, and a pseudo-aircraft control and simulation management station. The pseudo-aircraft control station also functions as a scenario design tool for coordinating human factors experiments. This station incorporates a pseudo-pilot interface designed to reduce workload for human operators piloting multiple aircraft simultaneously in real time. The application of this distributed simulation facility to support a study of the effect of shared information (via air-ground datalink) on pilot/controller shared situation awareness and re-route negotiation is also presented.

  18. Validating a bimodal intravascular ultrasound (IVUS) and near-infrared fluorescence (NIRF) catheter for atherosclerotic plaque detection in rabbits

    PubMed Central

    Abran, Maxime; Stähli, Barbara E.; Merlet, Nolwenn; Mihalache-Avram, Teodora; Mecteau, Mélanie; Rhéaume, Eric; Busseuil, David; Tardif, Jean-Claude; Lesage, Frédéric

    2015-01-01

    Coronary artery disease is characterized by atherosclerotic plaque formation. Despite impressive advances in intravascular imaging modalities, in vivo molecular plaque characterization remains challenging, and different multimodality imaging systems have been proposed. We validated an engineered bimodal intravascular ultrasound imaging (IVUS) / near-infrared fluorescence (NIRF) imaging catheter in vivo using a balloon injury atherosclerosis rabbit model. Rabbit aortas and right iliac arteries were scanned in vivo after indocyanine green (ICG) injection, and compared to corresponding ex vivo fluorescence and white light images. Areas of ICG accumulation were colocalized with macroscopic atherosclerotic plaque formation. In vivo imaging was performed with the bimodal catheter integrating ICG-induced fluorescence signals into cross-sectional IVUS imaging. In vivo ICG accumulation corresponded to ex vivo fluorescence signal intensity and IVUS identified plaques. PMID:26504648

  19. Advanced Analysis of Pharmaco-EEG Data in Humans.

    PubMed

    Jobert, Marc; Wilson, Frederick J

    2015-01-01

    Pharmaco-electroencephalography (EEG) is a non-invasive method used to assess the effects of pharmacological compounds on the central nervous system by processing the EEG signals which directly reveal the spontaneous synchronised postsynaptic neuronal activity of the cortex with high temporal resolution. The International Pharmaco-Encephalography Society (IPEG) has recently published guidelines, which were produced by a global panel of EEG experts, with the goal to increase the standardisation of pharmaco-EEG studies in human subjects and facilitate the comparability of data across laboratories, thus enabling data-pooling and meta-analyses. The recommended standard experimental procedure is to measure EEG activity under vigilance-controlled and resting conditions. The IPEG guidelines thoroughly present the technical details and therefore constitute a robust reference. The complementary aim of the present paper is to focus on practical aspects, pitfalls and precautions to be considered when processing pharmaco-EEG data by covering the following topics: (1) investigate the stability and reliability of 5-min EEG recordings under both vigilance-controlled and resting conditions; (2) assess the spontaneous time-dependent changes in spectral activity over time, and (3) apply the data-processing strategies suggested in the pharmaco-EEG guidelines and designed to optimally capture drug effects. For this purpose, the EEG data from a randomised, double-blind, crossover trial aimed at comparing the effect of diazepam (10 mg) and placebo in 16 healthy male volunteers is used to illustrate the discussion of the processing techniques and difficulties commonly faced when analysing pharmaco-EEG data.

  20. Advanced human machine interaction for an image interpretation workstation

    NASA Astrophysics Data System (ADS)

    Maier, S.; Martin, M.; van de Camp, F.; Peinsipp-Byma, E.; Beyerer, J.

    2016-05-01

    In recent years, many new interaction technologies have been developed that enhance the usability of computer systems and allow for novel types of interaction. The areas of application for these technologies have mostly been in gaming and entertainment. However, in professional environments, there are especially demanding tasks that would greatly benefit from improved human machine interfaces as well as an overall improved user experience. We, therefore, envisioned and built an image-interpretation-workstation of the future, a multi-monitor workplace comprised of four screens. Each screen is dedicated to a complex software product such as a geo-information system to provide geographic context, an image annotation tool, software to generate standardized reports and a tool to aid in the identification of objects. Using self-developed systems for hand tracking, pointing gestures and head pose estimation in addition to touchscreens, face identification, and speech recognition systems we created a novel approach to this complex task. For example, head pose information is used to save the position of the mouse cursor on the currently focused screen and to restore it as soon as the same screen is focused again while hand gestures allow for intuitive manipulation of 3d objects in mid-air. While the primary focus is on the task of image interpretation, all of the technologies involved provide generic ways of efficiently interacting with a multi-screen setup and could be utilized in other fields as well. In preliminary experiments, we received promising feedback from users in the military and started to tailor the functionality to their needs

  1. Advancing human health risk assessment: Integrating recent advisory committee recommendations

    PubMed Central

    Becker, Richard A.; Haber, Lynne T.; Pottenger, Lynn H.; Bredfeldt, Tiffany; Fenner-Crisp, Penelope A.

    2013-01-01

    Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose–response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose–response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches. PMID:23844697

  2. High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis

    PubMed Central

    Wang, Yi; Qiu, Juhui; Luo, Shisui; Xie, Xiang; Zheng, Yiming; Zhang, Kang; Ye, Zhiyi; Liu, Wanqian; Gregersen, Hans; Wang, Guixue

    2016-01-01

    Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes. Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts. Shear stress (SS) influences the formation and development of atherosclerosis. The current review focuses on the vulnerable plaques observed in the high shear stress (HSS) regions, which localizes at the proximal region of the plaque intruding into the lumen. The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation. These results greatly challenge the established belief that low shear stress is important for expansive remodelling, which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions. PMID:27482467

  3. A Framework for Human Performance Criteria for Advanced Reactor Operational Concepts

    SciTech Connect

    Jacques V Hugo; David I Gertman; Jeffrey C Joe

    2014-08-01

    This report supports the determination of new Operational Concept models needed in support of the operational design of new reactors. The objective of this research is to establish the technical bases for human performance and human performance criteria frameworks, models, and guidance for operational concepts for advanced reactor designs. The report includes a discussion of operating principles for advanced reactors, the human performance issues and requirements for human performance based upon work domain analysis and current regulatory requirements, and a description of general human performance criteria. The major findings and key observations to date are that there is some operating experience that informs operational concepts for baseline designs for SFR and HGTRs, with the Experimental Breeder Reactor-II (EBR-II) as a best-case predecessor design. This report summarizes the theoretical and operational foundations for the development of a framework and model for human performance criteria that will influence the development of future Operational Concepts. The report also highlights issues associated with advanced reactor design and clarifies and codifies the identified aspects of technology and operating scenarios.

  4. Inspiring engineering minds to advance human health: the Henry Samueli School of Engineering's Department of BME.

    PubMed

    Lee, Abraham; Wirtanen, Erik

    2012-07-01

    The growth of biomedical engineering at The Henry Samueli School of Engineering at the University of California, Irvine (UCI) has been rapid since the Center for Biomedical Engineering was first formed in 1998 [and was later renamed as the Department of Biomedical Engineering (BME) in 2002]. Our current mission statement, “Inspiring Engineering Minds to Advance Human Health,” serves as a reminder of why we exist, what we do, and the core principles that we value and by which we abide. BME exists to advance the state of human health via engineering innovation and practices. To attain our goal, we are empowering our faculty to inspire and mobilize our students to address health problems. We treasure the human being, particularly the human mind and health. We believe that BME is where minds are nurtured, challenged, and disciplined, and it is also where the health of the human is held as a core mission value that deserves our utmost priority (Figure 1). Advancing human health is not a theoretical practice; it requires bridging between disciplines (engineering and medicine) and between communities (academic and industry).

  5. Increased apolipoprotein E and c-fms gene expression without elevated interleukin 1 or 6 mRNA levels indicates selective activation of macrophage functions in advanced human atheroma.

    PubMed Central

    Salomon, R N; Underwood, R; Doyle, M V; Wang, A; Libby, P

    1992-01-01

    Cells found within atherosclerotic lesions can produce in culture protein mediators that may participate in atherogenesis. To test whether human atheromata actually contain transcripts for certain of these genes, we compared levels of mRNAs in carotid or coronary atheromata and in nonatherosclerotic human vessels by polymerase chain reaction (PCR) amplification of cDNAs reverse-transcribed from RNA. We measured PCR products (generated during exponential amplification) by incorporation of 32P-labeled primers. Levels of interleukin 1 alpha, 1 beta, or 6 mRNAs in plaques and controls did not differ. Compared to uninvolved vessels, plaques did contain higher levels of mRNA encoding platelet-derived growth factor A chain (42 +/- 24 vs. 12 +/- 10 fmol of product; mean +/- SD; n = 8 and 8, respectively; P = 0.007) and B chain (41 +/- 36 vs. 4 +/- 3 fmol of product, n = 14 and 6, respectively; P = 0.024). Atherosclerotic lesions consistently had much higher levels of apolipoprotein E (apoE) mRNA than did control vessels (131 +/- 71 vs. 5 +/- 3 fmol of product; n = 12 and 10, respectively; P less than 0.001). Direct RNA blot analyses confirmed elevated levels of apoE mRNA in plaque extracts. To test whether mononuclear phagocytes might be a source of the apoE mRNA, we studied a selective marker for cells of the monocytic lineage, the c-fms protooncogene, which encodes the receptor for macrophage colony-stimulating factor. Plaques also contained elevated levels of c-fms mRNA (30 +/- 17 vs. 5 +/- 3 fmol of product; n = 10 and 7, respectively; P = 0.002). Immunohistochemical colocalization demonstrated apoE protein in association with macrophages in plaques, whereas nonatherosclerotic vessels showed no immunoreactive apoE. ApoE produced locally in atheroma might modulate the functions of lesional T cells or promote "reverse cholesterol transport" by associating with high density lipoprotein particles, thus targeting them for peripheral uptake. Macrophages within the advanced

  6. Placing Advanced Placement® Human Geography: Its Role in U.S. Geography Education

    ERIC Educational Resources Information Center

    Bednarz, Sarah Witham

    2016-01-01

    This article examines Advanced Placement Human Geography (AP HG) in the context of its place in efforts to reform geography education. It presents a critical analysis of the AP program and its curriculum, asserting that it represents "powerful knowledge" as conceptualized by Young. It concludes with a call for research in AP HG aligned…

  7. Advanced Placement Human Geography and the Annual Meetings of the National Council for Geographic Education

    ERIC Educational Resources Information Center

    Sublett, Michael D.

    2007-01-01

    Members of the National Council for Geographic Education have been instrumental in the creation, launch, and early success of Advanced Placement Human Geography. Annual meetings of the Council have served as a forum for spreading the word about the course and its follow-up national examination and in helping teachers develop content confidence and…

  8. Perspectives on the Development and Future of Advanced Placement® Human Geography

    ERIC Educational Resources Information Center

    Hildebrant, Barbara

    2016-01-01

    Advanced Placement (AP) Human Geography faced a number of hurdles that nearly derailed the course before it launched in 2000-2001. A dedicated cadre of geography professionals and high school teachers rose to the challenge and the course remains one of the fastest growing AP courses currently offered by College Board. Seventeen readers and leaders…

  9. Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques.

    PubMed

    Bradfield, Paul F; Menon, Arjun; Miljkovic-Licina, Marijana; Lee, Boris P; Fischer, Nicolas; Fish, Richard J; Kwak, Brenda; Fisher, Edward A; Imhof, Beat A

    2016-01-01

    Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies.

  10. Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques

    PubMed Central

    Miljkovic-Licina, Marijana; Lee, Boris P.; Fischer, Nicolas; Fish, Richard J.; Kwak, Brenda; Fisher, Edward A.; Imhof, Beat A.

    2016-01-01

    Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies. PMID:27442505

  11. Advanced glycation end products in human cancer tissues: detection of Nepsilon-(carboxymethyl)lysine and argpyrimidine.

    PubMed

    van Heijst, Jeroen W J; Niessen, Hans W M; Hoekman, Klaas; Schalkwijk, Casper G

    2005-06-01

    Tumors are generally characterized by an increased glucose uptake and a high rate of glycolysis. Since one consequence of an elevated glycolysis is the nonenzymatic glycation of proteins, we studied the presence of advanced glycation end products (AGEs) in human cancer tissues. We detected the presence of the AGEs N(epsilon)-(carboxymethyl)lysine (CML) and argpyrimidine in several human tumors using specific antibodies. Because AGEs have been associated with the etiology of a variety of different diseases, these results suggest that CML and argpyrimidine could be implicated in the biology of human cancer.

  12. Workshop on Critical Issues in Microgravity Fluids, Transport, and Reaction Processes in Advanced Human Support Technology

    NASA Technical Reports Server (NTRS)

    Chiaramonte, Francis P.; Joshi, Jitendra A.

    2004-01-01

    This workshop was designed to bring the experts from the Advanced Human Support Technologies communities together to identify the most pressing and fruitful areas of research where success hinges on collaborative research between the two communities. Thus an effort was made to bring together experts in both advanced human support technologies and microgravity fluids, transport and reaction processes. Expertise was drawn from academia, national laboratories, and the federal government. The intent was to bring about a thorough exchange of ideas and develop recommendations to address the significant open design and operation issues for human support systems that are affected by fluid physics, transport and reaction processes. This report provides a summary of key discussions, findings, and recommendations.

  13. Advances in Robotic, Human, and Autonomous Systems for Missions of Space Exploration

    NASA Technical Reports Server (NTRS)

    Gross, Anthony R.; Briggs, Geoffrey A.; Glass, Brian J.; Pedersen, Liam; Kortenkamp, David M.; Wettergreen, David S.; Nourbakhsh, I.; Clancy, Daniel J.; Zornetzer, Steven (Technical Monitor)

    2002-01-01

    Space exploration missions are evolving toward more complex architectures involving more capable robotic systems, new levels of human and robotic interaction, and increasingly autonomous systems. How this evolving mix of advanced capabilities will be utilized in the design of new missions is a subject of much current interest. Cost and risk constraints also play a key role in the development of new missions, resulting in a complex interplay of a broad range of factors in the mission development and planning of new missions. This paper will discuss how human, robotic, and autonomous systems could be used in advanced space exploration missions. In particular, a recently completed survey of the state of the art and the potential future of robotic systems, as well as new experiments utilizing human and robotic approaches will be described. Finally, there will be a discussion of how best to utilize these various approaches for meeting space exploration goals.

  14. Human-System Safety Methods for Development of Advanced Air Traffic Management Systems

    SciTech Connect

    Nelson, W.R.

    1999-05-24

    The Idaho National Engineering and Environmental Laboratory (INEEL) is supporting the National Aeronautics and Space Administration in the development of advanced air traffic management (ATM) systems as part of the Advanced Air Transportation Technologies program. As part of this program INEEL conducted a survey of human-system safety methods that have been applied to complex technical systems, to identify lessons learned from these applications and provide recommendations for the development of advanced ATM systems. The domains that were surveyed included offshore oil and gas, commercial nuclear power, commercial aviation, and military. The survey showed that widely different approaches are used in these industries, and that the methods used range from very high-level, qualitative approaches to very detailed quantitative methods such as human reliability analysis (HRA) and probabilistic safety assessment (PSA). In addition, the industries varied widely in how effectively they incorporate human-system safety assessment in the design, development, and testing of complex technical systems. In spite of the lack of uniformity in the approaches and methods used, it was found that methods are available that can be combined and adapted to support the development of advanced air traffic management systems.

  15. Effects of an Advanced Reactor’s Design, Use of Automation, and Mission on Human Operators

    SciTech Connect

    Jeffrey C. Joe; Johanna H. Oxstrand

    2014-06-01

    The roles, functions, and tasks of the human operator in existing light water nuclear power plants (NPPs) are based on sound nuclear and human factors engineering (HFE) principles, are well defined by the plant’s conduct of operations, and have been validated by years of operating experience. However, advanced NPPs whose engineering designs differ from existing light-water reactors (LWRs) will impose changes on the roles, functions, and tasks of the human operators. The plans to increase the use of automation, reduce staffing levels, and add to the mission of these advanced NPPs will also affect the operator’s roles, functions, and tasks. We assert that these factors, which do not appear to have received a lot of attention by the design engineers of advanced NPPs relative to the attention given to conceptual design of these reactors, can have significant risk implications for the operators and overall plant safety if not mitigated appropriately. This paper presents a high-level analysis of a specific advanced NPP and how its engineered design, its plan to use greater levels of automation, and its expanded mission have risk significant implications on operator performance and overall plant safety.

  16. In vitro atherosclerotic plaque and calcium quantitation by intravascular ultrasound and electron-beam computed tomography.

    PubMed

    Gutfinger, D E; Leung, C Y; Hiro, T; Maheswaran, B; Nakamura, S; Detrano, R; Kang, X; Tang, W; Tobis, J M

    1996-05-01

    The purpose of this investigation was to compare the accuracy of intravascular ultrasound (IVUS) and electron-beam computed tomography (EBCT) in quantitating human atherosclerotic plaque and calcium. In experiment 1, 12 human atherosclerotic arterial segments were obtained at autopsy and imaged by using IVUS and EBCT. The plaque from each arterial segment was dissected and a volume measurement of the dissected plaque was obtained by water displacement. The plaque from each arterial segment was ashed at 700 degrees F, and the weight of the remaining ashes was used as an estimate of the calcium mass. In experiment II, 11 calcified arterial segments were obtained at autopsy and imaged by using IVUS at one site along the artery. A corresponding histologic cross section stained with Masson's trichrome was prepared. In experiment I, the mean plaque volume measured by water displacement was 165.3 +/- 118.4 microliters. The mean plaque volume calculated by IVUS was 166.1 +/- 114.4 microliters and correlated closely with that by water displacement (r = 0.98, p < 0.0001). The mean calcium mass measured by ashing was 19.4 +/- 15.8 mg. The mean calculated calcium mass by EBCT was 19.9 mg and correlated closely with that by ashing (r=0.98, p<0.001). The mean calculated calcium volume by IVUS was 18.6 +/- 11.2 microliters and correlated linearly with the calcium mass by ashing (r = 0.87, p < 0.0003). In experiment II, the mean cross-sectional area of the calcified matrix was 1.71 +/- 0.66 mm2 by histologic examination compared with 1.44 +/- 0.66 mm2 by IVUS. There was a good correlation between the calcified cross-sectional area by histologic examination and IVUS (r = 0.76, p < 0.007); however, IVUS may underestimate the amount of calcium present depending on the intralesional calcium morphologic characteristics. In conclusion, IVUS accurately quantitates atherosclerotic plaque volume as well as the cross-sectional area and volume of intralesional calcium, especially if the

  17. Improving human forensics through advances in genetics, genomics and molecular biology.

    PubMed

    Kayser, Manfred; de Knijff, Peter

    2011-03-01

    Forensic DNA profiling currently allows the identification of persons already known to investigating authorities. Recent advances have produced new types of genetic markers with the potential to overcome some important limitations of current DNA profiling methods. Moreover, other developments are enabling completely new kinds of forensically relevant information to be extracted from biological samples. These include new molecular approaches for finding individuals previously unknown to investigators, and new molecular methods to support links between forensic sample donors and criminal acts. Such advances in genetics, genomics and molecular biology are likely to improve human forensic case work in the near future.

  18. In vivo determination of arterial collagen synthesis in atherosclerotic rabbits

    SciTech Connect

    Opsahl, W.P.; DeLuca, D.J.; Ehrhart, L.A.

    1986-03-01

    Collagen and non-collagen protein synthesis rates were determined in vivo in tissues from rabbits fed a control or atherogenic diet supplemented with 2% peanut oil and 0.25% cholesterol for 4 months. Rabbits received a bolus intravenous injection of L-(/sup 3/H)-proline (1.0 mCi/kg) and unlabeled L-proline (7 mmoles/kg) in 0.9% NaCl. Plasma proline specific activity decreased only 20% over 5 hr and was similar to the specific activity of free proline in tissues. Thoracic aortas from atherosclerotic rabbits exhibited raised plaques covering at least 75% of the surface. Thoracic intima plus a portion of the media (TIM) was separated from the remaining media plus adventitia (TMA). Dry delipidated weight, total collagen content, and collagen as a percent of dry weight were increased significantly in the TIM of atherosclerotic rabbits. Collagen synthesis rates and collagen synthesis as a percent of total protein synthesis were likewise increased both in the TIM and in the abdominal aortas. No differences from controls either in collagen content or collagen synthesis rates were observed in the TMA, lung or skin. These results demonstrate for the first time in vivo that formation of atherosclerotic plaques is associated with increased rates of collagen synthesis. Furthermore, as previously observed with incubations in vitro, collagen synthesis was elevated to a greater extent than noncollagen protein synthesis in atherosclerotic aortas from rabbits fed cholesterol plus peanut oil.

  19. Cap buckling as a potential mechanism of atherosclerotic plaque vulnerability.

    PubMed

    Abdelali, Maria; Reiter, Steven; Mongrain, Rosaire; Bertrand, Michel; L'Allier, Philippe L; Kritikou, Ekaterini A; Tardif, Jean-Claude

    2014-04-01

    Plaque rupture in atherosclerosis is the primary cause of potentially deadly coronary events, yet about 40% of ruptures occur away from the plaque cap shoulders and cannot be fully explained with the current biomechanical theories. Here, cap buckling is considered as a potential destabilizing factor which increases the propensity of the atherosclerotic plaque to rupture and which may also explain plaque failure away from the cap shoulders. To investigate this phenomenon, quasistatic 2D finite element simulations are performed, considering the salient geometrical and nonlinear material properties of diverse atherosclerotic plaques over the range of physiological loads. The numerical results indicate that buckling may displace the location of the peak von Mises stresses in the deflected caps. Plaque buckling, together with its deleterious effects is further observed experimentally in plaque caps using a physical model of deformable mock coronary arteries with fibroatheroma. Moreover, an analytical approach combining quasistatic equilibrium equations with the Navier-Bresse formulas is used to demonstrate the buckling potential of a simplified arched slender cap under intraluminal pressure and supported by foundations. This analysis shows that plaque caps - calcified, fibrotic or cellular - may buckle in specific undulated shapes once submitted to critical loads. Finally, a preliminary analysis of intravascular ultrasonography recordings of patients with atherosclerotic coronary arteries corroborates the numerical, experimental and theoretical findings and shows that various plaque caps buckle in vivo. By displacing the sites of high stresses in the plaque cap, buckling may explain the atherosclerotic plaque cap rupture at various locations, including cap shoulders.

  20. Atherosclerotic changes of vessels caused by restriction of movement

    NASA Technical Reports Server (NTRS)

    Gvishiani, G. S.; Kobakhidze, N. G.; Mchedlishvili, M. G.; Dekanosidze, T. I.

    1980-01-01

    The effect of restriction of movement on the development of atheroscelerosis was studied in rabbits. Drastic restriction of movement for 20 and 30 days causes atherosclerotic alterations of the aorta and shifts in ECG which are characteristic of coronary atherosclerosis. At the same time, shortening of the duration of blood coagulation and an increase in the content of catecholamines and beta-lipoproteids occur.

  1. Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

    PubMed Central

    Khambata, Rayomand S.; Ghosh, Suborno M.; Rathod, Krishnaraj S.; Thevathasan, Tharssana; Filomena, Federica; Xiao, Qingzhong; Ahluwalia, Amrita

    2017-01-01

    Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO3−) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitrate-fed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease. PMID:28057862

  2. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease.

    PubMed

    Hulsmans, Maarten; Holvoet, Paul

    2013-10-01

    In addition to intracellular organelles, eukaryotic cells contain extracellular organelles which are released, or shed, into the microenvironment. In practice, most human studies have examined mixed populations containing both exosomes and shedding microvesicles (also called ectosomes or microparticles); only a few studies have rigorously distinguished between the two. Accordingly, in this review, exosomes and shedding microvesicles are collectively called microvesicles. The first aim of this review was to discuss the role of microvesicles in cell-to-cell communication in general and in specific interactions between cells in chronic inflammation associated with atherosclerotic disease. Hereby, we focused on cell-specific microvesicles derived from platelets, endothelial cells and monocyte and monocyte-derived cells. The latter were also found to be associated with inflammation in obesity and type 2 diabetes prior to atherosclerotic disease, and cancer. Our second aim was to discuss specific changes in microvesicle content in relation with inflammation associated with metabolic and atherosclerotic disease, and cancer. Because many studies supported the putative diagnostic value of microRNAs, we emphasized therein changes in microRNA content rather than protein or lipid content. The most interesting microRNAs in inflammatory microvesicles in association with metabolic and cardiovascular diseases were found to be the let-7 family, miR-17/92 family, miR-21, miR-29, miR-126, miR-133, miR-146, and miR-155. These data warrant further investigation of the potential of microvesicles as putative biomarkers and as novel carriers for the cell-specific transfer of microRNAs and other therapeutic agents.

  3. Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice

    PubMed Central

    Dang, Vi T.; Huang, Aric; Zhong, Lexy H.; Shi, Yuanyuan; Werstuck, Geoff H.

    2016-01-01

    Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis. PMID:27721472

  4. A feasibility study of carotid elastography for risk assessment of atherosclerotic plaques validated by magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Pan, Xiaochang; Huang, Lingyun; Huang, Manwei; Zhao, Xihai; He, Le; Yuan, Chun; Bai, Jing; Luo, Jianwen

    2014-03-01

    Stroke is a leading cause of mortality worldwide. One of its main reasons is rupture of carotid atherosclerotic plaques. Conventional B-mode ultrasound images and Doppler/color flow measurements are mostly used to evaluate degree of stenosis, which underestimates plaque vulnerability. Alternatively, the correspondence between multi-contrast magnetic resonance imaging (MRI) features, plaque composition and histology has been well established. In this study, the feasibility of ultrasound carotid elastography in risk assessment of carotid atherosclerotic plaques is investigated. Preliminarily in-vivo results on a small number of human subjects are initially validated by multi-contrast, highresolution MRI, and it shows that maximum strain rate might be feasible to evaluate the plaque vulnerability.

  5. Some inadequacies of the current human factors certification process of advanced aircraft technologies

    NASA Technical Reports Server (NTRS)

    Paries, Jean

    1994-01-01

    Automation related accidents or serious incidents are not limited to advanced technology aircraft. There is a full history of such accidents with conventional technology aircraft. However, this type of occurrence is far from sparing the newest 'glass cockpit' generation, and it even seems to be a growing contributor to its accident rate. Nevertheless, all these aircraft have been properly certificated according to the relevant airworthiness regulations. Therefore, there is a growing concern that with the technological advancement of air transport aircraft cockpits, the current airworthiness regulations addressing cockpit design and human factors may have reached some level of inadequacy. This paper reviews some aspects of the current airworthiness regulations and certification process related to human factors of cockpit design and focuses on questioning their ability to guarantee the intended safety objectives.

  6. A significant correlation between C - reactive protein levels in blood monocytes derived macrophages versus content in carotid atherosclerotic lesions

    PubMed Central

    2014-01-01

    Background Atherosclerosis is a complex disease involving different cell types, including macrophages that play a major role in the inflammatory events occurring in atherogenesis. C-Reactive Protein (CRP) is a sensitive systemic marker of inflammation and was identified as a biomarker of cardiovascular diseases. Histological studies demonstrate CRP presence in human atherosclerotic lesions, and we have previously shown that macrophages express CRP mRNA. CRP could be locally secreted in the atherosclerotic lesion by arterial macrophages and local regulation of CRP could affect its pro-atherogenic effects. Moreover, human blood derived macrophages (HMDM) expression of CRP could reflect atherosclerotic lesion secretion of CRP. Methods Ten type 2 diabetic patients and ten non-diabetic patients scheduled to undergo carotid endarterectomy were enrolled in this study, and their blood samples were used for serum CRP, lipid determination, and for preparation of HMDM further analyzed for their CRP mRNA expression and CRP content. Carotid lesions obtained from the patients were analyzed for their CRP and interleukin 6 (IL-6) content by immunohistochemistry. Results Lesions from diabetic patients showed substantially higher CRP levels by 62% (p = 0.05) than lesions from non diabetic patients, and CRP staining that co-localized with arterial macrophages. CRP carotid lesion levels positively correlated with CRP mRNA expression (r2 = 0.661) and with CRP content (r2 = 0.611) in the patient’s HMDM. Conclusions Diabetes up-regulated carotid plaques CRP levels and CRP measurements in HMDM could reflect atherosclerotic lesion macrophages secretion of CRP. Understanding the regulation of locally produced macrophage CRP in the arterial wall during atherogenesis could be of major importance in identifying the underlying mechanisms of inflammatory response pathways during atherogenesis. PMID:24588988

  7. Correlation of Respirator Fit Measured on Human Subjects and a Static Advanced Headform

    DTIC Science & Technology

    2016-04-19

    where both the test Address correspondence to: Ziqing Zhuang, Deputy Branch Chief, Technology Research Branch, National Personal Protective Technology ...Ziqing Zhuang1, Brian K. Heimbuch2, Ronald E. Shaffer1, Melanie Choe3, and Joseph D. Wander4 1National Personal Protective Technology Laboratory...Static Advanced Headform (StAH) and 10 human test subjects. Quantitative fit evaluations were performed on test subjects who made three visits to the

  8. Open Innovation at NASA: A New Business Model for Advancing Human Health and Performance Innovations

    NASA Technical Reports Server (NTRS)

    Davis, Jeffrey R.; Richard, Elizabeth E.; Keeton, Kathryn E.

    2014-01-01

    This paper describes a new business model for advancing NASA human health and performance innovations and demonstrates how open innovation shaped its development. A 45 percent research and technology development budget reduction drove formulation of a strategic plan grounded in collaboration. We describe the strategy execution, including adoption and results of open innovation initiatives, the challenges of cultural change, and the development of virtual centers and a knowledge management tool to educate and engage the workforce and promote cultural change.

  9. Advanced Information Systems Design: Technical Basis and Human Factors Review Guidance

    DTIC Science & Technology

    2000-03-01

    H^ NUREG /CR-6633 BNL- NUREG -52563 Advanced Information Systems Design: Technical Basis and Human Factors Review Guidance Brookhaven National...AVAILABILITY NOTICE Availability of Reference Materials Cited in NRC Publications NRC publications in the NUREG series, NRC regu- lations, and Title...Information Service Springfield, VA 22161 -0002 <http://www.ntis.gov> 1 -800-553-6847 or locally 703-605-6000 The NUREG series comprises (1) brochures

  10. Advances in radiation biology: Relative radiation sensitivities of human organ systems. Volume 12

    SciTech Connect

    Lett, J.T.; Altman, K.I.; Ehmann, U.K.; Cox, A.B.

    1987-01-01

    This volume is a thematically focused issue of Advances in Radiation Biology. The topic surveyed is relative radiosensitivity of human organ systems. Topics considered include relative radiosensitivities of the thymus, spleen, and lymphohemopoietic systems; relative radiosensitivities of the small and large intestine; relative rediosensitivities of the oral cavity, larynx, pharynx, and esophagus; relative radiation sensitivity of the integumentary system; dose response of the epidermal; microvascular, and dermal populations; relative radiosensitivity of the human lung; relative radiosensitivity of fetal tissues; and tolerance of the central and peripheral nervous system to therapeutic irradiation.

  11. On recent advances in human engineering Provocative trends in embryology, genetics, and regenerative medicine.

    PubMed

    Anton, Roman

    2016-01-01

    Advances in embryology, genetics, and regenerative medicine regularly attract attention from scientists, scholars, journalists, and policymakers, yet implications of these advances may be broader than commonly supposed. Laboratories culturing human embryos, editing human genes, and creating human-animal chimeras have been working along lines that are now becoming intertwined. Embryogenic methods are weaving traditional in vivo and in vitro distinctions into a new "in vivitro" (in life in glass) fabric. These and other methods known to be in use or thought to be in development promise soon to bring society to startling choices and discomfiting predicaments, all in a global effort to supply reliably rejuvenating stem cells, to grow immunologically non-provocative replacement organs, and to prevent, treat, cure, or even someday eradicate diseases having genetic or epigenetic mechanisms. With humanity's human-engineering era now begun, procedural prohibitions, funding restrictions, institutional controls, and transparency rules are proving ineffective, and business incentives are migrating into the most basic life-sciences inquiries, wherein lie huge biomedical potentials and bioethical risks. Rights, health, and heritage are coming into play with bioethical presumptions and formal protections urgently needing reassessment.

  12. Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo

    PubMed Central

    Yang, Jing-Jing; Li, Peng; Wang, Fu; Liang, Wen-Jing; Ma, Hui; Chen, Yuan; Ma, Zhi-Min; Li, Quan-Zhong; Peng, Qi-Sheng; Zhang, Yun; Wang, Shuang-Xi

    2016-01-01

    Aims Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis. PMID:27391154

  13. Ultrafast optical-ultrasonic system and miniaturized catheter for imaging and characterizing atherosclerotic plaques in vivo

    PubMed Central

    Li, Jiawen; Ma, Teng; Mohar, Dilbahar; Steward, Earl; Yu, Mingyue; Piao, Zhonglie; He, Youmin; Shung, K. Kirk; Zhou, Qifa; Patel, Pranav M.; Chen, Zhongping

    2015-01-01

    Atherosclerotic coronary artery disease (CAD) is the number one cause of death worldwide. The majority of CAD-induced deaths are due to the rupture of vulnerable plaques. Accurate assessment of plaques is crucial to optimize treatment and prevent death in patients with CAD. Current diagnostic techniques are often limited by either spatial resolution or penetration depth. Several studies have proved that the combined use of optical and ultrasonic imaging techniques increase diagnostic accuracy of vulnerable plaques. Here, we introduce an ultrafast optical-ultrasonic dual-modality imaging system and flexible miniaturized catheter, which enables the translation of this technology into clinical practice. This system can perform simultaneous optical coherence tomography (OCT)-intravascular ultrasound (IVUS) imaging at 72 frames per second safely in vivo, i.e., visualizing a 72 mm-long artery in 4 seconds. Results obtained in atherosclerotic rabbits in vivo and human coronary artery segments show that this ultrafast technique can rapidly provide volumetric mapping of plaques and clearly identify vulnerable plaques. By providing ultrafast imaging of arteries with high resolution and deep penetration depth simultaneously, this hybrid IVUS-OCT technology opens new and safe opportunities to evaluate in real-time the risk posed by plaques, detect vulnerable plaques, and optimize treatment decisions. PMID:26678300

  14. Biophysical regulation of Chlamydia pneumoniae-infected monocyte recruitment to atherosclerotic foci

    NASA Astrophysics Data System (ADS)

    Evani, Shankar J.; Ramasubramanian, Anand K.

    2016-01-01

    Chlamydia pneumoniae infection is implicated in atherosclerosis although the contributory mechanisms are poorly understood. We hypothesize that C. pneumoniae infection favors the recruitment of monocytes to atherosclerotic foci by altering monocyte biophysics. Primary, fresh human monocytes were infected with C. pneumoniae for 8 h, and the interactions between monocytes and E-selectin or aortic endothelium under flow were characterized by video microscopy and image analysis. The distribution of membrane lipid rafts and adhesion receptors were analyzed by imaging flow cytometry. Infected cells rolled on E-selectin and endothelial surfaces, and this rolling was slower, steady and uniform compared to uninfected cells. Infection decreases cholesterol levels, increases membrane fluidity, disrupts lipid rafts, and redistributes CD44, which is the primary mediator of rolling interactions. Together, these changes translate to higher firm adhesion of infected monocytes on endothelium, which is enhanced in the presence of LDL. Uninfected monocytes treated with LDL or left untreated were used as baseline control. Our results demonstrate that the membrane biophysical changes due to infection and hyperlipidemia are one of the key mechanisms by which C. pneumoniae can exacerbate atherosclerotic pathology. These findings provide a framework to characterize the role of ‘infectious burden’ in the development and progression of atherosclerosis.

  15. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.

    PubMed

    Evrard, Solene M; Lecce, Laura; Michelis, Katherine C; Nomura-Kitabayashi, Aya; Pandey, Gaurav; Purushothaman, K-Raman; d'Escamard, Valentina; Li, Jennifer R; Hadri, Lahouaria; Fujitani, Kenji; Moreno, Pedro R; Benard, Ludovic; Rimmele, Pauline; Cohain, Ariella; Mecham, Brigham; Randolph, Gwendalyn J; Nabel, Elizabeth G; Hajjar, Roger; Fuster, Valentin; Boehm, Manfred; Kovacic, Jason C

    2016-06-24

    Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.

  16. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability

    PubMed Central

    Evrard, Solene M.; Lecce, Laura; Michelis, Katherine C.; Nomura-Kitabayashi, Aya; Pandey, Gaurav; Purushothaman, K-Raman; d'Escamard, Valentina; Li, Jennifer R.; Hadri, Lahouaria; Fujitani, Kenji; Moreno, Pedro R.; Benard, Ludovic; Rimmele, Pauline; Cohain, Ariella; Mecham, Brigham; Randolph, Gwendalyn J.; Nabel, Elizabeth G.; Hajjar, Roger; Fuster, Valentin; Boehm, Manfred; Kovacic, Jason C.

    2016-01-01

    Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. ‘Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events. PMID:27340017

  17. Molecular Imaging of Activated von Willebrand Factor to Detect High-Risk Atherosclerotic Phenotype

    PubMed Central

    McCarty, Owen J. T.; Conley, Robert B.; Shentu, Weihui; Tormoen, Garth W.; Zha, Daogang; Xie, Aris; Qi, Yue; Zhao, Yan; Carr, Chad; Belcik, Todd; Keene, Douglas R.; de Groot, Philip G.; Lindner, Jonathan R.

    2011-01-01

    OBJECTIVES We hypothesized that noninvasive molecular imaging of activated von Willebrand factor (vWF) on the vascular endothelium could be used to detect a high-risk atherosclerotic phenotype. BACKGROUND Platelet-endothelial interactions have been linked to increased inflammatory activation and prothrombotic state in atherosclerosis. These interactions are mediated, in part, by platelet glycoprotein (GP) Ibα, suggesting that dysregulated endothelial vWF is a marker for high-risk atherosclerotic disease. METHODS Microbubbles targeted to activated vWF were prepared by surface conjugation of recombinant GPIbα. Flow-chamber studies were used to evaluate attachment of targeted microbubbles to immobile platelet aggregates bearing activated vWF. Contrast-enhanced ultrasound (CEU) molecular imaging of the aorta from mice was performed: 1) ex vivo after focal crush injury and blood perfusion; and 2) in vivo in mice with advanced atherosclerosis produced by deletion of the low-density lipoprotein receptor and ApoBec-1 editing peptide (LDLR−/−/ApoBec-1−/−). RESULTS In flow-chamber studies, tracer attachment to vWF was >10-fold greater for microbubbles bearing GPIbα compared with control microbubbles (p < 0.01). In the ex vivo aortic injury model, CEU signal enhancement for vWF-targeted microbubbles occurred primarily at the injury site and was 4-fold greater than at noninjured sites (p < 0.05). In LDLR−/−/ApoBec-1−/− mice, inflammatory cell infiltrates and dense vWF expression on the intact endothelium were seen in regions of severe plaque formation. Scanning electron microscopy demonstrated widespread platelet-endothelial interaction and only few sites of endothelial erosion. On CEU, signal enhancement for vWF-targeted microbubbles was approximately 4-fold greater (p < 0.05) in LDLR−/−/ApoBec-1−/− compared with wild-type mice. En face aortic microscopy demonstrated regions where platelet adhesion and microbubble attachment colocalized. CONCLUSIONS

  18. Lipid droplets in atherosclerotic fatty streaks of human aorta

    PubMed Central

    Lang, P. Dieter; Insull, William

    1970-01-01

    Preparations of lipid droplets and droplet-free tissue residue (cytoplasm + membranes + nuclei) were obtained by homogenization and centrifugal separation from intimal fatty streak lesions of aortic atherosclerosis of 21 adults who had died suddenly. Neutral lipids and phospholipids were analyzed by quantitative thin-layer chromatography and cholesteryl ester fatty acids by gas-liquid chromatography. Optical properties of droplets were evaluated by differential counting and sizing procedures with the polarizing microscope. The droplets occurred in mixtures of two forms distinguished by their optical properties, anisotropic (i.e. liquid crystals) and isotropic (true liquids). Both forms had average diameters of about 1.8 μ, with a range of 0.5-5μ. The proportions of the two forms varied with temperature as individual droplets changed their form; anisotropic forms averaged 83.7% at °C and 37.8% at 37°C, with isotropic forms being 16.3 and 62.2% respectively. The proportions of anisotropic forms at 22°C decreased with age. These forms were not separated for chemical analysis. The droplets contained about half the lipid in the lesions. The composition of the lipids of the droplet mixture was remarkably uniform and strikingly different from that of the droplet-free residue, respectively: cholesteryl esters 94.9% vs. 38.7%, free cholesterol 1.7% vs. 18.6%, total phospholipids 1.0% vs. 38.6%, and triglycerides 2.4% vs. 4.0%. The proportions of individual phospholipids, with the exception of lysolecithin, were also different between the preparations. In the droplets only the proportions of lecithin correlated positively with the proportion of anisotropic forms (at 22°C). Droplet cholesteryl esters were particularly rich in oleic acid and when compared to residue esters had more palmitoleic (+0.7%), oleic (+12.3%), and eicosatrienoic (+2.4%) and less palmitic (-2.2%), linoleic (-12.4%), and arachidonic (-1.6%) acids. The proportions of most individual fatty acids of droplets and residue correlated positively. The lipids of the residue closely resemble those reported for the normal intima. The observations that these droplets are prominent in the morphology of the fatty streak lesions, and that their high content of oleate-rich cholesteryl esters is similar to that reported for analysis of the whole lesions, suggest that the droplets may be involved in the pathogenesis of the fatty streak lesions of artherosclerosis in man. PMID:5431659

  19. Combination of Light and Melatonin Time Cues for Phase Advancing the Human Circadian Clock

    PubMed Central

    Burke, Tina M.; Markwald, Rachel R.; Chinoy, Evan D.; Snider, Jesse A.; Bessman, Sara C.; Jung, Christopher M.; Wright, Kenneth P.

    2013-01-01

    Study Objectives: Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure. Design: Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m2)-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m2)-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time. Setting: Sleep and chronobiology laboratory environment free of time cues. Participants: Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD). Results: Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances. Conclusion: Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders. Citation: Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian

  20. Zebrafish models in translational research: tipping the scales toward advancements in human health.

    PubMed

    Phillips, Jennifer B; Westerfield, Monte

    2014-07-01

    Advances in genomics and next-generation sequencing have provided clinical researchers with unprecedented opportunities to understand the molecular basis of human genetic disorders. This abundance of information places new requirements on traditional disease models, which have the potential to be used to confirm newly identified pathogenic mutations and test the efficacy of emerging therapies. The unique attributes of zebrafish are being increasingly leveraged to create functional disease models, facilitate drug discovery, and provide critical scientific bases for the development of new clinical tools for the diagnosis and treatment of human disease. In this short review and the accompanying poster, we highlight a few illustrative examples of the applications of the zebrafish model to the study of human health and disease.

  1. Advanced imaging and tissue engineering of the human limbal epithelial stem cell niche.

    PubMed

    Massie, Isobel; Dziasko, Marc; Kureshi, Alvena; Levis, Hannah J; Morgan, Louise; Neale, Michael; Sheth, Radhika; Tovell, Victoria E; Vernon, Amanda J; Funderburgh, James L; Daniels, Julie T

    2015-01-01

    The limbal epithelial stem cell niche provides a unique, physically protective environment in which limbal epithelial stem cells reside in close proximity with accessory cell types and their secreted factors. The use of advanced imaging techniques is described to visualize the niche in three dimensions in native human corneal tissue. In addition, a protocol is provided for the isolation and culture of three different cell types, including human limbal epithelial stem cells from the limbal niche of human donor tissue. Finally, the process of incorporating these cells within plastic compressed collagen constructs to form a tissue-engineered corneal limbus is described and how immunohistochemical techniques may be applied to characterize cell phenotype therein.

  2. Advanced Imaging and Tissue Engineering of the Human Limbal Epithelial Stem Cell Niche

    PubMed Central

    Massie, Isobel; Dziasko, Marc; Kureshi, Alvena; Levis, Hannah J.; Morgan, Louise; Neale, Michael; Sheth, Radhika; Tovell, Victoria E.; Vernon, Amanda J.; Funderburgh, James L.; Daniels, Julie T.

    2015-01-01

    The limbal epithelial stem cell niche provides a unique, physically protective environment in which limbal epithelial stem cells reside in close proximity with accessory cell types and their secreted factors. The use of advanced imaging techniques is described to visualize the niche in three dimensions in native human corneal tissue. In addition, a protocol is provided for the isolation and culture of three different cell types, including human limbal epithelial stem cells from the limbal niche of human donor tissue. Finally, the process of incorporating these cells within plastic compressed collagen constructs to form a tissue-engineered corneal limbus is described and how immunohistochemical techniques may be applied to characterize cell phenotype therein. PMID:25388395

  3. Imaging Modalities to Identity Inflammation in an Atherosclerotic Plaque

    PubMed Central

    Goel, Sunny; Miller, Avraham; Agarwal, Chirag; Zakin, Elina; Acholonu, Michael; Gidwani, Umesh; Sharma, Abhishek; Kulbak, Guy; Shani, Jacob; Chen, On

    2015-01-01

    Atherosclerosis is a chronic, progressive, multifocal arterial wall disease caused by local and systemic inflammation responsible for major cardiovascular complications such as myocardial infarction and stroke. With the recent understanding that vulnerable plaque erosion and rupture, with subsequent thrombosis, rather than luminal stenosis, is the underlying cause of acute ischemic events, there has been a shift of focus to understand the mechanisms that make an atherosclerotic plaque unstable or vulnerable to rupture. The presence of inflammation in the atherosclerotic plaque has been considered as one of the initial events which convert a stable plaque into an unstable and vulnerable plaque. This paper systemically reviews the noninvasive and invasive imaging modalities that are currently available to detect this inflammatory process, at least in the intermediate stages, and discusses the ongoing studies that will help us to better understand and identify it at the molecular level. PMID:26798515

  4. Intravascular photoacoustic tomography for characterization of atherosclerotic lipid and inflammation

    NASA Astrophysics Data System (ADS)

    Zhang, Jian; Qin, Huan; Shi, Yujiao; Yang, Sihua; Xing, Da

    2014-09-01

    Photoacoustic imaging is a fast growing imaging technology depending on its high optical resolution of optics while taking the advantage of the high penetration depth of ultrasound. In this paper, we demonstrate the new progress in the photoacoustic imaging. Atherosclerosis is characterized by a progressive build-up of lipid in the arterial wall, which is known as plaque. Histological studies demonstrate that the primary cause of acute cardiovascular events is the rupture of atherosclerotic plaques. Lipid and inflammation within the plaque are related to influence the propensity of plaques to disrupt. Photoacoustic intravascular tomography (IVPAT) holds a great advantage in providing comprehensive morphological and functional information of plaques. Lipid relative concentration maps of atherosclerotic aorta were obtained and compared with histology. Furthermore, by selectively targeting the intravascular inflammatory cytokines, IVPAT is also capable of mapping the inflamed area and determining the degree of inflammation.

  5. Adventitial inflammation and its interaction with intimal atherosclerotic lesions

    PubMed Central

    Akhavanpoor, Mohammadreza; Wangler, Susanne; Gleissner, Christian A.; Korosoglou, Grigorios; Katus, Hugo A.; Erbel, Christian

    2014-01-01

    The presence of adventitial inflammation in correlation with atherosclerotic lesions has been recognized for decades. In the last years, several studies have investigated the relevance and impact of adventitial inflammation on atherogenesis. In the abdominal aorta of elderly Apoe−/− mice, adventitial inflammatory structures were characterized as organized ectopic lymphoid tissue, and therefore termed adventitial tertiary lymphoid organs (ATLOs). These ATLOs possess similarities in development, structure and function to secondary lymphoid organs. A crosstalk between intimal atherosclerotic lesions and ATLOs has been suggested, and several studies could demonstrate a potential role for medial vascular smooth muscle cells in this process. We here review the development, phenotypic characteristics, and function of ATLOs in atherosclerosis. Furthermore, we discuss the possible role of medial vascular smooth muscle cells and their interaction between plaque and ATLOs. PMID:25152736

  6. A framework for advanced methods of control of human-induced vibrations

    NASA Astrophysics Data System (ADS)

    Reynolds, Paul

    2012-04-01

    The vibration serviceability of civil engineering structures under human dynamic excitation is becoming ever more critical with the design and redevelopment of structures with reduced mass, stiffness and damping. A large number of problems have been reported in floors, footbridges, sports stadia, staircases and other structures. Unfortunately, the range of options available to fix such problems are very limited and are primarily limited to structural modification or the implementation of passive vibration control measures, such as tuned mass dampers. This paper presents the initial development of a new framework for advanced methods of control of humaninduced vibrations in civil engineering structures. This framework includes both existing passive methods of vibration control and more advanced active, semi-active and hybrid control techniques, which may be further developed as practical solutions for these problems. Through the use of this framework, rational decisions as to the most appropriate technologies for particular human vibration problems may be made and pursued further. This framework is also intended to be used in the design of new civil engineering structures, where advanced control technologies may be used both to increase the achievable slenderness and to reduce the amount of construction materials used and hence their embodied energy. This will be an ever more important consideration with the current drive for structures with reduced environmental impact.

  7. Molecular aspects of anti-atherosclerotic effects of short peptides.

    PubMed

    Khavinson, V Kh; Lin'kova, N S; Evlashkina, E V; Durnova, A O; Kozlov, K L; Gutop, O E

    2014-11-01

    We studied molecular mechanisms of the vasoprotective effects of tripeptide T-38 and dipeptide RR-1. Short peptides T-38 and the RR-1 activate the processes of cell renewal in organotypic and dissociated cultures of vascular cells during aging by increasing the expression of Ki-67 and reducing the synthesis of p53 protein. T-38 and RR-1 reduce the synthesis of E-selectin, adhesion molecule involved in the formation of atherosclerotic plaques.

  8. From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk.

    PubMed

    Shapiro, Michael D; Fazio, Sergio

    2016-02-19

    The introduction of statins ≈ 30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels. Although the utility of triglyceride-lowering therapies remains uncertain, 2 large clinical trials are testing the influence of omega-3 polyunsaturated fatty acids on atherosclerotic events in hypertriglyceridemia. Novel antisense therapies targeting apolipoprotein C-III (for triglyceride reduction) and apo(a) (for lipoprotein(a) reduction) are showing a promising trajectory. Finally, 2 large clinical trials are formally putting the inflammatory hypothesis of atherosclerosis to the test and may open a new avenue for cardiovascular disease risk reduction.

  9. Macrophage-targeted photodynamic detection of vulnerable atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Tawakol, Ahmed; Castano, Ana P.; Gad, Faten; Zahra, Touqir; Ahmadi, Atosa; Stern, Jeremy; Ortel, Bernhard; Chirico, Stephanie; Shirazi, Azadeh; Syed, Sakeena; Muller, James E.

    2003-06-01

    Rupture of a vulnerable atherosclerotic plaque (VP) leading to coronary thrombosis is the chief cause of sudden cardiac death. VPs are angiographically insignificant lesions, which are excessively inflamed and characterized by dense macrophage infiltration, large necrotic lipid cores, thin fibrous caps, and paucity of smooth muscle cells. We have recently shown that chlorin(e6) conjugated with maleylated albumin can target macrophages with high selectivity via the scavenger receptor. We report the potential of this macrophage-targeted fluorescent probe to localize in VPs in a rabbit model of atherosclerosis, and allow detection and/or diagnosis by fluorescence spectroscopy or imaging. Atherosclerotic lesions were induced in New Zealand White rabbit aortas by balloon injury followed by administration of a high-fat diet. 24-hours after IV injection of the conjugate into atherosclerotic or normal rabbits, the animals were sacrificed, and aortas were removed, dissected and examined for fluorescence localization in plaques by fiber-based spectrofluorimetry and confocal microscopy. Dye uptake within the aortas was also quantified by fluorescence extraction of samples from aorta segments. Biodistribution of the dye was studied in many organs of the rabbits. Surface spectrofluorimetry after conjugate injection was able to distinguish between plaque and adjacent aorta, between atherosclerotic and normal aorta, and balloon-injured and normal iliac arteries with high significance. Discrete areas of high fluorescence (up to 20 times control were detected in the balloon-injured segments, presumably corresponding to macrophage-rich plaques. Confocal microscopy showed red ce6 fluorescence localized in plaques that showed abundant foam cells and macrophages by histology. Extraction data on aortic tissue corroborated the selectivity of the conjugate for plaques. These data support the strategy of employing macrophage-targeted fluorescent dyes to detect VP by intravascular

  10. The NADPH oxidase Nox4 has anti-atherosclerotic functions

    PubMed Central

    Schürmann, Christoph; Rezende, Flavia; Kruse, Christoph; Yasar, Yakub; Löwe, Oliver; Fork, Christian; van de Sluis, Bart; Bremer, Rolf; Weissmann, Norbert; Shah, Ajay M.; Jo, Hanjoong; Brandes, Ralf P.; Schröder, Katrin

    2015-01-01

    Aims Oxidative stress is thought to be a risk for cardiovascular disease and NADPH oxidases of the Nox family are important producers of reactive oxygen species. Within the Nox family, the NADPH oxidase Nox4 has a unique position as it is constitutively active and produces H2O2 rather than O2− . Nox4 is therefore incapable of scavenging NO and its low constitutive H2O2 production might even be beneficial. We hypothesized that Nox4 acts as an endogenous anti-atherosclerotic enzyme. Methods and results Tamoxifen-induced Nox4-knockout mice were crossed with ApoE−/− mice and spontaneous atherosclerosis under regular chow as well as accelerated atherosclerosis in response to partial carotid artery ligation under high-fat diet were determined. Deletion of Nox4 resulted in increased atherosclerosis formation in both models. Mechanistically, pro-atherosclerotic and pro-inflammatory changes in gene expression were observed prior to plaque development. Moreover, inhibition of Nox4 or deletion of the enzyme in the endothelium but not in macrophages resulted in increased adhesion of macrophages to the endothelial surface. Conclusions The H2O2-producing NADPH oxidase Nox4 is an endogenous anti-atherosclerotic enzyme. Nox4 inhibitors, currently under clinical evaluation, should be carefully monitored for cardiovascular side-effects. PMID:26385958

  11. Uniaxial tensile testing approaches for characterisation of atherosclerotic plaques.

    PubMed

    Walsh, M T; Cunnane, E M; Mulvihill, J J; Akyildiz, A C; Gijsen, F J H; Holzapfel, G A

    2014-03-03

    The pathological changes associated with the development of atherosclerotic plaques within arterial vessels result in significant alterations to the mechanical properties of the diseased arterial wall. There are several methods available to characterise the mechanical behaviour of atherosclerotic plaque tissue, and it is the aim of this paper to review the use of uniaxial mechanical testing. In the case of atherosclerotic plaques, there are nine studies that employ uniaxial testing to characterise mechanical behaviour. A primary concern regarding this limited cohort of published studies is the wide range of testing techniques that are employed. These differing techniques have resulted in a large variance in the reported data making comparison of the mechanical behaviour of plaques from different vasculatures, and even the same vasculature, difficult and sometimes impossible. In order to address this issue, this paper proposes a more standardised protocol for uniaxial testing of diseased arterial tissue that allows for better comparisons and firmer conclusions to be drawn between studies. To develop such a protocol, this paper reviews the acquisition and storage of the tissue, the testing approaches, the post-processing techniques and the stress-strain measures employed by each of the nine studies. Future trends are also outlined to establish the role that uniaxial testing can play in the future of arterial plaque mechanical characterisation.

  12. Artery buckling affects the mechanical stress in atherosclerotic plaques

    PubMed Central

    2015-01-01

    Background Tortuous arteries are often seen in patients with hypertension and atherosclerosis. While the mechanical stress in atherosclerotic plaque under lumen pressure has been studied extensively, the mechanical stability of atherosclerotic arteries and subsequent effect on the plaque stress remain unknown. To this end, we investigated the buckling and post-buckling behavior of model stenotic coronary arteries with symmetric and asymmetric plaque. Methods Buckling analysis for a model coronary artery with symmetric and asymmetric plaque was conducted using finite element analysis based on the dimensions and nonlinear anisotropic materials properties reported in the literature. Results Artery with asymmetric plaque had lower critical buckling pressure compared to the artery with symmetric plaque and control artery. Buckling increased the peak stress in the plaque and led to the development of a high stress concentration in artery with asymmetric plaque. Stiffer calcified tissue and severe stenosis increased the critical buckling pressure of the artery with asymmetric plaque. Conclusions Arteries with atherosclerotic plaques are prone to mechanical buckling which leads to a high stress concentration in the plaques that can possibly make the plaques prone to rupture. PMID:25603490

  13. Stress analysis of fracture of atherosclerotic plaques: crack propagation modeling.

    PubMed

    Rezvani-Sharif, Alireza; Tafazzoli-Shadpour, Mohammad; Kazemi-Saleh, Davood; Sotoudeh-Anvari, Maryam

    2016-12-09

    Traditionally, the degree of luminal obstruction has been used to assess the vulnerability of atherosclerotic plaques. However, recent studies have revealed that other factors such as plaque morphology, material properties of lesion components and blood pressure may contribute to the fracture of atherosclerotic plaques. The aim of this study was to investigate the mechanism of fracture of atherosclerotic plaques based on the mechanical stress distribution and fatigue analysis by means of numerical simulation. Realistic models of type V plaques were reconstructed based on histological images. Finite element method was used to determine mechanical stress distribution within the plaque. Assuming that crack propagation initiated at the sites of stress concentration, crack propagation due to pulsatile blood pressure was modeled. Results showed that crack propagation considerably changed the stress field within the plaque and in some cases led to initiation of secondary cracks. The lipid pool stiffness affected the location of crack formation and the rate and direction of crack propagation. Moreover, increasing the mean or pulse pressure decreased the number of cycles to rupture. It is suggested that crack propagation analysis can lead to a better recognition of factors involved in plaque rupture and more accurate determination of vulnerable plaques.

  14. Endovascular Management of Atherosclerotic Renal Artery Stenosis: Post-Cardiovascular Outcomes in Renal Atherosclerotic Lesions Era Winner or False Alarm?

    PubMed Central

    Karanikola, Evridiki; Karaolanis, Georgios; Galyfos, George; Barbaressos, Emmanuel; Palla, Viktoria; Filis, Konstantinos

    2017-01-01

    Renal artery stenosis (RAS) is frequently associated with severe comorbidities such as reduced renal perfusion, hypertension, and end-stage renal failure. In approximately 90% of patients, renal artery atherosclerosis is the main cause for RAS, and it is associated with an increased risk for fatal and non-fatal cardiovascular and renal complications. Endovascular management of atherosclerotic RAS (ARAS) has been recently evaluated by several randomized controlled trials that failed to demonstrate benefit of stenting. Furthermore, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions study did not demonstrate any benefit over the revascularization approach. In this review, we summarized the available data from retrospective, prospective and randomized trials on ARAS to provide clinicians with sufficient data in order to produce useful conclusions for everyday clinical practice. PMID:28377906

  15. Association between human papillomavirus and EGFR mutations in advanced lung adenocarcinoma

    PubMed Central

    Li, Ming; Deng, Fang; Qian, Li-Ting; Meng, Shui-Ping; Zhang, Yang; Shan, Wu-Lin; Zhang, Xiao-Lei; Wang, Bao-Long

    2016-01-01

    Previous studies have demonstrated an association between human papillomavirus (HPV) and mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer patients; however, few studies have investigated this association in advanced lung adenocarcinoma patients undergoing gefitinib treatment. The present study investigated the association between HPV and EGFR mutations in advanced lung adenocarcinoma patients. A total of 95 advanced lung adenocarcinoma patients were enrolled in the study. The HPV infection status and presence of EGFR mutations in tumor tissue was evaluated. Patient clinical characteristics were also determined and compared with HPV infection and EGFR mutation status to analyze their impact on progression-free survival. HPV DNA was identified in 27/95 (28.4%) lung adenocarcinoma tumors and was most common in patients with lymph node metastasis (P=0.016). A total of 44/95 (46.3%) cases exhibited EGFR mutations, which were predominantly observed in female patients and non-smokers. The presence of HPV DNA was significantly associated with EGFR mutations (P=0.012) and multivariate analysis also revealed that HPV DNA was significantly associated with EGFR mutations (odds ratio=3.971) in advanced lung adenocarcinoma. Patients with both HPV infections and EGFR mutations exhibit a marked decrease in the risk of lung cancer progression when compared with those without HPV infection or EGFR mutations (adjusted HR=0.640; 95% confidence interval: 0.488–0.840; P=0.001). HPV infection was significantly associated with EGFR mutations in advanced lung adenocarcinoma patients. Furthermore, patients with HPV infections exhibited the longest progression-free survival times, which may be due to good response to tyrosine kinase inhibitor- or platinum-based-adjuvant therapy in these patients. Patients with EGFR mutations exhibited a better prognosis when compared with those exhibiting wild-type EGFR, regardless of HPV status. PMID:27602120

  16. Nanotherapeutics for inhibition of atherogenesis and modulation of inflammation in atherosclerotic plaques

    PubMed Central

    Lewis, Daniel R.; Petersen, Latrisha K.; York, Adam W.; Ahuja, Sonali; Chae, Hoonbyung; Joseph, Laurie B.; Rahimi, Saum; Uhrich, Kathryn E.; Haser, Paul B.; Moghe, Prabhas V.

    2016-01-01

    Aims Atherosclerotic development is exacerbated by two coupled pathophysiological phenomena in plaque-resident cells: modified lipid trafficking and inflammation. To address this therapeutic challenge, we designed and investigated the efficacy in vitro and ex vivo of a novel ‘composite’ nanotherapeutic formulation with dual activity, wherein the nanoparticle core comprises the antioxidant α-tocopherol and the shell is based on sugar-derived amphiphilic polymers that exhibit scavenger receptor binding and counteract atherogenesis. Methods and results Amphiphilic macromolecules were kinetically fabricated into serum-stable nanoparticles (NPs) using a core/shell configuration. The core of the NPs comprised either of a hydrophobe derived from mucic acid, M12, or the antioxidant α-tocopherol (α-T), while an amphiphile based on PEG-terminated M12 served as the shell. These composite NPs were then tested and validated for inhibition of oxidized lipid accumulation and inflammatory signalling in cultures of primary human macrophages, smooth muscle cells, and endothelial cells. Next, the NPs were evaluated for their athero-inflammatory effects in a novel ex vivo carotid plaque model and showed similar effects within human tissue. Incorporation of α-T into the hydrophobic core of the NPs caused a pronounced reduction in the inflammatory response, while maintaining high levels of anti-atherogenic efficacy. Conclusions Sugar-based amphiphilic macromolecules can be complexed with α-T to establish new anti-athero-inflammatory nanotherapeutics. These dual efficacy NPs effectively inhibited key features of atherosclerosis (modified lipid uptake and the formation of foam cells) while demonstrating reduction in inflammatory markers based on a disease-mimetic model of human atherosclerotic plaques. PMID:26472131

  17. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium

    PubMed Central

    Turnbull, Irene C.; Karakikes, Ioannis; Serrao, Gregory W.; Backeris, Peter; Lee, Jia-Jye; Xie, Chaoqin; Senyei, Grant; Gordon, Ronald E.; Li, Ronald A.; Akar, Fadi G.; Hajjar, Roger J.; Hulot, Jean-Sébastien; Costa, Kevin D.

    2014-01-01

    Cardiac experimental biology and translational research would benefit from an in vitro surrogate for human heart muscle. This study investigated structural and functional properties and interventional responses of human engineered cardiac tissues (hECTs) compared to human myocardium. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs, >90% troponin-positive) were mixed with collagen and cultured on force-sensing elastomer devices. hECTs resembled trabecular muscle and beat spontaneously (1.18±0.48 Hz). Microstructural features and mRNA expression of cardiac-specific genes (α-MHC, SERCA2a, and ACTC1) were comparable to human myocardium. Optical mapping revealed cardiac refractoriness with loss of 1:1 capture above 3 Hz, and cycle length dependence of the action potential duration, recapitulating key features of cardiac electrophysiology. hECTs reconstituted the Frank-Starling mechanism, generating an average maximum twitch stress of 660 μN/mm2 at Lmax, approaching values in newborn human myocardium. Dose-response curves followed exponential pharmacodynamics models for calcium chloride (EC50 1.8 mM) and verapamil (IC50 0.61 μM); isoproterenol elicited a positive chronotropic but negligible inotropic response, suggesting sarcoplasmic reticulum immaturity. hECTs were amenable to gene transfer, demonstrated by successful transduction with Ad.GFP. Such 3-D hECTs recapitulate an early developmental stage of human myocardium and promise to offer an alternative preclinical model for cardiology research.—Turnbull, I. C., Karakikes, I., Serrao, G. W., Backeris, P., Lee, J.-J., Xie, C., Senyei, G., Gordon, R. E., Li, R. A., Akar, F. G., Hajjar, R. J., Hulot, J.-S., Costa, K. D. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. PMID:24174427

  18. DEVELOPMENT OF HUMAN FACTORS ENGINEERING GUIDANCE FOR SAFETY EVALUATIONS OF ADVANCED REACTORS.

    SciTech Connect

    O'HARA, J.; PERSENSKY, J.; SZABO, A.

    2006-10-01

    Advanced reactors are expected to be based on a concept of operations that is different from what is currently used in today's reactors. Therefore, regulatory staff may need new tools, developed from the best available technical bases, to support licensing evaluations. The areas in which new review guidance may be needed and the efforts underway to address the needs will be discussed. Our preliminary results focus on some of the technical issues to be addressed in three areas for which new guidance may be developed: automation and control, operations under degraded conditions, and new human factors engineering methods and tools.

  19. The development of transgenic crops to improve human health by advanced utilization of seed storage proteins.

    PubMed

    Maruyama, Nobuyuki; Mikami, Bunzo; Utsumi, Shigeru

    2011-01-01

    Seed storage proteins are a major component of mature seeds. They are utilized as protein sources in foods. We designed seed storage proteins containing bioactive peptides based on their three-dimensional structures. Furthermore, to create crops with enhanced food qualities, we developed transgenic crops producing seed storage proteins with bioactive peptides. This strategy promises to prevent lifestyle-related diseases by simple daily food consumption. In this review, we discuss a strategy to develop transgenic crops to improve human health by advanced utilization of seed storage proteins.

  20. Human response to nuclear and advanced technology weapons effects. Final report, January-December 1995

    SciTech Connect

    Coleman, J.L.

    1996-05-01

    The purpose of this study is to help the system survivability analyst estimate hardness requirements for systems exposed to nuclear weapons and advanced technology weapons (ATWs). The system survivability analyst is often asked to make quick, order-of-magnitude estimates on the hardness requirements for existing or proposed systems based upon human responses to the effects of nuclear weapons and ATWs. The intent of this report is to identity the general range of human survivability to nuclear weapons and ATWs and to provide simple example calcuiations and scenarios that can give the reader rough estimates of the effects of these weapons. While high-powered microwave (HPM) and laser weapons are considered in this report, the main emphasis is on nuclear weapons and their ionizing radiation effects.

  1. How Can Diet Affect the Accumulation of Advanced Glycation End-Products in the Human Body?

    PubMed Central

    Guilbaud, Axel; Niquet-Leridon, Celine; Boulanger, Eric; Tessier, Frederic J.

    2016-01-01

    The accumulation of advanced glycation end products (AGEs) is associated with the complications of diabetes, kidney disease, metabolic disorders and degenerative diseases. It is recognized that the pool of glycation products found in the human body comes not only from an endogenous formation, but also from a dietary exposure to exogenous AGEs. In recent years, the development of pharmacologically-active ingredients aimed at inhibiting endogenous glycation has not been successful. Since the accumulation of AGEs in the human body appears to be progressive throughout life, an early preventive action against glycation could be effective through dietary adjustments or supplementation with purified micronutrients. The present article provides an overview of current dietary strategies tested either in vitro, in vivo or both to reduce the endogenous formation of AGEs and to limit exposure to food AGEs. PMID:28231179

  2. Influence of shear stress magnitude and direction on atherosclerotic plaque composition

    PubMed Central

    Mehta, Vikram V.; Bovens, Sandra M.; Mohri, Zahra; Poulsen, Christian Bo; Gsell, Willy; Tremoleda, Jordi L.; Towhidi, Leila; de Silva, Ranil; Petretto, Enrico; Krams, Rob

    2016-01-01

    The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE−/− mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE−/− mice (n = 7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 µm resolution) eight to nine weeks after cuff placement. Computational fluid dynamics was then performed to compute six metrics that describe different aspects of atherogenic flow in terms of wall shear stress magnitude and/or direction. In a subset of four imaged animals, we performed histology to confirm the presence of advanced plaques and measure plaque length in each segment. Relative to the control artery, the region upstream of the cuff exhibited changes in shear stress magnitude only (p < 0.05), whereas the region downstream of the cuff exhibited changes in shear stress magnitude and direction (p < 0.05). These data suggest that shear stress magnitude contributes to the formation of advanced plaques with a vulnerable phenotype, whereas variations in both magnitude and direction promote the formation of plaques with stable features. PMID:27853578

  3. Influence of shear stress magnitude and direction on atherosclerotic plaque composition.

    PubMed

    Pedrigi, Ryan M; Mehta, Vikram V; Bovens, Sandra M; Mohri, Zahra; Poulsen, Christian Bo; Gsell, Willy; Tremoleda, Jordi L; Towhidi, Leila; de Silva, Ranil; Petretto, Enrico; Krams, Rob

    2016-10-01

    The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE(-/-) mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE(-/-) mice (n = 7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 µm resolution) eight to nine weeks after cuff placement. Computational fluid dynamics was then performed to compute six metrics that describe different aspects of atherogenic flow in terms of wall shear stress magnitude and/or direction. In a subset of four imaged animals, we performed histology to confirm the presence of advanced plaques and measure plaque length in each segment. Relative to the control artery, the region upstream of the cuff exhibited changes in shear stress magnitude only (p < 0.05), whereas the region downstream of the cuff exhibited changes in shear stress magnitude and direction (p < 0.05). These data suggest that shear stress magnitude contributes to the formation of advanced plaques with a vulnerable phenotype, whereas variations in both magnitude and direction promote the formation of plaques with stable features.

  4. Computational Hemodynamic Analysis for the Diagnosis of Atherosclerotic Changes in Intracranial Aneurysms: A Proof-of-Concept Study Using 3 Cases Harboring Atherosclerotic and Nonatherosclerotic Aneurysms Simultaneously

    PubMed Central

    Endo, Hidenori; Niizuma, Kuniyasu; Endo, Toshiki; Funamoto, Kenichi; Ohta, Makoto; Tominaga, Teiji

    2016-01-01

    This was a proof-of-concept computational fluid dynamics (CFD) study designed to identify atherosclerotic changes in intracranial aneurysms. We selected 3 patients with multiple unruptured aneurysms including at least one with atherosclerotic changes and investigated whether an image-based CFD study could provide useful information for discriminating the atherosclerotic aneurysms. Patient-specific geometries were constructed from three-dimensional data obtained using rotational angiography. Transient simulations were conducted under patient-specific inlet flow rates measured by phase-contrast magnetic resonance velocimetry. In the postanalyses, we calculated time-averaged wall shear stress (WSS), oscillatory shear index, and relative residence time (RRT). The volume of blood flow entering aneurysms through the neck and the mean velocity of blood flow inside aneurysms were examined. We applied the age-of-fluid method to quantitatively assess the residence of blood inside aneurysms. Atherosclerotic changes coincided with regions exposed to disturbed blood flow, as indicated by low WSS and long RRT. Blood entered aneurysms in phase with inlet flow rates. The mean velocities of blood inside atherosclerotic aneurysms were lower than those inside nonatherosclerotic aneurysms. Blood in atherosclerotic aneurysms was older than that in nonatherosclerotic aneurysms, especially near the wall. This proof-of-concept study demonstrated that CFD analysis provided detailed information on the exchange and residence of blood that is useful for the diagnosis of atherosclerotic changes in intracranial aneurysms. PMID:27703491

  5. Technology Roadmap Instrumentation, Control, and Human-Machine Interface to Support DOE Advanced Nuclear Energy Programs

    SciTech Connect

    Donald D Dudenhoeffer; Burce P Hallbert

    2007-03-01

    Instrumentation, Controls, and Human-Machine Interface (ICHMI) technologies are essential to ensuring delivery and effective operation of optimized advanced Generation IV (Gen IV) nuclear energy systems. In 1996, the Watts Bar I nuclear power plant in Tennessee was the last U.S. nuclear power plant to go on line. It was, in fact, built based on pre-1990 technology. Since this last U.S. nuclear power plant was designed, there have been major advances in the field of ICHMI systems. Computer technology employed in other industries has advanced dramatically, and computing systems are now replaced every few years as they become functionally obsolete. Functional obsolescence occurs when newer, more functional technology replaces or supersedes an existing technology, even though an existing technology may well be in working order.Although ICHMI architectures are comprised of much of the same technology, they have not been updated nearly as often in the nuclear power industry. For example, some newer Personal Digital Assistants (PDAs) or handheld computers may, in fact, have more functionality than the 1996 computer control system at the Watts Bar I plant. This illustrates the need to transition and upgrade current nuclear power plant ICHMI technologies.

  6. Advances in Pemphigus and its Endemic Pemphigus Foliaceus (Fogo Selvagem) Phenotype: A Paradigm of Human Autoimmunity

    PubMed Central

    Culton, Donna A.; Qian, Ye; Li, Ning; Rubenstein, David; Aoki, Valeria; Filhio, Gunter Hans; Rivitti, Evandro A.; Diaz, Luis A.

    2009-01-01

    Pemphigus encompasses a group of organ specific, antibody mediated autoimmune diseases of the skin characterized by keratinocyte detachment that leads to the development of blisters and erosions, which can become life-threatening. The pathogenic autoantibodies recognize desmogleins, which are members of the desmosomal cadherin family of cell adhesion molecules. Desmoglein 3 is targeted in pemphigus vulgaris while desmoglein 1 is targeted in pemphigus foliaceus and its endemic form, fogo selvagem. This review will briefly define the salient features of pemphigus and the proposed steps in pathogenesis. We will then summarize the most recent advances in three important areas of investigation: (i) epidemiologic, genetic, and immunologic features of fogo selvagem, (ii) molecular mechanisms of injury to the epidermis, and (iii) novel therapeutic strategies targeting specific steps in disease pathogenesis. The advances in each of these three seemingly separate areas contribute to the overall understanding of the pemphigus disease model. These recent advancements also underscore the dynamic interplay between the treatment of patients in a clinical setting and basic science research, which has led to an integrative understanding disease pathogenesis and treatment and allow pemphigus to serve as a paradigm of human autoimmunity. PMID:18838249

  7. Bright morning light advances the human circadian system without affecting NREM sleep homeostasis.

    PubMed

    Dijk, D J; Beersma, D G; Daan, S; Lewy, A J

    1989-01-01

    Eight male subjects were exposed to either bright light or dim light between 0600 and 0900 h for 3 consecutive days each. Relative to the dim light condition, the bright light treatment advanced the evening rise in plasma melatonin and the time of sleep termination (sleep onset was held constant) for an average approximately 1 h. The magnitude of the advance of the plasma melatonin rise was dependent on its phase in dim light. The reduction in sleep duration was at the expense of rapid-eye-movement (REM) sleep. Spectral analysis of the sleep electroencephalogram (EEG) revealed that the advance of the circadian pacemaker did not affect EEG power densities between 0.25 and 15.0 Hz during either non-REM or REM sleep. The data show that shifting the human circadian pacemaker by 1 h does not affect non-REM sleep homeostasis. These findings are in accordance with the predictions of the two-process model of sleep regulation.

  8. Identifying human disease genes: advances in molecular genetics and computational approaches.

    PubMed

    Bakhtiar, S M; Ali, A; Baig, S M; Barh, D; Miyoshi, A; Azevedo, V

    2014-07-04

    The human genome project is one of the significant achievements that have provided detailed insight into our genetic legacy. During the last two decades, biomedical investigations have gathered a considerable body of evidence by detecting more than 2000 disease genes. Despite the imperative advances in the genetic understanding of various diseases, the pathogenesis of many others remains obscure. With recent advances, the laborious methodologies used to identify DNA variations are replaced by direct sequencing of genomic DNA to detect genetic changes. The ability to perform such studies depends equally on the development of high-throughput and economical genotyping methods. Currently, basically for every disease whose origen is still unknown, genetic approaches are available which could be pedigree-dependent or -independent with the capacity to elucidate fundamental disease mechanisms. Computer algorithms and programs for linkage analysis have formed the foundation for many disease gene detection projects, similarly databases of clinical findings have been widely used to support diagnostic decisions in dysmorphology and general human disease. For every disease type, genome sequence variations, particularly single nucleotide polymorphisms are mapped by comparing the genetic makeup of case and control groups. Methods that predict the effects of polymorphisms on protein stability are useful for the identification of possible disease associations, whereas structural effects can be assessed using methods to predict stability changes in proteins using sequence and/or structural information.

  9. Heart research advances using database search engines, Human Protein Atlas and the Sydney Heart Bank.

    PubMed

    Li, Amy; Estigoy, Colleen; Raftery, Mark; Cameron, Darryl; Odeberg, Jacob; Pontén, Fredrik; Lal, Sean; Dos Remedios, Cristobal G

    2013-10-01

    This Methodological Review is intended as a guide for research students who may have just discovered a human "novel" cardiac protein, but it may also help hard-pressed reviewers of journal submissions on a "novel" protein reported in an animal model of human heart failure. Whether you are an expert or not, you may know little or nothing about this particular protein of interest. In this review we provide a strategic guide on how to proceed. We ask: How do you discover what has been published (even in an abstract or research report) about this protein? Everyone knows how to undertake literature searches using PubMed and Medline but these are usually encyclopaedic, often producing long lists of papers, most of which are either irrelevant or only vaguely relevant to your query. Relatively few will be aware of more advanced search engines such as Google Scholar and even fewer will know about Quertle. Next, we provide a strategy for discovering if your "novel" protein is expressed in the normal, healthy human heart, and if it is, we show you how to investigate its subcellular location. This can usually be achieved by visiting the website "Human Protein Atlas" without doing a single experiment. Finally, we provide a pathway to discovering if your protein of interest changes its expression level with heart failure/disease or with ageing.

  10. Ultra-high field MRI: Advancing systems neuroscience towards mesoscopic human brain function.

    PubMed

    Dumoulin, Serge O; Fracasso, Alessio; van der Zwaag, Wietske; Siero, Jeroen C W; Petridou, Natalia

    2017-01-16

    Human MRI scanners at ultra-high magnetic field strengths of 7 T and higher are increasingly available to the neuroscience community. A key advantage brought by ultra-high field MRI is the possibility to increase the spatial resolution at which data is acquired, with little reduction in image quality. This opens a new set of opportunities for neuroscience, allowing investigators to map the human cortex at an unprecedented level of detail. In this review, we present recent work that capitalizes on the increased signal-to-noise ratio available at ultra-high field and discuss the theoretical advances with a focus on sensory and motor systems neuroscience. Further, we review research performed at sub-millimeter spatial resolution and discuss the limits and the potential of ultra-high field imaging for structural and functional imaging in human cortex. The increased spatial resolution achievable at ultra-high field has the potential to unveil the fundamental computations performed within a given cortical area, ultimately allowing the visualization of the mesoscopic organization of human cortex at the functional and structural level.

  11. Quality assurance and risk management: Perspectives on Human Factors Certification of Advanced Aviation Systems

    NASA Technical Reports Server (NTRS)

    Taylor, Robert M.; Macleod, Iain S.

    1994-01-01

    This paper is based on the experience of engineering psychologists advising the U.K. Ministry of Defense (MoD) on the procurement of advanced aviation systems that conform to good human engineering (HE) practice. Traditional approaches to HE in systems procurement focus on the physical nature of the human-machine interface. Advanced aviation systems present increasingly complex design requirements for human functional integration, information processing, and cognitive task performance effectiveness. These developing requirements present new challenges for HE quality assurance (QA) and risk management, requiring focus on design processes as well as on design content or product. A new approach to the application of HE, recently adopted by NATO, provides more systematic ordering and control of HE processes and activities to meet the challenges of advanced aircrew systems design. This systematic approach to HE has been applied by MoD to the procurement of mission systems for the Royal Navy Merlin helicopter. In MoD procurement, certification is a judicial function, essentially independent of the service customer and industry contractor. Certification decisions are based on advice from MoD's appointed Acceptance Agency. Test and evaluation (T&E) conducted by the contractor and by the Acceptance Agency provide evidence for certification. Certification identifies limitations of systems upon release to the service. Evidence of compliance with HE standards traditionally forms the main basis of HE certification and significant non-compliance could restrict release. The systems HE approach shows concern for the quality of processes as well as for the content of the product. Human factors certification should be concerned with the quality of HE processes as well as products. Certification should require proof of process as well as proof of content and performance. QA criteria such as completeness, consistency, timeliness, and compatibility provide generic guidelines for

  12. Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig.

    PubMed Central

    Rath, M; Pauling, L

    1990-01-01

    Lipoprotein(a) [Lp(a)] is an extremely atherogenic lipoprotein. Lp(a) has been found in the plasma of humans and other primates, but until now only in a few other species. The mechanism by which it exerts its atherogenicity is still poorly understood. We observed that Lp(a) has been found in the plasma of several species unable to synthesize ascorbate and not in other species. We have now detected apoprotein(a) in the plasma of the guinea pig. We induced atherosclerosis in this animal by dietary ascorbate depletion and, using SDS/PAGE and subsequent immunoblotting, we identified Lp(a) as accumulating in the atherosclerotic plaque. Most importantly, adequate amounts of ascorbate (40 mg per kg of body weight per day) prevent the development of atherosclerotic lesions in this animal model and the accumulation of Lp(a) in the arterial wall. We suggest an analogous mechanism in humans because of the similarity between guinea pigs and humans with respect to both the lack of endogenous ascorbate production and the role of Lp(a) in human atherosclerosis. Images PMID:2147514

  13. Identification of Atherosclerotic Plaques in Carotid Artery by Fluorescence Spectroscopy

    NASA Astrophysics Data System (ADS)

    Rocha, Rick; Villaverde, Antonio Balbin; Silveira, Landulfo; Costa, Maricília Silva; Alves, Leandro Procópio; Pasqualucci, Carlos Augusto; Brugnera, Aldo

    2008-04-01

    The aim of this work was to identify the presence of atherosclerotic plaques in carotid artery using the Fluorescence Spectroscopy. The most important pathogeny in the cardiovascular disorders is the atherosclerosis, which may affect even younger individuals. With approximately 1.2 million heart attacks and 750,000 strokes afflicting an aging American population each year, cardiovascular disease remains the number one cause of death. Carotid artery samples were obtained from the Autopsy Service at the University of São Paulo (São Paulo, SP, Brazil) taken from cadavers. After a histopathological analysis the 60 carotid artery samples were divided into two groups: normal (26) and atherosclerotic plaques (34). Samples were irradiated with the wavelength of 488 nm from an Argon laser. A 600 μm core optical fiber, coupled to the Argon laser, was used for excitation of the sample, whereas another 600 optical fiber, coupled to the spectrograph entrance slit, was used for collecting the fluorescence from the sample. Measurements were taken at different points on each sample and then averaged. Fluorescence spectra showed a single broad line centered at 549 nm. The fluorescence intensity for each sample was calculated by subtracting the intensity at the peak (550 nm) and at the bottom (510 nm) and then data were statistically analyzed, looking for differences between both groups of samples. ANOVA statistical test showed a significant difference (p<0,05) between both types of tissues, with regard to the fluorescence peak intensities. Our results indicate that this technique could be used to detect the presence of the atherosclerotic in carotid tissue.

  14. Systemic Atherosclerotic Inflammation Following Acute Myocardial Infarction: Myocardial Infarction Begets Myocardial Infarction

    PubMed Central

    Joshi, Nikhil V; Toor, Iqbal; Shah, Anoop S V; Carruthers, Kathryn; Vesey, Alex T; Alam, Shirjel R; Sills, Andrew; Hoo, Teng Y; Melville, Adam J; Langlands, Sarah P; Jenkins, William S A; Uren, Neal G; Mills, Nicholas L; Fletcher, Alison M; van Beek, Edwin J R; Rudd, James H F; Fox, Keith A A; Dweck, Marc R; Newby, David E

    2015-01-01

    Background Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans. Methods and Results Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non–ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI. Conclusions The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization

  15. Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease

    PubMed Central

    Shapiro, Michael D.; Fazio, Sergio

    2017-01-01

    Cholesterol-rich, apolipoprotein B (apoB)-containing lipoproteins are now widely accepted as the most important causal agents of atherosclerotic cardiovascular disease. Multiple unequivocal and orthogonal lines of evidence all converge on low-density lipoprotein and related particles as being the principal actors in the genesis of atherosclerosis. Here, we review the fundamental role of atherogenic apoB-containing lipoproteins in cardiovascular disease and several other humoral and parietal factors that are required to initiate and maintain arterial degeneration. The biology of foam cells and their interactions with high-density lipoproteins, including cholesterol efflux, are also briefly reviewed. PMID:28299190

  16. Management of hypertriglyceridemia for prevention of atherosclerotic cardiovascular disease.

    PubMed

    Brinton, Eliot A

    2015-05-01

    Mendelian randomization data strongly suggest that hypertriglyceridemia (HTG) causes atherosclerotic cardiovascular disease (ASCVD), and so triglyceride (TG) level-lowering treatment in HTG is now more strongly recommended to address the residual ASCVD risk than has been the case in (generally earlier) published guidelines. Fibrates are the best-established agents for TG level lowering and are generally used as first-line treatment of TG levels greater than 500 mg/dL. Statins are the best-established agents for ASCVD prevention, and so are usually used as first-line treatment of TG levels less than 500 mg/dL.

  17. Biological effects of space radiation on human cells: history, advances and outcomes.

    PubMed

    Maalouf, Mira; Durante, Marco; Foray, Nicolas

    2011-01-01

    Exposure to radiation is one of the main concerns for space exploration by humans. By focusing deliberately on the works performed on human cells, we endeavored to review, decade by decade, the technological developments and conceptual advances of space radiation biology. Despite considerable efforts, the cancer and the toxicity risks remain to be quantified: 1) the nature and the frequency of secondary heavy ions need to be better characterized in order to estimate their contribution to the dose and to the final biological response; 2) the diversity of radiation history of each astronaut and the impact of individual susceptibility make very difficult any epidemiological analysis for estimating hazards specifically due to space radiation exposure. 3) Cytogenetic data undoubtedly revealed that space radiation exposure produce significant damage in cells. However, our knowledge of the basic mechanisms specific to low-dose, to repeated doses and to adaptive response is still poor. The application of new radiobiological techniques, like immunofluorescence, and the use of human tissue models different from blood, like skin fibroblasts, may help in clarifying all the above items.

  18. Current advances in lesion-symptom mapping of the human cerebellum.

    PubMed

    Timmann, D; Konczak, J; Ilg, W; Donchin, O; Hermsdörfer, J; Gizewski, E R; Schoch, B

    2009-09-01

    While high-resolution structural magnetic resonance imaging (MRI) combined with newer analysis methods has become a powerful tool in human cerebral lesion studies, comparatively few studies have used these advanced imaging techniques to study lesions of the human cerebellum and their associated symptoms. This review will summarize the methodology of MRI-based lesion-symptom mapping of the human cerebellum and discuss its potential for gaining insights into cerebellar function. The investigation of patients with defined focal lesions yields the greatest potential for obtaining meaningful correlations between lesion site and behavioral deficits. In smaller groups of patients overlay plots and subtraction analysis are good options. If larger groups of patients are available, different statistical techniques have been introduced to compare behavior and lesion site on a voxel-by-voxel basis. Although localization in degenerative cerebellar disorders is less accurate because of the diffuse nature of the disease, certain information about the supposed function of larger subdivisions of the cerebellum can be gained. Examples are given which show that lesion-symptom mapping allows to investigate the function of the intermediate zone and cerebellar nuclei. We conclude that meaningful correlations between lesion site and behavioral data can be obtained in patients with degenerative as well as focal cerebellar disorders.

  19. Dietary advanced lipid oxidation endproducts are risk factors to human health.

    PubMed

    Kanner, Joseph

    2007-09-01

    Lipid oxidation in foods is one of the major degradative processes responsible for losses in food quality. The oxidation of unsaturated fatty acids results in significant generation of dietary advanced lipid oxidation endproducts (ALEs) which are in part cytotoxic and genotoxic compounds. The gastrointestinal tract is constantly exposed to dietary oxidized food compounds, after digestion a part of them are absorbed into the lymph or directly into the blood stream. After ingestion of oxidized fats animals and human have been shown to excrete in urine increase amounts of malondialdehyde but also lipophilic carbonyl compounds. Oxidized cholesterol in the diet was found to be a source of oxidized lipoproteins in human serum. Some of the dietary ALEs, which are absorbed from the gut to the circulatory system, seems to act as injurious chemicals that activate an inflammatory response which affects not only circulatory system but also organs such as liver, kidney, lung, and the gut itself. We believe that repeated consumption of oxidized fat in the diet poses a chronic threat to human health. High concentration of dietary antioxidants could prevent lipid oxidation and ALEs generation not only in foods but also in stomach condition and thereby potentially decrease absorption of ALEs from the gut. This could explains the health benefit of diets containing large amounts of dietary antioxidants such those present in fruits and vegetables, or products such as red-wine or tea consuming during the meal.

  20. Structural and functional modifications of human aorta proteoglycans in atherosclerosis.

    PubMed

    Cherchi, G M; Coinu, R; Demuro, P; Formato, M; Sanna, G; Tidore, M; Tira, M E; De Luca, G

    1990-12-01

    Proteoglycans (PGs) were extracted from minced normal human aorta intima and media and adjacent atherosclerotic plaques. Samples obtained from each individual artery which showed different degrees of atherosclerotic involvement were studied separately. Comparing normal and atherosclerotic areas from the same aorta, the hexuronic acid content was always lower in the atherosclerotic minces. Atherosclerotic samples always contained a higher percentage amount of chondroitinase AC resistant material. PGs were sequentially extracted with increasing guanidine hydrochloride (GuHCl) concentrations. 0.4 M GuHCl extracted about 13% of total PGs, containing mostly chondroitin sulphate (CS), whilst 4 M GuHCl extracted about 50% of total PGs, containing CS, dermatan sulphate (DS), heparan sulphate and hyaluronic acid. PGs from atherosclerotic minces showed a higher DS amount, based on electrophoretic glycosaminoglycan (GAG) analysis. PGs extracted with 4 M GuHCl were further characterized by gel-chromatography and by CsCl density gradient centrifugation. The relative content of PGs with highest hydrodynamic size appeared to be markedly reduced in all the atherosclerotic samples. LDL/GAGs and LDL/PGs interactions were studied by affinity chromatography. GAGs obtained by papain digestion of PGs extracted from atherosclerotic areas contained a glycosaminoglycuronan interacting more strongly with human LDL than GAGs from normal areas of the same artery. The complete elution of PGs required higher NaCl concentration than GAGs. Moreover, PGs from atherosclerotic samples showed higher affinity for LDL than PGs from normal areas of the same aorta.

  1. Frequency Analysis of the Photoacoustic Signal Generated by Coronary Atherosclerotic Plaque.

    PubMed

    Daeichin, Verya; Wu, Min; De Jong, Nico; van der Steen, Antonius F W; van Soest, Gijs

    2016-08-01

    The identification of unstable atherosclerotic plaques in the coronary arteries is emerging as an important tool for guiding percutaneous coronary interventions and may enable preventive treatment of such plaques in the future. Assessment of plaque stability requires imaging of both structure and composition. Spectroscopic photoacoustic (sPA) imaging can visualize atherosclerotic plaque composition on the basis of the optical absorption contrast. It is an established fact that the frequency content of the photoacoustic (PA) signal is correlated with structural tissue properties. As PA signals can be weak, it is important to match the transducer bandwidth to the signal frequency content for in vivo imaging. In this ex vivo study on human coronary arteries, we combined sPA imaging and analysis of frequency content of the PA signals. Using a broadband transducer (-3-dB one-way bandwidth of 10-35 MHz) and a 1-mm needle hydrophone (calibrated for 1-20 MHz), we covered a large frequency range of 1-35 MHz for receiving the PA signals. Spectroscopic PA imaging was performed at wavelengths ranging from 1125 to 1275 nm with a step of 2 nm, allowing discrimination between plaque lipids and adventitial tissue. Under sPA imaging guidance, the frequency content of the PA signals from the plaque lipids was quantified. Our data indicate that more than 80% of the PA energy of the coronary plaque lipids lies in the frequency band below 8 MHz. This frequency information can guide the choice of the transducer element used for PA catheter fabrication.

  2. Studying brain functions with mesoscopic measurements: advances in electrocorticography for non-human primates

    PubMed Central

    Fukushima, Makoto; Chao, Zenas C.

    2015-01-01

    Our brain is organized in a modular structure. Information in different modalities is processed within distinct cortical areas. However, individual cortical areas cannot enable complex cognitive functions without interacting with other cortical areas. Electrocorticography (ECoG) has recently become an important tool for studying global network activity across cortical areas in animal models. With stable recordings of electrical field potentials from multiple cortical areas, ECoG provides an opportunity to systematically study large-scale cortical activity at a mesoscopic spatiotemporal resolution under various experimental conditions. Recent developments in thin, flexible ECoG electrodes permit recording field potentials from not only gyral but intrasulcal cortical surfaces. Our review here focuses on the recent advances of ECoG applications to non-human primates. PMID:25889531

  3. Recent Advances in Diagnosis, Prevention, and Treatment of Human Respiratory Syncytial Virus

    PubMed Central

    Bawage, Swapnil Subhash; Tiwari, Pooja Munnilal; Singh, Shree Ram

    2013-01-01

    Human respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and the elderly, leading to significant morbidity and mortality. The interdisciplinary fields, especially biotechnology and nanotechnology, have facilitated the development of modern detection systems for RSV. Many anti-RSV compounds like fusion inhibitors and RNAi molecules have been successful in laboratory and clinical trials. But, currently, there are no effective drugs for RSV infection even after decades of research. Effective diagnosis can result in effective treatment, but the progress in both of these facets must be concurrent. The development in prevention and treatment measures for RSV is at appreciable pace, but the implementation into clinical practice still seems a challenge. This review attempts to present the promising diverse research approaches and advancements in the area of diagnosis, prevention, and treatment that contribute to RSV management. PMID:24382964

  4. Human factors engineering guidance for the review of advanced alarm systems

    SciTech Connect

    O`Hara, J.M.; Brown, W.S.; Higgins, J.C.; Stubler, W.F.

    1994-09-01

    This report provides guidance to support the review of the human factors aspects of advanced alarm system designs in nuclear power plants. The report is organized into three major sections. The first section describes the methodology and criteria that were used to develop the design review guidelines. Also included is a description of the scope, organization, and format of the guidelines. The second section provides a systematic review procedure in which important characteristics of the alarm system are identified, described, and evaluated. The third section provides the detailed review guidelines. The review guidelines are organized according to important characteristics of the alarm system including: alarm definition; alarm processing and reduction; alarm prioritization and availability; display; control; automated; dynamic, and modifiable characteristics; reliability, test, maintenance, and failure indication; alarm response procedures; and control-display integration and layout.

  5. Recent advances in understanding and preventing human papillomavirus-related disease

    PubMed Central

    Hellner, Karin; Dorrell, Lucy

    2017-01-01

    High-risk human papillomaviruses (hrHPV) are responsible for anogenital and oropharyngeal cancers, which together account for at least 5% of cancers worldwide. Industrialised nations have benefitted from highly effective screening for the prevention of cervical cancer in recent decades, yet this vital intervention remains inaccessible to millions of women in low- and middle-income countries (LMICs), who bear the greatest burden of HPV disease. While there is an urgent need to increase investment in basic health infrastructure and rollout of prophylactic vaccination, there are now unprecedented opportunities to exploit recent scientific and technological advances in screening and treatment of pre-invasive hrHPV lesions and to adapt them for delivery at scale in resource-limited settings. In addition, non-surgical approaches to the treatment of cervical intraepithelial neoplasia and other hrHPV lesions are showing encouraging results in clinical trials of therapeutic vaccines and antiviral agents. Finally, the use of next-generation sequencing to characterise the vaginal microbial environment is beginning to shed light on host factors that may influence the natural history of HPV infections. In this article, we focus on recent advances in these areas and discuss their potential for impact on HPV disease. PMID:28357043

  6. Diagnosis and management of atherosclerotic cardiovascular disease in chronic kidney disease: a review.

    PubMed

    Mathew, Roy O; Bangalore, Sripal; Lavelle, Michael P; Pellikka, Patricia A; Sidhu, Mandeep S; Boden, William E; Asif, Arif

    2016-12-28

    Patients with chronic kidney disease (CKD) have a high prevalence of atherosclerotic cardiovascular disease, likely reflecting the presence of traditional risk factors. A greater distinguishing feature of atherosclerotic cardiovascular disease in CKD is the severity of the disease, which is reflective of an increase in inflammatory mediators and vascular calcification secondary to hyperparathyroidism of renal origin that are unique to patients with CKD. Additional components of atherosclerotic cardiovascular disease that are prominent in patients with CKD include microvascular disease and myocardial fibrosis. Therapeutic interventions that minimize cardiovascular events related to atherosclerotic cardiovascular disease in patients with CKD, as determined by well-designed clinical trials, are limited to statins. Data are lacking regarding other available therapeutic measures primarily due to exclusion of patients with CKD from major trials studying cardiovascular disease. Data from well-designed randomized controlled trials are needed to guide clinicians who care for this high-risk population in the management of atherosclerotic cardiovascular disease to improve clinical outcomes.

  7. Complications during renal artery stent placement for atherosclerotic ostial stenosis

    SciTech Connect

    Beek, Frederik J. A.; Kaatee, Robert; Beutler, Jaap J.; Ven, Peter J. van der; Mali, Willem P. T. M.

    1997-05-15

    Purpose. To describe short-term complications during stent placement for atherosclerotic renal artery ostial stenosis. Methods. Sixty-one arteries in 50 patients were treated with Palmaz stents. Nineteen patients had a single functioning kidney, 23 had a bilateral stenosis, which was stented bilaterally in 11, and 8 had a unilateral stenosis. The complications were grouped as those related to the catheterization procedure, those related to stent placement, and those possibly related to either category. The complications were divided into those with severe clinical significance (SCS), those with minor clinical significance (MCS), and radiological-technical complications (RTC). The stent placement procedures were ordered chronologically according to examination date and the complications were tabulated per group of 10 patients. Results. Five (10%) SCS, 5 (10%) MCS, and 8 (16%) RTC occurred in 50 patients. The catheterization procedure led to 2 SCS, 3 MCS, and 1 RTC. Stent placement gave rise to 7 RTC. Three SCS and 2 MCS could have been related to either catheterization or stent placement. More SCS occurred in the first group of 10 patients than in the following groups. Conclusion. Renal artery stent placement for atherosclerotic ostial stenosis has a considerable complication rate and a learning curve is present. The complications related to the actual stent placement were without clinical consequences.

  8. Inadequate dietary magnesium intake increases atherosclerotic plaque development in rabbits

    PubMed Central

    King, Jennifer L.; Miller, Rita J.; Blue, James P.; O'Brien, William D.; Erdman, John W.

    2012-01-01

    Epidemiological studies have shown dietary magnesium (Mg) intake and serum Mg levels to be inversely correlated with the development of atherosclerosis. We hypothesized that low levels of Mg would promote atherosclerotic plaque development in rabbits. New Zealand white rabbits (4 months old, n = 22) were fed an atherogenic diet containing 0.12% (−Mg), 0.27% (control), or 0.43% (+Mg) Mg for 8 weeks. Blood samples were obtained at baseline, 2, 4, 6, and 8 weeks and were assayed for total cholesterol, high-density lipoprotein (HDL), non-HDL, triglycerides (TG), C-reactive protein, serum Mg, and erythrocyte Mg. Aortas from −Mg had significantly more plaque, with an intima thickness 42% greater than control and 36% greater than +Mg. Serum cholesterol levels rose over time, and at 8 weeks, −Mg had the highest and +Mg the lowest total and non-HDL cholesterol and TG levels, although these results did not reach significance. Over time, serum Mg levels increased, and erythrocyte Mg levels decreased. C-reactive protein significantly increased in all groups at 4 and 6 weeks but returned to baseline levels by 8 weeks. This study supports the hypothesis that inadequate intake of Mg results in an increase in atherosclerotic plaque development in rabbits. PMID:19555816

  9. Imaging of the Fibrous Cap in Atherosclerotic Carotid Plaque

    SciTech Connect

    Saba, Luca; Potters, Fons; Lugt, Aad van der; Mallarini, Giorgio

    2010-08-15

    In the last two decades, a substantial number of articles have been published to provide diagnostic solutions for patients with carotid atherosclerotic disease. These articles have resulted in a shift of opinion regarding the identification of stroke risk in patients with carotid atherosclerotic disease. In the recent past, the degree of carotid artery stenosis was the sole determinant for performing carotid intervention (carotid endarterectomy or carotid stenting) in these patients. We now know that the degree of stenosis is only one marker for future cerebrovascular events. If one wants to determine the risk of these events more accurately, other parameters must be taken into account; among these parameters are plaque composition, presence and state of the fibrous cap (FC), intraplaque haemorrhage, plaque ulceration, and plaque location. In particular, the FC is an important structure for the stability of the plaque, and its rupture is highly associated with a recent history of transient ischaemic attack or stroke. The subject of this review is imaging of the FC.

  10. Noninvasive imaging of focal atherosclerotic lesions using fluorescence molecular tomography

    NASA Astrophysics Data System (ADS)

    Maji, Dolonchampa; Solomon, Metasebya; Nguyen, Annie; Pierce, Richard A.; Woodard, Pamela K.; Akers, Walter J.; Achilefu, Samuel; Culver, Joseph P.; Abendschein, Dana R.; Shokeen, Monica

    2014-11-01

    Insights into the etiology of stroke and myocardial infarction suggest that rupture of unstable atherosclerotic plaque is the precipitating event. Clinicians lack tools to detect lesion instability early enough to intervene, and are often left to manage patients empirically, or worse, after plaque rupture. Noninvasive imaging of the molecular events signaling prerupture plaque progression has the potential to reduce the morbidity and mortality associated with myocardial infarction and stroke by allowing early intervention. Here, we demonstrate proof-of-principle in vivo molecular imaging of C-type natriuretic peptide receptor in focal atherosclerotic lesions in the femoral arteries of New Zealand white rabbits using a custom built fiber-based, fluorescence molecular tomography (FMT) system. Longitudinal imaging showed changes in the fluorescence signal intensity as the plaque progressed in the air-desiccated vessel compared to the uninjured vessel, which was validated by ex vivo tissue studies. In summary, we demonstrate the potential of FMT for noninvasive detection of molecular events leading to unstable lesions heralding plaque rupture.

  11. Functional Heterogeneity of Nadph Oxidases in Atherosclerotic and Aneurysmal Diseases

    PubMed Central

    Kigawa, Yasuyoshi; Lei, Xiao-Feng; Kim-Kaneyama, Joo-ri; Miyazaki, Akira

    2017-01-01

    NADPH oxidases (NOX) are enzymes that catalyze the production of reactive oxygen species (ROS). Four species of NOX catalytic homologs (NOX1, NOX2, NOX4, and NOX5) are reportedly expressed in vascular tissues. The pro-atherogenic roles of NOX1, NOX2, and their organizer protein p47phox were manifested, and it was noted that the hydrogen peroxide-generating enzyme NOX4 possesses atheroprotective effects. Loss of NOX1 or p47phox appears to ameliorate murine aortic dissection and subsequent aneurysmal diseases; in contrast, the ablation of NOX2 exacerbates the aneurysmal diseases. It is possible that the loss of NOX2 activates inflammatory cascades in macrophages in the lesions. Roles of NOX5 in vascular functions are currently undetermined, owing to the absence of this enzyme in rodents and the limitation of the experimental procedure. Thus, it is possible that the NOX family of enzymes exhibits heterogeneity in the atherosclerotic diseases. In this aspect, subtype-selective NOX inhibitor may be promising when NOX systems serve as a molecular target for atherosclerotic and aneurysmal diseases. PMID:27476665

  12. Opening the Solar System: An Advanced Nuclear Spacecraft for Human Exploration

    NASA Technical Reports Server (NTRS)

    Werka, R. O.; Percy, T. K.

    2014-01-01

    Human exploration of the solar system is limited by our technology, not our imagination. We dream of a time when we can freely travel among the planets and truly become a spacefaring people. However, the current state of our technology limits our options for architecting missions to other planets. Instead of sailing the seas of space in the way that we cruise the seas of Earth, our limited propulsion technology requires us to depart Earth on a giant cluster of gas tanks and return in a lifeboat. This inefficient approach to exploration is evident in many of today's leading mission plans for human flights to Mars, asteroids, and other destinations. The cost and complexity of this approach to mission architecting makes it extremely difficult to realize our dreams of exploration beyond Low Earth Orbit (LEO). This does not need to be the case. Researchers at NASA's Marshall Space Flight Center (MSFC) have been investigating the feasibility of a new take on nuclear propulsion with the performance to enable a paradigm shift in human space exploration. During the fall of 2013, engineers at MSFC's Advanced Concepts Office developed a spacecraft concept (pictured below) around this new propulsion technology and redefined the human Mars mission to show its full potential. This spacecraft, which can be launched with a fleet of soon-to-be available SLS launch vehicles, is fueled primarily with hydrogen, and is fully reusable with no staging required. The reusable nature of this design enables a host of alternative mission architectures that more closely resemble an ocean voyage than our current piecemeal approach to exploration.

  13. A Probabilistic Risk Analysis (PRA) of Human Space Missions for the Advanced Integration Matrix (AIM)

    NASA Technical Reports Server (NTRS)

    Jones, Harry W.; Dillon-Merrill, Robin L.; Thomas, Gretchen A.

    2003-01-01

    The Advanced Integration Matrix (AIM) Project u7ill study and solve systems-level integration issues for exploration missions beyond Low Earth Orbit (LEO), through the design and development of a ground-based facility for developing revolutionary integrated systems for joint human-robotic missions. This paper describes a Probabilistic Risk Analysis (PRA) of human space missions that was developed to help define the direction and priorities for AIM. Risk analysis is required for all major NASA programs and has been used for shuttle, station, and Mars lander programs. It is a prescribed part of early planning and is necessary during concept definition, even before mission scenarios and system designs exist. PRA cm begin when little failure data are available, and be continually updated and refined as detail becomes available. PRA provides a basis for examining tradeoffs among safety, reliability, performance, and cost. The objective of AIM's PRA is to indicate how risk can be managed and future human space missions enabled by the AIM Project. Many critical events can cause injuries and fatalities to the crew without causing loss of vehicle or mission. Some critical systems are beyond AIM's scope, such as propulsion and guidance. Many failure-causing events can be mitigated by conducting operational tests in AIM, such as testing equipment and evaluating operational procedures, especially in the areas of communications and computers, autonomous operations, life support, thermal design, EVA and rover activities, physiological factors including habitation, medical equipment, and food, and multifunctional tools and repairable systems. AIM is well suited to test and demonstrate the habitat, life support, crew operations, and human interface. Because these account for significant crew, systems performance, and science risks, AIM will help reduce mission risk, and missions beyond LEO are far enough in the future that AIM can have significant impact.

  14. Symptomatic Atherosclerotic Disease and Decreased Risk of Cancer-Specific Mortality

    PubMed Central

    Benito-León, Julián; de la Aleja, Jesús González; Martínez-Salio, Antonio; Louis, Elan D.; Lichtman, Judith H.; Bermejo-Pareja, Félix

    2015-01-01

    Abstract The few studies that have assessed the association between symptomatic atherosclerotic disease and risk of cancer have had conflicting results. In addition, these studies ascertained participants either from treatment settings (ie, service-based studies) or by using a records linkage system (ie, medical records of patients evaluated at clinics or hospitals) and, therefore, were prone to selection bias. Our purpose was to estimate the risk of cancer mortality in a large population-based sample of elderly people, comparing participants with symptomatic atherosclerotic disease (atherosclerotic stroke and coronary disease) to their counterparts without symptomatic atherosclerotic disease (ie, controls) in the same population. In this population-based, prospective study (Neurological Disorders of Central Spain, NEDICES), 5262 elderly community-dwelling participants with and without symptomatic atherosclerotic disease were identified and followed for a median of 12.1 years, after which the death certificates of those who died were reviewed. A total of 2701 (53.3%) of 5262 participants died, including 314 (68.6%) of 458 participants with symptomatic atherosclerotic disease and 2387 (49.7%) of 4804 controls. Cancer mortality was reported significantly less often in those with symptomatic atherosclerotic disease (15.6%) than in controls (25.6%) (P < 0.001). In an unadjusted Cox model, risk of cancer-specific mortality was decreased in participants with symptomatic atherosclerotic disease (HR = 0.74, 95% confidence interval [CI], 0.55−0.98, P = 0.04) vs. those without symptomatic atherosclerotic disease (reference group). In an adjusted Cox model, HR = 0.58; 95% CI, 0.38−0.89; P = 0.01. This population-based, prospective study suggests that there is an inverse association between symptomatic atherosclerotic disease and risk of cancer mortality. PMID:26266364

  15. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques.

    PubMed

    Vinegoni, Claudio; Botnaru, Ion; Aikawa, Elena; Calfon, Marcella A; Iwamoto, Yoshiko; Folco, Eduardo J; Ntziachristos, Vasilis; Weissleder, Ralph; Libby, Peter; Jaffer, Farouc A

    2011-05-25

    New high-resolution molecular and structural imaging strategies are needed to visualize high-risk plaques that are likely to cause acute myocardial infarction, because current diagnostic methods do not reliably identify at-risk subjects. Although molecular imaging agents are available for low-resolution detection of atherosclerosis in large arteries, a lack of imaging agents coupled to high-resolution modalities has limited molecular imaging of atherosclerosis in the smaller coronary arteries. Here, we have demonstrated that indocyanine green (ICG), a Food and Drug Administration-approved near-infrared fluorescence (NIRF)-emitting compound, targets atheromas within 20 min of injection and provides sufficient signal enhancement for in vivo detection of lipid-rich, inflamed, coronary-sized plaques in atherosclerotic rabbits. In vivo NIRF sensing was achieved with an intravascular wire in the aorta, a vessel of comparable caliber to human coronary arteries. Ex vivo fluorescence reflectance imaging showed high plaque target-to-background ratios in atheroma-bearing rabbits injected with ICG compared to atheroma-bearing rabbits injected with saline. In vitro studies using human macrophages established that ICG preferentially targets lipid-loaded macrophages. In an early clinical study of human atheroma specimens from four patients, we found that ICG colocalized with plaque macrophages and lipids. The atheroma-targeting capability of ICG has the potential to accelerate the clinical development of NIRF molecular imaging of high-risk plaques in humans.

  16. Advances in Educational and Psychological Testing: Theory and Applications. Evaluation in Education and Human Services Series.

    ERIC Educational Resources Information Center

    Hambleton, Ronald K., Ed.; Zaal, Jac N., Ed.

    The 14 chapters of this book focus on the technical advances, advances in applied settings, and emerging topics in the testing field. Part 1 discusses methodological advances, Part 2 considers developments in applied settings, and Part 3 reviews emerging topics in the field of testing. Part 1 papers include: (1) "Advances in…

  17. DNA technological progress toward advanced diagnostic tools to support human hookworm control.

    PubMed

    Gasser, R B; Cantacessi, C; Loukas, A

    2008-01-01

    Blood-feeding hookworms are parasitic nematodes of major human health importance. Currently, it is estimated that 740 million people are infected worldwide, and more than 80 million of them are severely affected clinically by hookworm disease. In spite of the health problems caused and the advances toward the development of vaccines against some hookworms, limited attention has been paid to the need for improved, practical methods of diagnosis. Accurate diagnosis and genetic characterization of hookworms is central to their effective control. While traditional diagnostic methods have considerable limitations, there has been some progress toward the development of molecular-diagnostic tools. The present article provides a brief background on hookworm disease of humans, reviews the main methods that have been used for diagnosis and describes progress in establishing polymerase chain reaction (PCR)-based methods for the specific diagnosis of hookworm infection and the genetic characterisation of the causative agents. This progress provides a foundation for the rapid development of practical, highly sensitive and specific diagnostic and analytical tools to be used in improved hookworm prevention and control programmes.

  18. Classification of human colonic tissues using FTIR spectra and advanced statistical techniques

    NASA Astrophysics Data System (ADS)

    Zwielly, A.; Argov, S.; Salman, A.; Bogomolny, E.; Mordechai, S.

    2010-04-01

    One of the major public health hazards is colon cancer. There is a great necessity to develop new methods for early detection of cancer. If colon cancer is detected and treated early, cure rate of more than 90% can be achieved. In this study we used FTIR microscopy (MSP), which has shown a good potential in the last 20 years in the fields of medical diagnostic and early detection of abnormal tissues. Large database of FTIR microscopic spectra was acquired from 230 human colonic biopsies. Five different subgroups were included in our database, normal and cancer tissues as well as three stages of benign colonic polyps, namely, mild, moderate and severe polyps which are precursors of carcinoma. In this study we applied advanced mathematical and statistical techniques including principal component analysis (PCA) and linear discriminant analysis (LDA), on human colonic FTIR spectra in order to differentiate among the mentioned subgroups' tissues. Good classification accuracy between normal, polyps and cancer groups was achieved with approximately 85% success rate. Our results showed that there is a great potential of developing FTIR-micro spectroscopy as a simple, reagent-free viable tool for early detection of colon cancer in particular the early stages of premalignancy among the benign colonic polyps.

  19. Advancing environmental health surveillance in the US through a national human biomonitoring network.

    PubMed

    Latshaw, Megan Weil; Degeberg, Ruhiyyih; Patel, Surili Sutaria; Rhodes, Blaine; King, Ewa; Chaudhuri, Sanwat; Nassif, Julianne

    2016-09-17

    The United States lacks a comprehensive, nationally-coordinated, state-based environmental health surveillance system. This lack of infrastructure leads to: • varying levels of understanding of chemical exposures at the state & local levels • often inefficient public health responses to chemical exposure emergencies (such as those that occurred in the Flint drinking water crisis, the Gold King mine spill, the Elk river spill and the Gulf Coast oil spill) • reduced ability to measure the impact of public health interventions or environmental policies • less efficient use of resources for cleaning up environmental contamination Establishing the National Biomonitoring Network serves as a step toward building a national, state-based environmental health surveillance system. The Network builds upon CDC investments in emergency preparedness and environmental public health tracking, which have created advanced chemical analysis and information sharing capabilities in the state public health systems. The short-term goal of the network is to harmonize approaches to human biomonitoring in the US, thus increasing the comparability of human biomonitoring data across states and communities. The long-term goal is to compile baseline data on exposures at the state level, similar to data found in CDC's National Report on Human Exposure to Environmental Chemicals. Barriers to success for this network include: available resources, effective risk communication strategies, data comparability & sharing, and political will. Anticipated benefits include high quality data on which to base public health and environmental decisions, data with which to assess the success of public health interventions, improved risk assessments for chemicals, and new ways to prioritize environmental health research.

  20. Detection of advanced glycation end products (AGEs) on human skin by in vivo confocal Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Martin, A. A.; Pereira, L.; Ali, S. M.; Pizzol, C. D.; Tellez, C. A.; Favero, P. P.; Santos, L.; da Silva, V. V.; Praes, C. E. O.

    2016-03-01

    The aging process involves the reduction in the production of the major components of skin tissue. During intrinsic aging and photoaging processes, in dermis of human skin, fibroblasts become senescent and have decreased activity, which produce low levels of collagen. Moreover, there is accumulation of advanced glycation end products (AGEs). AGEs have incidence in the progression of age-related diseases, principally in diabetes mellitus and in Alzheimer's diseases. AGEs causes intracellular damage and/or apoptosis leading to an increase of the free radicals, generating a crosslink with skin proteins and oxidative stress. The aim of this study is to detect AGEs markers on human skin by in vivo Confocal Raman spectroscopy. Spectra were obtained by using a Rivers Diagnostic System, 785 nm laser excitation and a CCD detector from the skin surface down to 120 μm depth. We analyzed the confocal Raman spectra of the skin dermis of 30 women volunteers divided into 3 groups: 10 volunteers with diabetes mellitus type II, 65-80 years old (DEW); 10 young healthy women, 20-33 years old (HYW); and 10 elderly healthy women, 65-80 years old (HEW). Pentosidine and glucosepane were the principally identified AGEs in the hydroxyproline and proline Raman spectral region (1000-800 cm-1), in the 1.260-1.320 cm-1 region assignable to alpha-helical amide III modes, and in the Amide I region. Pentosidine and glucosepane calculated vibrational spectra were performed through Density Functional Theory using the B3LYP functional with 3-21G basis set. Difference between the Raman spectra of diabetic elderly women and healthy young women, and between healthy elderly women and healthy young women were also obtained with the purpose of identifying AGEs Raman bands markers. AGEs peaks and collagen changes have been identified and used to quantify the glycation process in human skin.

  1. Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

    2010-01-01

    Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

  2. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation.

    PubMed

    Fukuda, Kazuki; Matsumura, Takeshi; Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko; Nakao, Saya; Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji; Kawada, Teruo; Nishikawa, Takeshi; Araki, Eiichi

    2015-01-30

    The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.

  3. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man.

    PubMed Central

    Ylä-Herttuala, S; Palinski, W; Rosenfeld, M E; Parthasarathy, S; Carew, T E; Butler, S; Witztum, J L; Steinberg, D

    1989-01-01

    Three lines of evidence are presented that low density lipoproteins gently extracted from human and rabbit atherosclerotic lesions (lesion LDL) greatly resembles LDL that has been oxidatively modified in vitro. First, lesion LDL showed many of the physical and chemical properties of oxidized LDL, properties that differ from those of plasma LDL: higher electrophoretic mobility, a higher density, higher free cholesterol content, and a higher proportion of sphingomyelin and lysophosphatidylcholine in the phospholipid fraction. A number of lower molecular weight fragments of apo B were found in lesion LDL, similar to in vitro oxidized LDL. Second, both the intact apo B and some of the apo B fragments of lesion LDL reacted in Western blots with antisera that recognize malondialdehyde-conjugated lysine and 4-hydroxynonenal lysine adducts, both of which are found in oxidized LDL; plasma LDL and LDL from normal human intima showed no such reactivity. Third, lesion LDL shared biological properties with oxidized LDL: compared with plasma LDL, lesion LDL produced much greater stimulation of cholesterol esterification and was degraded more rapidly by macrophages. Degradation of radiolabeled lesion LDL was competitively inhibited by unlabeled lesion LDL, by LDL oxidized with copper, by polyinosinic acid and by malondialdehyde-LDL, but not by native LDL, indicating uptake by the scavenger receptor(s). Finally, lesion LDL (but not normal intimal LDL or plasma LDL) was chemotactic for monocytes, as is oxidized LDL. These studies provide strong evidence that atherosclerotic lesions, both in man and in rabbit, contain oxidatively modified LDL. Images PMID:2794046

  4. Gap junctional communication between vascular cells. Induction of connexin43 messenger RNA in macrophage foam cells of atherosclerotic lesions.

    PubMed Central

    Polacek, D.; Lal, R.; Volin, M. V.; Davies, P. F.

    1993-01-01

    The structure and function of blood vessels depend on the ability of vascular cells to receive and transduce signals and to communicate with each other. One means by which vascular cells have been shown to communicate is via gap junctions, specifically connexin43. In atherosclerosis, the normal physical patterns of communication are disrupted by the subendothelial infiltration and accumulation of blood monocytes, which in turn can differentiate into resident foam cells. In this paper we report that neither freshly isolated human peripheral blood monocytes nor differentiated monocytes/macrophages exhibit functional gap junctional dye transfer in homo-cellular culture or in co-culture with endothelial cells or smooth muscle cells. By Northern analysis, neither freshly isolated blood monocytes nor pure cultures of differentiated monocyte/macrophages expressed gap junction messenger RNA. However, immunohistochemical staining followed by in situ hybridization on sections of human atherosclerotic carotid arteries revealed strong expression of gap junction connexin43 messenger RNA by macrophage foam cells. These results suggest that tissue-specific conditions present in atherosclerotic arteries induce expression of connexin43 messenger RNA in monocyte/macrophages. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8382009

  5. The Helicobacter cinaedi antigen CAIP participates in atherosclerotic inflammation by promoting the differentiation of macrophages in foam cells

    PubMed Central

    D’Elios, Mario Milco; Vallese, Francesca; Capitani, Nagaja; Benagiano, Marisa; Bernardini, Maria Lina; Rossi, Mirko; Rossi, Gian Paolo; Ferrari, Mauro; Baldari, Cosima Tatiana; Zanotti, Giuseppe; de Bernard, Marina; Codolo, Gaia

    2017-01-01

    Recent studies have shown that certain specific microbial infections participate in atherosclerosis by inducing inflammation and immune reactions, but how the pathogens implicated in this pathology trigger the host responses remains unknown. In this study we show that Helicobacter cinaedi (Hc) is a human pathogen linked to atherosclerosis development since at least 27% of sera from atherosclerotic patients specifically recognize a protein of the Hc proteome, that we named Cinaedi Atherosclerosis Inflammatory Protein (CAIP) (n = 71). CAIP appears to be implicated in this pathology because atheromatous plaques isolated from atherosclerotic patients are enriched in CAIP-specific T cells (10%) which, in turn, we show to drive a Th1 inflammation, an immunopathological response typically associated to atherosclerosis. Recombinant CAIP promotes the differentiation and maintenance of the pro-inflammatory profile of human macrophages and triggers the formation of foam cells, which are a hallmark of atherosclerosis. This study identifies CAIP as a relevant factor in atherosclerosis inflammation linked to Hc infection and suggests that preventing and eradicating Hc infection could reduce the incidence of atherosclerosis. PMID:28074932

  6. Dietary Carnosine Prevents Early Atherosclerotic Lesion Formation in ApoE-null Mice

    PubMed Central

    Barski, Oleg A.; Xie, Zhengzhi; Baba, Shahid P.; Sithu, Srinivas D.; Agarwal, Abhinav; Cai, Jian; Bhatnagar, Aruni; Srivastava, Sanjay

    2013-01-01

    Objective Atherosclerotic lesions are associated with the accumulation of reactive aldehydes derived from oxidized lipids. Although inhibition of aldehyde metabolism has been shown to exacerbate atherosclerosis and enhance the accumulation of aldehyde-modified proteins in atherosclerotic plaques, no therapeutic interventions have been devised to prevent aldehyde accumulation in atherosclerotic lesions. Approach and Results We examined the efficacy of carnosine, a naturally occurring β-alanyl-histidine dipeptide in preventing aldehyde toxicity and atherogenesis in apoE-null mice. In vitro, carnosine reacted rapidly with lipid peroxidation-derived unsaturated aldehydes. Gas chromatography mass-spectrometry analysis showed that carnosine inhibits the formation of free aldehydes - HNE and malonaldialdehyde in Cu2+-oxidized LDL. Preloading bone marrow-derived macrophages with cell-permeable carnosine analogs reduced HNE-induced apoptosis. Oral supplementation with octyl-D-carnosine decreased atherosclerotic lesion formation in aortic valves of apoE-null mice and attenuated the accumulation of protein-acrolein, protein-HHE and protein-HNE adducts in atherosclerotic lesions, while urinary excretion of aldehydes as carnosine conjugates was increased. Conclusions The results of this study suggest that carnosine inhibits atherogenesis by facilitating aldehyde removal from atherosclerotic lesions. Endogenous levels of carnosine may be important determinants of atherosclerotic lesion formation and treatment with carnosine or related peptides could be a useful therapy for the prevention or the treatment of atherosclerosis. PMID:23559625

  7. Defining Advancement Career Paths and Succession Plans: Critical Human Capital Retention Strategies for High-Performing Advancement Divisions

    ERIC Educational Resources Information Center

    Croteau, Jon Derek; Wolk, Holly Gordon

    2010-01-01

    There are many factors that can influence whether a highly talented staff member will build a career within an institution or use it as a stepping stone. This article defines and explores the notions of developing career paths and succession planning and why they are critical human capital investment strategies in retaining the highest performers…

  8. Evaluation and percutaneous management of atherosclerotic peripheral vascular disease

    SciTech Connect

    Widlus, D.M.; Osterman, F.A. Jr. )

    1989-06-02

    Atherosclerotic peripheral vascular disease (PVD) of the lower extremities deprives a person of the ability to exercise to their satisfaction, later of the ability to perform the activities of their daily life, and finally of their legs themselves. Peripheral vascular disease has long been managed by the vascular surgeon utilizing endarterectomy and peripheral arterial bypass. Patient acceptance of nonsurgical, percutaneous procedures such as percutaneous transluminal balloon angioplasty (PTA) is high. Increased utilization of these procedures has led to improved techniques and adjuncts to therapy, as well as more critical review of long-term results. This article will review the evaluation and nonoperative management of PVD, with an emphasis on the newer modalities of management presently being investigated.

  9. Non-atherosclerotic vascular disease in the young.

    PubMed

    Camilo, Osvaldo; Goldstein, Larry B

    2005-10-01

    There are a large variety of non-atherosclerotic causes of ischemic stroke in the young. Arterial dissection, most commonly associated with non-traumatic causes, is among the most common. Both the carotid and vertebrobasilar circulations can be affected. The vasculitidies represent a rare, but potentially treatable series of conditions that can lead to stroke through diverse mechanisms. Moyamoya is a nonatherosclerotic, noninflammatory, nonamyloid vasculopathy characterized by chronic progressive stenosis or occlusion of the distal internal carotid arteries and/or proximal portions of the middle and/or anterior cerebral arteries. Moyamoya can be idiopathic (moyamoya disease) or the result of other conditions. An appreciation of the unusual causes of stroke in the young is important when considering secondary prevention measures.

  10. CD154: the atherosclerotic risk factor in rheumatoid arthritis?

    PubMed Central

    2013-01-01

    Atherosclerosis, now regarded as a chronic inflammatory disease of the arterial wall, and its clinical manifestations have increasingly been associated with rheumatoid arthritis (RA), supporting the notion that autoimmune diseases and vascular disorders share common etiological features. Indeed, evidence pertaining to this matter indicates that inflammation and its multiple components are the driving force behind the pathogenesis of these disorders. Interestingly, CD154 and its receptors have emerged as major players in the development of RA and atherosclerosis, which raises the possibility that this axis may represent an important biological link between both complications. Indeed, CD154 signaling elicits critical inflammatory responses that are common to the pathogenesis of both diseases. Here, we provide an overview of the traditional and disease-related interrelations between RA and vascular abnormalities, while focusing on CD154 as a potential mediator in the development of atherosclerotic events in RA patients. PMID:23433179

  11. Bilateral atherosclerotic internal carotid artery occlusion and recurrent ischaemic stroke.

    PubMed

    Amin, Osama S M

    2015-06-08

    Bilateral internal carotid artery occlusion (BICAO) is a rare disease that carries a gloomy prognosis. We report a case of a 52-year-old man who developed ischaemic infarction at the region of the right middle cerebral artery; he was found to have atherosclerotic occlusion of both internal carotid arteries on Doppler-duplex examination. He received medical treatment only. After 1 year, he developed a new infarction at the region of the left middle cerebral artery. Conventional angiography revealed bilateral occlusion of internal carotid arteries at their origin, approximately 50% stenosis of the common carotid bulbs and mild stenosis of the origin of external carotid arteries. The patient did not undergo any form of surgical revascularisation procedures and died of severe aspiration pneumonia approximately 2 months after the second stroke. BICAO portends a poor outcome and carries a risk of recurrent ischaemic events. The best management strategy for this vascular occlusion remains unclear.

  12. Lipid and protein maps defining arterial layers in atherosclerotic aorta

    PubMed Central

    Martin-Lorenzo, Marta; Balluff, Benjamin; Maroto, Aroa S.; Carreira, Ricardo J.; van Zeijl, Rene J.M.; Gonzalez-Calero, Laura; de la Cuesta, Fernando; Barderas, Maria G; Lopez-Almodovar, Luis F; Padial, Luis R; McDonnell, Liam A.; Vivanco, Fernando; Alvarez-Llamas, Gloria

    2015-01-01

    Subclinical atherosclerosis cannot be predicted and novel therapeutic targets are needed. The molecular anatomy of healthy and atherosclerotic tissue is pursued to identify ongoing molecular changes in atherosclerosis development. Mass Spectrometry Imaging (MSI) accounts with the unique advantage of analyzing proteins and metabolites (lipids) while preserving their original localization; thus two dimensional maps can be obtained. Main molecular alterations were investigated in a rabbit model in response to early development of atherosclerosis. Aortic arterial layers (intima and media) and calcified regions were investigated in detail by MALDI-MSI and proteins and lipids specifically defining those areas of interest were identified. These data further complement main findings previously published in J Proteomics (M. Martin-Lorenzo et al., J. Proteomics. (In press); M. Martin-Lorenzo et al., J. Proteomics 108 (2014) 465–468.) [1,2]. PMID:26217810

  13. Assessing the Influence of Human Activities on Global Water Resources Using an Advanced Land Surface Model

    NASA Astrophysics Data System (ADS)

    Pokhrel, Y.; Hanasaki, N.; Koirala, S.; Kanae, S.; Oki, T.

    2010-12-01

    In order to examine the impact of human intervention on the global hydrological cycle, a Land Surface Model was enhanced with schemes to assess the anthropogenic disturbance on the natural water flow at the global scale. Four different schemes namely; reservoir operation, crop growth, environmental flow, and anthropogenic water withdrawal modules from a state-of-the-art global water resources assessment model called H08 were integrated into an offline version of LSM, Minimal Advance Treatment of Surface Interaction and Runoff (MATSIRO). MATSIRO represents majority of the hydrological processes of water and energy exchange between the land surface and the atmosphere on a physical basis and is designed to be coupled with GCM. The integrated model presented here thus has the capability to simulate both natural and anthropogenic flows of water globally at a spatial resolution of 1°x1°, considering dam operation, domestic, industrial and agricultural water withdrawals and environmental flow requirements. The model can also be coupled with climate models to assess the impact of human activities on the climate system. A simple groundwater scheme was also incorporated and the model can be used to assess the change in water table due to groundwater pumping for irrigation. The model was validated by comparing simulated soil moisture, river discharge and Terrestrial Water Storage Anomaly (TWSA) with observations. The model performs well in simulating TWSA as compared to GRACE observation in different river basins ranging from very wet to very dry. Soil moisture cannot be validated globally because of the lack of validation datasets. For Illinois region, where long term soil moisture observations are available, the model captures the seasonal variation quite well. The simulated global potential irrigation demand is about 1100km3/year, which is within the range of previously published estimates based on various water balance models and LSMs. The model has an advanced option

  14. Fluorescence characteristics of atherosclerotic plaque and malignant tumors

    NASA Astrophysics Data System (ADS)

    Andersson-Engels, Stefan; Baert, Luc; Berg, Roger; D'Hallewin, Marie-Ange; Johansson, Jonas; Stenram, Unne; Svanberg, Katarina; Svanberg, Sune

    1991-06-01

    Two series of investigations utilizing laser-induced fluorescence (LIF) in characterizing diseased tissue are presented. In one in vitro investigation the fluorescence from normal and atherosclerotically diseased arteries are studied. In another clinical study the fluorescence in vivo from superficial urinary bladder malignancies in patients who had received a low-dose injection of Hematoporphyrin Derivative (HpD) is investigated. Additionally, the fluorescence properties of L-tryptophan, collagen-I powder, elastin powder, nicotinamide adenine dinucleotide and (beta) -carothene were investigated and compared with the spectra from the tissue samples. A nitrogen laser (337 nm) alone or in connection with a dye laser (405 nm) was used together with an optical multichannel analyzer (OMA) to study the fluorescence spectra. The fluorescence decay characteristics of atherosclerotic plaque were examined utilizing a mode locked argon ion laser, synchronously pumping a picosecond dye laser. A fast detection system based on photon counting was employed. The fluorescence decay curves were evaluated on a PC computer allowing up to three lifetime components to be determined. A fluorescence peak at 390 nm in fibrotic plaque was identified as due to collagen fibers, while a fluorescence peak at 520 nm was connected to (beta) -carotene. The in vivo measurements of urinary bladder malignancies were performed with the optical fiber of the OMA system inserted through the biopsy channel of a cystoscope during the diagnostical procedure. The spectral recordings from urinary bladders, obtained at 337 nm and 405 nm excitation, revealed fluorescence features which can be used to demarcate tumor areas from normal mucosa. The fluorescence emission might also be useful to characterize different degrees of dysplasia.

  15. Cadmium exposure and atherosclerotic carotid plaques –Results from the Malmö diet and Cancer study

    SciTech Connect

    Fagerberg, Björn; Barregard, Lars; Sallsten, Gerd; Forsgard, Niklas; Östling, Gerd; Persson, Margaretha; Borné, Yan; and others

    2015-01-15

    Background: Epidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease. Objectives: To examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery. Methods: A population sample of 4639 Swedish middle-aged women and men was examined in 1991–1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry. Results: Comparing quartile 4 with quartile 1 of blood cadmium, the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6–2.2) after adjustment for sex and, age; 1.4 (1.1–1.8) after additional adjustment for smoking status; 1.4 (1.1–1.7) after the addition of education level and life style factors; 1.3 (1.03–1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0–2.1) and 1.4 (0.9–2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques. Conclusions: These results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure. - Highlights: • Blood cadmium level is associated with atherosclerotic plaques in the carotid artery. • The results extend previous knowledge of cadmium exposure and clinical events. • The role of smoking remains unclear.

  16. Next Generation Life Support Project: Development of Advanced Technologies for Human Exploration Missions

    NASA Technical Reports Server (NTRS)

    Barta, Daniel J.

    2012-01-01

    Next Generation Life Support (NGLS) is one of several technology development projects sponsored by the National Aeronautics and Space Administration s Game Changing Development Program. NGLS is developing life support technologies (including water recovery, and space suit life support technologies) needed for humans to live and work productively in space. NGLS has three project tasks: Variable Oxygen Regulator (VOR), Rapid Cycle Amine (RCA) swing bed, and Alternative Water Processing. The selected technologies within each of these areas are focused on increasing affordability, reliability, and vehicle self sufficiency while decreasing mass and enabling long duration exploration. The RCA and VOR tasks are directed at key technology needs for the Portable Life Support System (PLSS) for an Exploration Extravehicular Mobility Unit (EMU), with focus on prototyping and integrated testing. The focus of the Rapid Cycle Amine (RCA) swing-bed ventilation task is to provide integrated carbon dioxide removal and humidity control that can be regenerated in real time during an EVA. The Variable Oxygen Regulator technology will significantly increase the number of pressure settings available to the space suit. Current spacesuit pressure regulators are limited to only two settings while the adjustability of the advanced regulator will be nearly continuous. The Alternative Water Processor efforts will result in the development of a system capable of recycling wastewater from sources expected in future exploration missions, including hygiene and laundry water, based on natural biological processes and membrane-based post treatment. The technologies will support a capability-driven architecture for extending human presence beyond low Earth orbit to potential destinations such as the Moon, near Earth asteroids and Mars.

  17. Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE{sup -/-} mice

    SciTech Connect

    Campen, Matthew J.; Lund, Amie K.; Knuckles, Travis L.; Conklin, Daniel J.; Bishop, Barbara; Young, David; Seilkop, Steven; Seagrave, JeanClare; Reed, Matthew D.; McDonald, Jacob D.

    2010-02-01

    Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high-fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/day for 50 days. Aortas were subsequently assayed for alterations in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease.

  18. Therapeutic Potential of Modulating microRNAs in Atherosclerotic Vascular Disease

    PubMed Central

    Araldi, Elisa; Chamorro-Jorganes, Aranzazu; van Solingen, Coen; Fernández-Hernando, Carlos; Suárez, Yajaira

    2013-01-01

    Atherosclerosis (also known as arteriosclerotic vascular disease) is a chronic inflammatory disease of the arterial wall, characterized by the formation of lipid-laden lesions. The activation of endothelial cells at atherosclerotic lesion–prone sites in the arterial tree results in the up-regulation of cell adhesion molecules and chemokines, which mediate the recruitment of circulating monocytes. Accumulation of monocytes and monocyte-derived phagocytes in the wall of large arteries leads to chronic inflammation and the development and progression of atherosclerosis. The lesion experiences the following steps: foam cell formation, fatty streak accumulation, migration and proliferation of vascular smooth muscle cells, and fibrous cap formation. Finally, the rupture of the unstable fibrous cap causes thrombosis in complications of advanced lesions that leads to unstable coronary syndromes, myocardial infarction and stroke. MicroRNAs have recently emerged as a novel class of gene regulators at the post-transcriptional level. Several functions of vascular cells, such as cell differentiation, contraction, migration, proliferation and inflammation that are involved in angiogenesis, neointimal formation and lipid metabolism underlying various vascular diseases, have been found to be regulated by microRNAs and are described in the present review as well as their potential therapeutic application. PMID:23713860

  19. Hepatocyte growth factor protects human endothelial cells against advanced glycation end products-induced apoposis

    SciTech Connect

    Zhou Yijun . E-mail: zhou-yijun@hotmail.com; Wang Jiahe; Zhang Jin

    2006-06-02

    Advanced glycation end products (AGEs) form by a non-enzymatic reaction between reducing sugars and biological proteins, which play an important role in the pathogenesis of atherosclerosis. In this study, we assessed AGEs effects on human umbilical vein endothelial cells (HUVECs) growth, proliferation and apoptosis. Additionally, we investigated whether hepatocyte growth factor (HGF), an anti-apoptotic factor for endothelial cells, prevents AGEs-induced apoptosis of HUVECs. HUVECs were treated with AGEs in the presence or absence of HGF. Treatment of HUVECs with AGEs changed cell morphology, decreased cell viability, and induced DNA fragmentation, leading to apoptosis. Apoptosis was induced by AGEs in a dose- and time-dependent fashion. AGEs markedly elevated Bax and decreased NF-{kappa}B, but not Bcl-2 expression. Additionally, AGEs significantly inhibited cell growth through a pro-apoptotic action involving caspase-3 and -9 activations in HUVECs. Most importantly, pretreatment with HGF protected against AGEs-induced cytotoxicity in the endothelial cells. HGF significantly promoted the expression of Bcl-2 and NF-{kappa}B, while decreasing the activities of caspase-3 and -9 without affecting Bax level. Our data suggest that AGEs induce apoptosis in endothelial cells. HGF effectively attenuate AGEs-induced endothelial cell apoptosis. These findings provide new perspectives in the role of HGF in cardiovascular disease.

  20. Singlet oxygen induced advanced glycation end-product photobleaching of in vivo human fingertip autofluorescence

    NASA Astrophysics Data System (ADS)

    Deng, Bin; Simental, Anabel; Lutz, Patrick; Shaheen, George; Chaiken, Joseph

    2012-01-01

    Nonenzymatic glycation and oxidation of ubiquitous proteins in vivo leads to irreversible formation of advanced glycation end products (AGEs). Due to their relatively long half life and low clearance rate AGEs tend to accumulate within static tissues and the circulatory system. Spectra obtained using 830 nm near-infrared (NIR) excitation suggest that the so-called "autofluorescence" from all tissues has a finite number of sources but the fact that senior and diabetic subjects produce more than other members of the general population suggests that a significant portion of the total autofluorescence from all sources originates from AGEs. Using pentosidine generated in a reaction mixture as described by Monnier as representative, an in vitro study unveiled very similar fluorescence and photobleaching pattern as observed for autofluorescence in vivo. A series of oxygen, air and argon purging experiments on the pentosidine-generating reaction mixture suggests that pentosidine is a singlet oxygen sensitizer and secondary reactions between the pentosidine itself and/or other fluorophores and the photosensitized singlet oxygen explain the observed photobleaching. Ab initio Gaussian calculations on pentosidine reveal the existence of low-lying triplet excited states required for the sensitization of ground state oxygen. A commercially available product known as singlet oxygen sensor green (SOSG) that specifically serves as a singlet oxygen detection reagent confirms the generation of singlet oxygen from NIR irradiated pentosidine trimixture. This study provides one definite chemical mechanism for understanding in vivo human skin autofluorescence and photobleaching.

  1. Advancing Coupled Human-Earth System Models: The Integrated Ecosystem Demography Model (iED) Project

    NASA Astrophysics Data System (ADS)

    Hurtt, G. C.; Chini, L. P.; Clarke, L.; Calvin, K. V.; Chambers, J. Q.; Dubayah, R.; Dolan, K.; Edmonds, J. A.; Fisk, J. P.; Flanagan, S.; Frolking, S.; Janetos, A. C.; LePage, Y.; Morton, D. C.; Patel, P.; Rourke, O.; Sahajpal, R.; Thomson, A. M.; Wise, M.; Ying, Q.

    2012-12-01

    Recent studies with integrated assessment models, models linking human and natural systems at a global scale, highlight the importance of terrestrial systems in climate stabilization efforts. Here we introduce a new modeling framework iED, designed to link advanced remote sensing data (active and passive.), height-structured terrestrial ecosystem dynamics (ED), gridded land-use change projections (GLM), and integrated assessment modeling (GCAM) into a single coupled modeling framework with unprecedented spatial resolution and process-level detail. Our research aims to reduce uncertainties associated with forest modeling within integrated assessments, and to quantify the impacts of climate change on forest growth, mortality, and productivity for integrated assessments of terrestrial carbon management. iED is being used to address key science questions including: (1) What are the opportunities for land-use strategies such as afforestation or woody bioenergy crop production to contribute to stabilization of atmospheric CO2 concentrations? (2) How could potentially altered disturbance rates from tropical cyclones and Amazonian fires affect vegetation, carbon stocks and fluxes, and the development of climate change mitigation strategies? (3) What are the linked remote sensing/ecosystem modeling requirements for improving integrated assessments of climate mitigation strategies? With its strong connections to data and conceptual linkages to other models in development, iED is also designed to inform the next generation of remote sensing and integrated Earth system modeling efforts.

  2. [18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs

    PubMed Central

    Tarkia, Miikka; Saraste, Antti; Stark, Christoffer; Vähäsilta, Tommi; Savunen, Timo; Strandberg, Marjatta; Saunavaara, Virva; Tolvanen, Tuula; Teuho, Jarmo; Teräs, Mika; Metsälä, Olli; Rinne, Petteri; Heinonen, Ilkka; Savisto, Nina; Pietilä, Mikko; Saukko, Pekka; Roivainen, Anne; Knuuti, Juhani

    2015-01-01

    Objective Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model. Methods First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG). Results Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4). Conclusions We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques. PMID:26120829

  3. Biochemical characterization of atherosclerotic plaques by endogenous multispectral fluorescence lifetime imaging microscopy

    PubMed Central

    Park, Jesung; Pande, Paritosh; Shrestha, Sebina; Clubb, Fred; Applegate, Brian E.; Jo, Javier A.

    2011-01-01

    OBJECTIVE To investigate the potential of endogenous multispectral fluorescence lifetime imaging microscopy (FLIM) for biochemical characterization of human coronary atherosclerotic plaques. METHODS Endogenous multispectral FLIM imaging was performed on the lumen of 58 segments of postmortem human coronary artery. The fluorescence was separated into three emission bands targeting the three main arterial endogenous fluorophores (390±20 nm for collagen, 452±22.5 nm for elastin, and 550±20 for lipids). The fluorescence normalized intensity and average lifetime from each emission band was used to classify each pixel of an image as either “High-Collagen”, “High-Lipids” or “Low-Collagen/Lipids” via multiclass Fisher’s linear discriminant analysis. RESULTS Classification of plaques as either “High-Collagen”, “High-Lipids” or “Low-Collagen/Lipids” based on the endogenous multispectral FLIM was achieved with a sensitivity/specificity of 96/98%, 89/99%, and 99/99%, respectively, where histopathology served as the gold standard. CONCLUSION The endogenous multispectral FLIM approach we have taken, which can readily be adapted for in vivo intravascular catheter based imaging, is capable of reliably identifying plaques with high content of either collagen or lipids. PMID:22138141

  4. Combination therapy of advanced invasive pulmonary aspergillosis in transiently neutropenic rats using human pharmacokinetic equivalent doses of voriconazole and anidulafungin.

    PubMed

    van de Sande, Wendy W J; Mathot, Ron A A; ten Kate, Marian T; van Vianen, Wim; Tavakol, Mehri; Rijnders, Bart J A; Bakker-Woudenberg, Irma A J M

    2009-05-01

    At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.

  5. Characterization of atherosclerotic plaque-depositions by infrared, Raman and CARS microscopy

    NASA Astrophysics Data System (ADS)

    Matthäus, Christian; Bergner, Gero; Krafft, Christoph; Dietzek, Benjamin; Romeike, Bernd F. M.; Brehm, Bernhard R.; Popp, Jürgen

    2011-07-01

    Atherosclerotic plaques are mainly composed of proteoglycans, triglycerides, cholesterol, cholesterolester and crystalline calcium. From histopathological characterizations it is known that the composition of these atherosclerotic plaques can vary to a great extent, due to different risk factors as smoking, hyperlipedemia, or genetic background ect. The individual plaque components can be spectroscopically easily identified. Furthermore, spectroscopic imaging technologies offer the possibility to study the plaque compositions in a more quantitative manner than traditional staining techniques. Here, we compare the potential of IR, Raman and CARS microscopy to characterize the constitution of atherosclerotic plaques as well as the structure of the surrounding tissue. For data analysis and image reconstruction spectral decomposition algorithms such as vertex component analysis (VCA) were introduced. The results are in good agreement with the histopathology. Aim of the study is to correlate the compositional characteristics of atherosclerotic plaques with individual disease patterns.

  6. Impact of the B Cell Growth Factor APRIL on the Qualitative and Immunological Characteristics of Atherosclerotic Plaques

    PubMed Central

    van Leuven, Sander I.; Zheng, Kang H.; Havik, Stefan R.; Versloot, Miranda V.; van Duivenvoorde, Leonie M.; Hahne, Michael; Stroes, Erik S. G.; Baeten, Dominique L.; Hamers, Anouk A. J.

    2016-01-01

    Studies on the role of B lymphocytes in atherosclerosis development, have yielded contradictory results. Whereas B lymphocyte-deficiency aggravates atherosclerosis in mice; depletion of mature B lymphocytes reduces atherosclerosis. These observations led to the notion that distinct B lymphocyte subsets have different roles. B1a lymphocytes exert an atheroprotective effect, which has been attributed to secretion of IgM, which can be deposited in atherosclerotic lesions thereby reducing necrotic core formation. Tumor necrosis factor (TNF)-family member ‘A Proliferation-Inducing Ligand’ (APRIL, also known as TNFSF13) was previously shown to increase serum IgM levels in a murine model. In this study, we investigated the effect of APRIL overexpression on advanced lesion formation and composition, IgM production and B cell phenotype. We crossed APRIL transgenic (APRIL-Tg) mice with ApoE knockout (ApoE-/-) mice. After a 12-week Western Type Diet, ApoE-/-APRIL-Tg mice and ApoE-/- littermates showed similar increases in body weight and lipid levels. Histologic evaluation showed no differences in lesion size, stage or necrotic area. However, smooth muscle cell (α-actin stain) content was increased in ApoE-/-APRIL-Tg mice, implying more stable lesions. In addition, increases in both plaque IgM deposition and plasma IgM levels were found in ApoE-/-APRIL-Tg mice compared with ApoE-/- mice. Flow cytometry revealed a concomitant increase in peritoneal B1a lymphocytes in ApoE-/-APRIL-Tg mice. This study shows that ApoE-/-APRIL-Tg mice have increased oxLDL-specific serum IgM levels, potentially mediated via an increase in B1a lymphocytes. Although no differences in lesion size were found, transgenic ApoE-/-APRIL-Tg mice do show potential plaque stabilizing features in advanced atherosclerotic lesions. PMID:27820817

  7. Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions.

    PubMed Central

    Fu, Tao; Borensztajn, Jayme

    2002-01-01

    Foam cells found in atherosclerotic lesions are believed to derive from macrophages that take up aggregated low-density lipoprotein (LDL) particles bound to the extracellular matrix of arterial walls. C-reactive protein (CRP) is an acute-phase protein found in atherosclerotic lesions, which when immobilized on a solid phase, can bind and cluster LDL particles in a calcium-dependent manner. In the present study, we examined whether CRP-bound aggregated LDL could be taken up by macrophages in culture. CRP molecules were aggregated in the presence of calcium and immobilized on the surface of polystyrene microtitre wells. Human LDL added to the wells bound to and aggregated on the immobilized CRP, also in a calcium-dependent manner. On incubation with macrophages, the immobilized CRP-bound LDL aggregates were readily taken up by the cells, as demonstrated by immunofluorescence microscopy, by the cellular accumulation of cholesterol and by the overexpression of adipophilin. Immunofluorescence microscopy and flow-cytometry analysis established that the uptake of the LDL-CRP complex was not mediated by the CRP receptor CD32. These observations with immobilized CRP and LDL, approximating the conditions that exist in the extracellular matrix of the arterial wall, thus suggest that CRP may contribute to the formation of foam cells in atherosclerotic lesions by causing the aggregation of LDL molecules that are then taken up by macrophages through a CD32-independent pathway. PMID:12033985

  8. Technology Alignment and Portfolio Prioritization (TAPP): Advanced Methods in Strategic Analysis, Technology Forecasting and Long Term Planning for Human Exploration and Operations, Advanced Exploration Systems and Advanced Concepts

    NASA Technical Reports Server (NTRS)

    Funaro, Gregory V.; Alexander, Reginald A.

    2015-01-01

    The Advanced Concepts Office (ACO) at NASA, Marshall Space Flight Center is expanding its current technology assessment methodologies. ACO is developing a framework called TAPP that uses a variety of methods, such as association mining and rule learning from data mining, structure development using a Technological Innovation System (TIS), and social network modeling to measure structural relationships. The role of ACO is to 1) produce a broad spectrum of ideas and alternatives for a variety of NASA's missions, 2) determine mission architecture feasibility and appropriateness to NASA's strategic plans, and 3) define a project in enough detail to establish an initial baseline capable of meeting mission objectives ACO's role supports the decision­-making process associated with the maturation of concepts for traveling through, living in, and understanding space. ACO performs concept studies and technology assessments to determine the degree of alignment between mission objectives and new technologies. The first step in technology assessment is to identify the current technology maturity in terms of a technology readiness level (TRL). The second step is to determine the difficulty associated with advancing a technology from one state to the next state. NASA has used TRLs since 1970 and ACO formalized them in 1995. The DoD, ESA, Oil & Gas, and DoE have adopted TRLs as a means to assess technology maturity. However, "with the emergence of more complex systems and system of systems, it has been increasingly recognized that TRL assessments have limitations, especially when considering [the] integration of complex systems." When performing the second step in a technology assessment, NASA requires that an Advancement Degree of Difficulty (AD2) method be utilized. NASA has used and developed or used a variety of methods to perform this step: Expert Opinion or Delphi Approach, Value Engineering or Value Stream, Analytical Hierarchy Process (AHP), Technique for the Order of

  9. Fluorescence lifetime imaging for the characterization of the biochemical composition of atherosclerotic plaques

    NASA Astrophysics Data System (ADS)

    Phipps, Jennifer; Sun, Yinghua; Saroufeem, Ramez; Hatami, Nisa; Fishbein, Michael C.; Marcu, Laura

    2011-09-01

    This study investigates the ability of a flexible fiberoptic-based fluorescence lifetime imaging microscopy (FLIM) technique to resolve biochemical features in plaque fibrotic cap associated with plaque instability and based solely on fluorescence decay characteristics. Autofluorescence of atherosclerotic human aorta (11 autopsy samples) was measured at 48 locations through two filters, F377: 377/50 and F460: 460/60 nm (center wavelength/bandwidth). The fluorescence decay dynamic was described by average lifetime (τ) and four Laguerre coefficients (LECs) retrieved through a Laguerre deconvolution technique. FLIM-derived parameters discriminated between four groups [elastin-rich (ER), elastin and macrophage-rich (E+M), collagen-rich (CR), and lipid-rich (LR)]. For example, τF377 discriminated ER from CR (R = 0.84); τF460 discriminated E+M from CR and ER (R = 0.60 and 0.54, respectively); LEC-1F377 discriminated CR from LR and E+M (R = 0.69 and 0.77, respectively); P < 0.05 for all correlations. Linear discriminant analysis was used to classify this data set with specificity >87% (all cases) and sensitivity as high as 86%. Current results demonstrate for the first time that clinically relevant features (e.g., ratios of lipid versus collagen versus elastin) can be evaluated with a flexible-fiber based FLIM technique without the need for fluorescence intensity information or contrast agents.

  10. Mechanical modeling of cholesterol crystallization in atherosclerotic plaques base on Micro-OCT images (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Luo, Yuemei; Liu, Xinyu; Chen, Si; Cui, Dongyao; Wang, Xianghong; Liu, Linbo

    2016-02-01

    Plaque rupture is the critical cause of cardiovascular thrombosis but this process is still under discussion. Recent studies show that, during crystallization, cholesterol crystals in atheromatous plaques accumulate rapidly in a limited space and may result in plaque rupture. However, the actual role of cholesterol crystals on plaque rupture remains unclear due to the lack of detailed morphological information of cholesterol crystals. In this study, we used a Micro-optical coherence tomography (µOCT) setup with 1-2 µm spatial resolution to extract the geometry of cholesterol crystals from human atherosclerotic artery ex vivo firstly. With measured dimensions of cholesterol crystals by this µOCT system (the average length and thickness of 269.1±80.16 µm and 3.0±0.33 µm), we developed a two-dimensional mechanical model in which rectangular shaped cholesterol crystals distribute at different locations spatially. We predicted the stress on the thin cap induced by the expansion of cholesterol crystals by use of finite-element method. Since a large portion of plaques (58%) rupture at points of peak circumferential stress (PCS), we used PCS as the primary indicator of plaque stability with blood pressure of 14.6 kPa on the lumen. The results demonstrate that loading of the concentrated crystals especially at the cap shoulder destabilize the plaque by proportionally increasing the PCS, while evenly distributed crystals loading along the cap might impose less PCS to the plaque than the concentrated case.

  11. Fatty acid binding protein 4 in circulating leucocytes reflects atherosclerotic lesion progression in Apoe(-/-) mice.

    PubMed

    Agardh, Hanna E; Gertow, Karl; Salvado, Dolores M; Hermansson, Andreas; van Puijvelde, Gijs H; Hansson, Göran K; n-Berne, Gabrielle Paulsso; Gabrielsen, Anders

    2013-02-01

    Discovery of novel biomarkers for atherosclerosis is important to aid in early diagnosis of pre-symptomatic patients at high risk of cardiovascular events. The aim of the present study was therefore to identify potential biomarkers in circulating cells reflecting atherosclerotic lesion progression in the vessel wall. We performed gene arrays on circulating leucocytes from atherosclerosis prone Apoe(-/-) mice with increasing ages, using C57BL/6 mice as healthy controls. We identified fatty acid binding protein 4 (FABP4) mRNA to be augmented in mice with established disease compared with young Apoe(-/-) or controls. Interestingly, the transcript FABP4 correlated significantly with lesion size, further supporting a disease associated increase. In addition, validation of our finding on protein level showed augmented FABP4 in circulating leucocytes whereas, importantly, no change could be observed in plasma. Immunofluorescence analysis demonstrated FABP4 to be present mainly in circulating neutrophils and to some extent in monocytes. Moreover, FABP4-positive neutrophils and macrophages could be identified in the subintimal space in the plaque. Using human circulating leucocytes, we confirmed the presence of FABP4 protein in neutrophils and monocytes. In conclusion, we have showed that cellular levels of FABP4 in circulating leucocytes associate with lesion development in the experimental Apoe(-/-) model. The increased expression is primarily localized to neutrophils, but also in monocytes. We have identified FABP4 in leucocytes as a potential and easy accessible biomarker of atherosclerosis which could be of future clinical relevance.

  12. Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease.

    PubMed Central

    Holvoet, P; Perez, G; Zhao, Z; Brouwers, E; Bernar, H; Collen, D

    1995-01-01

    The murine monoclonal antibody mAb-1H11 raised against malondialdehyde (MDA)-modified LDL, was used to detect cross-reacting material in human atheromatous tissue and in plasma. MDA-modified LDL levels in plasma were 0.19 +/- 0.02 mg/dl (mean +/- SEM) in 44 control subjects, 0.24 +/- 0.02 mg/dl in 15 patients with chronic stable angina pectoris (P = NS vs LDL cholesterol matched controls), 1.4 +/- 0.1 mg/dl in 60 patients with acute myocardial infarction (P < 0.001 vs controls), and 0.86 +/- 0.11 mg/dl in 22 patients with carotid atherosclerosis (P < 0.001 vs controls). Modified LDL, isolated from pooled LDL of 10 patients, showed a higher electrophoretic mobility on agarose gels, a higher content of thiobarbituric acid reactive substances, and a higher cholesterol/protein ratio than native LDL and had a similar reactivity (antigen/protein ratio) in the assay as the in vitro MDA-modified LDL used for calibration. Its apo B-100 moiety was not fragmented. Uptake of this modified LDL by macrophages resulted in foam cell generation. In conclusion, elevated plasma levels of atherogenic MDA-modified LDL may be a marker for unstable atherosclerotic cardiovascular disease. Images PMID:7769103

  13. Automated classification of atherosclerotic plaque from magnetic resonance images using predictive models.

    PubMed

    Anderson, Russell W; Stomberg, Christopher; Hahm, Charles W; Mani, Venkatesh; Samber, Daniel D; Itskovich, Vitalii V; Valera-Guallar, Laura; Fallon, John T; Nedanov, Pavel B; Huizenga, Joel; Fayad, Zahi A

    2007-01-01

    The information contained within multicontrast magnetic resonance images (MRI) promises to improve tissue classification accuracy, once appropriately analyzed. Predictive models capture relationships empirically, from known outcomes thereby combining pattern classification with experience. In this study, we examine the applicability of predictive modeling for atherosclerotic plaque component classification of multicontrast ex vivo MR images using stained, histopathological sections as ground truth. Ten multicontrast images from seven human coronary artery specimens were obtained on a 9.4 T imaging system using multicontrast-weighted fast spin-echo (T1-, proton density-, and T2-weighted) imaging with 39-mum isotropic voxel size. Following initial data transformations, predictive modeling focused on automating the identification of specimen's plaque, lipid, and media. The outputs of these three models were used to calculate statistics such as total plaque burden and the ratio of hard plaque (fibrous tissue) to lipid. Both logistic regression and an artificial neural network model (Relevant Input Processor Network-RIPNet) were used for predictive modeling. When compared against segmentation resulting from cluster analysis, the RIPNet models performed between 25 and 30% better in absolute terms. This translates to a 50% higher true positive rate over given levels of false positives. This work indicates that it is feasible to build an automated system of plaque detection using MRI and data mining.

  14. Endothelial Expression of Guidance Cues in Vessel Wall Homeostasis: Dysregulation under pro-atherosclerotic conditions

    PubMed Central

    van Gils, Janine M.; Ramkhelawon, Bhama; Fernandes, Luciana; Stewart, Merran C.; Guo, Liang; Seibert, Tara; Menezes, Gustavo B.; Cara, Denise C.; Chow, Camille; Kinane, T. Bernard; Fisher, Edward A.; Balcells, Mercedes; Alvarez-Leite, Jacqueline; Moore, Kathryn J.

    2013-01-01

    Objective Emerging evidence suggests that neuronal guidance cues, typically expressed during development, are involved in both physiological and pathological immune responses. We hypothesized that endothelial expression of such guidance cues may regulate leukocyte trafficking into the vascular wall during atherogenesis. Approach/Results We demonstrate that members of the Netrin, Semaphorin and Ephrin family of guidance molecules are differentially regulated under conditions that promote or protect from atherosclerosis. Netrin-1 and Semaphorin3A are expressed by coronary artery endothelial cells and potently inhibit chemokine-directed migration of human monocytes. Endothelial expression of these negative guidance cues is down-regulated by pro-atherogenic factors, including oscillatory shear stress and pro-inflammatory cytokines associated with monocyte entry into the vessel wall. Furthermore, we show using intravital microscopy that inhibition of Netrin-1 or Semaphorin3A using blocking peptides increases leukocyte adhesion to the endothelium. Unlike Netrin-1 and Semaphorin3A, the guidance cue EphrinB2 is up-regulated under pro-atherosclerotic flow conditions and functions as a chemoattractant, increasing leukocyte migration in the absence of additional chemokines. Conclusions The concurrent regulation of negative and positive guidance cues may facilitate leukocyte infiltration of the endothelium through a balance between chemoattraction and chemorepulsion. These data indicate a previously unappreciated role for axonal guidance cues in maintaining the endothelial barrier and regulating leukocyte trafficking during atherogenesis. PMID:23430612

  15. Advancement of a 30K W Solar Electric Propulsion System Capability for NASA Human and Robotic Exploration Missions

    NASA Technical Reports Server (NTRS)

    Smith, Bryan K.; Nazario, Margaret L.; Manzella, David H.

    2012-01-01

    Solar Electric Propulsion has evolved into a demonstrated operational capability performing station keeping for geosynchronous satellites, enabling challenging deep-space science missions, and assisting in the transfer of satellites from an elliptical orbit Geostationary Transfer Orbit (GTO) to a Geostationary Earth Orbit (GEO). Advancing higher power SEP systems will enable numerous future applications for human, robotic, and commercial missions. These missions are enabled by either the increased performance of the SEP system or by the cost reductions when compared to conventional chemical propulsion systems. Higher power SEP systems that provide very high payload for robotic missions also trade favorably for the advancement of human exploration beyond low Earth orbit. Demonstrated reliable systems are required for human space flight and due to their successful present day widespread use and inherent high reliability, SEP systems have progressively become a viable entrant into these future human exploration architectures. NASA studies have identified a 30 kW-class SEP capability as the next appropriate evolutionary step, applicable to wide range of both human and robotic missions. This paper describes the planning options, mission applications, and technology investments for representative 30kW-class SEP mission concepts under consideration by NASA

  16. Emergency EC-IC bypass for symptomatic atherosclerotic ischemic stroke.

    PubMed

    Horiuchi, Tetsuyoshi; Nitta, Junpei; Ishizaka, Shigetoshi; Kanaya, Kohei; Yanagawa, Takao; Hongo, Kazuhiro

    2013-10-01

    Previous studies have shown that extracranial-intracranial (EC-IC) bypass surgery has no preventive effect on subsequent ipsilateral ischemic stroke in patients with symptomatic atherosclerotic internal carotid occlusion and hemodynamic cerebral ischemia. A few studies have assessed whether an urgent EC-IC bypass surgery is an effective treatment for main trunk stenosis or occlusion in acute stage. The authors retrospectively reviewed 58 consecutive patients who underwent urgent EC-IC bypass for symptomatic internal carotid artery or the middle cerebral artery stenosis or occlusion between January 2003 and December 2011. Clinical characteristics and neuroimagings were evaluated and analyzed. Based on preoperative angiogram, responsible lesions were the internal carotid artery in 19 (32.8%) patients and the middle cerebral artery in 39 (67.2%). No hemorrhagic complication occurred. Sixty-nine percent of patients showed improvement of neurological function after surgery, and 74.1% of patients had favorable outcome. Unfavorable outcome was associated with insufficient collateral flow and new infarction after bypass surgery.

  17. Mechanical functional role of non-atherosclerotic intimal thickening.

    PubMed

    Glagov, S; Zarins, C K; Masawa, N; Xu, C P; Bassiouny, H; Giddens, D P

    1993-01-01

    Arteries adjust to alterations in wall shear stress or tensile stress by changes in diameter, wall thickness, structure and composition. The intima participates in these adaptive reactions, particularly when changes in mechanical stresses are imposed after physiologic stress levels have been established during growth. Decreased wall shear stress due to decreased flow, flow separation or complex flow patterns, or increases in tensile stress due to increases in pressure or radius stimulate non-atherosclerotic intimal proliferation. Intimal fibrocellular hypertrophy (IFH), in the form of compact fibrocellular layers resembling the media, stabilizes when the lumen diameter is reduced sufficiently or wall thickness is increased sufficiently to restore baseline wall shear or tensile stress. Reactive-adaptive intimal proliferation is not necessarily self-limiting and may continue in the form of intimal hyperplasia (IH) which is relatively matrix-free and poorly organized. If mural and intimal changes do not result in restoration of baseline wall shear and tensile stress, IH may proceed to further narrowing and stenosis. Identification of the cellular and molecular mechanisms which underly the responses which link flow to diameter, diameter and pressure to mural restructuring, and mural restructuring to intimal thickening should provide new insights into the nature of vessel adaptations in the absence or presence of atherogenesis.

  18. Paramagnetic Manganese in the Atherosclerotic Plaque of Carotid Arteries

    PubMed Central

    Chelyshev, Yury; Ignatyev, Igor; Zanochkin, Alexey; Mamin, Georgy; Sorokin, Boris; Sorokina, Alexandra; Lyapkalo, Natalya; Gizatullina, Nazima; Orlinskii, Sergei

    2016-01-01

    The search for adequate markers of atherosclerotic plaque (AP) instability in the context of assessment of the ischemic stroke risk in patients with atherosclerosis of the carotid arteries as well as for solid physical and chemical factors that are connected with the AP stability is extremely important. We investigate the inner lining of the carotid artery specimens from the male patients with atherosclerosis (27 patients, 42–64 years old) obtained during carotid endarterectomy by using different analytical tools including ultrasound angiography, X-ray analysis, immunological, histochemical analyses, and high-field (3.4 T) pulse electron paramagnetic resonance (EPR) at 94 GHz. No correlation between the stable and unstable APs in the sense of the calcification is revealed. In all of the investigated samples, the EPR spectra of manganese, namely, Mn2+ ions, are registered. Spectral and relaxation characteristics of Mn2+ ions are close to those obtained for the synthetic (nano) hydroxyapatite species but differ from each other for stable and unstable APs. This demonstrates that AP stability could be specified by the molecular organization of their hydroxyapatite components. The origin of the obtained differences and the possibility of using EPR of Mn2+ as an AP stability marker are discussed. PMID:28078287

  19. Preventing restenosis in atherosclerotic miniswine with photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Hsiang, York N.; Crespo, M. T.; To, Eleanor C.; Sobeh, Mohammed S.; Greenwald, Stephen E.; Bower, Robert D.

    1995-05-01

    The purpose of this study was to determine whether the addition of Photodynamic Therapy (PDT) using the photosensitizer Photofrin* (P*) following balloon angioplasty (BA) could prevent restenosis in an atherosclerotic animal model. Bilateral iliac atherosclerosis was created in 21 Yucatan miniswine. Six weeks later, P* 2.5 mg/kg was given IV 24 hours prior to BA (4 mm X 20 mm, 1 inflation). Following BA, swine were randomly allocated to receive PDT via a fiberoptic probe with laser energy or the same probe without laser energy. The fiberoptic probe had a 1 cm cylindrical diffusing tip and was passed co-axially through a custom catheter to ensure central location of the probe. A continuous wave argon ion-pumped dye laser tuned to 630 nm was used to provide a fluence of 100 J/cm2. Four weeks later, swine were sacrificed and vessels perfusion-fixed in-situ with glutaraldehyde and analyzed by ocular micrometry. Five occlusions occurred, all in the PDT + BA group. Percentage intimal thickness (mean +/- SD) was 51.0 +/- 29.5 in the BA group and 71.2 +/- 35.2 in the BA + PDT group (p equals 0.21). These results suggest that the addition of PDT following BA does not prevent restenosis.

  20. Multimodal spectroscopy detects features of vulnerable atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Šćepanović, Obrad R.; Fitzmaurice, Maryann; Miller, Arnold; Kong, Chae-Ryon; Volynskaya, Zoya; Dasari, Ramachandra R.; Kramer, John R.; Feld, Michael S.

    2011-01-01

    Early detection and treatment of rupture-prone vulnerable atherosclerotic plaques is critical to reducing patient mortality associated with cardiovascular disease. The combination of reflectance, fluorescence, and Raman spectroscopy-termed multimodal spectroscopy (MMS)-provides detailed biochemical information about tissue and can detect vulnerable plaque features: thin fibrous cap (TFC), necrotic core (NC), superficial foam cells (SFC), and thrombus. Ex vivo MMS spectra are collected from 12 patients that underwent carotid endarterectomy or femoral bypass surgery. Data are collected by means of a unitary MMS optical fiber probe and a portable clinical instrument. Blinded histopathological analysis is used to assess the vulnerability of each spectrally evaluated artery lesion. Modeling of the ex vivo MMS spectra produce objective parameters that correlate with the presence of vulnerable plaque features: TFC with fluorescence parameters indicative of collagen presence; NC/SFC with a combination of diffuse reflectance β-carotene/ceroid absorption and the Raman spectral signature of lipids; and thrombus with its Raman signature. Using these parameters, suspected vulnerable plaques can be detected with a sensitivity of 96% and specificity of 72%. These encouraging results warrant the continued development of MMS as a catheter-based clinical diagnostic technique for early detection of vulnerable plaques.

  1. Experimental Studies of Two Replicated Atherosclerotic Carotid Bifurcations

    NASA Astrophysics Data System (ADS)

    Bale-Glickman, Jocelyn; Selby, Kathy; Saloner, David; Savas, Omer

    2004-11-01

    Detailed flow visualization and particle image velocimetry (PIV) studies are carried out at the stenosis in two atherosclerotic carotid bifurcation models under physiological flow conditions. Companion experiments are also carried out with sinusoidal and steady input flows. The complex internal geometry of the diseased artery combined with pulsatile input flows gives complex, model-specific flow patterns, with details that vary from cycle to cycle. Both models show a jet leaving the stenosis, with an associated recirculation zone on one side. Other flow features include separation points, recirculation zones, internal jets, three-dimensional shear layers, and stagnation lines. The wall shear stresses (WSS) are estimated from the PIV data. The profile WSS along the arterial lumen is unique for each artery, but similar profiles are observed for both physiological and steady flow for each artery. The WSS at the narrowest point in the stenotic neck varies chaotically from cycle to cycle, but typically ranges from 5 Pa to -40 Pa. The peak WSS values are found at peak systole.

  2. Primary Prevention of Atherosclerotic Cardiovascular Disease in Women

    PubMed Central

    McKibben, Rebeccah A.; Al Rifai, Mahmoud; Mathews, Lena M.; Michos, Erin D.

    2016-01-01

    Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among women. Despite improvements in cardiovascular disease prevention efforts, there remain gaps in cardiovascular disease awareness among women, as well as age and racial disparities in ASCVD outcomes for women. Disparity also exists in the impact the traditional risk factors confer on ASCVD risk between women and men, with smoking and diabetes both resulting in stronger relative risks in women compared to men. Additionally there are risk factors that are unique to women (such as pregnancy-related factors) or that disproportionally affect women (such as auto-immune disease) where preventive efforts should be targeted. Risk assessment and management must also be sex-specific to effectively reduce cardiovascular disease and improve outcomes among women. Evidence supports the use of statin therapy for primary prevention in women at higher ASCVD risk. However, some pause should be given to prescribing aspirin therapy in women without known ASCVD, with most evidence supporting the use of aspirin for women≥65 years not at increased risk for bleeding. This review article will summarize (1) traditional and non-traditional assessments of ASCVD risk and (2) lifestyle and pharmacologic therapies for the primary prevention of ASCVD in women. PMID:28149430

  3. [Management of atherosclerotic renal-artery stenosis in 2016].

    PubMed

    Fournier, Thomas; Sens, Florence; Rouvière, Olivier; Millon, Antoine; Juillard, Laurent

    2017-02-01

    Endovascular revascularization as treatment of atherosclerotic renal-artery stenosis (aRAS) is controversial since 3 large and multicentric randomised trials (CORAL, ASTRAL, STAR) failed to prove the superiority of percutaneous transluminal renal-artery stenting (PTRAS) over medical treatment only (MT). However, considering the multiple bias of these trials, among which questionable inclusion criterias, these results must be extrapolated in clinical practice with caution. New pathophysiological data have been helping to understand why restoring blood flow does not necessarily lead to kidney function improvement. Today, the diagnostic approach must in one hand confirm the artery stenosis and on the other hand assess its severity and impact on the kidney. Therapeutic options still lie on the American guidelines published in 2006, since no study data can be reasonably used in everyday practice. However, particular sub-groups of patients who could benefit from revascularisation have been identified through recent cohort studies. Further prospective studies are needed in order to confirm the superiority of PTRAS in these populations. Meanwhile, multidisciplinary approach should be promoted, in order to provide the best treatment for each patient.

  4. Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models

    PubMed Central

    Gargiulo, Sara; Gramanzini, Matteo; Mancini, Marcello

    2016-01-01

    Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE−/− and ApoE−/−Fbn1C1039G+/− mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state-of-the-art preclinical molecular imaging strategies. PMID:27618031

  5. Directional spatial frequency analysis of lipid distribution in atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Korn, Clyde; Reese, Eric; Shi, Lingyan; Alfano, Robert; Russell, Stewart

    2016-04-01

    Atherosclerosis is characterized by the growth of fibrous plaques due to the retention of cholesterol and lipids within the artery wall, which can lead to vessel occlusion and cardiac events. One way to evaluate arterial disease is to quantify the amount of lipid present in these plaques, since a higher disease burden is characterized by a higher concentration of lipid. Although therapeutic stimulation of reverse cholesterol transport to reduce cholesterol deposits in plaque has not produced significant results, this may be due to current image analysis methods which use averaging techniques to calculate the total amount of lipid in the plaque without regard to spatial distribution, thereby discarding information that may have significance in marking response to therapy. Here we use Directional Fourier Spatial Frequency (DFSF) analysis to generate a characteristic spatial frequency spectrum for atherosclerotic plaques from C57 Black 6 mice both treated and untreated with a cholesterol scavenging nanoparticle. We then use the Cauchy product of these spectra to classify the images with a support vector machine (SVM). Our results indicate that treated plaque can be distinguished from untreated plaque using this method, where no difference is seen using the spatial averaging method. This work has the potential to increase the effectiveness of current in-vivo methods of plaque detection that also use averaging methods, such as laser speckle imaging and Raman spectroscopy.

  6. Primary Prevention of Atherosclerotic Cardiovascular Disease in Women.

    PubMed

    McKibben, Rebeccah A; Al Rifai, Mahmoud; Mathews, Lena M; Michos, Erin D

    2016-01-01

    Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among women. Despite improvements in cardiovascular disease prevention efforts, there remain gaps in cardiovascular disease awareness among women, as well as age and racial disparities in ASCVD outcomes for women. Disparity also exists in the impact the traditional risk factors confer on ASCVD risk between women and men, with smoking and diabetes both resulting in stronger relative risks in women compared to men. Additionally there are risk factors that are unique to women (such as pregnancy-related factors) or that disproportionally affect women (such as auto-immune disease) where preventive efforts should be targeted. Risk assessment and management must also be sex-specific to effectively reduce cardiovascular disease and improve outcomes among women. Evidence supports the use of statin therapy for primary prevention in women at higher ASCVD risk. However, some pause should be given to prescribing aspirin therapy in women without known ASCVD, with most evidence supporting the use of aspirin for women≥65 years not at increased risk for bleeding. This review article will summarize (1) traditional and non-traditional assessments of ASCVD risk and (2) lifestyle and pharmacologic therapies for the primary prevention of ASCVD in women.

  7. Human Dignity and Humiliation Studies: A Global Network Advancing Dignity through Dialogue

    ERIC Educational Resources Information Center

    Lindner, Evelin G.; Hartling, Linda M.; Spalthoff, Ulrich

    2011-01-01

    Human rights are universally based on the concept of human dignity. Various international organizations are developing the theoretical, legal, and political framework for human rights. The underlying concept of human dignity is less disputed, but also receives less attention. This shortcoming is addressed by a worldwide group of scholars and…

  8. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi.

    PubMed

    Ahrens, Ingo; Chen, Yung-Chih; Topcic, Danijal; Bode, Michael; Haenel, David; Hagemeyer, Christoph E; Seeba, Hannah; Duerschmied, Daniel; Bassler, Nicole; Jandeleit-Dahm, Karin A; Sweet, Matthew J; Agrotis, Alex; Bobik, Alex; Peter, Karlheinz

    2015-11-01

    High mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice. Thus, we hypothesised an interaction between HMGB1 and activated platelets. Binding of recombinant HMGB1 to platelets was assessed by flow cytometry. HMGB1 bound to thrombin-activated human platelets (MFI 2.49 vs 25.01, p=0.0079). Blood from wild-type, TLR4 and RAGE knockout mice was used to determine potential HMGB1 receptors on platelets. HMGB1 bound to platelets from wild type C57Bl6 (MFI 2.64 vs 20.3, p< 0.05), and TLR4-/- mice (MFI 2.11 vs 25.65, p< 0.05) but failed to show binding to platelets from RAGE-/- mice (p > 0.05). RAGE expression on human platelets was detected by RT-PCR with mRNA extracted from highly purified platelets and confirmed by Western blot and immunofluorescence microscopy. Platelet activation increased RAGE surface expression (MFI 4.85 vs 6.74, p< 0.05). Expression of HMGB1 in human coronary artery thrombi was demonstrated by immunohistochemistry and revealed high expression levels. Platelets bind HMGB1 upon thrombin-induced activation. Platelet specific expression of RAGE could be detected at the mRNA and protein level and is involved in the binding of HMGB1. Furthermore, platelet activation up-regulates platelet surface expression of RAGE. HMGB1 is highly expressed in platelet-rich human coronary artery thrombi pointing towards a central role for HMGB1 in atherothrombosis, thereby suggesting the possibility of platelet targeted anti-inflammatory therapies for atherothrombosis.

  9. Transcript Profiling Identifies Iqgap2−/− Mouse as a Model for Advanced Human Hepatocellular Carcinoma

    PubMed Central

    Gnatenko, Dmitri V.; Xu, Xiao; Zhu, Wei; Schmidt, Valentina A.

    2013-01-01

    It is broadly accepted that genetically engineered animal models do not always recapitulate human pathobiology. Therefore identifying best-fit mouse models of human cancers that truly reflect the corresponding human disease is of vital importance in elucidating molecular mechanisms of tumorigenesis and developing preventive and therapeutic approaches. A new hepatocellular carcinoma (HCC) mouse model lacking a novel putative tumor suppressor IQGAP2 has been generated by our laboratory. The aim of this study was to obtain the molecular signature of Iqgap2−/− HCC tumors and establish the relevance of this model to human disease. Here we report a comprehensive transcriptome analysis of Iqgap2−/− livers and a cross-species comparison of human and Iqgap2−/− HCC tumors using Significance Analysis of Microarray (SAM) and unsupervised hierarchical clustering analysis. We identified the Wnt/β-catenin signaling pathway as the top canonical pathway dysregulated in Iqgap2−/− livers. We also demonstrated that Iqgap2−/− hepatic tumors shared genetic signatures with HCC tumors from patients with advanced disease as evidenced by a 78% mouse-to-human microarray data set concordance rate with 117 out of 151 identified ortholog genes having similar expression profiles across the two species. Collectively, these results indicate that the Iqgap2 knockout mouse model closely recapitulates human HCC at the molecular level and supports its further application for the study of this disease. PMID:23951254

  10. Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

    PubMed Central

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564

  11. Induction of synthesis and secretion of interleukin 1 beta in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts.

    PubMed

    Westwood, M E; Thornalley, P J

    1996-04-01

    Human serum albumin modified with 1-2 methylglyoxal residues per molecule of protein (MGmin-HSA) stimulated the synthesis and secretion of interleukin 1 beta (IL-1 beta) from human monocytic THP-1 cells in vitro. It was a more potent inducer of IL-1 beta synthesis than human serum albumin highly-modified with glucose-derived advanced glycation endproducts (AGE-HSA). With 20 microM ligand. IL-1 beta synthesis was (pg/10(6) cells): MGmin-HSA 484.5 +/- 50.3; AGE-HSA 30.6 +/- 2.0 (n = 3). IL-1 beta synthesis increased markedly with MGmin-HSA concentrations > 5 microM. IL-1 beta synthesis and secretion from monocytes in response to methylglyoxal-modified proteins in vivo may contribute to the development of macro- and micro-angiopathy, particularly in diabetes mellitus.

  12. The F11 receptor (F11R/JAM-A) in atherothrombosis: overexpression of F11R in atherosclerotic plaques.

    PubMed

    Babinska, Anna; Azari, Bani M; Salifu, Moro O; Liu, Ruijie; Jiang, Xian-Cheng; Sobocka, Malgorzata B; Boo, Dorothy; Al Khoury, George; Deitch, Jonathan S; Marmur, Jonathan D; Ehrlich, Yigal H; Kornecki, Elizabeth

    2007-02-01

    F11R is the gene name for an adhesion protein, called the F11-receptor, aka JAM-A, which under normal physiological conditions is expressed constitutively on the surface of platelets and localized within tight junctions of endothelial cells (EC). Previous studies of the interactions between human platelets and EC suggested that F11R/JAM-A plays a crucial role in inflammatory thrombosis and atherosclerosis. The study reported here obtained in-vivo confirmation of this conclusion by investigating F11R/JAM-A protein and mRNA in patients with aortic and peripheral vascular disease and in an animal model of atherosclerosis. Molecular and immunofluorescence determinations revealed very high levels of F11R/JAM-A mRNA and F11R/JAM-A protein in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with 12-week-old atherosclerosis-prone apoE-/- mice, an age in which atherosclerotic plaques are well established. Enhanced expression of the F11R/JAM-A message in cultured EC from human aortic and venous vessels was observed following exposure of the cells to cytokines. Determinations of platelet adhesion to cultured EC inflamed by combined cytokine treatment in the presence of F11R/JAM-A - antagonists provided data indicating that de novo expression of F11R/JAM-A on the luminal surface of inflamed EC has an important role in the conversion of EC to a thrombogenic surface. Further studies of these interactions under flow conditions and under in-vivo settings could provide a final proof of a causal role for F11R/JAM-A in the initiation of thrombosis. Based on our in-vitro and in-vivo studies to date, we propose that therapeutic drugs which antagonize the function of F11R/JAM-A should be tested as novel means for the prevention and treatment of atherosclerosis, heart attacks and stroke.

  13. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

    SciTech Connect

    Fukuda, Kazuki; Matsumura, Takeshi; Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko; Nakao, Saya; Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji; Kawada, Teruo; Nishikawa, Takeshi; Araki, Eiichi

    2015-01-30

    Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects

  14. Recent findings from the Human Proteome Project: opening the mass spectrometry toolbox to advance cancer diagnosis, surveillance and treatment.

    PubMed

    Cantor, David I; Nice, Edouard C; Baker, Mark S

    2015-06-01

    The Human Proteome Project stands to eclipse the Human Genome Project in terms of scope, content and interpretation. Its outputs, in conjunction with recent developments across the proteomics community, provide new tools for cancer research with the potential of providing clinically relevant insights into the disease. These collectively may guide the development of future diagnosis, surveillance and treatment strategies. Having established a robust organizational framework within the international community, the Human Proteome Organization and the proteomics community at large have made significant advances in biomarker discovery, detection, molecular imaging and in exploring tumor heterogeneity. Here, the authors discuss some developments in cancer proteomics and how they can be implemented to reduce the global burden of the disease.

  15. Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease.

    PubMed

    Barquera, Simon; Pedroza-Tobías, Andrea; Medina, Catalina; Hernández-Barrera, Lucía; Bibbins-Domingo, Kirsten; Lozano, Rafael; Moran, Andrew E

    2015-07-01

    Atherosclerotic cardiovascular disease (ACD) is the leading cause of mortality worldwide. The objective of this paper is to provide an overview of the global burden of ACD and its risk factors and to discuss the main challenges and opportunities for prevention. Publicly available data from the Global Burden of Disease Study were analyzed for ischemic heart disease (IHD), ischemic stroke and ACD risk factors. Data from the WHO Global Health Observatory were used to describe prevalence of diverse cardiometabolic risk factors. World Bank Gross Domestic Product per capita (GDPc) information was used to categorize countries according to income level. Cardiovascular mortality decreased globally from 1990-2010 with important differences by GDPc; during 1990 there was a positive association between IHD mortality and GDPc. Higher-income countries had higher rates compared to those of lower-income countries. High levels of body mass index (BMI), blood pressure, glucose and cholesterol have a differential contribution to mortality by income group over time; high-income countries have been able to reduce the contribution from these risk factors in the last 20 years, whereas lower/middle income countries show an increasing trend in mortality attributable to high BMI and glucose. Although age-adjusted ACD mortality rate trends decreased globally, the absolute number of ACD deaths is increasing in part due to the growth of the population and aging, as well as to important lifestyle and food-system changes that likely attenuate gains in prevention. Population and individual level preventable causes of ACD must be aggressively and efficiently targeted in countries of lower economic development in order to reduce the growing burden of disease due to ACD.

  16. Atherosclerotic cardiovascular disease in patients with chronic inflammatory joint disorders.

    PubMed

    Agca, R; Heslinga, S C; van Halm, V P; Nurmohamed, M T

    2016-05-15

    Inflammatory joint disorders (IJD), including rheumatoid arthritis (RA), ankylosing spondylitis (ASp) and psoriatic arthritis (PsA), are prevalent conditions worldwide with a considerable burden on healthcare systems. IJD are associated with increased cardiovascular (CV) disease-related morbidity and mortality. In this review, we present an overview of the literature. Standardised mortality ratios are increased in IJD compared with the general population, that is, RA 1.3-2.3, ASp 1.6-1.9 and PsA 0.8-1.6. This premature mortality is mainly caused by atherosclerotic events. In RA, this CV risk is comparable to that in type 2 diabetes. Traditional CV risk factors are more often present and partially a consequence of changes in physical function related to the underlying IJD. Also, chronic systemic inflammation itself is an independent CV risk factor. Optimal control of disease activity with conventional synthetic, targeted synthetic and biological disease-modifying antirheumatic drugs decreases this excess risk. High-grade inflammation as well as anti-inflammatory treatment alter traditional CV risk factors, such as lipids. In view of the above-mentioned CV burden in patients with IJD, CV risk management is necessary. Presently, this CV risk management is still lacking in usual care. Patients, general practitioners, cardiologists, internists and rheumatologists need to be aware of the substantially increased CV risk in IJD and should make a combined effort to timely initiate CV risk management in accordance with prevailing guidelines together with optimal control of rheumatic disease activity. CV screening and treatment strategies need to be implemented in usual care.

  17. Support vector machine based classification and mapping of atherosclerotic plaques using fluorescence lifetime imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Fatakdawala, Hussain; Gorpas, Dimitris S.; Bec, Julien; Ma, Dinglong M.; Yankelevich, Diego R.; Bishop, John W.; Marcu, Laura

    2016-02-01

    The progression of atherosclerosis in coronary vessels involves distinct pathological changes in the vessel wall. These changes manifest in the formation of a variety of plaque sub-types. The ability to detect and distinguish these plaques, especially thin-cap fibroatheromas (TCFA) may be relevant for guiding percutaneous coronary intervention as well as investigating new therapeutics. In this work we demonstrate the ability of fluorescence lifetime imaging (FLIm) derived parameters (lifetime values from sub-bands 390/40 nm, 452/45 nm and 542/50 nm respectively) for generating classification maps for identifying eight different atherosclerotic plaque sub-types in ex vivo human coronary vessels. The classification was performed using a support vector machine based classifier that was built from data gathered from sixteen coronary vessels in a previous study. This classifier was validated in the current study using an independent set of FLIm data acquired from four additional coronary vessels with a new rotational FLIm system. Classification maps were compared to co-registered histological data. Results show that the classification maps allow identification of the eight different plaque sub-types despite the fact that new data was gathered with a different FLIm system. Regions with diffuse intimal thickening (n=10), fibrotic tissue (n=2) and thick-cap fibroatheroma (n=1) were correctly identified on the classification map. The ability to identify different plaque types using FLIm data alone may serve as a powerful clinical and research tool for studying atherosclerosis in animal models as well as in humans.

  18. Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

    PubMed Central

    Karadimou, Glykeria; Folkersen, Lasse; Berg, Martin; Perisic, Ljubica; Discacciati, Andrea; Roy, Joy; Hansson, Göran K.; Persson, Jonas; Paulsson-Berne, Gabrielle

    2017-01-01

    Aims Processes in the development of atherosclerotic lesions can lead to plaque rupture or erosion, which can in turn elicit myocardial infarction or ischaemic stroke. The aims of this study were to determine whether Toll-like receptor 7 (TLR7) gene expression levels influence patient outcome and to explore the mechanisms linked to TLR7 expression in atherosclerosis. Methods and results Atherosclerotic plaques were removed by carotid endarterectomy (CEA) and subjected to gene array expression analysis (n = 123). Increased levels of TLR7 transcript in the plaques were associated with better outcome in a follow-up study over a maximum of 8 years. Patients with higher TLR7 transcript levels had a lower risk of experiencing major cardiovascular and cerebrovascular events (MACCE) during the follow-up period after CEA (hazard ratio: 2.38, P = 0.012, 95% CI 1.21–4.67). TLR7 was expressed in all plaques by T cells, macrophages and endothelial cells in capillaries, as shown by immunohistochemistry. In short-term tissue cultures, ex vivo treatment of plaques with the TLR7 ligand imiquimod elicited dose-dependent secretion of IL-10, TNF-α, GM-CSF, and IL-12/IL-23p40. This secretion was blocked with a TLR7 inhibitor. Immunofluorescent tissue analysis after TLR7 stimulation showed IL-10 expression in T cells, macrophages and vascular smooth muscle cells. TLR7 mRNA levels in the plaques were correlated with IL-10 receptor (r = 0.4031, P < 0.0001) and GM-CSF receptor A (r = 0.4354, P < 0.0001) transcripts. Conclusion These findings demonstrate that TLR7 is abundantly expressed in human atherosclerotic plaques. TLR7 ligation elicits the secretion of pro-inflammatory and anti-inflammatory cytokines, and high TLR7 expression in plaques is associated with better patient outcome, suggesting that TLR7 is a potential therapeutic target for prevention of complications of atherosclerosis. PMID:27864310

  19. A new humanized in vivo model of KIT D816V+ advanced systemic mastocytosis monitored using a secreted luciferase

    PubMed Central

    Bibi, Siham; Zhang, Yanyan; Hugonin, Caroline; Mangean, Mallorie Depond; He, Liang; Wedeh, Ghaith; Launay, Jean-Marie; Van Rijn, Sjoerd; Würdinger, Thomas; Louache, Fawzia; Arock, Michel

    2016-01-01

    Systemic mastocytosis are rare neoplasms characterized by accumulation of mast cells in at least one internal organ. The majority of systemic mastocytosis patients carry KIT D816V mutation, which activates constitutively the KIT receptor. Patient with advanced forms of systemic mastocytosis, such as aggressive systemic mastocytosis or mast cell leukemia, are poorly treated to date. Unfortunately, the lack of in vivo models reflecting KIT D816V+ advanced disease hampers pathophysiological studies and preclinical development of new therapies for such patients. Here, we describe a new in vivo model of KIT D816V+ advanced systemic mastocytosis developed by transplantation of the human ROSAKIT D816V-Gluc mast cell line in NOD-SCID IL-2R g−/− mice, using Gaussia princeps luciferase as a reporter. Intravenous injection of ROSAKIT D816V-Gluc cells led, in 4 weeks, to engraftment in all injected primary recipient mice. Engrafted cells were found at high levels in bone marrow, and at lower levels in spleen, liver and peripheral blood. Disease progression was easily monitored by repeated quantification of Gaussia princeps luciferase activity in peripheral blood. This quantification evidenced a linear relationship between the number of cells injected and the neoplastic mast cell burden in mice. Interestingly, the secondary transplantation of ROSAKIT D816V-Gluc cells increased their engraftment capability. To conclude, this new in vivo model mimics at the best the features of human KIT D816V+ advanced systemic mastocytosis. In addition, it is a unique and convenient tool to study the kinetics of the disease and the potential in vivo activity of new drugs targeting neoplastic mast cells. PMID:27783996

  20. Current advances in the generation of human iPS cells: implications in cell-based regenerative medicine.

    PubMed

    Revilla, Ana; González, Clara; Iriondo, Amaia; Fernández, Bárbara; Prieto, Cristina; Marín, Carlos; Liste, Isabel

    2016-11-01

    Over the last few years, the generation of induced pluripotent stem cells (iPSCs) from human somatic cells has proved to be one of the most potentially useful discoveries in regenerative medicine. iPSCs are becoming an invaluable tool to study the pathology of different diseases and for drug screening. However, several limitations still affect the possibility of applying iPS cell-based technology in therapeutic prospects. Most strategies for iPSCs generation are based on gene delivery via retroviral or lentiviral vectors, which integrate into the host's cell genome, causing a remarkable risk of insertional mutagenesis and oncogenic transformation. To avoid such risks, significant advances have been made with non-integrative reprogramming strategies. On the other hand, although many different kinds of somatic cells have been employed to generate iPSCs, there is still no consensus about the ideal type of cell to be reprogrammed. In this review we present the recent advances in the generation of human iPSCs, discussing their advantages and limitations in terms of safety and efficiency. We also present a selection of somatic cell sources, considering their capability to be reprogrammed and tissue accessibility. From a translational medicine perspective, these two topics will provide evidence to elucidate the most suitable combination of reprogramming strategy and cell source to be applied in each human iPSC-based therapy. The wide variety of diseases this technology could treat opens a hopeful future for regenerative medicine. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Addressing Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Advanced Practice Nursing Education.

    ERIC Educational Resources Information Center

    Nokes, Kathleen M.; Stein, Gary L.

    1997-01-01

    A survey of 23 advanced practice nursing programs showed only 3 had HIV-specific graduate-level nursing courses. Recommendations were made for HIV-specific courses, integration of HIV content into other courses, use of Centers for Disease Control and Occupational Safety and Health Administration guidelines, and subspecialties in HIV nursing. (SK)

  2. Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

    DTIC Science & Technology

    2015-09-01

    populations were successfully established from the corresponding parental cell lines (Figure 2). To generate quantized cell populations a single ...individual cells from the SN291 parental culture. Each dot represents a single cell. Color gradient indicates enrichment score for either published CD133... parental lines and quantized cell types (Specific Aim 5). We believe this program has significantly advanced genomic, proteomic and single -cell

  3. Oversized vein grafts develop advanced atherosclerosis in hypercholesterolemic minipigs

    PubMed Central

    2012-01-01

    Background Accelerated atherosclerosis is the main cause of late aortocoronary vein graft failure. We aimed to develop a large animal model for the study of pathogenesis and treatment of vein graft atherosclerosis. Methods An autologous reversed jugular vein graft was inserted end-to-end into the transected common carotid artery of ten hypercholesteroemic minipigs. The vein grafts were investigated 12-14 weeks later with ultrasound and angiograpy in vivo and microscopy post mortem. Results One minipig died during follow up (patent vein graft at autopsy), and one vein graft thrombosed early. In the remaining eight patent vein grafts, the mean (standard deviation) intima-media thickness was 712 μm (276 μm) versus 204 μm (74 μm) in the contralateral control internal jugular veins (P < .01). Advanced atherosclerotic plaques were found in three of four oversized vein grafts (diameter of graft > diameter of artery). No plaques were found in four non-oversized vein grafts (P < .05). Conclusions Our model of jugular vein graft in the common carotid artery of hypercholesterolemic minipigs displayed the components of human vein graft disease, i.e. thrombosis, intimal hyperplasia, and atherosclerosis. Advanced atherosclerosis, the main cause of late failure of human aortocoronary vein grafts was only seen in oversized grafts. This finding suggests that oversized vein grafts may have detrimental effects on patient outcome. PMID:22463679

  4. Antibody-labeled liposomes for CT imaging of atherosclerotic plaques: in vitro investigation of an anti-ICAM antibody-labeled liposome containing iohexol for molecular imaging of atherosclerotic plaques via computed tomography.

    PubMed

    Danila, Delia; Partha, Ranga; Elrod, Don B; Lackey, Melinda; Casscells, S Ward; Conyers, Jodie L

    2009-01-01

    We evaluated the specific binding of anti-intercellular adhesion molecule 1 (ICAM-1) conjugated liposomes (immunoliposomes, or ILs) to activated human coronary artery endothelial cells (HCAEC) with the purpose of designing a computed tomographic imaging agent for early detection of atherosclerotic plaques. Covalent attachment of anti-ICAM-1 monoclonal antibodies to pre-formed liposomes stabilized with polyethylene glycol yielded ILs, with a coupling efficiency of the ICAM-1 to the liposomes of 10% to 24%. The anti-ICAM-1-labeled ILs had an average diameter of 136 nm as determined by dynamic light-scattering and cryogenic electron microscopy. The ILs' encapsulation of 5-[N-acetyl-(2,3-dihydroxypropyl)-amino)-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-benzene-1,3-dicarboxamide (iohexol) was determined to be 18% to 19% by a dialysis technique coupled with ultraviolet detection of free iohexol. This encapsulation corresponded to 30 to 38 mg iodine per mL IL solution, and the ILs exhibited 91% to 98.5% iohexol retention at room temperature and under physiologic conditions. The specific binding of the ILs to cultured, activated HCAEC was measured using flow cytometry, enzyme-linked immunosorbent assays, and fluorescence microscopy. The immunosorbent assays demonstrated the specificity of binding of anti-ICAM-1 to ICAM-1 compared with control studies using nonspecific immunoglobulin G-labeled ILs. Flow cytometry and fluorescence microscopy experiments demonstrated the expression of ICAM-1 on the surface of activated HCAEC. Therefore, our iohexol-filled ILs demonstrated potential for implementation in computed tomographic angiography to noninvasively detect atherosclerotic plaques that are prone to rupture.

  5. Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer

    PubMed Central

    Boér, Katalin

    2016-01-01

    Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years. In 2012, a new molecularly targeted therapeutic strategy, inhibition of mammalian target of rapamycin with everolimus, was introduced into clinical practice. Everolimus, in combination with a steroidal aromatase inhibitor, exemestane, resulted in an increase in progression-free survival, but not overall survival in patients with estrogen receptor (ER)+ve advanced disease who had progressed on hormone therapy. In 2015, the first cyclin-dependent kinases 4/6 (CDK4/6) inhibitor, palbociclib, received accelerated US Food and Drug Administration approval for use in combination with letrozole for the treatment of postmenopausal ER+ve/HER2−ve advanced breast cancer as initial, endocrine-based therapy. The addition of palbociclib to endocrine therapy resulted in longer progression-free survival than letrozole alone. One year later, palbociclib received a new indication, use in combination with fulvestrant, in both premenopausal and postmenopausal females with advanced breast cancer of the same subtype with disease progression following endocrine therapy. Adding palbociclib to fulvestrant resulted in a significantly increased median progression-free survival compared to fulvestrant monotherapy. These new combination regimens of palbociclib with endocrine agents represent an important

  6. Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice.

    PubMed

    Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa; Luciano, Amelia; Skroblin, Philipp; Abonnenc, Mélanie; Perrotta, Paola; Yin, Xiaoke; Bauer, Ashley; Leslie, Kristen L; Zhang, Pei; Aryal, Binod; Montgomery, Rusty L; Thum, Thomas; Martin, Kathleen; Suarez, Yajaira; Mayr, Manuel; Fernandez-Hernando, Carlos; Sessa, William C

    2016-06-01

    Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA-miR-29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR-29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA-miR-29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR-29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions.

  7. Vulnerable atherosclerotic carotid plaque evaluation by ultrasound, computed tomography angiography, and magnetic resonance imaging: an overview.

    PubMed

    Naim, Cyrille; Douziech, Maxime; Therasse, Eric; Robillard, Pierre; Giroux, Marie-France; Arsenault, Frederic; Cloutier, Guy; Soulez, Gilles

    2014-08-01

    Ischemic syndromes associated with carotid atherosclerotic disease are often related to plaque rupture. The benefit of endarterectomy for high-grade carotid stenosis in symptomatic patients has been established. However, in asymptomatic patients, the benefit of endarterectomy remains equivocal. Current research seeks to risk stratify asymptomatic patients by characterizing vulnerable, rupture-prone atherosclerotic plaques. Plaque composition, biology, and biomechanics are studied by noninvasive imaging techniques such as magnetic resonance imaging, computed tomography, ultrasound, and ultrasound elastography. These techniques are at a developmental stage and have yet to be used in clinical practice. This review will describe noninvasive techniques in ultrasound, magnetic resonance imaging, and computed tomography imaging modalities used to characterize atherosclerotic plaque, and will discuss their potential clinical applications, benefits, and drawbacks.

  8. [The effect of carotid endarterectomy on cognitive disturbances in patients with atherosclerotic stenosis of carotid arteries].

    PubMed

    Iakhno, N N; Fedorova, T S; Damulin, I V; Shcherbiuk, A N; Vinogradov, O A; Lavrent'ev, A V

    2011-01-01

    Clinical and neuropsychological features of non-dementia cognitive disturbances were studied in 102 patients with atherosclerotic carotid stenosis. Cognitive disturbances were assessed after the carotid endarterectomy (CEAE). Mild cognitive impairment was found in 37 (36,3%) of patients, moderate cognitive impairment was diagnosed in 36 (35,3%)patients. Moderate cognitive impairment was found more often in patients with symptomatic carotid stenosis with structural brain changes confirmed by neuroimaging data and with instable atherosclerotic plaques with the predomination of hypodensity component. It allows to suggest that both the reduction of perfusion and arterio-arterial microemboli may cause cognitive dysfunction in patients with atherosclerotic carotid stenosis. The data on the positive effect of CEAE on cognitive functions have been obtained. The positive changes were more distinct in patients with asymptomatic course of carotid stenosis. However CEAE may have a negative effect on cognitive functions in patients with moderate cognitive impairment of dysmnestic character and symptomatic carotid stenosis.

  9. Human Exploration System Test-Bed for Integration and Advancement (HESTIA) Support of Future NASA Deep-Space Missions

    NASA Technical Reports Server (NTRS)

    Marmolejo, Jose; Ewert, Michael

    2016-01-01

    The Engineering Directorate at the NASA - Johnson Space Center is outfitting a 20-Foot diameter hypobaric chamber in Building 7 to support future deep-space Environmental Control & Life Support System (ECLSS) research as part of the Human Exploration System Test-bed for Integration and Advancement (HESTIA) Project. This human-rated chamber is the only NASA facility that has the unique experience, chamber geometry, infrastructure, and support systems capable of conducting this research. The chamber was used to support Gemini, Apollo, and SkyLab Missions. More recently, it was used to conduct 30-, 60-, and 90-day human ECLSS closed-loop testing in the 1990s to support the International Space Station and life support technology development. NASA studies show that both planetary surface and deep-space transit crew habitats will be 3-4 story cylindrical structures driven by human occupancy volumetric needs and launch vehicle constraints. The HESTIA facility offers a 3-story, 20-foot diameter habitat consistent with the studies' recommendations. HESTIA operations follow stringent processes by a certified test team that including human testing. Project management, analysis, design, acquisition, fabrication, assembly and certification of facility build-ups are available to support this research. HESTIA offers close proximity to key stakeholders including astronauts, Human Research Program (who direct space human research for the agency), Mission Operations, Safety & Mission Assurance, and Engineering Directorate. The HESTIA chamber can operate at reduced pressure and elevated oxygen environments including those proposed for deep-space exploration. Data acquisition, power, fluids and other facility resources are available to support a wide range of research. Recently completed HESTIA research consisted of unmanned testing of ECLSS technologies. Eventually, the HESTIA research will include humans for extended durations at reduced pressure and elevated oxygen to demonstrate

  10. Distribution of selected elements in atherosclerotic plaques of apoE/LDLR-double knockout mice subjected to dietary and pharmacological treatments

    NASA Astrophysics Data System (ADS)

    Gajda, Mariusz; Kowalska, Joanna; Banaś, Agnieszka; Banaś, Krzysztof; Kwiatek, Wojciech M.; Kostogrys, Renata B.; Mateuszuk, łukasz; ChŁopicki, Stefan; Litwin, Jan A.; Appel, Karen

    2011-10-01

    Gene-targeted, apolipoprotein E and LDL receptor-double knockout (apoE/LDLR -/-) mice represent a new animal model that displays severe hyperlipidemia and atherosclerosis. The aim of the present study was to show changes in histomorphology and in distribution of selected elements in atherosclerotic plaques of apoE/LDLR -/- mice fed egg-rich proatherosclerotic diet (5% egg-yolk lyophilisate) supplemented or not with perindopril (inhibitor of angiotensin converting enzyme; 2 mg/kg b.w.). Synchrotron radiation micro-X-ray fluorescence spectrometry was combined with histological stainings to determine distribution and concentration of trace and essential elements in atherosclerotic lesions. More advanced atherosclerotic lesions expressed by total area occupied by lipids (oil red-O staining) and by macrophages (CD68 immunohistochemistry) were observed in animals fed egg-rich diet. The perindopril treatment attenuated these effects. No significant differences were observed in the number of intimal smooth muscle cells (smooth muscle actin immunohistochemistry). In animals fed egg-rich diet significantly higher concentrations of Ca and significantly lower contents of S, Cl, , Fe, Cu, Zn and Se in atheromas were seen in comparison to chow diet-fed animals. After pharmacological treatment, concentrations of S, Cl, Fe, Cu, Zn and Se showed the tendency to achieve levels like in animals fed normal diet. K level differed only in group treated with perindopril. Concentration of P did not significantly vary in all experimental groups. Perindopril showed its potency to reduce atherosclerosis, as estimated by the size of the atheroma and content of pro- and antiatherogenic elements.

  11. Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy.

    PubMed

    Tracqui, Philippe; Broisat, Alexis; Toczek, Jackub; Mesnier, Nicolas; Ohayon, Jacques; Riou, Laurent

    2011-04-01

    Several studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance. In this work, force mapping experiments using atomic force microscopy (AFM) were conducted in apolipoprotein E-deficient (ApoE(-/-)) mouse, which represents the most widely used experimental model for studying mechanisms underlying the development of atherosclerotic lesions. To obtain the elastic material properties of fibrous caps and lipidic cores of atherosclerotic plaques, serial cross-sections of aortic arch lesions were probed at different sites. Atherosclerotic plaque sub-structures were subdivided into cellular fibrotic, hypocellular fibrotic and lipidic rich areas according to histological staining. Hertz's contact mechanics were used to determine elasticity (Young's) moduli that were related to the underlying histological plaque structure. Cellular fibrotic regions exhibit a mean Young modulus of 10.4±5.7kPa. Hypocellular fibrous caps were almost six-times stiffer, with average modulus value of 59.4±47.4kPa, locally rising up to ∼250kPa. Lipid rich areas exhibit a rather large range of Young's moduli, with average value of 5.5±3.5kPa. Such precise quantification of plaque stiffness heterogeneity will allow investigators to have prospectively a better monitoring of atherosclerotic disease evolution, including arterial wall remodeling and plaque rupture, in response to mechanical constraints imposed by vascular shear stress and blood pressure.

  12. Advances in Electronic-Nose Technologies for the Detection of Volatile Biomarker Metabolites in the Human Breath

    PubMed Central

    Wilson, Alphus D.

    2015-01-01

    Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs) and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs. PMID:25738426

  13. Advances in electronic-nose technologies for the detection of volatile biomarker metabolites in the human breath.

    PubMed

    Wilson, Alphus D

    2015-03-02

    Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs) and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs.

  14. Prevalence and risk factors for atherosclerotic carotid stenosis and plaque

    PubMed Central

    Woo, Shin Young; Joh, Jin Hyun; Han, Sang-Ah; Park, Ho-Chul

    2017-01-01

    Abstract Atherosclerotic carotid stenosis (ACS) is a major cause of ischemic stroke. Screening for asymptomatic ACS is important to identify the patients who require longitudinal surveillance, medication, or endovascular surgery. The aim of this study was to assess the prevalence and risk factors for ACS and carotid plaque (CP) in Korea using a population-based screening study. We recruited participants during visits to several community welfare centers in Korea. The baseline characteristics of the study population were collected. All patients underwent duplex ultrasonography to examine their bilateral carotid arteries. ACS was defined as the presence of plaque with ≥50% vessel diameter reduction and peak systolic velocity (PSV) ≥125 cm/s or PSV ratio ≥2.0. CP was defined as the presence of plaque with <50% vessel diameter reduction. The Mann–Whitney test, χ2 test, Fisher exact test, and logistic regression were used in the statistical analysis. A total of 3030 participants were enrolled in this study (male 43.7% and female 56.3%). The prevalence of ACS and CP was 1.1% and 5.7%, respectively. Significant risk factors for CP included age ≥80 years (odds ratio [OR], 8.11; 95% confidence interval [CI], 3.45–18.93), male sex (OR, 2.16; 95% CI, 1.29–3.61), hypertension (OR, 1.72; 95% CI, 1.21–2.45), and hyperlipidemia (OR, 1.84; 95% CI, 1.30–2.62). The presence of ACS was significantly associated with age (OR, 1.07; 95% CI, 1.03–1.12), hypertension (OR, 3.16; 95% CI, 1.34–7.46), and being an ex-smoker (OR, 6.81; 95% CI, 1.66–27.93) or current smoker (OR, 6.97; 95% CI, 1.78–27.31) after adjusting for confounding factors. This population-based screening study revealed that ACS was uncommon and had a prevalence of 1.1% in the study population. Age, hypertension, and smoking were risk factors for ACS. Further investigations into the prevalence and risk factors of ACS are required, as are studies on the cost-effectiveness of a national screening

  15. Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.

    PubMed

    Poredos, P; Zizek, B

    1996-03-01

    -macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease.

  16. [Expression and significance of integrin α5β1 and fibronectin in atherosclerotic plaques from autopsy specimens].

    PubMed

    Yu, X; Zhang, Q Q; Wang, B; Sun, L

    2017-03-08

    Objective: To investigate the expression of integrin α5β1 and fibronectin in the human aorta and coronary artery, and their effects in the development of atherosclerosis. Methods: One hundred and twenty autopsy aorta and coronary artery specimens were collected, and the expression of CD68, actin, integrin α5β1 and fibronectin was detected by immunohistochemical staining. Atherosclerotic plaques were located by CD68 and actin staining, and the degree of coronary artery stenosis was determined by elastic fiber staining and NIH Scion Image(60.1) software. The coronary artery tissues were divided into groups A (0-25%); B (26%-50%); C (51%-75%) and D (76%-100%) according to the degree of stenosis. Results: Integrin α5β1 showed cytoplasmic expression in endothelium, foam cells, monocytes, smooth muscle cells and adjacent tissue around calcification. In both the aorta and coronary artery, integrin α5β1 expression was stronger in the smooth muscle cells in the internal elastic lamina than in the tunica. The expression intensity in coronary artery smooth muscle decreased with increasing degree of coronary artery stenosis. Fibronectin showed cytoplasmic expression in foam cells, monocytes, smooth muscle cells of the internal elastic lamina and adjacent tissue around calcification. There was positive correlation of fibronectin and integrin α5β1 expression in smooth muscle cells and adjacent tissue around calcification. Conclusions: In the development of atherosclerosis, integrin α5β1 and fibronectin may participate in the regulating the migration of smooth muscle cells to the intima, and promote the formation of local calcification of atherosclerotic plaques. But integrin α5β1 is not involved in the late stage of atherosclerosis with increasing coronary artery stenosis.

  17. A case of atherosclerotic inferior mesenteric artery aneurysm secondary to high flow state.

    PubMed

    Troisi, Nicola; Esposito, Giovanni; Cefalì, Pietro; Setti, Marco

    2011-07-01

    Inferior mesenteric artery aneurysms are very rare and they are among the rarest of visceral artery aneurysms. Sometimes, the distribution of the blood flow due to chronic atherosclerotic occlusion of some arteries can establish an increased flow into a particular supplying district (high flow state). A high flow state in a stenotic inferior mesenteric artery in compensation for a mesenteric occlusive disease can produce a rare form of aneurysm. We report the case of an atherosclerotic inferior mesenteric aneurysm secondary to high flow state (association with occlusion of the celiac trunk and severe stenosis of the superior mesenteric artery), treated by open surgical approach.

  18. Immunostaining of macrophages, endothelial cells and smooth muscle cells in the atherosclerotic mouse aorta

    PubMed Central

    Menon, Prashanthi; Fisher, Edward A.

    2016-01-01

    The atherosclerotic mouse aorta consists of a heterogeneous population of cells, including macrophages, endothelial cells (EC) and smooth muscle cells (SMC), that play critical roles in cardiovascular disease. Identification of these vascular cells in the vessel wall is important to understanding their function in pathological conditions. Immunohistochemistry is an invaluable technique used to detect the presence of cells in different tissues. Here, we describe immunohistochemical techniques commonly used for the detection of the vascular cells in the atherosclerotic mouse aorta using cell specific markers. PMID:26445786

  19. Renovascular heart failure: heart failure in patients with atherosclerotic renal artery disease.

    PubMed

    Kawarada, Osami; Yasuda, Satoshi; Noguchi, Teruo; Anzai, Toshihisa; Ogawa, Hisao

    2016-07-01

    Atherosclerotic renal artery disease presents with a broad spectrum of clinical features, including heart failure as well as hypertension, and renal failure. Although recent randomized controlled trials failed to demonstrate renal artery stenting can reduce blood pressure or the number of cardiovascular or renal events more so than medical therapy, increasing attention has been paid to flash pulmonary edema and congestive heart failure associated with atherosclerotic renal artery disease. This clinical entity "renovascular heart failure" is diagnosed retrospectively. Given the increasing global burden of heart failure, this review highlights the background and catheter-based therapeutic aspects for renovascular heart failure.

  20. Characterization of atherosclerotic plaques by cross-polarization optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Gubarkova, Ekaterina V.; Dudenkova, Varvara V.; Feldchtein, Felix I.; Timofeeva, Lidia B.; Kiseleva, Elena B.; Kuznetsov, Sergei S.; Moiseev, Alexander A.; Gelikonov, Gregory V.; Vitkin, Alex I.; Gladkova, Natalia D.

    2016-02-01

    We combined cross-polarization optical coherence tomography (CP OCT) and non-linear microscopy based on second harmonic generation (SHG) and two-photon-excited fluorescence (2PEF) to assess collagen and elastin fibers in the development of the atherosclerotic plaque (AP). The study shows potential of CP OCT for the assessment of collagen and elastin fibers condition in atherosclerotic arteries. Specifically, the additional information afforded by CP OCT, related to birefringence and cross-scattering properties of arterial tissues, may improve the robustness and accuracy of assessment about the microstructure and composition of the plaque for different stages of atherosclerosis.

  1. Chimney stent technique for treatment of severe abdominal aortic atherosclerotic stenosis.

    PubMed

    Ritter, Jens C; Ghosh, Jonathan; Butterfield, John S; McCollum, Charles N; Ashleigh, Raymond

    2011-03-01

    Application of the "chimney" stent technique is described in a case of complex multilevel atherosclerotic disease involving the juxtarenal aorta. A patient with significant comorbidities was unsuitable for major open reconstructive surgery. He was treated with a combined procedure consisting of chimney stent placement in the juxtarenal aorta, iliac "kissing" stent placement, and right-sided common femoral artery (CFA) replacement. This case shows that the chimney stent technique can be a feasible alternative to leaving a safety wire in the renal arteries and observation during primary angioplasty in complex atherosclerotic lesions of the abdominal aorta.

  2. Enhanced Biosensor Platforms for Detecting the Atherosclerotic Biomarker VCAM1 Based on Bioconjugation with Uniformly Oriented VCAM1-Targeting Nanobodies

    PubMed Central

    Ta, Duy Tien; Guedens, Wanda; Vranken, Tom; Vanschoenbeek, Katrijn; Steen Redeker, Erik; Michiels, Luc; Adriaensens, Peter

    2016-01-01

    Surface bioconjugation of biomolecules has gained enormous attention for developing advanced biomaterials including biosensors. While conventional immobilization (by physisorption or covalent couplings using the functional groups of the endogenous amino acids) usually results in surfaces with low activity, reproducibility and reusability, the application of methods that allow for a covalent and uniformly oriented coupling can circumvent these limitations. In this study, the nanobody targeting Vascular Cell Adhesion Molecule-1 (NbVCAM1), an atherosclerotic biomarker, is engineered with a C-terminal alkyne function via Expressed Protein Ligation (EPL). Conjugation of this nanobody to azidified silicon wafers and Biacore™ C1 sensor chips is achieved via Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” chemistry to detect VCAM1 binding via ellipsometry and surface plasmon resonance (SPR), respectively. The resulting surfaces, covered with uniformly oriented nanobodies, clearly show an increased antigen binding affinity, sensitivity, detection limit, quantitation limit and reusability as compared to surfaces prepared by random conjugation. These findings demonstrate the added value of a combined EPL and CuAAC approach as it results in strong control over the surface orientation of the nanobodies and an improved detecting power of their targets—a must for the development of advanced miniaturized, multi-biomarker biosensor platforms. PMID:27399790

  3. Actin is a target of T-cell reactivity in patients with advanced carotid atherosclerotic plaques.

    PubMed

    Profumo, Elisabetta; Buttari, Brigitta; Petrone, Linda; Lacroce, Giada; Tesori, Maria Chiara; Capoano, Raffaele; Salvati, Bruno; Riganò, Rachele

    2013-01-01

    Atherosclerosis is a chronic inflammatory disease of the arterial wall associated with autoimmune reactions. In a previous study, we observed the presence of actin-specific antibodies in sera from patients with carotid atherosclerosis. To extend our previous results we evaluated the possible role of actin as antigenic target of cell-mediated immune reactions in carotid atherosclerosis. Peripheral blood mononuclear cells (PBMC) from 17 patients and 16 healthy subjects were tested by cell proliferation assay and by ELISA for cytokine production. Actin induced a proliferative response in 47% of patients' PBMC samples, with SI ranging from 2.6 to 21.1, and in none of the healthy subjects' samples (patients versus healthy subjects, P = 0.02). The presence of diabetes in patients was significantly associated with proliferative response to actin (P = 0.04). IFN- γ and TNF- α concentrations were higher in PBMC from patients than in those from healthy subjects and in PBMC proliferating to actin than in nonproliferating ones. Our data demonstrate for the first time a role of actin as a target autoantigen of cellular immune reactions in patients with carotid atherosclerosis. The preferential proinflammatory Th1 activation suggests that actin could contribute to endothelial dysfunction, tissue damage, and systemic inflammation in carotid atherosclerosis.

  4. In Vitro Oxidation of Collagen Promotes the Formation of Advanced Oxidation Protein Products and the Activation of Human Neutrophils.

    PubMed

    Bochi, Guilherme Vargas; Torbitz, Vanessa Dorneles; de Campos, Luízi Prestes; Sangoi, Manuela Borges; Fernandes, Natieli Flores; Gomes, Patrícia; Moretto, Maria Beatriz; Barbisan, Fernanda; da Cruz, Ivana Beatrice Mânica; Moresco, Rafael Noal

    2016-04-01

    The accumulation of advanced oxidation protein products (AOPPs) has been linked to several pathological conditions. Here, we investigated collagen as a potential source for AOPP formation and determined the effects of hypochlorous acid (HOCl)-treated collagen (collagen-AOPPs) on human neutrophil activity. We also assessed whether alpha-tocopherol could counteract these effects. Exposure to HOCl increased the levels of collagen-AOPPs. Collagen-AOPPs also stimulated the production of AOPPs, nitric oxide (NO), superoxide radicals (O2(-)), and HOCl by neutrophils. Collagen-AOPPs induced apoptosis and decreased the number of viable cells. Alpha-tocopherol prevented the formation of collagen-AOPPs, strongly inhibited the collagen-AOPP-induced production of O2(-) and HOCl, and increased the viability of neutrophils. Our results suggest that collagen is an important protein that interacts with HOCl to form AOPPs, and consequently, collagen-AOPP formation is related to human neutrophil activation and cell death.

  5. Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

    DTIC Science & Technology

    2013-07-01

    extending the period of performance soon. The Ivy Center for Advanced Brain Tumor Treatment at the Swedish Neuroscience Institute (SNI) has...markers: (A) GFAP/astrocytes, (B), TUJ-1/neurons and (C) O4/oligodendrocytes. Cells were grown in NSA media without growth factors (EGF and FGF-2...Treatment at the Swedish Neuroscience Institute (SNI) has collected potentially eligible tumor tissue from over forty GBM patients. • Primary GBM cell

  6. An implantable, designed-for-human-use peripheral nerve stimulation and recording system for advanced prosthetics.

    PubMed

    Lachapelle, John R; Bjune, Caroline K; Kindle, Alexander L; Czarnecki, Andrew; Burns, John R; Grainger, Julianne E; Segura, Carlos A; Nugent, Brian D; Sriram, Tirunelveli S; Parks, Philip D; Keefer, Edward; Cheng, Jonathan

    2016-08-01

    Complex suture prostheses that deliver sensory and position feedback require a more sophisticated integration with the human user. Here a micro-size active implantable system that provides many-degree-of-freedom neural feedback in both sensory stimulation and motor control is shown, as one potential human-use solution in DARPA's HAPTIX program. Various electrical and mechanical challenge and solutions in meeting both sensory /motor performance as well as ISO 14708 FDA-acceptable human use in an aspirin-size active implementation are discussed.

  7. Human Engineering Operations and Habitability Assessment: A Process for Advanced Life Support Ground Facility Testbeds

    NASA Technical Reports Server (NTRS)

    Connolly, Janis H.; Arch, M.; Elfezouaty, Eileen Schultz; Novak, Jennifer Blume; Bond, Robert L. (Technical Monitor)

    1999-01-01

    Design and Human Engineering (HE) processes strive to ensure that the human-machine interface is designed for optimal performance throughout the system life cycle. Each component can be tested and assessed independently to assure optimal performance, but it is not until full integration that the system and the inherent interactions between the system components can be assessed as a whole. HE processes (which are defining/app lying requirements for human interaction with missions/systems) are included in space flight activities, but also need to be included in ground activities and specifically, ground facility testbeds such as Bio-Plex. A unique aspect of the Bio-Plex Facility is the integral issue of Habitability which includes qualities of the environment that allow humans to work and live. HE is a process by which Habitability and system performance can be assessed.

  8. Detection of Rupture-Prone Atherosclerotic Plaques by Time-Resolved Laser Induced Fluorescence Spectroscopy

    PubMed Central

    Marcu, Laura; Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Reil, Todd; Qiao, Jian-Hua; Baker, J. Dennis; Freischlag, Julie A.; Fishbein, Michael C.

    2009-01-01

    Objective Plaque with dense inflammatory cells, including macrophages, thin fibrous cap and superficial necrotic/lipid core is thought to be prone-to-rupture. We report a time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) technique for detection of such markers of plaque vulnerability in human plaques. Methods The autofluorescence of carotid plaques (65 endarterectomy patients) induced by a pulsed laser (337 nm, 0.7 ns) was measured from 831 distinct areas. The emission was resolved spectrally- (360–550 nm range) and temporally- (0.3 ns resolution) using a prototype fiber-optic TR-LIFS apparatus. Lesions were evaluated microscopically and quantified as to the % of different components (fibrous cap, necrotic core, inflammatory cells, foam cells, mature and degraded collagen, elastic fibers, calcification, and smooth muscle cell of the vessel wall). Results We determined that the spectral intensities and time-dependent parameters at discrete emission wavelengths 1) allow for discrimination (sensitivity >81%, specificity >94%) of various compositional and pathological features associated with plaque vulnerability including infiltration of macrophages into intima and necrotic/lipid core under a thin fibrous cap, and 2) show a linear correlation with plaque biochemical content: elastin (P<0.008), collagen (P<0.02), inflammatory cells (P<0.003), necrosis (P<0.004). Conclusion Our results demonstrate the feasibility of TR-LIFS as a method for the identification of markers of plaque vulnerability. Current findings enable future development of TR-LIFS based clinical devices for rapid investigation of atherosclerotic plaques and detection of those at high-risk. PMID:18926540

  9. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?

    PubMed

    Wyss, Markus; Schulze, Andreas

    2002-01-01

    Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further

  10. Extent of flow recirculation governs expression of atherosclerotic and thrombotic biomarkers in arterial bifurcations

    PubMed Central

    Martorell, Jordi; Santomá, Pablo; Kolandaivelu, Kumaran; Kolachalama, Vijaya B.; Melgar-Lesmes, Pedro; Molins, José J.; Garcia, Lawrence; Edelman, Elazer R.; Balcells, Mercedes

    2014-01-01

    Aims Atherogenesis, evolution of plaque, and outcomes following endovascular intervention depend heavily on the unique vascular architecture of each individual. Patient-specific, multiscale models able to correlate changes in microscopic cellular responses with relevant macroscopic flow, and structural conditions may help understand the progression of occlusive arterial disease, providing insights into how to mitigate adverse responses in specific settings and individuals. Methods and results Vascular architectures mimicking coronary and carotid bifurcations were derived from clinical imaging and used to generate conjoint computational meshes for in silico analysis and biocompatible scaffolds for in vitro models. In parallel with three-dimensional flow simulations, geometrically realistic scaffolds were seeded with human smooth muscle cells (SMC) or endothelial cells and exposed to relevant, physiological flows. In vitro surrogates of endothelial health, atherosclerotic progression, and thrombosis were locally quantified and correlated best with an quantified extent of flow recirculation occurring within the bifurcation models. Oxidized low-density lipoprotein uptake, monocyte adhesion, and tissue factor expression locally rose up to three-fold, and phosphorylated endothelial nitric oxide synthase and Krüppel-like factor 2 decreased up to two-fold in recirculation areas. Isolated testing in straight-tube idealized constructs subject to static, oscillatory, and pulsatile conditions, indicative of different recirculant conditions corroborated these flow-mediated dependencies. Conclusions Flow drives variations in vascular reactivity and vascular beds. Endothelial health was preserved by arterial flow but jeopardized in regions of flow recirculation in a quasi-linear manner. Similarly, SMC exposed to flow were more thrombogenic in large recirculating regions. Health, thrombosis, and atherosclerosis biomarkers correlate with the extent of recirculation in vascular

  11. In-vitro study of the effects of Congo Red on the ablation of atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Beyerbacht, Hugo P.; Aggarwal, Shanti J.; Jansen, E. Duco; Welch, Ashley J.

    1991-06-01

    The possible application of the vital dye Congo Red to enhance the selective ablation of plaque was investigated. Fresh healthy human aorta samples and samples with varying degrees of atherosclerotic disease were incubated for 3 minutes in a 0.25 mg/ml solution of Congo Red in saline, washed and then irradiated either in air or under saline using an argon laser ((lambda) equals 488 and 514.5 nm, spotsize equals 1.1 mm). The experiments were repeated with undyed healthy and diseased tissue samples. The effect of Congo Red staining on ablation was evaluated by comparing the minimum irradiance and the average amount of time needed to create ablation onset, which was defined as a 'pop' sound followed by carbonization of tissue in air. Ablation thresholds in air for dyed normal tissue, fatty and fibrous plaque were lowered by 42, 60 and 66% respectively. The average time to start ablation dropped from 40 to 2 s, 13 to 1 s and 20 to 14 s respectively. When tissue samples were submerged under saline, Congo Red paradoxically reduced the difference between the ablation threshold of healthy tissue and fatty threshold. During the initial irradiation a concentration of dye around the irradiation spot was observed. This unusual finding may be due to the transport of dye during irradiation. This may explain the observed effect that tissue adjacent to the initial irradiation site had a lowered ablation threshold. By examining the complex mechanisms involved in dye enhanced ablation in may be possible to select a combination of dye and irradiation parameters to achieve selective ablation of plaque.

  12. Serious Gaming Technologies Support Human Factors Investigations of Advanced Interfaces for Semi-Autonomous Vehicles

    DTIC Science & Technology

    2006-06-01

    Human Factors Integration ( HFI – Human Systems Integration, or HSI, in the US) over a broad range of military domains. The HFI DTC consists of a...together a number of research themes and generic or “enabling” technologies (Stone, 2003) into four broad Work Packages: (a) HFI and Network- Enabled...Capability (NEC), (b) education and training, (c) updating MoD HFI processes and (d) HFI awareness/exploitation. The work described herein, whilst

  13. Quasi-conformal remapping for compensation of human visual field defects - Advances in image remapping for human field defects

    NASA Technical Reports Server (NTRS)

    Juday, Richard D.; Loshin, David S.

    1989-01-01

    Image coordinate transformations are investigated for possible use in a low vision aid for human patients. These patients typically have field defects with localized retinal dysfunction predominately central (age related maculopathy) or peripheral (retinitis pigmentosa). Previously simple eccentricity-only remappings which do not maintain conformality were shown. Initial attempts on developing images which hold quasi-conformality after remapping are presented. Although the quasi-conformal images may have less local distortion, there are discontinuities in the image which may counterindicate this type of transformation for the low vision application.

  14. Air Force Policy for Advanced Education: Production of Human Capital or Cheap Signals?

    DTIC Science & Technology

    2011-01-01

    many reasons to be discouraged or dissatis­ fied with our current system —limited PME in-residence slots, limited advanced degree opportunities, or...improve their ability to serve the Air Force—or both. To help dissect and answer this question about the role of AADs in our promotion systems , the...analyzed promotion data, a perusal of the list of off-duty education programs mar­ keted to military personnel, such as those offered by American

  15. Towards Precision Medicine: Advances in Computational Approaches for the Analysis of Human Variants

    PubMed Central

    Peterson, Thomas A; Doughty, Emily; Kann, Maricel G

    2013-01-01

    Variations and similarities in our individual genomes are part of our history, our heritage, and our identity. Some human genomic variants are associated with common traits such as hair and eye color, while others are associated with susceptibility to disease or response to drug treatment. Identifying the human variations producing clinically relevant phenotypic changes is critical for providing accurate and personalized diagnosis, prognosis, and treatment for diseases. Furthermore, a better understanding of the molecular underpinning of disease can lead to development of new drug targets for precision medicine. Several resources have been designed for collecting and storing human genomic variations in highly structured, easily accessible databases. Unfortunately, a vast amount of information about these genetic variants and their functional and phenotypic associations is currently buried in the literature, only accessible by manual curation or sophisticated text mining technology to extract the relevant information. In addition, the low cost of sequencing technologies coupled with increasing computational power has enabled the development of numerous computational methodologies to predict the pathogenicity of human variants. This review provides a detailed comparison of current human variant resources, including HGMD, OMIM, ClinVar, and UniProt/Swiss-Prot, followed by an overview of the computational methods and techniques used to leverage the available data to predict novel deleterious variants. We expect these resources and tools to become the foundation for understanding the molecular details of genomic variants leading to disease, which in turn will enable the promise of precision medicine. PMID:23962656

  16. Probing the bioinorganic chemistry of toxic metals in the mammalian bloodstream to advance human health.

    PubMed

    Gailer, Jürgen

    2012-03-01

    The etiology of numerous grievous human diseases, including Alzheimer's and Parkinson's Disease is not well understood. Conversely, the concentration toxic metals and metalloids, such as As, Cd, Hg and Pb in human blood of the average population is well established, yet we know strikingly little about the role that they might play in the etiology of disease processes. Establishing functional connections between the chronic exposure of humans to these and other inorganic pollutants and the etiology of certain human diseases is therefore viewed by many as one of the greatest challenges in the post-genomic era. Conceptually, this task requires us to uncover hitherto unknown biomolecular mechanisms which must explain how small doses of a toxic metal/metalloid compound (low μg per day) - or mixtures thereof - may eventually result in a particular human disease. The biological complexity that is inherently associated with mammals, however, makes the discovery of these mechanisms a truly monumental task. Recent findings suggest that a better understanding of the bioinorganic chemistry of inorganic pollutants in the mammalian bloodstream represents a fruitful strategy to unravel relevant biomolecular mechanisms. The adverse effect(s) that toxic metals/metalloid compounds exert on the transport of essential ultratrace elements to internal organs appear particularly pertinent. A brief overview of the effect that arsenite and Hg(2+) exert on the mammalian metabolism of selenium is presented.

  17. Advancing sexual health through human rights: the role of the law.

    PubMed

    Kismödi, Eszter; Cottingham, Jane; Gruskin, Sofia; Miller, Alice M

    2015-01-01

    Since the International Conference on Population and Development, definitions of sexuality and sexual health have been greatly elaborated alongside widely accepted recognition that sexual health requires respect, protection and fulfilment of human rights. Considerable progress has also been made in enacting or changing laws that affect sexuality and sexual health, in line with human rights standards. These measures include legal guarantees against non-discrimination and violence, decriminalisation of consensual sexual conduct and guaranteeing availability, accessibility, acceptability and quality of sexual health information and services to all. Such legal actions have had positive effects on health and specifically on sexual health, particularly for marginalised populations. Yet in all regions of the world, laws still exist which jeopardise health, including sexual health, and violate human rights. In order to ensure accountability for the rights and health of their populations, states have an obligation to bring their laws into line with international, regional and national human rights standards. These rights-based legal guarantees, while insufficient alone, are essential for effective systems of accountability, achieving positive sexual health outcomes and the respect and protection of human rights.

  18. Advancing sexual health through human rights: The role of the law

    PubMed Central

    Kismödi, Eszter; Cottingham, Jane; Gruskin, Sofia; Miller, Alice M.

    2015-01-01

    Since the International Conference on Population and Development, definitions of sexuality and sexual health have been greatly elaborated alongside widely accepted recognition that sexual health requires respect, protection and fulfilment of human rights. Considerable progress has also been made in enacting or changing laws that affect sexuality and sexual health, in line with human rights standards. These measures include legal guarantees against non-discrimination and violence, decriminalisation of consensual sexual conduct and guaranteeing availability, accessibility, acceptability and quality of sexual health information and services to all. Such legal actions have had positive effects on health and specifically on sexual health, particularly for marginalised populations. Yet in all regions of the world, laws still exist which jeopardise health, including sexual health, and violate human rights. In order to ensure accountability for the rights and health of their populations, states have an obligation to bring their laws into line with international, regional and national human rights standards. These rights-based legal guarantees, while insufficient alone, are essential for effective systems of accountability, achieving positive sexual health outcomes and the respect and protection of human rights. PMID:25539286

  19. "The state of the heart": Recent advances in engineering human cardiac tissue from pluripotent stem cells.

    PubMed

    Sirabella, Dario; Cimetta, Elisa; Vunjak-Novakovic, Gordana

    2015-08-01

    The pressing need for effective cell therapy for the heart has led to the investigation of suitable cell sources for tissue replacement. In recent years, human pluripotent stem cell research expanded tremendously, in particular since the derivation of human-induced pluripotent stem cells. In parallel, bioengineering technologies have led to novel approaches for in vitro cell culture. The combination of these two fields holds potential for in vitro generation of high-fidelity heart tissue, both for basic research and for therapeutic applications. However, this new multidisciplinary science is still at an early stage. Many questions need to be answered and improvements need to be made before clinical applications become a reality. Here we discuss the current status of human stem cell differentiation into cardiomyocytes and the combined use of bioengineering approaches for cardiac tissue formation and maturation in developmental studies, disease modeling, drug testing, and regenerative medicine.

  20. Human performance measurement: Validation procedures applicable to advanced manned telescience systems

    NASA Technical Reports Server (NTRS)

    Haines, Richard F.

    1990-01-01

    As telescience systems become more and more complex, autonomous, and opaque to their operators it becomes increasingly difficult to determine whether the total system is performing as it should. Some of the complex and interrelated human performance measurement issues are addressed as they relate to total system validation. The assumption is made that human interaction with the automated system will be required well into the Space Station Freedom era. Candidate human performance measurement-validation techniques are discussed for selected ground-to-space-to-ground and space-to-space situations. Most of these measures may be used in conjunction with an information throughput model presented elsewhere (Haines, 1990). Teleoperations, teleanalysis, teleplanning, teledesign, and teledocumentation are considered, as are selected illustrative examples of space related telescience activities.

  1. Advances in the diagnosis of Ascaris suum infections in pigs and their possible applications in humans.

    PubMed

    Vlaminck, Johnny; Levecke, Bruno; Vercruysse, Jozef; Geldhof, Peter

    2014-12-01

    Ascariasis is one of the most common parasitic diseases in both humans and pigs. It has been shown to cause growth deficits in both species and to impair cognitive development in children. Notwithstanding its substantial impact on pig economy and public health, diagnosis of ascariasis has mostly relied on the detection of eggs in stool and further development of novel, more sensitive methods has been limited or non-existent. Here, we discuss the currently available techniques for the diagnosis of ascariasis in pigs, their caveats, and the implications of a new serological detection technique for the evaluation of both pig and human ascariasis.

  2. Advancing the sexual and reproductive health and human rights of women living with HIV: a review of UN, regional and national human rights norms and standards

    PubMed Central

    Khosla, Rajat; Van Belle, Nuna; Temmerman, Marleen

    2015-01-01

    regarding the human rights of women living with HIV in relation to SRH. Conclusions A systematic approach to health and human rights considerations related to women living with HIV and SRH by international, regional and national bodies is needed to advance the agenda and ensure that policies and programmes related to SRH systematically take into account the health and human rights of women living with HIV. PMID:26643455

  3. Differentiation of Vascular Stem Cells Contributes to Ectopic Calcification of Atherosclerotic Plaque.

    PubMed

    Leszczynska, Aleksandra; O'Doherty, Aideen; Farrell, Eric; Pindjakova, Jana; O'Brien, Fergal J; O'Brien, Timothy; Barry, Frank; Murphy, Mary

    2016-04-01

    The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis.

  4. Annexin A5-Functionalized Bimodal Nanoparticles for MRI and Fluorescence Imaging of Atherosclerotic Plaques

    PubMed Central

    van Tilborg, Geralda A. F.; Vucic, Esad; Strijkers, Gustav J.; Cormode, David P.; Mani, Venkatesh; Skajaa, Torjus; Reutelingsperger, Chris P. M.; Fayad, Zahi A.; Mulder, Willem J. M.; Nicolay, Klaas

    2011-01-01

    Apoptosis and macrophage burden are believed to correlate with atherosclerotic plaque vulnerability and are therefore considered important diagnostic and therapeutic targets for atherosclerosis. These cell types are characterized by the exposure of phosphatidylserine (PS) at their surface. In the present study, we developed and applied a small micellar fluorescent annexin A5-functionalized nanoparticle for noninvasive magnetic resonance imaging (MRI) of PS exposing cells in atherosclerotic lesions. Annexin A5-mediated target-specificity was confirmed with ellipsometry and in vitro binding to apoptotic Jurkat cells. In vivo T1-weighted MRI of the abdominal aorta in atherosclerotic ApoE−/− mice revealed enhanced uptake of the annexin A5-micelles as compared to control-micelles, which was corroborated with ex vivo near-infrared fluorescence images of excised whole aortas. Confocal laser scanning microscopy (CLSM) demonstrated that the targeted agent was associated with macrophages and apoptotic cells, whereas the nonspecific control agent showed no clear uptake by such cells. In conclusion, the annexin A5-conjugated bimodal micelles displayed potential for noninvasive assessment of cell types that are considered to significantly contribute to plaque instability and therefore may be of great value in the assessment of atherosclerotic lesion phenotype. PMID:20804153

  5. Detection of atherosclerotic lesions and intimal macrophages using CD36-targeted nanovesicles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Current approaches to the diagnosis and therapy of atherosclerosis cannot target to lesion-determinant cells in the artery wall. Intimal macrophage infiltration promotes atherosclerotic lesion development by facilitating the accumulation of oxidized low-density lipoproteins (oxLDL) and increasing in...

  6. Characterization of atherosclerotic arterial tissue using combined SHG and FLIM microscopy

    NASA Astrophysics Data System (ADS)

    Cicchi, Riccardo; Baria, Enrico; Matthäus, Christian; Lange, Marta; Lattermann, Annika; Brehm, Bernhard R.; Popp, Jürgen; Pavone, Francesco S.

    2015-07-01

    Atherosclerosis is among the most widespread cardiovascular diseases and one of the leading cause of death in the Western World. Characterization of arterial tissue in atherosclerotic condition is extremely interesting from the diagnostic point of view, especially for what is concerning collagen content and organization because collagen plays a crucial role in plaque vulnerability. Routinely used diagnostic methods, such as histopathological examination, are limited to morphological analysis of the examined tissues, whereas an exhaustive characterization requires immunehistochemical examination and a morpho-functional approach. Non-linear microscopy techniques offer the potential for providing morpho-functional information on the examined tissues in a label-free way. In this study, we employed combined SHG and FLIM microscopy for characterizing collagen organization in both normal arterial wall and within atherosclerotic plaques. Image pattern analysis of SHG images allowed characterizing collagen organization in different tissue regions. In addition, the analysis of collagen fluorescence decay contributed to the characterization of the samples based on collagen fluorescence lifetime. Different values of collagen fiber mean size, collagen distribution, and collagen anisotropy and collagen fluorescence lifetime were found in normal arterial wall and within plaque depositions, prospectively allowing for automated classification of atherosclerotic lesions and plaque vulnerability. The presented method represents a promising diagnostic tool for evaluating atherosclerotic tissue and has the potential to find a stable place in clinical setting as well as to be applied in vivo in the near future.

  7. Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models.

    PubMed

    Laplante, Marc-André; Charbonneau, Alexandre; Avramoglu, Rita Kohen; Pelletier, Patricia; Fang, Xiangping; Bachelard, Hélène; Ylä-Herttuala, Seppo; Laakso, Markku; Després, Jean-Pierre; Deshaies, Yves; Sweeney, Gary; Mathieu, Patrick; Marette, André

    2013-09-01

    Cholesterol and triglyceride-rich Western diets are typically associated with an increased occurrence of type 2 diabetes and vascular diseases. This study aimed to assess the relative impact of dietary cholesterol and triglycerides on glucose tolerance, insulin sensitivity, atherosclerotic plaque formation, and endothelial function. C57BL6 wild-type (C57) mice were compared with atherosclerotic LDLr(-/-) ApoB(100/100) (LRKOB100) and atherosclerotic/diabetic IGF-II × LDLr(-/-) ApoB(100/100) (LRKOB100/IGF) mice. Each group was fed either a standard chow diet, a 0.2% cholesterol diet, a high-fat diet (HFD), or a high-fat 0.2% cholesterol diet for 6 mo. The triglyceride-rich HFD increased body weight, glucose intolerance, and insulin resistance but did not alter endothelial function or atherosclerotic plaque formation. Dietary cholesterol, however, increased plaque formation in LRKOB100 and LRKOB100/IGF animals and decreased endothelial function regardless of genotype. However, cholesterol was not associated with an increase of insulin resistance in LRKOB100 and LRKOB100/IGF mice and, unexpectedly, was even found to reduce the insulin-resistant effect of dietary triglycerides in these animals. Our data indicate that dietary triglycerides and cholesterol have distinct metabolic and vascular effects in obese atherogenic mouse models resulting in dissociation between the impairment of glucose homeostasis and the development of atherosclerosis.

  8. VCAM-1-targeting gold nanoshell probe for photoacoustic imaging of atherosclerotic plaque in mice.

    PubMed

    Rouleau, Leonie; Berti, Romain; Ng, Vanessa W K; Matteau-Pelletier, Carl; Lam, Tina; Saboural, Pierre; Kakkar, Ashok K; Lesage, Frédéric; Rhéaume, Eric; Tardif, Jean-Claude

    2013-01-01

    The development of molecular probes and novel imaging modalities, allowing better resolution and specificity, is associated with an increased potential for molecular imaging of atherosclerotic plaques especially in basic and pre-clinical research applications. In that context, a photoacoustic molecular probe based on gold nanoshells targeting VCAM-1 in mice (immunonanoshells) was designed. The molecular probe was validated in vitro and in vivo, showing no noticeable acute toxic effects. We performed the conjugation of gold nanoshells displaying near-infrared absorption properties with VCAM-1 antibody molecules and PEG to increase their biocompatibility. The resulting immunonanoshells obtained under different conditions of conjugation were then assessed for specificity and sensitivity. Photoacoustic tomography was performed to determine the ability to distinguish gold nanoshells from blood both in phantoms and in vivo. Ex vivo optical projection tomography of hearts and aortas from atherosclerotic and control mice confirmed the selective accumulation of the immunonanoshells in atherosclerotic-prone regions in mice, thus validating the utility of the probe in vivo in small animals for pre-clinical research. These immunonanoshells represent an adequate mean to target atherosclerotic plaques in small animals, leading to new tools to follow the effect of therapies on the progression or regression of the disease.

  9. Non-linear imaging and characterization of atherosclerotic arterial tissue using combined SHG and FLIM microscopy

    NASA Astrophysics Data System (ADS)

    Cicchi, Riccardo; Matthäus, Christian; Meyer, Tobias; Lattermann, Annika; Dietzek, Benjamin; Brehm, Bernhard R.; Popp, Jürgen; Pavone, Francesco S.

    2015-03-01

    Atherosclerosis is among the most widespread cardiovascular diseases and one of the leading cause of death in the Western World. Characterization of arterial tissue in atherosclerotic condition is extremely interesting from the diagnostic point of view, especially for what is concerning collagen content and organization because collagen plays a crucial role in plaque vulnerability. Routinely used diagnostic methods, such as histopathological examination, are limited to morphological analysis of the examined tissues, whereas an exhaustive characterization requires immune-histochemical examination and a morpho-functional approach. Non-linear microscopy techniques offer the potential for providing morpho-functional information on the examined tissues in a label-free way. In this study, we employed combined SHG and FLIM microscopy for characterizing collagen organization in both normal arterial wall and within atherosclerotic plaques. Image pattern analysis of SHG images allowed characterizing collagen organization in different tissue regions. In addition, the analysis of collagen fluorescence decay contributed to the characterization of the samples on the basis of collagen fluorescence lifetime. Different values of collagen fiber mean size, collagen distribution, collagen anisotropy and collagen fluorescence lifetime were found in normal arterial wall and within plaque depositions, prospectively allowing for automated classification of atherosclerotic lesions and plaque vulnerability. The presented method represents a promising diagnostic tool for evaluating atherosclerotic tissue and has the potential to find a stable place in clinical setting as well as to be applied in vivo in the near future.

  10. Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation.

    PubMed

    Bot, Martine; de Jager, Saskia C A; MacAleese, Luke; Lagraauw, H Maxime; van Berkel, Theo J C; Quax, Paul H A; Kuiper, Johan; Heeren, Ron M A; Biessen, Erik A L; Bot, Ilze

    2013-05-01

    Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.

  11. Numerical observer for atherosclerotic plaque classification in spectral computed tomography.

    PubMed

    Lorsakul, Auranuch; Fakhri, Georges El; Worstell, William; Ouyang, Jinsong; Rakvongthai, Yothin; Laine, Andrew F; Li, Quanzheng

    2016-07-01

    Spectral computed tomography (SCT) generates better image quality than conventional computed tomography (CT). It has overcome several limitations for imaging atherosclerotic plaque. However, the literature evaluating the performance of SCT based on objective image assessment is very limited for the task of discriminating plaques. We developed a numerical-observer method and used it to assess performance on discrimination vulnerable-plaque features and compared the performance among multienergy CT (MECT), dual-energy CT (DECT), and conventional CT methods. Our numerical observer was designed to incorporate all spectral information and comprised two-processing stages. First, each energy-window domain was preprocessed by a set of localized channelized Hotelling observers (CHO). In this step, the spectral image in each energy bin was decorrelated using localized prewhitening and matched filtering with a set of Laguerre-Gaussian channel functions. Second, the series of the intermediate scores computed from all the CHOs were integrated by a Hotelling observer with an additional prewhitening and matched filter. The overall signal-to-noise ratio (SNR) and the area under the receiver operating characteristic curve (AUC) were obtained, yielding an overall discrimination performance metric. The performance of our new observer was evaluated for the particular binary classification task of differentiating between alternative plaque characterizations in carotid arteries. A clinically realistic model of signal variability was also included in our simulation of the discrimination tasks. The inclusion of signal variation is a key to applying the proposed observer method to spectral CT data. Hence, the task-based approaches based on the signal-known-exactly/background-known-exactly (SKE/BKE) framework and the clinical-relevant signal-known-statistically/background-known-exactly (SKS/BKE) framework were applied for analytical computation of figures of merit (FOM). Simulated data of a

  12. The apolipoprotein(a) component of lipoprotein(a) mediates binding to laminin: contribution to selective retention of lipoprotein(a) in atherosclerotic lesions.

    PubMed

    D'Angelo, Angela; Geroldi, Diego; Hancock, Mark A; Valtulina, Viviana; Cornaglia, Antonia I; Spencer, Craig A; Emanuele, Enzo; Calligaro, Alberto; Koschinsky, Marlys L; Speziale, Pietro; Visai, Livia

    2005-02-21

    Lipoprotein(a) [Lp(a)] entrapment by vascular extracellular matrix may be important in atherogenesis. We sought to determine whether laminin, a major component of the basal membrane, may contribute to Lp(a) retention in the arterial wall. First, immunohistochemistry experiments were performed to examine the relative distribution of Lp(a) and laminin in human carotid artery specimens. There was a high degree of co-localization of Lp(a) and laminin in atherosclerotic specimens, but not in non-atherosclerotic sections. We then studied the binding interaction between Lp(a) and laminin in vitro. ELISA experiments showed that native Lp(a) particles and 17K and 12K recombinant apolipoprotein(a) [r-apo(a)] variants interacted strongly with laminin whereas LDL, apoB-100, and the truncated KIV(6-P), KIV(8-P), and KIV(9-P) r-apo(a) variants did not. Overall, the ELISA data demonstrated that Lp(a) binding to laminin is mediated by apo(a) and a combination of the lysine analogue epsilon-aminocaproic acid and salt effectively decreases apo(a) binding to laminin. Secondary binding analyses with 125I-labeled r-apo(a) revealed equilibrium dissociation constants (K(d)) of 180 and 360 nM for the 17K and 12K variants binding to laminin, respectively. Such similar K(d) values between these two r-apo(a) variants suggest that isoform size does not appear to influence apo(a) binding to laminin. In summary, our data suggest that laminin may bind to apo(a) in the atherosclerotic intima, thus contributing to the selective retention of Lp(a) in this milieu.

  13. Perspectives on Urban Geography in Advanced Placement® Human Geography

    ERIC Educational Resources Information Center

    Benton-Short, Lisa; Monk, Liliana

    2016-01-01

    "Perspectives on Urban Geography" constitutes a major part of the AP Human Geography course outline. In this article, urban core revitalization and rising suburban poverty are considered as two challenges facing cities in developed countries; and industrialization and the growth of megacities as two challenges facing cities in developing…

  14. Leveraging Small Aquarium Fishes to Advance Understanding of Environmentally Influenced Human Disorders and Diseases

    EPA Science Inventory

    Small aquarium fishes provide a model organism that recapitulates the development, physiology and specific disease processes present in humans without the many limitations of rodent-based models currently in use. Fish models offer advantages in cost, rapid life-cycles, and extern...

  15. A Human Capital Framework for a Stronger Teacher Workforce. Advancing Teaching--Improving Learning. White Paper

    ERIC Educational Resources Information Center

    Myung, Jeannie; Martinez, Krissia; Nordstrum, Lee

    2013-01-01

    Building a stronger teacher workforce requires the thoughtful orchestration of multiple processes working together in a human capital system. This white paper presents a framework that can be used to take stock of current efforts to enhance the teacher workforce in school districts or educational organizations, as well as their underlying theories…

  16. Space Station Human Factors Research Review. Volume 4: Inhouse Advanced Development and Research

    NASA Technical Reports Server (NTRS)

    Tanner, Trieve (Editor); Clearwater, Yvonne A. (Editor); Cohen, Marc M. (Editor)

    1988-01-01

    A variety of human factors studies related to space station design are presented. Subjects include proximity operations and window design, spatial perceptual issues regarding displays, image management, workload research, spatial cognition, virtual interface, fault diagnosis in orbital refueling, and error tolerance and procedure aids.

  17. Toward A Multilevel Theory of Career Development: Advancing Human Resource Development Theory Building

    ERIC Educational Resources Information Center

    Upton, Matthew G.; Egan, Toby Marshall

    2007-01-01

    The established limitations of career development (CD) theory and human resource development (HRD) theory building are addressed by expanding the framing of these issues to multilevel contexts. Multilevel theory building is an approach most effectively aligned with HRD literature and CD and HRD practice realities. An innovative approach multilevel…

  18. Advancing health equity in the global marketplace: how human rights can help.

    PubMed

    Schrecker, Ted; Chapman, Audrey R; Labonté, Ronald; De Vogli, Roberto

    2010-10-01

    The WHO Commission on Social Determinants of Health (CSDH) ascribed health disparities within and between countries to "a toxic combination of poor social policies and programmes, unfair economic arrangements, and bad politics." This article analyzes the relevance of the international human rights framework (IHRF) to the Commission's goal of reducing health disparities with reference to both social scientific and legal scholarship. We begin with an overview of the IHRF, demonstrating its potential as a challenge to the normative foundations of the emerging global economic order. We then survey the research literature on mechanisms to ensure accountability for realization of health-related rights, emphasizing the potential effectiveness of making human rights enforceable through the courts, and the special need for mechanisms to hold countries and international institutions accountable for obligations related to the human right to health. We conclude by identifying three key directions for further research, policy and advocacy: comparative human rights litigation, specifically the willingness of courts to address broad policy and budgetary issues; the conditions under which governments legislate or constitutionalize economic and social rights; and how rich, powerful countries affect economic and social rights outside their borders.

  19. Advanced Placement® Human Geography: Looking Back and Looking Ahead

    ERIC Educational Resources Information Center

    Lanegran, David A.; Zeigler, Donald J.

    2016-01-01

    Over the past fifteen years, AP Human Geography has grown in numbers and spread to almost every state. This article synopsizes the early history of the subject, summarizes the course and the exam, highlights positive impacts on the discipline of geography, and focuses on the following three issues: teachers who come to the course having majored in…

  20. Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis

    PubMed Central

    Ip, Blanche C.; Habib, Chloe; Ritou, Eleni; Grammatopoulos, Tom N.; Steenkamp, Devin; Dooms, Hans; Apovian, Caroline M.; Lauffenburger, Douglas A.

    2017-01-01

    Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96) analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes. PMID:28178278

  1. The i5K Initiative: Advancing arthropod genomics for knowledge, human health, agriculture, and the environment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insects and their arthropod relatives including mites, spiders, and crustaceans, play major roles in the world’s terrestrial, aquatic, and marine ecosystems. Arthropods compete with humans for food and transmit devastating diseases. They also comprise the most diverse and successful branch of metazo...

  2. Can Human Pluripotent Stem Cell-Derived Cardiomyocytes Advance Understanding of Muscular Dystrophies?

    PubMed

    Kalra, Spandan; Montanaro, Federica; Denning, Chris

    2016-08-30

    Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement.

  3. Distribution of somatostatin receptors in normal and neoplastic human tissues: recent advances and potential relevance.

    PubMed

    Reubi, J C; Schaer, J C; Markwalder, R; Waser, B; Horisberger, U; Laissue, J

    1997-01-01

    This short review describes the localization of somatostatin receptors with in vitro receptor autoradiography techniques in several non-classical, normal human somatostatin target tissues as well as in selected human tumors. In addition to brain, gut and neuroendocrine localizations, somatostatin receptors are expressed in most lymphatic tissues, including gut-associated lymphatic tissue, spleen and thymus; in the cortical and medullary area of the kidney; in the stroma of the prostate and in the epithelial cells of the thyroid. Among human tumors, the extremely high density of somatostatin receptors in medulloblastomas should be stressed as well as the favorable prognostic role of the presence of somatostatin receptors in neuroblastomas. Moreover, several types of mesenchymal tumors have somatostatin receptors as well. The receptor subtypes expressed by distinct tumors may vary: Whereas medulloblastomas and neuroblastomas predominantly express sst2, prostate cancers express sst1 rather than sst2. A further emerging somatostatin target is represented by the peritumoral veins, also known to express sst2 receptors. The multiple somatostatin targets in normal and pathological human tissues represents the basis for potential diagnostic and clinical applications of somatostatin analogs.

  4. Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis.

    PubMed

    Nicholas, Dequina; Proctor, Elizabeth A; Raval, Forum M; Ip, Blanche C; Habib, Chloe; Ritou, Eleni; Grammatopoulos, Tom N; Steenkamp, Devin; Dooms, Hans; Apovian, Caroline M; Lauffenburger, Douglas A; Nikolajczyk, Barbara S

    2017-01-01

    Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96) analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes.

  5. Agriculture, Food Production, and Rural Land Use in Advanced Placement® Human Geography

    ERIC Educational Resources Information Center

    Moseley, William G.; Watson, Nancy H.

    2016-01-01

    ''Agriculture, Food, and Rural Land Use" constitutes a major part of the AP Human Geography course outline. This article explores challenging topics to teach, emerging research trends in agricultural geography, and sample teaching approaches for concretizing abstract topics. It addresses content identified as "essential knowledge"…

  6. Can Human Pluripotent Stem Cell-Derived Cardiomyocytes Advance Understanding of Muscular Dystrophies?

    PubMed Central

    Kalra, Spandan; Montanaro, Federica; Denning, Chris

    2016-01-01

    Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement. PMID:27854224

  7. The successful management of programs for human factors certification of advanced aviation technologies

    NASA Technical Reports Server (NTRS)

    Baldwin, Rod

    1994-01-01

    In recent years there have been immense pressures to enact changes on the air traffic control organizations of most states. In addition, many of these states are or have been subject to great political, sociological and economic changes. Consequently, any new schemes must be considered within the context of national or even international changes. Europe has its own special problems, and many of these are particularly pertinent when considering human factors certification programs. Although these problems must also be considered in the wider context of change, it is usually very difficult to identify which forces are pressing in support of human factors aspects and which forces are resisting change. There are a large number of aspects which must be taken into account if human factors certification programs are to be successfully implemented. Certification programs would be new ventures, and like many new ventures it will be essential to ensure that managers have the skills, commitment and experience to manage the programs effectively. However, they must always be aware of the content and the degree of certainty to which the human factors principles can be applied - as Debons and Horne have carefully described. It will be essential to avoid the well known pitfalls which occur in the implementation of performance appraisal schemes. While most appraisal schemes are usually extremely well thought out, they often do not produce good results because they are not implemented properly and staff therefore do not have faith in them. If the manager does not have the commitment and interest in his/her staff as human beings, then the schemes will not be effective. Thus, one aspect of considering human factors certification schemes is within the context of a managed organization. This paper outlines some of the management factors which need to be considered for the air traffic control services. Many of the points received attention during the plenary sessions while others were

  8. Advanced Technologies for Robotic Exploration Leading to Human Exploration: Results from the SpaceOps 2015 Workshop

    NASA Technical Reports Server (NTRS)

    Lupisella, Mark L.; Mueller, Thomas

    2016-01-01

    This paper will provide a summary and analysis of the SpaceOps 2015 Workshop all-day session on "Advanced Technologies for Robotic Exploration, Leading to Human Exploration", held at Fucino Space Center, Italy on June 12th, 2015. The session was primarily intended to explore how robotic missions and robotics technologies more generally can help lead to human exploration missions. The session included a wide range of presentations that were roughly grouped into (1) broader background, conceptual, and high-level operations concepts presentations such as the International Space Exploration Coordination Group Roadmap, followed by (2) more detailed narrower presentations such as rover autonomy and communications. The broader presentations helped to provide context and specific technical hooks, and helped lay a foundation for the narrower presentations on more specific challenges and technologies, as well as for the discussion that followed. The discussion that followed the presentations touched on key questions, themes, actions and potential international collaboration opportunities. Some of the themes that were touched on were (1) multi-agent systems, (2) decentralized command and control, (3) autonomy, (4) low-latency teleoperations, (5) science operations, (6) communications, (7) technology pull vs. technology push, and (8) the roles and challenges of operations in early human architecture and mission concept formulation. A number of potential action items resulted from the workshop session, including: (1) using CCSDS as a further collaboration mechanism for human mission operations, (2) making further contact with subject matter experts, (3) initiating informal collaborative efforts to allow for rapid and efficient implementation, and (4) exploring how SpaceOps can support collaboration and information exchange with human exploration efforts. This paper will summarize the session and provide an overview of the above subjects as they emerged from the SpaceOps 2015

  9. Differentiation of human basophils: an overview of recent advances and pending questions.

    PubMed

    Arock, Michel; Schneider, Elke; Boissan, Mathieu; Tricottet, Viviane; Dy, Michel

    2002-04-01

    Basophils are rare, circulating leukocytes derived from hematopoietic CD34+ progenitors. The identification of cytokines promoting their development in vitro has led to substantial advances in understanding their differentiation process. An important role could be assigned to interleukin-3 (IL-3), which supports the maturation of hematopoietic progenitors into basophils in vitro and in vivo. In contrast to other myeloid lineages, a specific basophil growth factor has not yet been discovered. Furthermore, it is still unclear whether basophils possess a lineage-restricted progenitor or whether they share a common ancestor with mast cells (MC), eosinophils, or even megakaryocytes. Partial answers to these questions could be provided using in vitro culture systems or taking advantage of hematological disorders, such as chronic and acute myeloid leukemia (CML and AML), some myelodysplastic syndromes, and the very rare acute basophilic leukemia in which basophilic differentiation occurs.

  10. Meta-analysis of the effects of lifestyle modifications on coronary and carotid atherosclerotic burden.

    PubMed

    Jhamnani, Sunny; Patel, Dhavalkumar; Heimlich, Layla; King, Fred; Walitt, Brian; Lindsay, Joseph

    2015-01-15

    Lifestyle modifications are the crux of atherosclerotic disease management. The goal of this study was to determine the effectiveness of diet and exercise in decreasing coronary and carotid atherosclerotic burden. Randomized controlled trials examining the effects of intensive lifestyle measures on atherosclerotic progression in coronary and carotid arteries as measured by baseline and follow-up quantitative coronary angiogram and ultrasonographic carotid intimal-medial thickness (CIMT), respectively, were included. Studies were excluded if the intervention additionally included a medication. MEDLINE, EMBASE, CINAHL, Cochrane Controlled Trials Registers, reports, and abstracts from major cardiology meetings were searched by 2 researchers independently and verified by the primary investigator. Standardized mean difference (SMD) with 95% confidence intervals (CIs) was calculated using random-effects model. Publication bias and heterogeneity were assessed. Fourteen trials were included. Seven used quantitative coronary angiogram, and 7 used CIMT; 1,343 lesions in 340 patients in the coronary group and 919 patients in the carotid group were analyzed. Overall, lifestyle modifications were associated with a decrease in coronary atherosclerotic burden in percent stenosis by -0.34 (95% CI -0.48 to -0.21) SMD, with no significant publication bias and heterogeneity (p = 0.21, I(2) = 28.25). Similarly, in the carotids, there was a decrease in the CIMT, in millimeter, by -0.21 (95% CI -0.36 to -0.05) SMD and by -0.13 (95% CI -0.25 to -0.02) SMD, before and after accounting for publication bias and heterogeneity (p = 0.13, I(2) = 39.91; p = 0.54, I(2) = 0), respectively. In conclusion, these results suggest that intensive lifestyle modifications are associated with a decrease in coronary and carotid atherosclerotic burden.

  11. Hybridization-based detection of Helicobacter pylori at human body temperature using advanced locked nucleic acid (LNA) probes.

    PubMed

    Fontenete, Sílvia; Guimarães, Nuno; Leite, Marina; Figueiredo, Céu; Wengel, Jesper; Filipe Azevedo, Nuno

    2013-01-01

    The understanding of the human microbiome and its influence upon human life has long been a subject of study. Hence, methods that allow the direct detection and visualization of microorganisms and microbial consortia (e.g. biofilms) within the human body would be invaluable. In here, we assessed the possibility of developing a variant of fluorescence in situ hybridization (FISH), named fluorescence in vivo hybridization (FIVH), for the detection of Helicobacter pylori. Using oligonucleotide variations comprising locked nucleic acids (LNA) and 2'-O-methyl RNAs (2'OMe) with two types of backbone linkages (phosphate or phosphorothioate), we were able to successfully identify two probes that hybridize at 37 °C with high specificity and sensitivity for H. pylori, both in pure cultures and in gastric biopsies. Furthermore, the use of this type of probes implied that toxic compounds typically used in FISH were either found to be unnecessary or could be replaced by a non-toxic substitute. We show here for the first time that the use of advanced LNA probes in FIVH conditions provides an accurate, simple and fast method for H. pylori detection and location, which could be used in the future for potential in vivo applications either for this microorganism or for others.

  12. Plant-based vaccines for animals and humans: recent advances in technology and clinical trials

    PubMed Central

    Takeyama, Natsumi; Kiyono, Hiroshi; Yuki, Yoshikazu

    2015-01-01

    It has been about 30 years since the first plant engineering technology was established. Although the concept of plant-based pharmaceuticals or vaccines motivates us to develop practicable commercial products using plant engineering, there are some difficulties in reaching the final goal: to manufacture an approved product. At present, the only plant-made vaccine approved by the United States Department of Agriculture is a Newcastle disease vaccine for poultry that is produced in suspension-cultured tobacco cells. The progress toward commercialization of plant-based vaccines takes much effort and time, but several candidate vaccines for use in humans and animals are in clinical trials. This review discusses plant engineering technologies and regulations relevant to the development of plant-based vaccines and provides an overview of human and animal vaccines currently under clinical trials. PMID:26668752

  13. A new medical research model: ethically and responsibly advancing health for humans and animals.

    PubMed

    Olson, Patricia N; Ganzert, Robin R

    2015-01-01

    With the increasing use of genomics, computational analytics, emerging technologies, and personalized medicine, the possibility of a new research model is emerging. Using the clues from thousands of species living on our planet, scientists from many disciplines (medicine, veterinary medicine, wildlife) must collaborate, prioritize, and strategize on how to address causes of health and disease. Such clues should guide disease prevention, as well as the development of innovative, efficacious, and gentler therapies. Geographic and language barriers must be broken down, and scientists--even within a single academic, corporate, or government research site--must be vigilant in seeking the help of nonmedical disciplines of colleagues from whence answers might come. The public will become more interested in and demanding of such a model, desiring that all family members (humans and animals) have an opportunity for a long and healthy life. Above all, such activities will be humanely conducted with outcomes having the greatest chance for success.

  14. Certify for success: A methodology for human-centered certification of advanced aviation systems

    NASA Technical Reports Server (NTRS)

    Small, Ronald L.; Rouse, William B.

    1994-01-01

    This position paper uses the methodology in Design for Success as a basis for a human factors certification program. The Design for Success (DFS) methodology espouses a multi-step process to designing and developing systems in a human-centered fashion. These steps are as follows: (1) naturalizing - understand stakeholders and their concerns; (2) marketing - understand market-oriented alternatives to meeting stakeholder concerns; (3) engineering - detailed design and development of the system considering tradeoffs between technology, cost, schedule, certification requirements, etc.; (4) system evaluation - determining if the system meets its goal(s); and (5) sales and service - delivering and maintaining the system. Because the main topic of this paper is certification, we will focus our attention on step 4, System Evaluation, since it is the natural precursor to certification. Evaluation involves testing the system and its parts for their correct behaviors. Certification focuses not only on ensuring that the system exhibits the correct behaviors, but ONLY the correct behaviors.

  15. Advances in biological control in relation to vectors of human diseases

    PubMed Central

    Weiser, J.

    1963-01-01

    In recent years, increased knowledge of insect pathology and ecology and the development of insecticide-resistance have led to a revival of interest in biological methods of controlling insects that carry human diseases. The author of this paper reviews the information at present available with regard to the various pathogens, predators and parasites of insect vectors of human disease—cockroaches, lice, bugs, fleas, mosquitos, flies and ticks—and suggests lines of future research that might prove profitable. In this connexion he stresses that only a world-wide investigation of the diseases of medically important insects will yield data on which a balanced biological research programme can be based—a programme leading to the development of practicable control procedures and their integration with chemical and other methods of control. PMID:20604158

  16. Advancing the Capabilities of an Authentic Ex Vivo Model of Primary Human Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    After five days in culture, slices were incubated in PBS with the ethidium homodimer-1 and calcein AM reagents that emit red fluorescence in dead...cells and green in viable cells, respectively. Visualization under a fluorescent microscope revealed primarily red (dead) cells in the benign slices...of the benign and malignant human prostate. Lab Invest 94, 208 (Feb, 2014). 3. S. A. Bigler, R. E. Deering , M. K. Brawer, Comparison of microscopic

  17. Proceedings of the topical meeting on advances in human factors research on man/computer interactions

    SciTech Connect

    Not Available

    1990-01-01

    This book discusses the following topics: expert systems and knowledge engineering-I; verification and validation of software; methods for modeling UMAN/computer performance; MAN/computer interaction problems in producing procedures -1-2; progress and problems with automation-1-2; experience with electronic presentation of procedures-2; intelligent displays and monitors; modeling user/computer interface; and computer-based human decision-making aids.

  18. Increased activity of guanylate cyclase in the atherosclerotic rabbit aorta: role of non-endothelial nitric oxide synthases.

    PubMed Central

    Rupin, A.; Behr, D.; Verbeuren, T. J.

    1996-01-01

    1. Experiments were performed to examine the effects of putative non-endothelial nitric oxide on the soluble guanylate cyclase activity of severe atherosclerotic aortae from hypercholesterolaemic rabbits fed a cholesterol rich diet for 45 weeks. 2. The guanosine 3':5'-cyclic monophosphate (cyclic GMP) content of aortae from rabbits fed either a control diet or a diet containing 0.3% cholesterol for 45 weeks was quantified in saline extracts or in trichloracetic acid/either extracts by use of a competitive immunoenzymatic assay. Rabbit anti-cyclic GMP immunoglobulin G was covalently linked to the solid phase, in order to avoid false positive results due to high rabbit immunoglobulin G concentrations in the atherosclerotic saline extracts. 3. Saline extracts of atherosclerotic aortae which were harvested immediately after death (intact aortae) contained about 6 fold more cyclic GMP than control aortae when expressed in pmol cyclic GMP mg-1 protein. The cyclic GMP concentrations in trichloracetic acid/ether extracts of atherosclerotic and control aortae expressed in pmol mg-1 fresh tissue were not significantly different. 4. Neointimal-medial explants from atherosclerotic and control aortae were placed in a physiological saline solution and incubated at 37 degrees C for six hours in an incubator gassed with 5% CO2. Before the incubation, the cyclic GMP concentrations in saline extracts of atherosclerotic explants (0.74 +/- 0.27 pmol mg-1) were found to be 17 fold higher than those of control explants (0.043 +/- 0.008 pmol mg-1). The cyclic GMP content of control explants decreased significantly after 6 h of incubation, while that of atherosclerotic explants remained elevated. 5. Chronic administration of NG-nitro-L-arginine methyl ester, a non selective inhibitor of nitric oxide synthases, at 12 mg kg-1 day-1 subcutaneously for one month did not reduce the cyclic GMP concentration of intact atherosclerotic aortae, while that of intact aortae from control rabbits

  19. Effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells (MSCs) in vitro.

    PubMed

    Lu, Yi-Qun; Lu, Yan; Li, Hui-Juan; Cheng, Xing-Bo

    2012-10-01

    This study aims to explore the effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells in vitro and the underlying mechanism. Bone marrow cell proliferation was determined by WST-8 assay using Cell Counting Kit-8 under the intervention of AGEs. In addition, the content of maldondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were also measured. The proliferation activity of mesenchymal stem cells (MSCs) was significantly inhibited when AGEs were added to culture medium, and this effect was dose-dependent and time-dependent. As the concentration of AGEs-bovine serum albumin increased, the content of intracellular MDA was significantly increased, but the activity of SOD in cell homogenates was significantly suppressed, which also showed a dose-dependent manner. AGEs could significantly inhibit the proliferation of MSCs in vitro by improving the oxidative stress in MSCs and breaking the homeostasis of intracellular environment.

  20. Novel genotype-phenotype associations in human cancers enabled by advanced molecular platforms and computational analysis of whole slide images.

    PubMed

    Cooper, Lee A D; Kong, Jun; Gutman, David A; Dunn, William D; Nalisnik, Michael; Brat, Daniel J

    2015-04-01

    Technological advances in computing, imaging, and genomics have created new opportunities for exploring relationships between histology, molecular events, and clinical outcomes using quantitative methods. Slide scanning devices are now capable of rapidly producing massive digital image archives that capture histological details in high resolution. Commensurate advances in computing and image analysis algorithms enable mining of archives to extract descriptions of histology, ranging from basic human annotations to automatic and precisely quantitative morphometric characterization of hundreds of millions of cells. These imaging capabilities represent a new dimension in tissue-based studies, and when combined with genomic and clinical endpoints, can be used to explore biologic characteristics of the tumor microenvironment and to discover new morphologic biomarkers of genetic alterations and patient outcomes. In this paper, we review developments in quantitative imaging technology and illustrate how image features can be integrated with clinical and genomic data to investigate fundamental problems in cancer. Using motivating examples from the study of glioblastomas (GBMs), we demonstrate how public data from The Cancer Genome Atlas (TCGA) can serve as an open platform to conduct in silico tissue-based studies that integrate existing data resources. We show how these approaches can be used to explore the relation of the tumor microenvironment to genomic alterations and gene expression patterns and to define nuclear morphometric features that are predictive of genetic alterations and clinical outcomes. Challenges, limitations, and emerging opportunities in the area of quantitative imaging and integrative analyses are also discussed.

  1. The transplantation of human fetal neuroretinal cells in advanced retinitis pigmentosa patients: results of a long-term safety study.

    PubMed

    Das, T; del Cerro, M; Jalali, S; Rao, V S; Gullapalli, V K; Little, C; Loreto, D A; Sharma, S; Sreedharan, A; del Cerro, C; Rao, G N

    1999-05-01

    The purpose of this study was to determine the long-term safety of transplanting human fetal neuroretinal cells (14 to 18 week gestational age) into a series of patients with advanced retinitis pigmentosa (RP). After obtaining informed consent, both hosts and mothers of donors were screened for transmissible diseases. Pre- and postoperative clinical exams, visual acuity, electroretinograms, and fluorescein angiograms were performed and visual field testing was attempted in each case. Surgically, an anterior approach through pars plana ciliaris was used. A retinotomy was performed in the paramacular area and a two-function cannula was introduced into the subretinal space to deliver a suspension of donor cells. The cell suspension carried approximately 4000 cells/microl; the volume injected did not exceed 150 microl. The patients were examined for periods ranging from 12 to 40 months posttransplantation. To date, no evidence of inflammation, infection, or overt rejection of the graft was noted in the host eye, neither was any change observed in the contralateral, unoperated eye. In conclusion, neuroretinal cells were injected into the subretinal space of 14 patients with advanced RP with no clinical appearance of detrimental effects at the time of surgery or up to 40 months postinjection except in 1 patient who developed retinal detachment. This sets the stage for a phase II clinical trial to determine the possible beneficial effects of this procedure in patients blinded by degenerative retinal disease.

  2. Characterization of signal properties in atherosclerotic plaque components by intravascular MRI.

    PubMed

    Rogers, W J; Prichard, J W; Hu, Y L; Olson, P R; Benckart, D H; Kramer, C M; Vido, D A; Reichek, N

    2000-07-01

    Magnetic resonance imaging (MRI) is capable of distinguishing between atherosclerotic plaque components solely on the basis of biochemical differences. However, to date, the majority of plaque characterization has been performed by using high-field strength units or special coils, which are not clinically applicable. Thus, the purpose of the present study was to evaluate MRI properties in histologically verified plaque components in excised human carotid endarterectomy specimens with the use of a 5F catheter-based imaging coil, standard acquisition software, and a clinical scanner operating at 0.5 T. Human carotid endarterectomy specimens from 17 patients were imaged at 37 degrees C by use of an opposed solenoid intravascular radiofrequency coil integrated into a 5F double-lumen catheter interfaced to a 0.5-T General Electric interventional scanner. Cross-sectional intravascular MRI (156x250 microm in-plane resolution) that used different imaging parameters permitted the calculation of absolute T1and T2, the magnetization transfer contrast ratio, the magnitude of regional signal loss associated with an inversion recovery sequence (inversion ratio), and regional signal loss in gradient echo (gradient echo-to-spin echo ratio) in plaque components. Histological staining included hematoxylin and eosin, Masson's trichrome, Kossa, oil red O, and Gomori's iron stain. X-ray micrographs were also used to identify regions of calcium. Seven plaque components were evaluated: fibrous cap, smooth muscle cells, organizing thrombus, fresh thrombus, lipid, edema, and calcium. The magnetization transfer contrast ratio was significantly less in the fibrous cap (0.62+/-13) than in all other components (P<0.05) The inversion ratio was greater in lipid (0.91+/-0.09) than all other components (P<0.05). Calcium was best distinguished by using the gradient echo-to-spin echo ratio, which was lower in calcium (0.36+/-0.2) than in all plaque components, except for the organizing thrombus (P<0

  3. A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans.

    PubMed

    Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali

    2016-04-15

    Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.

  4. Anthropology and Geosciences: Training and Collaboration Advancing Interdisciplinary Research of Human-environment Interaction

    NASA Astrophysics Data System (ADS)

    Brondizio, E.; Moran, E.

    2005-05-01

    Over the past thirteen years the Anthropological Center for Training and Research on Global Environmental Change (ACT) at Indiana University has pioneered the use of anthropological and environmental research approaches to address issues of land use change, and population-environment interaction, particularly in the Amazon. Our research and training objectives focus on how particular local populations manage resources and how those activities may be studied by integrating time-tested ethnographic methods, survey instruments, ecological field studies, and the spatial and temporal perspectives of remote sensing and Geographical Information Systems. The globalization of the environment crisis bears the risk of the research and training at universities being purely global or large scale in nature. This would fail to take into account the highly variable local causes of human activities or to discover sustainable solutions to the use, conservation, and restoration of human ecosystems. Our approach combines institutional and international collaboration, formal and hands-on laboratory and field activities developed within an interdisciplinary environment, but based on the strength of disciplinary programs. Over the past years, we have particularly emphasized collaboration between American and Brazilian scholars and students and intense work with local farmers and communities both during data collection and field research, as well as in returning data and results using different formats. In this paper, we address our experience, the challenges and advantages of theoretical and methodological development for students approaching interdisciplinary problems, innovations in linking levels of analysis, and new opportunities for international and collaborative training and research on human-environment interaction.

  5. An advanced computational bioheat transfer model for a human body with an embedded systemic circulation.

    PubMed

    Coccarelli, Alberto; Boileau, Etienne; Parthimos, Dimitris; Nithiarasu, Perumal

    2016-10-01

    In the present work, an elaborate one-dimensional thermofluid model for a human body is presented. By contrast to the existing pure conduction-/perfusion-based models, the proposed methodology couples the arterial fluid dynamics of a human body with a multi-segmental bioheat model of surrounding solid tissues. In the present configuration, arterial flow is included through a network of elastic vessels. More than a dozen solid segments are employed to represent the heat conduction in the surrounding tissues, and each segment is constituted by a multilayered circular cylinder. Such multi-layers allow flexible delineation of the geometry and incorporation of properties of different tissue types. The coupling of solid tissue and fluid models requires subdivision of the arterial circulation into large and small arteries. The heat exchange between tissues and arterial wall occurs by convection in large vessels and by perfusion in small arteries. The core region, including the heart, provides the inlet conditions for the fluid equations. In the proposed model, shivering, sweating, and perfusion changes constitute the basis of the thermoregulatory system. The equations governing flow and heat transfer in the circulatory system are solved using a locally conservative Galerkin approach, and the heat conduction in the surrounding tissues is solved using a standard implicit backward Euler method. To investigate the effectiveness of the proposed model, temperature field evolutions are monitored at different points of the arterial tree and in the surrounding tissue layers. To study the differences due to flow-induced convection effects on thermal balance, the results of the current model are compared against those of the widely used modelling methodologies. The results show that the convection significantly influences the temperature distribution of the solid tissues in the vicinity of the arteries. Thus, the inner convection has a more predominant role in the human body heat

  6. Advances in Human-Computer Interaction: Graphics and Animation Components for Interface Design

    NASA Astrophysics Data System (ADS)

    Cipolla Ficarra, Francisco V.; Nicol, Emma; Cipolla-Ficarra, Miguel; Richardson, Lucy

    We present an analysis of communicability methodology in graphics and animation components for interface design, called CAN (Communicability, Acceptability and Novelty). This methodology has been under development between 2005 and 2010, obtaining excellent results in cultural heritage, education and microcomputing contexts. In studies where there is a bi-directional interrelation between ergonomics, usability, user-centered design, software quality and the human-computer interaction. We also present the heuristic results about iconography and layout design in blogs and websites of the following countries: Spain, Italy, Portugal and France.

  7. Human-centered design of a cyber-physical system for advanced response to Ebola (CARE).

    PubMed

    Dimitrov, Velin; Jagtap, Vinayak; Skorinko, Jeanine; Chernova, Sonia; Gennert, Michael; Padir, Taşkin

    2015-01-01

    We describe the process towards the design of a safe, reliable, and intuitive emergency treatment unit to facilitate a higher degree of safety and situational awareness for medical staff, leading to an increased level of patient care during an epidemic outbreak in an unprepared, underdeveloped, or disaster stricken area. We start with a human-centered design process to understand the design challenge of working with Ebola treatment units in Western Africa in the latest Ebola outbreak, and show preliminary work towards cyber-physical technologies applicable to potentially helping during the next outbreak.

  8. Recent advances in clinical application of optical coherence tomography of human skin

    PubMed Central

    Gambichler, Thilo; Pljakic, Azem; Schmitz, Lutz

    2015-01-01

    Optical coherence tomography (OCT) is an emerging noninvasive imaging method that uses infrared light and interferometric techniques. The method has become increasingly popular in skin research as well as daily dermatology practice. In the present brief review, we focused on recent (2009–2014) OCT studies on the human skin, which included a reasonable sample size and statistics. Twenty-five papers were selected and briefly described OCT of epidermal thickness, skin appendages, wound healing, extracellular matrix and skin fibrosis, vascular malformations, and skin tumors such as basal cell carcinoma, actinic keratoses, and malignant melanoma. PMID:26185462

  9. [Human origin and evolution. A review of advances in paleoanthropology, comparative genetics, and evolutionary psychology].

    PubMed

    Markov, A V

    2009-01-01

    In his main work, "On the origin of species", Darwin has refrained from discusion of the origin of man; be only mentioned that his theory would "throw light" on this problem. This famous Darwin's phrase turned out to be one of the most succesful scientific predictions. In the present paper some of the most important recent adavnces in paleoanthroplogy, comparative genetics and evolutionary psychology are reviewed. These three disciplines currently contribute most to our knowledge of anthropogenesis. The review demonstrates that Darwin's ideas not only "threw light" on human origin and evolution; they provided a comprehensive framework for a great variety of studies concerning different aspects of anthropogenesis.

  10. Advances In very high resolution satellite imagery analysis for Monitoring human settlements

    SciTech Connect

    Vatsavai, Raju; Cheriyadat, Anil M; Bhaduri, Budhendra L

    2014-01-01

    The high rate of urbanization, political conflicts and ensuing internal displacement of population, and increased poverty in the 20th century has resulted in rapid increase of informal settlements. These unplanned, unauthorized, and/or unstructured homes, known as informal settlements, shantytowns, barrios, or slums, pose several challenges to the nations, as these settlements are often located in most hazardous regions and lack basic services. Though several World Bank and United Nations sponsored studies stress the importance of poverty maps in designing better policies and interventions, mapping slums of the world is a daunting and challenging task. In this paper, we summarize our ongoing research on settlement mapping through the utilization of Very high resolution (VHR) remote sensing imagery. Most existing approaches used to classify VHR images are single instance (or pixel-based) learning algorithms, which are inadequate for analyzing VHR imagery, as single pixels do not contain sufficient contextual information (see Figure 1). However, much needed spatial contextual information can be captured via feature extraction and/or through newer machine learning algorithms in order to extract complex spatial patterns that distinguish informal settlements from formal ones. In recent years, we made significant progress in advancing the state of art in both directions. This paper summarizes these results.

  11. Advanced Spacecraft Designs in Support of Human Missions to Earth's Neighborhood

    NASA Technical Reports Server (NTRS)

    Fletcher, David

    2002-01-01

    NASA's strategic planning for technology investment draws on engineering studies of potential future missions. A number of hypothetical mission architectures have been studied. A recent study completed by The NASA/JSC Advanced Design Team addresses one such possible architecture strategy for missions to the moon. This conceptual study presents an overview of each of the spacecraft elements that would enable such missions. These elements include an orbiting lunar outpost at lunar L1 called the Gateway, a lunar transfer vehicle (LTV) which ferries a crew of four from the ISS to the Gateway, a lunar lander which ferries the crew from the Gateway to the lunar surface, and a one-way lunar habitat lander capable of supporting the crew for 30 days. Other supporting elements of this architecture discussed below include the LTV kickstage, a solar-electric propulsion (SEP) stage, and a logistics lander capable of re-supplying the 30-day habitat lander and bringing other payloads totaling 10.3 mt in support of surface mission activities. Launch vehicle infrastructure to low-earth orbit includes the Space Shuttle, which brings up the LTV and crew, and the Delta-IV Heavy expendable launch vehicle which launches the landers, kickstage, and SEP.

  12. Recent advances in the biology of human circulating tumour cells and metastasis

    PubMed Central

    Gkountela, Sofia; Szczerba, Barbara; Donato, Cinzia; Aceto, Nicola

    2016-01-01

    The development of a metastatic disease is recognised as the cause of death of over 90% of patients diagnosed with cancer. Understanding the biological features of metastasis has been hampered for a long time by the difficulties to study widespread cancerous lesions in patients, and by the absence of reliable methods to isolate viable metastatic cells during disease progression. These difficulties negatively impact on our ability to develop new agents that are tailored to block the spread of cancer. Yet, recent advances in specialised devices for the isolation of circulating tumour cells (CTCs), hand-in-hand with technologies that enable single cell resolution interrogation of their genome and transcriptome, are now paving the way to understanding those molecular mechanisms that drive the formation of metastasis. In this review, we aim to summarise some of the latest discoveries in CTC biology in the context of several types of cancer, and to highlight those findings that have a potential to improve the clinical management of patients with metastatic cancer. PMID:27843628

  13. Final LDRD report human interaction with complex systems: advances in hybrid reachability and control.