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Sample records for stimulated vascular response

  1. Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

    Science.gov (United States)

    Jacob, G.; Costa, F.; Shannon, J.; Robertson, D.; Biaggioni, I.

    2000-01-01

    Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

  2. The influence of nifedipine and pertussis toxin (PTX) on vascular responsiveness to alpha1- and alpha2-adrenergic stimulation of isolated femoral arteries

    Czech Academy of Sciences Publication Activity Database

    Líšková, Silvia; Kuneš, Jaroslav; Paulis, Ĺudovít; Zicha, Josef

    2006-01-01

    Roč. 48, č. 4 (2006), s. 769-769 ISSN 0194-911X. [Annual Meeting of the European Council for Cardiovascular Research (ECCR) /11./. 29.09.2006-01.10.2006, La Colle sur Loup] R&D Projects: GA MZd NR7786 Institutional research plan: CEZ:AV0Z50110509 Keywords : nifedipine * pertussis toxin * vascular responsiveness * alpha1- and alpha2-adrenergic stimulation * femorel arteria Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  3. Effects of vitamin C supplement on vascular responses induced by ...

    African Journals Online (AJOL)

    Effects of vitamin C supplement on vascular responses induced by warmth or cold stimulation in normal Nigerians. SI Jaja, SI Aisuodionwe, S Gbenebitse, MO Kehinde. Abstract. No abstract. Nigerian Quarterly Journal of Hospital Medicine Vol. 13(1-2): 61-64. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD ...

  4. Effects of different frequencies of transcutaneous electrical nerve stimulation on venous vascular reactivity

    Energy Technology Data Exchange (ETDEWEB)

    Franco, O.S.; Paulitsch, F.S.; Pereira, A.P.C.; Teixeira, A.O. [Universidade Federal do Rio Grande, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Rio Grande, RS, Brasil, Programa de Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, RS (Brazil); Martins, C.N. [Universidade Federal do Rio Grande, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Fisiologia Animal Comparada, Rio Grande, RS, Brasil, Programa de Pós-Graduação em Fisiologia Animal Comparada, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS (Brazil); Silva, A.M.V. [Universidade Federal de Santa Maria, Departamento de Fisioterapia e Reabilitação, Santa Maria, RS, Brasil, Departamento de Fisioterapia e Reabilitação, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Plentz, R.D.M. [Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Ciências da Reabilitação, Programa de Pós-Graduação em Ciências da Saúde, Porto Alegre, RS, Brasil, Programa de Pós-Graduação em Ciências da Saúde, Programa de Pós-Graduação em Ciências da Reabilitação, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Irigoyen, M.C. [Faculdade de Medicina, Universidade de São Paulo, Instituto do Coração, Unidade de Hipertensão, São Paulo, SP, Brasil, Unidade de Hipertensão, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Signori, L.U. [Universidade Federal do Rio Grande, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Rio Grande, RS, Brasil, Programa de Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, RS (Brazil); Universidade Federal do Rio Grande, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Fisiologia Animal Comparada, Rio Grande, RS, Brasil, Programa de Pós-Graduação em Fisiologia Animal Comparada, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS (Brazil); Universidade Federal de Santa Maria, Departamento de Fisioterapia e Reabilitação, Santa Maria, RS, Brasil, Departamento de Fisioterapia e Reabilitação, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)

    2014-04-04

    Transcutaneous electrical nerve stimulation (TENS) is a type of therapy used primarily for analgesia, but also presents changes in the cardiovascular system responses; its effects are dependent upon application parameters. Alterations to the cardiovascular system suggest that TENS may modify venous vascular response. The objective of this study was to evaluate the effects of TENS at different frequencies (10 and 100 Hz) on venous vascular reactivity in healthy subjects. Twenty-nine healthy male volunteers were randomized into three groups: placebo (n=10), low-frequency TENS (10 Hz, n=9) and high-frequency TENS (100 Hz, n=10). TENS was applied for 30 min in the nervous plexus trajectory from the superior member (from cervical to dorsal region of the fist) at low (10 Hz/200 μs) and high frequency (100 Hz/200 μs) with its intensity adjusted below the motor threshold and intensified every 5 min, intending to avoid accommodation. Venous vascular reactivity in response to phenylephrine, acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) was assessed by the dorsal hand vein technique. The phenylephrine effective dose to achieve 70% vasoconstriction was reduced 53% (P<0.01) using low-frequency TENS (10 Hz), while in high-frequency stimulation (100 Hz), a 47% increased dose was needed (P<0.01). The endothelium-dependent (acetylcholine) and independent (sodium nitroprusside) responses were not modified by TENS, which modifies venous responsiveness, and increases the low-frequency sensitivity of α1-adrenergic receptors and shows high-frequency opposite effects. These changes represent an important vascular effect caused by TENS with implications for hemodynamics, inflammation and analgesia.

  5. Effects of different frequencies of transcutaneous electrical nerve stimulation on venous vascular reactivity

    International Nuclear Information System (INIS)

    Franco, O.S.; Paulitsch, F.S.; Pereira, A.P.C.; Teixeira, A.O.; Martins, C.N.; Silva, A.M.V.; Plentz, R.D.M.; Irigoyen, M.C.; Signori, L.U.

    2014-01-01

    Transcutaneous electrical nerve stimulation (TENS) is a type of therapy used primarily for analgesia, but also presents changes in the cardiovascular system responses; its effects are dependent upon application parameters. Alterations to the cardiovascular system suggest that TENS may modify venous vascular response. The objective of this study was to evaluate the effects of TENS at different frequencies (10 and 100 Hz) on venous vascular reactivity in healthy subjects. Twenty-nine healthy male volunteers were randomized into three groups: placebo (n=10), low-frequency TENS (10 Hz, n=9) and high-frequency TENS (100 Hz, n=10). TENS was applied for 30 min in the nervous plexus trajectory from the superior member (from cervical to dorsal region of the fist) at low (10 Hz/200 μs) and high frequency (100 Hz/200 μs) with its intensity adjusted below the motor threshold and intensified every 5 min, intending to avoid accommodation. Venous vascular reactivity in response to phenylephrine, acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) was assessed by the dorsal hand vein technique. The phenylephrine effective dose to achieve 70% vasoconstriction was reduced 53% (P<0.01) using low-frequency TENS (10 Hz), while in high-frequency stimulation (100 Hz), a 47% increased dose was needed (P<0.01). The endothelium-dependent (acetylcholine) and independent (sodium nitroprusside) responses were not modified by TENS, which modifies venous responsiveness, and increases the low-frequency sensitivity of α1-adrenergic receptors and shows high-frequency opposite effects. These changes represent an important vascular effect caused by TENS with implications for hemodynamics, inflammation and analgesia

  6. Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic

    Science.gov (United States)

    Chen, Shih-Chieh; Chang, Chao-Yuah; Lin, Ming-Lu

    2018-01-01

    The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

  7. Vascular Growth in Ischemic Limbs: A Review of Mechanisms and Possible Therapeutic Stimulation

    NARCIS (Netherlands)

    Weel, V. van; Tongeren, R.B. van; Hinsbergh, V.W.M. van; Bockel, J.H. van; Quax, P.H.A.

    2008-01-01

    Stimulation of vascular growth to treat limb ischemia is promising, and early results obtained from uncontrolled clinical trials using angiogenic agents, e.g., vascular endothelial growth factor, led to high expectations. However, negative results from recent placebo-controlled trials warrant

  8. Anal sphincter responses after perianal electrical stimulation

    DEFF Research Database (Denmark)

    Pedersen, Ejnar; Klemar, B; Schrøder, H D

    1982-01-01

    not fatigued by repeated stimulation, were most dependent on placement of stimulating and recording electrodes, and always had a higher threshold than the third response. The third response was constantly present in normal subjects. It had the longest EMG response and the latency decreased with increasing...

  9. Anal sphincter responses after perianal electrical stimulation

    DEFF Research Database (Denmark)

    Pedersen, Ejnar; Klemar, B; Schrøder, H D

    1982-01-01

    not fatigued by repeated stimulation, were most dependent on placement of stimulating and recording electrodes, and always had a higher threshold than the third response. The third response was constantly present in normal subjects. It had the longest EMG response and the latency decreased with increasing......By perianal electrical stimulation and EMG recording from the external anal sphincter three responses were found with latencies of 2-8, 13-18 and 30-60 ms, respectively. The two first responses were recorded in most cases. They were characterised by constant latency and uniform pattern, were...

  10. Inactivation of mechano-sensitive dilatation upon repetitive mechanical stimulation of the musculo-vascular network in the rabbit.

    Science.gov (United States)

    Turturici, M; Roatta, S

    2013-06-01

    Mechano-sensitivity of the vascular network is known to be implicated in the rapid dilatation at the onset of exercise, however, it is not known how this mechanism responds to repetitive mechanical stimulation. This study tests the hypothesis that the mechanically-induced hyperaemia undergoes some attenuation upon repetitive stimulation. Muscle blood flow was recorded from 9 masseteric arteries (5 right, 4 left) in 6 anesthetized rabbits. Two mechanical stimuli, masseter muscle compression (MC) and occlusion of the masseteric artery (AO), were provided in different combinations: A) repeated stimulation (0.5 Hz, for 40 s); B) single stimuli delivered at decreasing inter-stimulus interval (ISI) from 4 min to 2 s, C) single AO delivered before and immediately after a series of 20 MCs at 0.5 Hz, and vice-versa. Repetitive AO stimulation at 0.5 Hz produced a transient hyperaemia (378 ±189%) peaking at 4.5 ±1.4 s and then decaying before the end of stimulation. The hyperaemic response to individual AOs progressively decreased by 74 ±39% with decreasing ISI from 4 min to 2 s (psensitivity of the vascular network is attenuated by previous mechanical stimulation. It is suggested that the mechano-sensitive dilatory mechanisms undergoes some inactivation whose recovery time is in the order of a few minutes.

  11. Vagus nerve stimulation blocks vascular permeability following burn injury in both local and distal sites

    Science.gov (United States)

    Ortiz-Pomales, Yan T; Krzyzaniak, Michael; Coimbra, Raul; Baird, Andrew; Eliceiri, Brian P.

    2012-01-01

    Recent studies have shown that vagus nerve stimulation (VNS) can block the burn injury-induced systemic inflammatory response (SIRS). In this study we examined the potential for VNS to modulate vascular permeability (VP) in local sites (i.e. skin) and in secondary sites (i.e. lung) following burn injury. In a 30% total body surface area burn injury model, VP was measured using intravascular fluorescent dextran for quantification of the VP response in skin and lung. A peak in VP of the skin was observed 24 hours post-burn injury, that was blocked by VNS. Moreover, in the lung, VNS led to a reduction in burn-induced VP compared to sham-treated animals subjected to burn injury alone. The protective effects of VNS in this model were independent of the spleen, suggesting that the spleen was not a direct mediator of VNS. These studies identify a role for VNS in the regulation of VP in burns, with the translational potential of attenuating lung complications following burn injury. PMID:22694873

  12. Assessment of Vascular Stent Heating with Repetitive Transcranial Magnetic Stimulation.

    Science.gov (United States)

    Varnerin, Nicole; Mirando, David; Potter-Baker, Kelsey A; Cardenas, Jesus; Cunningham, David A; Sankarasubramanian, Vishwanath; Beall, Erik; Plow, Ela B

    2017-05-01

    A high proportion of patients with stroke do not qualify for repetitive transcranial magnetic stimulation (rTMS) clinical studies due to the presence of metallic stents. The ultimate concern is that any metal could become heated due to eddy currents. However, to date, no clinical safety data are available regarding the risk of metallic stents heating with rTMS. We tested the safety of common rTMS protocols (1 Hz and 10 Hz) with stents used commonly in stroke, nitinol and elgiloy. In our method, stents were tested in gelled saline at 2 different locations: at the center and at the lobe of the coil. In addition, at each location, stent heating was evaluated in 3 different orientations: parallel to the long axis of coil, parallel to the short axis of the coil, and perpendicular to the plane of the coil. We found that stents did not heat to more than 1°C with either 1 Hz rTMS or 10 Hz rTMS in any configuration or orientation. Heating in general was greater at the lobe when the stent was oriented perpendicularly. Our study represents a new method for ex vivo quantification of stent heating. We have found that heating of stents was well below the Food and Drug Administration standards of 2°C. Thus, our study paves the way for in vivo testing of rTMS (≤10 Hz) in the presence of implanted magnetic resonance imaging-compatible stents in animal studies. When planning human safety studies though, geometry, orientation, and location relative to the coil would be important to consider as well. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  13. Chronic non-vascular cytomegalovirus infection: effects on the neointimal response to experimental vascular injury.

    Science.gov (United States)

    Zhou, Y F; Shou, M; Harrell, R F; Yu, Z X; Unger, E F; Epstein, S E

    2000-03-01

    Epidemiologic and mechanistic evidence implicates a role for cytomegalovirus (CMV) in atherogenesis. Recently, we demonstrated that CMV has the capacity to causally contribute to atherogenesis; acute infection of rats with rat CMV (RCMV) 1 day after carotid artery injury increased neointimal accumulation. Importantly, in the injured vessel infectious virus could not be detected and viral genome was present only transiently, suggesting that additional mechanisms play a role in the virus-induced exacerbation of the vascular injury response other than the changes caused by direct infection of vessel wall cells. The present investigation was designed to determine whether chronic persistent RCMV infection, more relevant to the clinical situation, also exacerbates the response to injury and, if so, whether similar mechanisms are operative. Sixty 3-week-old male Spraque-Dawley rats received an i.p. injection of either 10(6) TCID50 RCMV (Priscott strain) or normal saline. The left carotid artery was balloon-injured 3 months after infection. Rats were killed 6 weeks later. This model produces persistent infection, as demonstrated by presence of infectious virus in the salivary glands at time of sacrifice. The neointima to media (N/M) ratio of the injured vessel was 41% greater in the RCMV-infected than in control rats (1.40 +/- 0.48 vs. 0.99 +/- 0.45; P = 0.003). The aorta never contained infectious RCMV, and exhibited RCMV DNA, detected by PCR, only transiently. The persistent infection of non-vascular tissues was associated with increased serum levels of IL-2, IL-4 and IFN-gamma. CMV infection of young rats causes persistent infection of non-vascular tissues and increased cytokine levels. The neointimal response to subsequent vascular injury is increased, despite absence of virus from the vessel wall. These findings, as in acute infection following vascular injury, suggest that inflammatory and immune responses to chronic persistent CMV infection contribute to an

  14. Vascular endothelial growth factor A-stimulated signaling from endosomes in primary endothelial cells.

    Science.gov (United States)

    Fearnley, Gareth W; Smith, Gina A; Odell, Adam F; Latham, Antony M; Wheatcroft, Stephen B; Harrison, Michael A; Tomlinson, Darren C; Ponnambalam, Sreenivasan

    2014-01-01

    The vascular endothelial growth factor A (VEGF-A) is a multifunctional cytokine that stimulates blood vessel sprouting, vascular repair, and regeneration. VEGF-A binds to VEGF receptor tyrosine kinases (VEGFRs) and stimulates intracellular signaling leading to changes in vascular physiology. An important aspect of this phenomenon is the spatiotemporal coordination of VEGFR trafficking and intracellular signaling to ensure that VEGFR residence in different organelles is linked to downstream cellular outputs. Here, we describe a series of assays to evaluate the effects of VEGF-A-stimulated intracellular signaling from intracellular compartments such as the endosome-lysosome system. These assays include the initial isolation and characterization of primary human endothelial cells, performing reverse genetics for analyzing protein function; methods used to study receptor trafficking, signaling, and proteolysis; and assays used to measure changes in cell migration, proliferation, and tubulogenesis. Each of these assays has been exemplified with studies performed in our laboratories. In conclusion, we describe necessary techniques for studying the role of VEGF-A in endothelial cell function. © 2014 Elsevier Inc. All rights reserved.

  15. Effect of Chronic hypoxia on Carotid vascular responses to ...

    African Journals Online (AJOL)

    Aim: The aim of the present study was to examine whether chronic hypoxia would alter the noradrenaline (NA)-evoked vascular responses in carotid circulation in rats. Furthermore, whether the carotid autoregulatory response to NA-evoked rise in arterial blood pressure (ABP) is compromised by chronic hypoxia or not. Also ...

  16. Evoked Electrical and Cerebral Vascular Responses Following Sleep Deprivation

    Science.gov (United States)

    Schei, Jennifer L.; Rector, David M.

    2011-01-01

    Neuronal activity elicits vascular dilation, delivering additional blood and metabolites to the activated region. With increasing neural activity, vessels stretch and may become less compliant. Most functional imaging studies assume that limits to vascular expansion are not normally reached except under pathological conditions, with the possibility that metabolism could outpace supply. However, we previously demonstrated that evoked hemodynamic responses were larger during quiet sleep when compared to both waking and REM sleep, suggesting that high basal activity during wake may elicit blunted evoked hemodynamic responses due to vascular expansion limits. We hypothesized that extended brain activity through sleep deprivation will further dilate blood vessels, and exacerbate the blunted evoked hemodynamic responses observed during wake, and dampen responses in subsequent sleep. We measured evoked electrical and hemodynamic responses from rats using auditory clicks (0.5 s, 10 Hz, 2–13 s random ISIs) for one hour following 2, 4, or 6 hours of sleep deprivation. Time-of-day matched controls were recorded continuously for 7 hours. Within quiet sleep periods following deprivation, ERP amplitude did not differ; however, the evoked vascular response was smaller with longer sleep deprivation periods. These results suggest that prolonged neural activity periods through sleep deprivation may diminish vascular compliance as indicated by the blunted vascular response. Subsequent sleep may allow vessels to relax, restoring their ability to deliver blood. These results also suggest that severe sleep deprivation or chronic sleep disturbances could push the vasculature to critical limits, leading to metabolic deficit and the potential for tissue trauma. PMID:21854966

  17. Repetitive muscle compression reduces vascular mechano-sensitivity and the hyperemic response to muscle contraction.

    Science.gov (United States)

    Messere, A; Turturici, M; Millo, G; Roatta, S

    2017-06-01

    Animal studies have shown that the rapid hyperemic response to external muscle compression undergoes inactivation upon repetitive stimulation, but this phenomenon has never been observed in humans. The aim of the present study was to determine whether 1) the vascular mechano-sensitivity underlying muscle compression-induced hyperemia is inactivated in an inter-stimulus interval (ISI)-dependent fashion upon repetitive stimulation, as suggested by animal studies, and 2) whether such inactivation also attenuates contraction-induced hyperemia. Brachial artery blood flow was measured by echo Doppler sonography in 13 healthy adults in response to 1) single and repetitive cuff muscle compression (CMC) of the forearm (20 CMCs, 1 s ISI); 2) a sequence of CMC delivered at decreasing ISI from 120 to 2 s; and 3) electrically-stimulated contraction of the forearm muscles before and after repetitive CMC. The peak amplitude of hyperemia in response to CMC normalized to baseline decreased from 2.2 ± 0.6 to 1.4 ± 0.4 after repetitive CMC and, in general, was decreased at ISI < 240 s. The peak amplitude of contraction-induced hyperemia was attenuated after as compared to before repeated CMC (1.7 ± 0.4 and 2.6 ± 0.6, respectively). Mechano-sensitivity of the vascular network can be conditioned by previous mechanical stimulation, and such preconditioning may substantially decrease contraction-induced hyperemia.

  18. Impact of AT2-receptor stimulation on vascular biology, kidney function, and blood pressure

    DEFF Research Database (Denmark)

    Danyel, L.A.; Schmerler, P.; Paulis, L.

    2013-01-01

    angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect...... of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely - at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able......, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage....

  19. Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation.

    Directory of Open Access Journals (Sweden)

    Iván eRodríguez

    2014-09-01

    Full Text Available Physiological vascular function regulation is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the main risk factors of cardiovascular pathology, where the imbalance between the synthesis of vasodilator and vasoconstrictor molecules is common in the development of vascular disorders in systemic and placental circulation. In the placenta, an organ without autonomic innervations, the local control of vascular tone is critical for maintenance of fetal growth and mechanisms that underlie shear stress response induced by blood flow are essential during pregnancy. In this field, shear stress induced by moderate exercise is one of the most important mechanisms to improve vascular function through nitric oxide (NO synthesis and stimulation of mechanical response of endothelial cells triggered by ion channels, caveolae, endothelial NO synthase (eNOS and vascular endothelial growth factor (VEGF, among others. The demand for oxygen and nutrients by tissues and organs, especially in placentation and pregnancy, determines blood flow parameters and physiological adaptations of vascular beds for covering metabolic requirements. In this regard, moderate exercise versus sedentarism shows potential benefits for improving vascular function associated with the enhancement of molecular mechanisms induced by shear stress. In this review, we collect evidence about molecular bases of physiological response to shear stress in order to highlight the relevance of moderate exercise-training for vascular health in adult and fetal life.

  20. Vascular endothelial growth factor mediates ceramide 1-phosphate-stimulated macrophage proliferation.

    Science.gov (United States)

    Ouro, Alberto; Arana, Lide; Riazy, Maziar; Zhang, Peng; Gomez-Larrauri, Ana; Steinbrecher, Urs; Duronio, Vincent; Gomez-Muñoz, Antonio

    2017-12-15

    The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates cell division in a variety of cell types including macrophages. However, the mechanisms involved in this action are not completely understood. In the present work we show that C1P stimulates the release of vascular endothelial growth factor (VEGF) in RAW264.7 macrophages, and that this growth factor is essential for stimulation of cell proliferation by C1P. The stimulation of VEGF release was dependent upon activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB-1 also known as Akt-1), and mitogen-activated protein kinase-kinase (MEK)/extracellularly regulated kinase-2 (ERK-2) pathways, as inhibition of these kinases with selective pharmacological inhibitors or with specific gene silencing siRNA, abrogated VEGF release. A key observation was that sequestration of VEGF with a neutralizing antibody, or treatment with VEGF siRNA abolished C1P-stimulated macrophage growth. Also, inhibition of the pathways involved in C1P-stimulated VEGF release inhibited the stimulation of macrophage growth by C1P. Moreover, blockade of VEGF receptor-2 (VEGFR-2), which is the primary receptor for VEGF, with the pharmacological inhibitor DMH4, or with specific VEGFR-2 siRNA, substantially inhibited C1P-stimulated cell growth. It can be concluded that stimulation of VEGF release is a key factor in the promotion of macrophage proliferation by C1P. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Resveratrol induces vascular smooth muscle cell differentiation through stimulation of SirT1 and AMPK.

    Directory of Open Access Journals (Sweden)

    Anne Marie Thompson

    Full Text Available Phenotypic plasticity in vascular smooth muscle cells (VSMC is necessary for vessel maintenance, repair and adaptation to vascular changes associated with aging. De-differentiated VSMC contribute to pathologies including atherosclerosis and intimal hyperplasia. As resveratrol has been reported to have cardio- protective effects, we investigated its role in VSMC phenotypic modulation. We demonstrated the novel finding that resveratrol promoted VSMC differentiation as measured by contractile protein expression, contractile morphology and contraction in collagen gels. Resveratrol induced VSMC differentiation through stimulation of SirT1 and AMPK. We made the novel finding that low or high dose resveratrol had an initially different mechanism on induction of differentiation. We found that low dose resveratrol stimulated differentiation through SirT1-mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK-mediated inhibition of the mTORC1 pathway, allowing activation of AKT. The health effects of resveratrol in cardiovascular diseases, cancer and longevity are an area of active research. We have demonstrated a supplemental avenue where-by resveratrol may promote health by maintaining and enhancing plasticity of the vasculature.

  2. Brain stimulation for intractable epilepsy: Anterior thalamus and responsive stimulation

    Directory of Open Access Journals (Sweden)

    Vibhor Krishna

    2014-01-01

    Full Text Available Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying ′response′ to brain stimulation are desired.

  3. Alteration of rat lung vascular response to radiation with drugs

    International Nuclear Information System (INIS)

    Evans, M.L.; Graham, M.M.; Mahler, A.; Rasey, J.S.

    1987-01-01

    Vascular permeability to albumin increases in the lung at one day after radiation to the thorax, returns to normal, and increases again at three weeks after exposure. To block different proposed pathways of permeability increase, several drugs were given to irradiated rats. Each drug was selected for its ability to act at a different point in the hypothesized pathway leading to elevated vascular permeability and subsequent pulmonary fibrosis. To obtain maximum effect, each was delivered continuously in drinking water from two days before 18 Gy whole thorax radiation to measurement of response at 1 or 21 days. Dexamethasone (a glucocorticoid) was most effective at 21 days, reducing vascular permeability to below control levels. Epsilonamino caproic acid (a protease inhibitor) and diethylcarbamazine (an anti-leukotriene) were also somewhat effective, reducing permeability by 26% and 37% respectively. Dapsone (a neutrophil migration inhibitor) and indomethacin (an anti-prostaglandin) had no effect. Suppression of vascular permeability with drugs, and observation of the effects of suppression on subsequent development of fibrosis should help clarify the role of vascular permeability in the development of radiation induced fibrosis

  4. Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

    International Nuclear Information System (INIS)

    Bae, Ok-Nam; Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung; Kim, Eun-Sun; Jeong, Tae Cheon; Chun, Young-Jin; Lee, Ai-Young; Noh, Minsoo

    2015-01-01

    Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. - Highlights: • Pro-inflammatory cytokines induced VEGF production in normal human

  5. Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Ok-Nam [College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791 (Korea, Republic of); Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung [College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742 (Korea, Republic of); Kim, Eun-Sun [College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791 (Korea, Republic of); Jeong, Tae Cheon [College of Pharmacy, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Chun, Young-Jin [College of Pharmacy, Chung-Ang University, Seoul 156-756 (Korea, Republic of); Lee, Ai-Young, E-mail: leeay@duih.org [Department of Dermatology, Dongguk University Ilsan Hospital, Goyang 410-773 (Korea, Republic of); Noh, Minsoo, E-mail: minsoo@alum.mit.edu [College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2015-03-01

    Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. - Highlights: • Pro-inflammatory cytokines induced VEGF production in normal human

  6. RhoA–Rho kinase and Platelet Activating Factor Stimulation of Ovine Fetal Pulmonary Vascular Smooth Muscle Cell Proliferation

    Science.gov (United States)

    Renteria, Lissette S.; Austin, Monique; Lazaro, Mariecon; Andrews, Mari Ashley; Lustina, Jennessee; Raj, J. Usha; Ibe, Basil O.

    2013-01-01

    Objectives Platelet Activating Factor (PAF) is produced by pulmonary vascular smooth muscle Cells (PVSMC). We studied effect of Rho kinase on PAF stimulation of PVSMC proliferation in an attempt to understand a role for RhoA/Rho kinase on PAF-induced ovine fetal pulmonary vascular remodeling. Our hypothesis is that PAF acts through Rho kinase, as one of its downstream signaling, to induce arterial (SMC-PA) and venous (SMC-PV) growth in the hypoxic lung environment of the fetus in utero. Materials and methods Rho kinase and MAPK effects on PAF receptor (PAFR)-mediated cell growth and PAFR expression were studied by DNA synthesis, Western and immunocytochemistry. Effects of constructs T19N and G14V on PAF-induced cell proliferation was also studied. Results Hypoxia increased PVSMC proliferation and the Rho kinase inhibitors, Y-27632 and Fasudil (HA-1077) as well as MAPK inhibitors PD 98059 and SB 203580 attenuated PAF stimulation of cell proliferation. RhoA T19N and G14V stimulated cell proliferation, but co-incubation with PAF did not affect proliferative effects of the constructs. PAFR protein expression was significantly down-regulated in both cell types by both Y-27632 and HA-1077 with comparable profiles. Also cells treated with Y-27632 showed less PAF receptor fluorescence with significant disruption of the cell morphology. Conclusions Our results show that Rho kinase nonspecifically modulates PAFR-mediated responses via a translational modification of PAFR protein and suggest that, in vivo, activation of Rho kinase by PAF may be one other pathway to sustain PAFR-mediated PVSMC growth. PMID:24033386

  7. RhoA-Rho kinase and platelet-activating factor stimulation of ovine foetal pulmonary vascular smooth muscle cell proliferation.

    Science.gov (United States)

    Renteria, L S; Austin, M; Lazaro, M; Andrews, M A; Lustina, J; Raj, J U; Ibe, B O

    2013-10-01

    Platelet-activating factor (PAF) is produced by pulmonary vascular smooth muscle cells (PVSMC). We studied effects of Rho kinase on PAF stimulation of PVSMC proliferation in an attempt to understand the role of RhoA/Rho kinase on PAF-induced ovine foetal pulmonary vascular remodelling. Our hypothesis is that PAF acts through Rho kinase, as one of its downstream signals, to induce arterial (SMC-PA) and venous (SMC-PV) cell proliferation in the hypoxic lung environment of the foetus, in utero. Rho kinase and MAPK effects on PAF receptor (PAFR)-mediated cell population expansion, and PAFR expression, were studied by DNA synthesis, western blot analysis and immunocytochemistry. Effects of constructs T19N and G14V on PAF-induced cell proliferation were also investigated. Hypoxia increased PVSMC proliferation and Rho kinase inhibitors, Y-27632 and Fasudil (HA-1077) as well as MAPK inhibitors PD 98059 and SB 203580 attenuated PAF stimulation of cell proliferation. RhoA T19N and G14V stimulated cell proliferation, but co-incubation with PAF did not affect proliferative effects of the constructs. PAFR protein expression was significantly downregulated in both cell types by both Y-27632 and HA-1077, with comparable profiles. Also, cells treated with Y-27632 had less PAF receptor fluorescence with significant disruption of cell morphology. Our results show that Rho kinase non-specifically modulated PAFR-mediated responses by a translational modification of PAFR protein, and suggest that, in vivo, activation of Rho kinase by PAF may be a further pathway to sustain PAFR-mediated PVSMC proliferation. © 2013 John Wiley & Sons Ltd.

  8. Multimodality Imaging of the Long-term Vascular Responses Following Implantation of Metallic and Bioresorbable Devices

    NARCIS (Netherlands)

    V.D. Gkogkas (Vasileios)

    2014-01-01

    markdownabstract__Abstract__ The pattern of vascular responses following stent/scaffold implantation in conventional interventional practice has been assessed by coronary angiography, intravascular ultrasound or optical coherence tomography and manifests as in-stent vascular response (focal or

  9. Time course of the hemodynamic responses to aortic depressor nerve stimulation in conscious spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Durand, M.T.; Mota, A.L.; Barale, A.R.; Castania, J.A.; Fazan, R. Jr.; Salgado, H.C.

    2012-01-01

    The time to reach the maximum response of arterial pressure, heart rate and vascular resistance (hindquarter and mesenteric) was measured in conscious male spontaneously hypertensive (SHR) and normotensive control rats (NCR; Wistar; 18-22 weeks) subjected to electrical stimulation of the aortic depressor nerve (ADN). The parameters of stimulation were 1 mA intensity and 2 ms pulse length applied for 5 s, using frequencies of 10, 30, and 90 Hz. The time to reach the hemodynamic responses at different frequencies of ADN stimulation was similar for SHR (N = 15) and NCR (N = 14); hypotension = NCR (4194 ± 336 to 3695 ± 463 ms) vs SHR (3475 ± 354 to 4494 ± 300 ms); bradycardia = NCR (1618 ± 152 to 1358 ± 185 ms) vs SHR (1911 ± 323 to 1852 ± 431 ms), and the fall in hindquarter vascular resistance = NCR (6054 ± 486 to 6550 ± 847 ms) vs SHR (4849 ± 918 to 4926 ± 646 ms); mesenteric = NCR (5574 ± 790 to 5752 ± 539 ms) vs SHR (5638 ± 648 to 6777 ± 624 ms). In addition, ADN stimulation produced baroreflex responses characterized by a faster cardiac effect followed by a vascular effect, which together contributed to the decrease in arterial pressure. Therefore, the results indicate that there is no alteration in the conduction of the electrical impulse after the site of baroreceptor mechanical transduction in the baroreflex pathway (central and/or efferent) in conscious SHR compared to NCR

  10. Time course of the hemodynamic responses to aortic depressor nerve stimulation in conscious spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Durand, M.T.; Mota, A.L. [Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Barale, A.R. [Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG (Brazil); Castania, J.A.; Fazan, R. Jr.; Salgado, H.C. [Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2012-03-16

    The time to reach the maximum response of arterial pressure, heart rate and vascular resistance (hindquarter and mesenteric) was measured in conscious male spontaneously hypertensive (SHR) and normotensive control rats (NCR; Wistar; 18-22 weeks) subjected to electrical stimulation of the aortic depressor nerve (ADN). The parameters of stimulation were 1 mA intensity and 2 ms pulse length applied for 5 s, using frequencies of 10, 30, and 90 Hz. The time to reach the hemodynamic responses at different frequencies of ADN stimulation was similar for SHR (N = 15) and NCR (N = 14); hypotension = NCR (4194 ± 336 to 3695 ± 463 ms) vs SHR (3475 ± 354 to 4494 ± 300 ms); bradycardia = NCR (1618 ± 152 to 1358 ± 185 ms) vs SHR (1911 ± 323 to 1852 ± 431 ms), and the fall in hindquarter vascular resistance = NCR (6054 ± 486 to 6550 ± 847 ms) vs SHR (4849 ± 918 to 4926 ± 646 ms); mesenteric = NCR (5574 ± 790 to 5752 ± 539 ms) vs SHR (5638 ± 648 to 6777 ± 624 ms). In addition, ADN stimulation produced baroreflex responses characterized by a faster cardiac effect followed by a vascular effect, which together contributed to the decrease in arterial pressure. Therefore, the results indicate that there is no alteration in the conduction of the electrical impulse after the site of baroreceptor mechanical transduction in the baroreflex pathway (central and/or efferent) in conscious SHR compared to NCR.

  11. Time course of the hemodynamic responses to aortic depressor nerve stimulation in conscious spontaneously hypertensive rats

    Directory of Open Access Journals (Sweden)

    M.T. Durand

    2012-05-01

    Full Text Available The time to reach the maximum response of arterial pressure, heart rate and vascular resistance (hindquarter and mesenteric was measured in conscious male spontaneously hypertensive (SHR and normotensive control rats (NCR; Wistar; 18-22 weeks subjected to electrical stimulation of the aortic depressor nerve (ADN under thiopental anesthesia. The parameters of stimulation were 1 mA intensity and 2 ms pulse length applied for 5 s, using frequencies of 10, 30, and 90 Hz. The time to reach the hemodynamic responses at different frequencies of ADN stimulation was similar for SHR (N = 15 and NCR (N = 14; hypotension = NCR (4194 ± 336 to 3695 ± 463 ms vs SHR (3475 ± 354 to 4494 ± 300 ms; bradycardia = NCR (1618 ± 152 to 1358 ± 185 ms vs SHR (1911 ± 323 to 1852 ± 431 ms, and the fall in hindquarter vascular resistance = NCR (6054 ± 486 to 6550 ± 847 ms vs SHR (4849 ± 918 to 4926 ± 646 ms; mesenteric = NCR (5574 ± 790 to 5752 ± 539 ms vs SHR (5638 ± 648 to 6777 ± 624 ms. In addition, ADN stimulation produced baroreflex responses characterized by a faster cardiac effect followed by a vascular effect, which together contributed to the decrease in arterial pressure. Therefore, the results indicate that there is no alteration in the conduction of the electrical impulse after the site of baroreceptor mechanical transduction in the baroreflex pathway (central and/or efferent in conscious SHR compared to NCR.

  12. In vitro stimulation of vascular endothelial growth factor by borate-based glass fibers under dynamic flow conditions.

    Science.gov (United States)

    Chen, Sisi; Yang, Qingbo; Brow, Richard K; Liu, Kun; Brow, Katherine A; Ma, Yinfa; Shi, Honglan

    2017-04-01

    Bioactive borate glass has been recognized to have both hard and soft tissue repair and regeneration capabilities through stimulating both osteogenesis and angiogenesis. However, the underlying biochemical and cellular mechanisms remain unclear. In this study, dynamic flow culturing modules were designed to simulate the micro-environment near the vascular depletion and hyperplasia area in wound-healing regions, thus to better investigate the mechanisms underlying the biocompatibility and functionality of borate-based glass materials. Glass fibers were dosed either upstream or in contact with the pre-seeded cells in the dynamic flow module. Two types of borate glasses, doped with (1605) or without (13-93B3) CuO and ZnO, were studied along with the silicate-based glass, 45S5. Substantial fiber dissolution in cell culture medium was observed, leading to the release of ions (boron, sodium and potassium) and the deposition of a calcium phosphate phase. Different levels of vascular endothelial growth factor secretion were observed from cells exposed to these three glass fibers, and the copper/zinc containing borate 1605 fibers exhibited the most positive influence. These results indicate that dynamic studies of in vitro bioactivity provide useful information to understand the in vivo response to bioactive borate glasses. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Consecutive Acupuncture Stimulations Lead to Significantly Decreased Neural Responses

    NARCIS (Netherlands)

    Yeo, S.; Choe, I.H.; Noort, M.W.M.L. van den; Bosch, M.P.C.; Lim, S.

    2010-01-01

    Objective: Functional magnetic resonance imaging (fMRI), in combination with block design paradigms with consecutive acupuncture stimulations, has often been used to investigate the neural responses to acupuncture. In this study, we investigated whether previous acupuncture stimulations can affect

  14. Efficacy of cognitive stimulation therapy for older adults with vascular dementia

    Directory of Open Access Journals (Sweden)

    Federica Piras

    Full Text Available ABSTRACT. Background: Cognitive stimulation therapy (CST is an evidence-based psychosocial intervention for people with mild-to-moderate dementia due to various etiological factors. Objective: The aim of the present study was to assess the efficacy of the CST program, Italian adaptation -CST-IT-, in individuals who have vascular dementia (VaD. Methods: Older adults with mild-to-moderate VaD (N = 35 were assigned to one of two programs: one group (N = 21 attended the 14 sessions of the CST-IT program, while the other, active control group (N = 14 took part in alternative activities. The following domains were examined: cognitive functioning, quality of life, mood, behavior, functional activities of daily living. Results: Compared with the active controls, the CST-IT group showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the Mini-Mental State Examination and decrease on the Alzheimer's Disease Assessment Scale – Cognitive subscale. A trend towards improvement was also identified in short-term/working memory – the backward digit span task- and perceived quality of life (Quality of Life – Alzheimer's Disease scale. No significant differences emerged between the two groups for the other domains considered. Conclusion: The present results support the efficacy of CST in people with vascular dementia.

  15. Stimulation of dendritic cells enhances immune response after photodynamic therapy

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

    2009-02-01

    Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

  16. Heterogeneous Vascular Bed Responses to Pulmonary Titanium Dioxide Nanoparticle Exposure

    Directory of Open Access Journals (Sweden)

    Alaeddin B. Abukabda

    2017-05-01

    Full Text Available A growing body of research links engineered nanomaterial (ENM exposure to adverse cardiovascular endpoints. The purpose of this study was to evaluate the impact of ENM exposure on vascular reactivity in discrete segments so that we may determine the most sensitive levels of the vasculature where these negative cardiovascular effects are manifest. We hypothesized that acute nano-TiO2 exposure differentially affects reactivity with a more robust impairment in the microcirculation. Sprague-Dawley rats (8–10 weeks were exposed to nano-TiO2via intratracheal instillation (20, 100, or 200 µg suspended per 250 µL of vehicle 24 h prior to vascular assessments. A serial assessment across distinct compartments of the vascular tree was then conducted. Wire myography was used to evaluate macrovascular active tension generation specifically in the thoracic aorta, the femoral artery, and third-order mesenteric arterioles. Pressure myography was used to determine vascular reactivity in fourth- and fifth-order mesenteric arterioles. Vessels were treated with phenylephrine, acetylcholine (ACh, and sodium nitroprusside. Nano-TiO2 exposure decreased endothelium-dependent relaxation in the thoracic aorta and femoral arteries assessed via ACh by 53.96 ± 11.6 and 25.08 ± 6.36%, respectively. Relaxation of third-order mesenteric arterioles was impaired by 100 and 20 µg nano-TiO2 exposures with mean reductions of 50.12 ± 8.7 and 68.28 ± 8.7%. Cholinergic reactivity of fourth- and fifth-order mesenteric arterioles was negatively affected by nano-TiO2 with diminished dilations of 82.86 ± 12.6% after exposure to 200 µg nano-TiO2, 42.6 ± 12.6% after 100 µg nano-TiO2, and 49.4 ± 12.6% after 20 µg nano-TiO2. Endothelium-independent relaxation was impaired in the thoracic aorta by 34.05 ± 25% induced by exposure to 200 µg nano-TiO2 and a reduction in response of 49.31 ± 25% caused by 100 µg nano-TiO2

  17. Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.

    Science.gov (United States)

    Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana; Koudelka, Adolf; Rudolph, Tanja K; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

    2016-11-01

    Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.

    Science.gov (United States)

    Joseph, Elizabeth K; Green, Paul G; Bogen, Oliver; Alvarez, Pedro; Levine, Jon D

    2013-02-13

    Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1 hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1 hyperalgesia. A role for protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1 hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hindlimb vibration) and in a model of endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of ATP in response to mechanical stimulation; ATP in turn acts at the nociceptor P2X(2/3) receptor.

  19. Cardiovascular Response Patterns to Sympathetic Stimulation by Central Hypovolemia

    NARCIS (Netherlands)

    Bronzwaer, Anne-Sophie G. T.; Verbree, Jasper; Stok, Wim J.; van Buchem, Mark A.; Daemen, Mat J. A. P.; van Osch, Matthias J. P.; van Lieshout, Johannes J.

    2016-01-01

    In healthy subjects, variation in cardiovascular responses to sympathetic stimulation evoked by submaximal lower body negative pressure (LBNP) is considerable. This study addressed the question whether inter-subject variation in cardiovascular responses coincides with consistent and reproducible

  20. Mobilization of endothelial precursor cells: systemic vascular response to musculoskeletal trauma.

    LENUS (Irish Health Repository)

    Laing, A J

    2012-02-03

    Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.

  1. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    International Nuclear Information System (INIS)

    Taub, Mary

    2016-01-01

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10 −5  M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  2. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    Energy Technology Data Exchange (ETDEWEB)

    Taub, Mary, E-mail: biochtau@buffalo.edu

    2016-03-11

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10{sup −5} M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  3. Cerebral haemodynamic response to somatosensory stimulation in near-term fetal sheep.

    Science.gov (United States)

    Nakamura, S; Walker, D W; Wong, F Y

    2017-02-15

    Cerebral haemodynamic response to neural stimulation has been extensively investigated in animal and clinical studies, in both adult and paediatric populations, but little is known about cerebral haemodynamic functional response in the fetal brain. The present study describes the cerebral haemodynamic response measured by near-infrared spectroscopy to somatosensory stimulation in fetal sheep. The cerebral haemodynamic response in the fetal sheep brain changes from a positive (increase in oxyhaemoglobin (oxyHb)) response pattern to a negative or biphasic response pattern when the duration of somatosensory stimulation is increased, probably due to cerebral vasoconstriction with prolonged stimulations. In contrast to adult studies, we have found that changes in fetal cerebral blood flow and oxyHb are positively increased in response to somatosensory stimulation during hypercapnia. We propose this is related to reduced vascular resistance and recruitment of cerebral vasculature in the fetal brain during hypercapnia. Functional hyperaemia induced by a localised increase in neuronal activity has been suggested to occur in the fetal brain owing to a positive blood oxygen level-dependent (BOLD) signal recorded by functional magnetic resonance imaging following acoustic stimulation. To study the effect of somatosensory input on local cerebral perfusion we used near-infrared spectroscopy (NIRS) in anaesthetised, partially exteriorised fetal sheep where the median nerve was stimulated with trains of pulses (2 ms, 3.3 Hz) for durations of 1.8, 4.8 and 7.8 s. Signal averaging of cerebral NIRS responses to 20 stimulus trains repeated every 60 s revealed that a short duration of stimulation (1.8 s) increased oxyhaemoglobin in the contralateral cortex consistent with a positive functional response, whereas longer durations of stimulation (4.8, 7.8 s) produced more variable oxyhaemoglobin responses including positive, negative and biphasic patterns of change. Mean arterial

  4. Cerebral haemodynamic response to somatosensory stimulation in near‐term fetal sheep

    Science.gov (United States)

    Nakamura, S.; Walker, D. W.

    2016-01-01

    Key points Cerebral haemodynamic response to neural stimulation has been extensively investigated in animal and clinical studies, in both adult and paediatric populations, but little is known about cerebral haemodynamic functional response in the fetal brain.The present study describes the cerebral haemodynamic response measured by near‐infrared spectroscopy to somatosensory stimulation in fetal sheep.The cerebral haemodynamic response in the fetal sheep brain changes from a positive (increase in oxyhaemoglobin (oxyHb)) response pattern to a negative or biphasic response pattern when the duration of somatosensory stimulation is increased, probably due to cerebral vasoconstriction with prolonged stimulations.In contrast to adult studies, we have found that changes in fetal cerebral blood flow and oxyHb are positively increased in response to somatosensory stimulation during hypercapnia. We propose this is related to reduced vascular resistance and recruitment of cerebral vasculature in the fetal brain during hypercapnia. Abstract Functional hyperaemia induced by a localised increase in neuronal activity has been suggested to occur in the fetal brain owing to a positive blood oxygen level‐dependent (BOLD) signal recorded by functional magnetic resonance imaging following acoustic stimulation. To study the effect of somatosensory input on local cerebral perfusion we used near‐infrared spectroscopy (NIRS) in anaesthetised, partially exteriorised fetal sheep where the median nerve was stimulated with trains of pulses (2 ms, 3.3 Hz) for durations of 1.8, 4.8 and 7.8 s. Signal averaging of cerebral NIRS responses to 20 stimulus trains repeated every 60 s revealed that a short duration of stimulation (1.8 s) increased oxyhaemoglobin in the contralateral cortex consistent with a positive functional response, whereas longer durations of stimulation (4.8, 7.8 s) produced more variable oxyhaemoglobin responses including positive, negative and biphasic patterns of

  5. Src Kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Wang Jing

    2002-12-01

    Full Text Available Abstract Background The cytoplasmic tyrosine kinase, Src, has been found to play a crucial role in VEGF (vascular endothelial growth factor – dependent vascular permeability involved in angiogenesis. The two main VEGFRs present on vascular endothelial cells are KDR/Flk-1 (kinase insert domain-containing receptor/fetal liver kinase-1 and Flt-1 (Fms-like tyrosine kinase-1. However, to date, it has not been determined which VEGF receptor (VEGFR is involved in binding to and activating Src kinase following VEGF stimulation of the receptors. Results In this report, we demonstrate that Src preferentially associates with KDR/Flk-1 rather than Flt-1 in human umbilical vein endothelial cells (HUVECs, and that VEGF stimulation resulted in an increase of Src activity associated with activated KDR/Flk-1. These findings were determined through immunoprecipitation-kinase experiments and coimmunoprecipitation studies, and were further confirmed by GST-pull-down assays and Far Western studies. However, Fyn and Yes, unlike Src, were found to associate preferentially with Flt-1. Conclusions Thus, Src preferentially associates with KDR/Flk-1, rather than with Flt-1, upon VEGF stimulation in endothelial cells. Our findings further highlight the potential significance of upregulated KDR/Flk-1-associated Src activity in the process of angiogenesis, and help to elucidate more clearly the specific roles and mechanisms involving Src family tyrosine kinase in VEGF-stimulated signal transduction events.

  6. Baroreflex-mediated heart rate and vascular resistance responses 24 h after maximal exercise

    Science.gov (United States)

    Convertino, Victor A.

    2003-01-01

    condition (-0.83 +/- 0.14 beats x min-1 x mm Hg-1). CONCLUSION: Expansion of vascular volume after acute exercise is associated with altered operational range for CVP and reduced HR response to arterial baroreceptor stimulation.

  7. Human transient response under local thermal stimulation

    Directory of Open Access Journals (Sweden)

    Wang Lijuan

    2017-01-01

    Full Text Available Human body can operate physiological thermoregulation system when it is exposed to cold or hot environment. Whether it can do the same work when a local part of body is stimulated by different temperatures? The objective of this paper is to prove it. Twelve subjects are recruited to participate in this experiment. After stabilizing in a comfort environment, their palms are stimulated by a pouch of 39, 36, 33, 30, and 27°C. Subject’s skin temperature, heart rate, heat flux of skin, and thermal sensation are recorded. The results indicate that when local part is suffering from harsh temperature, the whole body is doing physiological thermoregulation. Besides, when the local part is stimulated by high temperature and its thermal sensation is warm, the thermal sensation of whole body can be neutral. What is more, human body is more sensitive to cool stimulation than to warm one. The conclusions are significant to reveal and make full use of physiological thermoregulation.

  8. Pancreatic exocrine responses to parasympathetic stimulation in anaesthetized pigs.

    Science.gov (United States)

    Halfacree, Z J; Read, P A; Edwards, A V

    2001-03-23

    Pancreatic exocrine responses to stimulation of the peripheral ends of the vagus nerves intermittently have been investigated in anaesthetized pigs and compared with the effects of continuous stimulation at corresponding frequencies. At relatively low frequencies Hz in bursts or 2 Hz continuously) both the flow of pancreatic juice and the output of protein therein were potentiated by stimulating in bursts. Thus stimulation at 20 Hz in bursts produced a significantly greater flow of pancreatic juice than stimulation at 2 Hz continuously (10.9+/-0.9 compared to 4.8+/-0.7 microl min(-1) (g gland)-1 , respectively; PHz (144+/-23 microg min(-1) (g gland)-1) far exceeded that produced during continuous stimulation at 2 Hz (49+/-9 microg min(-1) (g gland)-1; PHz) and substantially reduced the output of protein during intermittent stimulation (to 27+/-7 ng min(-1) (g gland)-1; PHz in bursts). These results show that a variety of pancreatic exocrine responses can be enhanced by stimulating the parasympathetic innervation in bursts. They are also consistent with the contention that the secretion of protein from the gland, in response to parasympathetic stimulation, is dependent mainly on activation of muscarinic receptors. They confirm that the flow of pancreatic juice is due mainly to the release of VIP and show that, in the absence of atropine, this is restricted by muscarinic inhibition which may be presynaptic as elsewhere.

  9. Effects of BAY K 8644 on the responses of rabbit ear artery to electrical stimulation

    International Nuclear Information System (INIS)

    Pan, M.; Scriabine, A.; Steinsland, O.S.

    1988-01-01

    BAY K 8644 at 6.25 nM to 1 microM enhanced, in a concentration-dependent manner, both phases of the vasoconstrictor response of the isolated perfused rabbit ear artery to electrical stimulation. At 1 microM, BAY K 8644 enhanced the constrictor response by more than 250%. To study possible involvement of neurotransmitter release in the enhancement of the vasoconstrictor response by BAY K 8644, rabbit ear arteries were preincubated with [ 3 H]norepinephrine and stimulated either electrically (for 1 or 5 min) or by 60 mM K+. BAY K 8644 (1 microM) had no effect on tritium release caused by 1-min periods of electrical stimulation. However, tritium release caused by 5-min periods of electrical stimulation or by 60 mM K+ was enhanced in the presence of BAY K 8644. It was concluded that BAY K 8644 enhances vasoconstrictor effects of electrical stimulation of rabbit ear artery by primarily a direct agonist action on Ca2+ channels in vascular smooth muscle cells. Following sustained depolarization, however, the drug may also enhance the release of neurotransmitter from sympathetic nerve endings. Under certain conditions, this release may contribute to the overall action of BAY K 8644

  10. Nociceptive responses to thermal and mechanical stimulations in awake pigs

    DEFF Research Database (Denmark)

    di Giminiani, Pierpaolo; Petersen, Lars Jelstrup; Herskin, Mette S.

    2013-01-01

    body sizes (30 and 60 kg) were exposed to thermal (CO(2) laser) and mechanical (pressure application measurement device) stimulations to the flank and the hind legs in a balanced order. The median response latency and the type of behavioural response were recorded. RESULTS: Small pigs exhibited...... animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different...... significantly lower pain thresholds (shorter latency to response) than large pigs to thermal and mechanical stimulations. Stimulations at the two anatomical locations elicited very distinct sets of behavioural responses, with different levels of sensitivity between the flank and the hind legs. Furthermore...

  11. Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.

    Science.gov (United States)

    Bae, Ok-Nam; Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung; Kim, Eun-Sun; Jeong, Tae Cheon; Chun, Young-Jin; Lee, Ai-Young; Noh, Minsoo

    2015-03-01

    Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Microsecond-pulsed dielectric barrier discharge plasma stimulation of tissue macrophages for treatment of peripheral vascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Miller, V., E-mail: vmiller@coe.drexel.edu; Lin, A.; Brettschneider, J.; Fridman, G.; Fridman, A. [AJ Drexel Plasma Institute, Drexel University, Camden, New Jersey 08103 (United States); Kako, F.; Gabunia, K.; Kelemen, S.; Autieri, M. [Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 (United States)

    2015-12-15

    Angiogenesis is the formation of new blood vessels from pre-existing vessels and normally occurs during the process of inflammatory reactions, wound healing, tissue repair, and restoration of blood flow after injury or insult. Stimulation of angiogenesis is a promising and an important step in the treatment of peripheral artery disease. Reactive oxygen species have been shown to be involved in stimulation of this process. For this reason, we have developed and validated a non-equilibrium atmospheric temperature and pressure short-pulsed dielectric barrier discharge plasma system, which can non-destructively generate reactive oxygen species and other active species at the surface of the tissue being treated. We show that this plasma treatment stimulates the production of vascular endothelial growth factor, matrix metalloproteinase-9, and CXCL 1 that in turn induces angiogenesis in mouse aortic rings in vitro. This effect may be mediated by the direct effect of plasma generated reactive oxygen species on tissue.

  13. Comparison of cortical responses to the activation of retina by visual stimulation and transcorneal electrical stimulation.

    Science.gov (United States)

    Sun, Pengcheng; Li, Heng; Lu, Zhuofan; Su, Xiaofan; Ma, Zengguang; Chen, Jianpin; Li, Liming; Zhou, Chuanqing; Chen, Yao; Chai, Xinyu

    2018-02-21

    Electrical stimulation has been widely used in many ophthalmic diseases to modulate neuronal activities or restore partial visual function. Due to the different processing pathways and mechanisms, responses to visual and electrical stimulation in the primary visual cortex and higher visual areas might be different. This differences would shed some light on the properties of cortical responses evoked by electrical stimulation. This study's goal was to directly compare the cortical responses evoked by visual and electrical stimulation and investigate the cortical processing of visual information and extrinsic electrical signal. Optical imaging of intrinsic signals (OIS) was used to probe the cortical hemodynamic responses in 11 cats. Transcorneal electrical stimulation (TES) through an ERG-jet contact lens electrode was used to activate visual cortices. Full-field and peripheral drifting gratings were used as the visual stimuli. The response latency evoked by TES was shorter than that responding to visual stimulation (VS). Cortical responses evoked by VS were retinotopically organized, which was consistent with previous studies. On the other hand, the cortical region activated by TES was preferentially located in the secondary visual cortex (Area 18), while the primary visual cortex (Area 17) was activated by a higher current intensity. Compared with the full-field VS, the cortical response in Area 18 to TES with a current intensity above 1.2 mA was significantly stronger. According to our results, we provided some evidence that the cortical processing of TES was influenced by the distribution of the electrical field in the retina and the activating threshold of different retinal ganglion cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Prediction and control of neural responses to pulsatile electrical stimulation

    Science.gov (United States)

    Campbell, Luke J.; Sly, David James; O'Leary, Stephen John

    2012-04-01

    This paper aims to predict and control the probability of firing of a neuron in response to pulsatile electrical stimulation of the type delivered by neural prostheses such as the cochlear implant, bionic eye or in deep brain stimulation. Using the cochlear implant as a model, we developed an efficient computational model that predicts the responses of auditory nerve fibers to electrical stimulation and evaluated the model's accuracy by comparing the model output with pooled responses from a group of guinea pig auditory nerve fibers. It was found that the model accurately predicted the changes in neural firing probability over time to constant and variable amplitude electrical pulse trains, including speech-derived signals, delivered at rates up to 889 pulses s-1. A simplified version of the model that did not incorporate adaptation was used to adaptively predict, within its limitations, the pulsatile electrical stimulus required to cause a desired response from neurons up to 250 pulses s-1. Future stimulation strategies for cochlear implants and other neural prostheses may be enhanced using similar models that account for the way that neural responses are altered by previous stimulation.

  15. Incorporation of a prolyl hydroxylase inhibitor into scaffolds: a strategy for stimulating vascularization.

    Science.gov (United States)

    Sham, Adeline; Martinez, Eliana C; Beyer, Sebastian; Trau, Dieter W; Raghunath, Michael

    2015-03-01

    Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam(®)). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.

  16. Abnormal hemodynamic response to forepaw stimulation in rat brain after cocaine injection

    Science.gov (United States)

    Chen, Wei; Park, Kicheon; Choi, Jeonghun; Pan, Yingtian; Du, Congwu

    2015-03-01

    Simultaneous measurement of hemodynamics is of great importance to evaluate the brain functional changes induced by brain diseases such as drug addiction. Previously, we developed a multimodal-imaging platform (OFI) which combined laser speckle contrast imaging with multi-wavelength imaging to simultaneously characterize the changes in cerebral blood flow (CBF), oxygenated- and deoxygenated- hemoglobin (HbO and HbR) from animal brain. Recently, we upgraded our OFI system that enables detection of hemodynamic changes in response to forepaw electrical stimulation to study potential brain activity changes elicited by cocaine. The improvement includes 1) high sensitivity to detect the cortical response to single forepaw electrical stimulation; 2) high temporal resolution (i.e., 16Hz/channel) to resolve dynamic variations in drug-delivery study; 3) high spatial resolution to separate the stimulation-evoked hemodynamic changes in vascular compartments from those in tissue. The system was validated by imaging the hemodynamic responses to the forepaw-stimulations in the somatosensory cortex of cocaine-treated rats. The stimulations and acquisitions were conducted every 2min over 40min, i.e., from 10min before (baseline) to 30min after cocaine challenge. Our results show that the HbO response decreased first (at ~4min) followed by the decrease of HbR response (at ~6min) after cocaine, and both did not fully recovered for over 30min. Interestingly, while CBF decreased at 4min, it partially recovered at 18min after cocaine administration. The results indicate the heterogeneity of cocaine's effects on vasculature and tissue metabolism, demonstrating the unique capability of optical imaging for brain functional studies.

  17. Emotional responses to subcortical electrical stimulation in psychiatric patients.

    Science.gov (United States)

    Laitinen, L V

    1979-01-01

    Subcortical electrical stimulation was applied to the prospective surgical target area during 158 stereotactic operations in 135 psychiatric patients. The following target areas were studied: rostral cingulum below and in front of the genu of the corpus callosum (52 cases) genu (46) cingululum just above the genu (11) middle cingulum (6) anterior internal capsule (33) subcaudate region, 'substantia innominata' (10 cases). Forty-seven per cent of the cases reacted to stimulation with subjective emotional sensory responses. Stimulation of differ targets had significantly different results. Responses were obtained most frequently from the cingulum and genu, and least frequently from the anterior capsule and subcaudate regions. Stimulation of the rostral cingulum often caused 'negative' responses, i.e. an increase in or the appearance of anxiety and tension (11/15 cases). The opposite was true of the adjacent genu of the corpus callosum; on stimulation of this structure anxiety and tension disappeared or diminished (18/19 cases). Schizophrenic patients experienced such 'positive' responses significantly more often than non-schizophrenics. In non-anesthetized patients autonomic reactions were very rare.

  18. T Lymphocytes Inhibit the Vascular Response to Injury

    Science.gov (United States)

    Hansson, Goran K.; Holm, Jan; Holm, Susanna; Fotev, Zisi; Hedrich, Hans-Jurgen; Fingerle, Jurgen

    1991-12-01

    The proliferation of vascular smooth muscle cells is controlled by specific growth factors and cytokines acting in paracrine networks. Macrophage products such as the platelet-derived growth factor and interleukin 1 promote smooth muscle proliferation and are released in the arterial wall during atherosclerosis and repair processes. T lymphocytes are also present in vascular tissue, but their role in vascular growth control in vivo has been unclear. We now demonstrate that rats in which T lymphocytes have been eliminated by a monoclonal antibody develop larger proliferative arterial lesions after balloon-catheter injury. Larger lesions also develop in athymic rnu/rnu rats that lack T lymphocytes, when compared with rnu/+ littermates with normal T-cell levels. Finally, injection of the lymphokine interferon γ inhibits smooth muscle proliferation and results in smaller lesions compared with controls injected with buffer alone. These results indicate that T lymphocytes modulate smooth muscle proliferation during vascular repair. We propose that T lymphocytes may play an important, immunologically nonspecific role in tissue repair processes.

  19. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  20. Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-01-01

    Highlights: ► PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. ► Metformin suppressed TNF-α-induced COX-2 and iNOS mRNA expression. ► Compound C and bpv (pic) increased iNOS and COX-2 protein expression. ► NF-κB activation was restored by inhibiting AMPK and PTEN. ► AMPK and PTEN regulated TNF-α-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK–PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the

  1. Modeling auditory-nerve responses to electrical stimulation

    DEFF Research Database (Denmark)

    Joshi, Suyash Narendra; Dau, Torsten; Epp, Bastian

    2014-01-01

    Cochlear implants (CI) directly stimulate the auditory nerve (AN), bypassing the mechano-electrical transduction in the inner ear. Trains of biphasic, charge balanced pulses (anodic and cathodic) are used as stimuli to avoid damage of the tissue. The pulses of either polarity are capable......μs, which is large enough to affect the temporal coding of sounds and hence, potentially, the communication abilities of the CI listener. In the present study, two recently proposed models of electric stimulation of the AN [1,2] were considered in terms of their efficacy to predict the spike timing...... for anodic and cathodic stimulation of the AN of cat [3]. The models’ responses to the electrical pulses of various shapes [4,5,6] were also analyzed. It was found that, while the models can account for the firing rates in response to various biphasic pulse shapes, they fail to correctly describe the timing...

  2. Electrical field stimulation-induced excitatory responses of ...

    African Journals Online (AJOL)

    effect of the endothelium on electrical field stimulation (EFS)-induced excitatory responses of pulmonary artery segments from pulmonary hypertensive rats. Methods: Pulmonary hypertension was induced in rats with a single dose of monocrotaline (60 mg/kg) and 21 days later, arterial rings were set up for isometric tension ...

  3. Chenodeoxycholic acid stimulated fibroblast growth factor 19 response

    DEFF Research Database (Denmark)

    Borup, C; Wildt, S; Rumessen, J J

    2017-01-01

    BACKGROUND: Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid...

  4. Effects of nitric oxide synthase inhibition on cutaneous vasodilation in response to acupuncture stimulation in humans.

    Science.gov (United States)

    Kimura, Kenichi; Takeuchi, Hayato; Yuri, Kuniko; Wakayama, Ikuro

    2013-03-01

    The aim of the present study was to elucidate the mechanism of cutaneous vasodilation following acupuncture stimulation by investigating the roles of nitric oxide (NO) and axon reflex vasodilation. The subjects were 17 healthy male volunteers. The role of NO was investigated by administering N(G)-nitro-l-arginine methyl ester hydrochloride (L-NAME, 20 mM), an NO synthase inhibitor or Ringer's solution (control site), via intradermal microdialysis (protocol 1; n=7). The role of axon reflex vasodilation by local sensory neurones was investigated by comparing vasodilation at sites treated with 'eutectic mixture of local anaesthetics' (EMLA) cream (2.5% lidocaine and 2.5% prilocaine) with untreated sites (control site) (protocol 2; n=10). After 5 min of baseline recording, acupuncture was applied to PC4 and a control site in proximity to PC4 for 10 min and scanning was performed for 60 min after acupuncture stimulation. Skin blood flow (SkBF) was evaluated by laser Doppler perfusion imaging. Cutaneous vascular conductance (CVC) was calculated from the ratio of SkBF to mean arterial blood pressure. In the first protocol, sites administered L-NAME showed significant reductions in CVC responses following acupuncture stimulation compared to control sites (administered Ringer's solution) (pacupuncture stimulation did not differ significantly between treated sites with EMLA cream and untreated sites (p>0.05). These data suggest that cutaneous vasodilation in response to acupuncture stimulation may not occur through an axon reflex as previously reported. Rather, NO mechanisms appear to contribute to the vasodilator response.

  5. Vascular adaptive responses to physical exercise and to stress are affected differently by nandrolone administration

    Directory of Open Access Journals (Sweden)

    T. Bruder-Nascimento

    2011-04-01

    Full Text Available Androgenic anabolic steroid, physical exercise and stress induce cardiovascular adaptations including increased endothelial function. The present study investigated the effects of these conditions alone and in combination on the vascular responses of male Wistar rats. Exercise was started at 8 weeks of life (60-min swimming sessions 5 days per week for 8 weeks, while carrying a 5% body-weight load. One group received nandrolone (5 mg/kg, twice per week for 8 weeks, im. Acute immobilization stress (2 h was induced immediately before the experimental protocol. Curves for noradrenaline were obtained for thoracic aorta, with and without endothelium from sedentary and trained rats, submitted or not to stress, treated or not with nandrolone. None of the procedures altered the vascular reactivity to noradrenaline in denuded aorta. In intact aorta, stress and exercise produced vascular adaptive responses characterized by endothelium-dependent hyporeactivity to noradrenaline. These conditions in combination did not potentiate the vascular adaptive response. Exercise-induced vascular adaptive response was abolished by nandrolone. In contrast, the aortal reactivity to noradrenaline of sedentary rats and the vascular adaptive response to stress of sedentary and trained rats were not affected by nandrolone. Maximum response for 7-10 rats/group (g: sedentary 3.8 ± 0.2 vs trained 3.0 ± 0.2*; sedentary/stress 2.7 ± 0.2 vs trained/stress 3.1 ± 0.1*; sedentary/nandrolone 3.6 ± 0.1 vs trained/nandrolone 3.8 ± 0.1; sedentary/stress/nandrolone 3.2 ± 0.1 vs trained/stress/nandrolone 2.5 ± 0.1*; *P < 0.05 compared to its respective control. Stress and physical exercise determine similar vascular adaptive response involving distinct mechanisms as indicated by the observation that only the physical exercise-induced adaptive response was abolished by nandrolone.

  6. Stimulation of demand response through evaluation and training

    International Nuclear Information System (INIS)

    Encinas, N.; Alfonso, D.; Alvarez, C.; Mendez, C.; Rodriguez, J.; Perez-Navarro, A.; Gabaldon, A.

    2004-01-01

    The objective of Demand Response is to enhance customer choice opportunities by means of price-responsive mechanisms in contrast to direct load control practices and associated revenues based on fixed incentives. In this way, the new approach complements the traditional concept of Demand Side Management by including the voluntary nature to customer participation. This voluntary feature implies a change in customers' traditional behaviour and therefore stimulation and training is needed to achieve an optimal participation. This paper presents a methodology developed to stimulate and train customers for Demand Response practices as well as to identify the suitable products for different customers. Finally, the paper includes an example of the methodology considering a university as a customer. (au)

  7. Oscillatory frontal theta responses are increased upon bisensory stimulation.

    Science.gov (United States)

    Sakowitz, O W; Schürmann, M; Başar, E

    2000-05-01

    To investigate the functional correlation of oscillatory EEG components with the interaction of sensory modalities following simultaneous audio-visual stimulation. In an experimental study (15 subjects) we compared auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) to bimodal evoked potentials (BEPs; simultaneous auditory and visual stimulation). BEPs were assumed to be brain responses to complex stimuli as a marker for intermodal associative functioning. Frequency domain analysis of these EPs showed marked theta-range components in response to bimodal stimulation. These theta components could not be explained by linear addition of the unimodal responses in the time domain. Considering topography the increased theta-response showed a remarkable frontality in proximity to multimodal association cortices. Referring to methodology we try to demonstrate that, even if various behavioral correlates of brain oscillations exist, common patterns can be extracted by means of a systems-theoretical approach. Serving as an example of functionally relevant brain oscillations, theta responses could be interpreted as an indicator of associative information processing.

  8. Modulation of untruthful responses with noninvasive brain stimulation

    Directory of Open Access Journals (Sweden)

    Shirley eFecteau

    2013-02-01

    Full Text Available Deceptive abilities have long been studied in relation to personality traits. More recently, studies explored the neural substrates associated with deceptive skills suggesting a critical role of the prefrontal cortex. Here we investigated whether noninvasive brain stimulation over the dorsolateral prefrontal cortex (DLPFC could modulate generation of untruthful responses about subject’s personal life across contexts (i.e., deceiving on guilt-free questions on daily activities; generating previously memorized lies about past experience; and producing spontaneous lies about past experience, as well as across modality responses (verbal and motor responses. Results reveal that real, but not sham, transcranial direct current stimulation (tDCS over the DLPFC can reduce response latency for untruthful over truthful answers across contexts and modality responses. Also, contexts of lies seem to incur a different hemispheric laterality. These findings add up to previous studies demonstrating that it is possible to modulate some processes involved in generation of untruthful answers by applying noninvasive brain stimulation over the DLPFC and extend these findings by showing a differential hemispheric contribution of DLPFCs according to contexts.

  9. Time-Dependent Increase in Network Response to Stimulation.

    Directory of Open Access Journals (Sweden)

    Franz Hamilton

    Full Text Available In vitro neuronal cultures have become a popular method with which to probe network-level neuronal dynamics and phenomena in controlled laboratory settings. One of the key dynamics of interest in these in vitro studies has been the extent to which cultured networks display properties indicative of learning. Here we demonstrate the effects of a high frequency electrical stimulation signal in training cultured networks of cortical neurons. Networks receiving this training signal displayed a time-dependent increase in the response to a low frequency probing stimulation, particularly in the time window of 20-50 ms after stimulation. This increase was found to be statistically significant as compared to control networks that did not receive training. The timing of this increase suggests potentiation of synaptic mechanisms. To further investigate this possibility, we leveraged the powerful Cox statistical connectivity method as previously investigated by our group. This method was used to identify and track changes in network connectivity strength.

  10. Inner Retinal Oxygen Extraction Fraction in Response to Light Flicker Stimulation in Humans.

    Science.gov (United States)

    Felder, Anthony E; Wanek, Justin; Blair, Norman P; Shahidi, Mahnaz

    2015-10-01

    Light flicker has been shown to stimulate retinal neural activity, increase blood flow, and alter inner retinal oxygen metabolism (MO2) and delivery (DO2). The purpose of the study was to determine the change in MO2 relative to DO2 due to light flicker stimulation in humans, as assessed by the inner retinal oxygen extraction fraction (OEF). An optical imaging system, based on a modified slit lamp biomicroscope, was developed for simultaneous measurements of retinal vascular diameter (D) and oxygen saturation (SO2). Retinal images were acquired in 20 healthy subjects before and during light flicker stimulation. Arterial and venous D (DA and DV) and SO2 (SO2A and SO2V) were quantified within a circumpapillary region. Oxygen extraction fraction was defined as the ratio of MO2 to DO2 and was calculated as (SO2A - SO2V)/SO2A. Reproducibility of measurements was assessed. Coefficients of variation and intraclass correlation coefficients of repeated measurements were flicker stimulation, DA, DV , and SO2V significantly increased (P ≤ 0.004). Oxygen extraction fraction was 0.37 ± 0.08 before light flicker and significantly decreased to 0.31 ± 0.07 during light flicker (P = 0.001). Oxygen extraction fraction before and during light flicker stimulation is reported in human subjects for the first time. Oxygen extraction fraction decreased during light flicker stimulation, indicating the change in DO2 exceeded that of MO2. This technology is potentially useful for the detection of changes in OEF response to light flicker in physiological and pathological retinal conditions.

  11. Inner Retinal Oxygen Extraction Fraction in Response to Light Flicker Stimulation in Humans

    Science.gov (United States)

    Felder, Anthony E.; Wanek, Justin; Blair, Norman P.; Shahidi, Mahnaz

    2015-01-01

    Purpose Light flicker has been shown to stimulate retinal neural activity, increase blood flow, and alter inner retinal oxygen metabolism (MO2) and delivery (DO2). The purpose of the study was to determine the change in MO2 relative to DO2 due to light flicker stimulation in humans, as assessed by the inner retinal oxygen extraction fraction (OEF). Methods An optical imaging system, based on a modified slit lamp biomicroscope, was developed for simultaneous measurements of retinal vascular diameter (D) and oxygen saturation (SO2). Retinal images were acquired in 20 healthy subjects before and during light flicker stimulation. Arterial and venous D (DA and DV) and SO2 (SO2A and SO2V) were quantified within a circumpapillary region. Oxygen extraction fraction was defined as the ratio of MO2 to DO2 and was calculated as (SO2A − SO2V)/SO2A. Reproducibility of measurements was assessed. Results Coefficients of variation and intraclass correlation coefficients of repeated measurements were <5% and ≥0.83, respectively. During light flicker stimulation, DA, DV , and SO2V significantly increased (P ≤ 0.004). Oxygen extraction fraction was 0.37 ± 0.08 before light flicker and significantly decreased to 0.31 ± 0.07 during light flicker (P = 0.001). Conclusions Oxygen extraction fraction before and during light flicker stimulation is reported in human subjects for the first time. Oxygen extraction fraction decreased during light flicker stimulation, indicating the change in DO2 exceeded that of MO2. This technology is potentially useful for the detection of changes in OEF response to light flicker in physiological and pathological retinal conditions. PMID:26469748

  12. A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.

    Directory of Open Access Journals (Sweden)

    Timothy Gatheral

    Full Text Available Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of gram negative and some gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.

  13. Evoked electrical and cerebral vascular responses during sleep and following sleep deprivation.

    Science.gov (United States)

    Schei, Jennifer L; Rector, David M

    2011-01-01

    Neuronal activity elicits vascular dilation, delivering additional blood and metabolites to the activated region. With increasing neural activity, vessels stretch and may become less compliant. Most functional imaging studies assume that limits to vascular expansion are not normally reached except under pathological conditions, with the possibility that metabolism could outpace supply. However, we previously demonstrated that evoked hemodynamic responses were larger during quiet sleep when compared to both waking and rapid eye movement (REM) sleep, suggesting that high basal activity during wake may elicit blunted evoked hemodynamic responses due to vascular expansion limits. We hypothesized that extended brain activity through sleep deprivation will further dilate blood vessels and exacerbate the blunted evoked hemodynamic responses observed during wake, and dampen responses in subsequent sleep. We measured evoked electrical and hemodynamic responses from rats using auditory clicks (0.5s, 10 Hz, 2-13s random ISIs) for 1h following 2, 4, or 6h of sleep deprivation. Time-of-day matched controls were recorded continuously for 7h. Within quiet sleep periods following deprivation, evoked response potential (ERP) amplitude did not differ; however, the evoked vascular response was smaller with longer sleep deprivation periods. These results suggest that prolonged neural activity periods through sleep deprivation may diminish vascular compliance as indicated by the blunted vascular response. Subsequent sleep may allow vessels to relax, restoring their ability to deliver blood. These results also suggest that severe sleep deprivation or chronic sleep disturbances could push the vasculature to critical limits, leading to metabolic deficit and the potential for tissue trauma. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Influence of soluble or matrix-bound isoforms of vascular endothelial growth factor-A on tumor response to vascular-targeted strategies.

    Science.gov (United States)

    Akerman, Simon; Fisher, Matthew; Daniel, Rachel A; Lefley, Diane; Reyes-Aldasoro, Constantino C; Lunt, Sarah Jane; Harris, Sheila; Bjorndahl, Meit; Williams, Leigh J; Evans, Helen; Barber, Paul R; Prise, Vivien E; Vojnovic, Borivoj; Kanthou, Chryso; Tozer, Gillian M

    2013-12-01

    Antiangiogenic therapy based on blocking the actions of vascular endothelial growth factor-A (VEGF) can lead to "normalization" of blood vessels in both animal and human tumors. Differential expression of VEGF isoforms affects tumor vascular maturity, which could influence the normalization process and response to subsequent treatment. Fibrosarcoma cells expressing only VEGF120 or VEGF188 isoforms were implanted either subcutaneously (s.c.) or in dorsal skin-fold "window" chambers in SCID mice. VEGF120 was associated with vascular fragility and hemorrhage. Tumor-bearing mice were treated with repeat doses of SU5416, an indolinone receptor tyrosine kinase inhibitor with activity against VEGFR-2 and proven preclinical ability to induce tumor vascular normalization. SU5416 reduced vascularization in s.c. implants of both VEGF120 and VEGF188 tumors. However, in the window chamber, SU5416 treatment increased red cell velocity in VEGF120 (representing vascular normalization) but not VEGF188 tumors. SU5416 treatment had no effect on growth or necrosis levels in either tumor type but tended to counteract the increase in interstitial fluid pressure seen with growth of VEGF120 tumors. SU5416 pretreatment resulted in the normally fragile blood vessels in VEGF120-expressing tumors becoming resistant to the vascular damaging effects of the tubulin-binding vascular disrupting agent (VDA), combretastatin A4 3-O-phosphate (CA4P). Thus, vascular normalization induced by antiangiogenic treatment can reduce the efficacy of subsequent VDA treatment. Expression of VEGF120 made tumors particularly susceptible to vascular normalization by SU5416, which in turn made them resistant to CA4P. Therefore, VEGF isoform expression may be useful for predicting response to both antiangiogenic and vascular-disrupting therapy. Copyright © 2013 UICC.

  15. The surrounding tissue modifies the placental stem villous vascular responses

    DEFF Research Database (Denmark)

    Brøgger, Torbjørn; Forman, Axel; Aalkjær, Christian

    2014-01-01

    or endotheline-1. These differences partly disappeared in the presence of L-NAME. Conclusion: The perivascular tissue significantly reduces sensitivity and force development of stem villous arteries, partly due to release of NO This represents a new mechanism for control of human stem villous artery tone.......46619, 5-HT and endothelin-1 were significantly lower in preparations with intact trophoblast compared to preparations where the trophoblast had been removed. Moreover, maximal force development (Emax) was lower in arteries with intact trophoblast after stimulation with high extracellular [K+], PGF2α...

  16. Bisensory stimulation increases gamma-responses over multiple cortical regions.

    Science.gov (United States)

    Sakowitz, O W; Quiroga, R Q; Schürmann, M; Başar, E

    2001-04-01

    In the framework of the discussion about gamma (approx. 40 Hz) oscillations as information carriers in the brain, we investigated the relationship between gamma responses in the EEG and intersensory association. Auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) were compared with bisensory evoked potentials (BEPs; simultaneous auditory and visual stimulation) in 15 subjects. Gamma responses in AEPs, VEPs and BEPs were assessed by means of wavelet decomposition. Overall maximum gamma-components post-stimulus were highest in BEPs (P < 0.01). Bisensory evoked gamma-responses also showed significant central, parietal and occipital amplitude-increases (P < 0.001, P < 0.01, P < 0.05, respectively; prestimulus interval as baseline). These were of greater magnitude when compared with the unisensory responses. As a correlate of the marked gamma responses to bimodal stimulation we suggest a process of 'intersensory association', i.e. one of the steps between sensory transmission and perception. Our data may be interpreted as a further example of function-related gamma responses in the EEG.

  17. Transcription factor cAMP response element modulator (Crem) restrains Pdgf-dependent proliferation of vascular smooth muscle cells in mice.

    Science.gov (United States)

    Seidl, M D; Steingräber, A K; Wolf, C T; Sur, T M H; Hildebrandt, I; Witten, A; Stoll, M; Fischer, J W; Schmitz, W; Müller, F U

    2015-10-01

    Transcription factors of the cAMP response element-binding protein (Creb)/cAMP response element modulator (Crem) family were linked to the switch from a contractile to a proliferating phenotype in vascular smooth muscle cells (VSMCs). Here, we analyzed the vascular function of Crem in mice with a global inactivation of Crem (Crem(-/-)). CRE-mediated transcriptional activity was enhanced in primary Crem(-/-) VSMCs under nonstimulated conditions and under stimulation with Forskolin and platelet-derived growth factor (Pdgf) whereas stimulation with nitric oxide or cGMP showed no effect. This elevated CRE-mediated transcriptional activity as a result of Crem inactivation did not alter aortic contractility or fractions of proliferating or apoptotic aortic VSMCs in situ, and no impact of Crem inactivation on the development of atherosclerotic plaques was observed. Crem(-/-) mice exhibited an increased neointima formation after carotid ligation associated with an increased proliferation of VSMCs in the carotid media. Pdgf-stimulated proliferation of primary aortic Crem(-/-) VSMCs was increased along with an upregulation of messenger RNA (mRNA) levels of Pdgf receptor, alpha polypeptide (Pdgfra), cyclophilin A (Ppia), the regulator of G-protein signaling 5 (Rgs5), and Rho GTPase-activating protein 12 (Arhgap12). Taken together, our data reveal the inhibition of Pdgf-stimulated proliferation of VSMCs by repressing the Pdgf-stimulated CRE-mediated transcriptional activation as the predominant function of Crem in mouse vasculature suggesting an important role of Crem in vasculoproliferative diseases.

  18. Different protein of Echinococcus granulosus stimulates dendritic induced immune response.

    Science.gov (United States)

    Wang, Yana; Wang, Qiang; Lv, Shiyu; Zhang, Shengxiang

    2015-06-01

    Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.

  19. Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model.

    Science.gov (United States)

    Gnann, Laís Angelo; Castro, Rafael Ferreira; Azzalis, Ligia Ajaime; Feder, David; Perazzo, Fabio Ferreira; Pereira, Edimar Cristiano; Rosa, Paulo César Pires; Junqueira, Virginia Berlanga Campos; Rocha, Katya Cristina; Machado, Carlos D' Aparecida; Paschoal, Francisco Camargo; de Abreu, Luiz Carlos; Valenti, Vitor Engrácia; Fonseca, Fernando Luiz Affonso

    2013-10-29

    Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity.

  20. Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development.

    Science.gov (United States)

    Leonard, M G; Prazad, P; Puppala, B; Gulati, A

    2015-11-01

    Endothelin, vascular endothelial growth factor and nerve growth factor play important roles in development of the central nervous system. ET(B) receptors have been shown to promote neurovascular remodeling in the adult ischemic brain through an increase in VEGF and NGF. It is possible that ET(B) receptors may be involved in postnatal development of the brain through VEGF and NGF. In the present study, the brains of male rat pups on postnatal days 1, 7, 14 and 28 were analyzed for expression of ET(B) receptors, VEGF and NGF. In order to determine the effect of ET(B) receptor stimulation, a separate group of pups were administered saline or ET(B) receptor agonist, IRL-1620, on day 21, and their brains were analyzed on day 28. The intensity of ET(B) receptor and VEGF staining in the vasculature as well as the number of blood vessels of normal pups increased with age and was significantly higher on postnatal day 14 compared to day 1 and day 7. In contrast, both ET(B) and NGF staining intensity in the cortex and subventricular zones decreased (Pbrain (Pdevelopment of the CNS and selective stimulation of ET(B) receptors enhances VEGF but not NGF in the postnatal rat brain. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Modeling auditory-nerve responses to electrical stimulation

    DEFF Research Database (Denmark)

    Joshi, Suyash Narendra; Dau, Torsten; Epp, Bastian

    2014-01-01

    large enough to affect the temporal coding of sounds and hence, potentially, the communication abilities of the CI listener. In the present study, two recently proposed models of electric stimulationof the AN [1, 2, 3] were considered in terms of their efficacy to predict the spike timing for anodic...... andcathodic stimulation of the AN of cat [4]. The models' responses to the electrical pulses of variousshapes [5] were also analyzed. It was found that, while the models can account for the ring rates inresponse to various biphasic pulse shapes, they fail to correctly describe the timing of AP in response...

  2. The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity

    Directory of Open Access Journals (Sweden)

    Stephanie eWallner

    2015-08-01

    Full Text Available Granulocyte-colony stimulating factor (G-CSF is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-15

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

  4. TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.

    Directory of Open Access Journals (Sweden)

    Xudong Shi

    Full Text Available Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signaling protein Smad3 ∶ 1 are up-regulated following vascular injury, 2 together drive smooth muscle cell (SMC proliferation and migration and 3 enhance the development of intimal hyperplasia. In order to determine a mechanism through which TGF-β/Smad3 promote these effects, Affymetrix gene expression arrays were performed on primary rat SMCs infected with Smad3 and stimulated with TGF-β or infected with GFP alone. More than 200 genes were differentially expressed (>2.0 fold change, p<0.05 in TGF-β/Smad3 stimulated SMCs. We then performed GO term enrichment analysis using the DAVID bioinformatics database and found that TGF-β/Smad3 activated the expression of multiple genes related to either development or cell differentiation, several of which have been shown to be associated with multipotent stem or progenitor cells. Quantitative real-time PCR confirmed up-regulation of several developmental genes including FGF1, NGF, and Wnt11 (by 2.5, 6 and 7 fold, respectively as well as stem/progenitor cell associated genes CD34 and CXCR4 (by 10 and 45 fold, respectively. In addition, up-regulation of these factors at protein levels were also confirmed by Western blotting, or by immunocytochemistry (performed for CXCR4 and NGF. Finally, TGF-β/Smad3 down regulated transcription of SMC contractile genes as well as protein production of smooth muscle alpha actin, calponin, and smooth muscle myosin heavy chain. These combined results suggest that TGF-β/Smad3 stimulation drives SMCs to a phenotypically altered state of de-differentiation through the up-regulation of developmental related genes.

  5. Response to ovarian stimulation in patients facing gonadotoxic therapy.

    Science.gov (United States)

    Johnson, Lauren N C; Dillon, Katherine E; Sammel, Mary D; Efymow, Brenda L; Mainigi, Monica A; Dokras, Anuja; Gracia, Clarisa R

    2013-04-01

    Chemotherapy naïve patients undergoing embryo/oocyte banking for fertility preservation (FP) were assessed for response to ovarian stimulation. Fifty FP patients facing gonadotoxic therapy were matched by age, race, cycle number, date of stimulation and fertilization method to patients undergoing IVF for infertility or oocyte donation. There were no differences in baseline FSH, anti-Müllerian hormone, antral follicle count and total gonadotrophin dose. FP patients had more immature oocytes (2.2 versus 1.1; P=0.03) and lower fertilization rates per oocyte retrieved (52% versus 70%; P=0.002). There were no differences in numbers of oocytes retrieved, mature oocytes or fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses (3077IU versus 2259IU; P=0.0477) and had more immature oocytes (3.4 versus 1.2; P=0.03) than matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. Overall, chemotherapy naïve FP patients had similar ovarian reserve, response to stimulation and oocyte and embryo yield compared to controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole. With improvement in cancer survival rates, there has been a shift in attention toward management of long-term consequences of cancer therapy, including infertility. Many young women with cancer, particularly those who will be treated with chemotherapy, pursue fertility preservation (FP) strategies for the purpose of banking oocytes or embryos for future use. We examined patients with no prior exposure to chemotherapy who underwent IVF to freeze embryos or oocytes for FP. Fifty FP patients were identified and matched to healthy controls by age, race, cycle number, date of stimulation and fertilization

  6. Effects of sympathetic histamine on vasomotor responses of blood vessels in rabbit ear to electrical stimulation.

    Science.gov (United States)

    Chen, Ying-Ying; Lv, Jun; Xue, Xiao-Yan; He, Gong-Hao; Zhou, Ying; Jia, Min; Luo, Xiao-Xing

    2010-06-01

    To investigate the effects of histamine receptor antagonists on vasoconstriction induced by electrical stimulation (ES) on posterior auricular nerve, and to explore the pre- and post-synaptic effects of sympathetic histamine on the vasomotor responses of vascular smooth muscle in rabbit ear. ES was applied to posterior auricular nerves of the whole rabbit ear at 10 Hz, 20 Hz and 40 Hz, respectively. Besides, the whole ear was perfused with different histamine receptor antagonists under constant perfusion pressure, and the changes in the flow rate of perfusate were observed. The flow rate of venous outflow was decreased by ES at all the 3 frequencies. The ES-induced vasoconstriction at 20 Hz and 40 Hz could be partly inhibited by H(1) receptor antagonist chlorpheniramine (P functions of sympathetic histamine vary from pre-synaptic modulation to post-synaptic vasoconstriction or vasodilatation, via activation of different histamine receptors.

  7. Vascular responses to radiotherapy and androgendeprivation therapy in experimental prostate cancer

    LENUS (Irish Health Repository)

    2012-05-23

    AbstractBackgroundRadiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC.MethodsUsing mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI.ResultsCompared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density ( VD), and vessel area fraction ( VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores ( AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve ( AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size ( VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after

  8. Viral evasion of DNA-stimulated innate immune responses.

    Science.gov (United States)

    Christensen, Maria H; Paludan, Søren R

    2017-01-01

    Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.

  9. Cold stimulates the behavioral response to hypoxia in newborn mice.

    Science.gov (United States)

    Bollen, Bieke; Bouslama, Myriam; Matrot, Boris; Rotrou, Yann; Vardon, Guy; Lofaso, Frédéric; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2009-05-01

    In newborns, hypoxia elicits increased ventilation, arousal followed by defensive movements, and cries. Cold is known to affect the ventilatory response to hypoxia, but whether it affects the arousal response remains unknown. The aim of the present study was to assess the effects of cold on the ventilatory and arousal responses to hypoxia in newborn mice. We designed an original platform measuring noninvasively and simultaneously the breathing pattern by whole body plethysmography, body temperature by infrared thermography, as well as motor and ultrasonic vocal (USV) responses. Six-day-old mice were exposed twice to 10% O(2) for 3 min at either cold temperature (26 degrees C) or thermoneutrality (33 degrees C). At 33 degrees C, hypoxia elicited a marked increase in ventilation followed by a small ventilatory decline, small motor response, and almost no USVs. Body temperature was not influenced by hypoxia, and oxygen consumption (Vo(2)) displayed minimal changes. At 26 degrees C, hypoxia elicited a slight increase in ventilation with a large ventilatory decline and a large drop of Vo(2). This response was accompanied by marked USV and motor responses. Hypoxia elicited a small decrease in temperature after the return to normoxia, thus precluding any causal influence on the motor and USV responses to hypoxia. In conclusion, cold stimulated arousal and stress responses to hypoxia, while depressing hypoxic hyperpnea. Arousal is an important defense mechanism against sleep-disordered breathing. The dissociation between ventilatory and behavioral responses to hypoxia suggests that deficits in the arousal response associated with sleep breathing disorders cannot be attributed to a depressed hypoxic response.

  10. Autonomic response to exercise as measured by cardio- vascular ...

    African Journals Online (AJOL)

    Motivation. There is growing interest in the use of cardiovas- cular variability indicators as measures of autonomic activity, even though reported results are not always comparable or as expected. This review aims to determine the consistency of re- sults reported on the autonomic response to physical exercise as measured ...

  11. Leuprolide acetate-stimulated androgen response during female puberty.

    Science.gov (United States)

    Hernandez, María Isabel; Martinez-Aguayo, Alejandro; Cavada, Gabriel; Avila, Alejandra; Iñiguez, German; Mericq, Veronica

    2015-08-01

    A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders. The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls. To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity. Prospective study of healthy girls (6-12 years) from the local community (n = 63). Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 μg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated. Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins. In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with

  12. Vascular responsiveness in the microcirculation of patients with systemic lupus erythematosus is not impaired

    NARCIS (Netherlands)

    de Leeuw, K.; Blaauw, J.; Smit, A. J.; Kallenberg, C. G.; Bijl, M.

    2008-01-01

    As endothelial dysfunction is one of the earliest signs of atherosclerosis, which is accelerated in systemic lupus erythematosus (SLE), we assessed whether vascular responses of the cutaneous microcirculation are disturbed in SLE patients and influenced by Raynaud's phenomenon (RP). Laser Doppler

  13. Inflammation and vascular responses to acute mental stress : implications for the triggering of myocardial infarction

    NARCIS (Netherlands)

    Paine, N.J.; Bosch, J.A.; Veldhuijzen Van Zanten, J.J.C.S.

    2012-01-01

    There is evidence that mental stress can trigger myocardial infarction. Even though the underlying mechanisms remain to be determined, both inflammation and vascular responses to mental stress have been implicated as contributing factors. This review explores the effects of inflammation on the

  14. c-Ski inhibits the proliferation of vascular smooth muscle cells via suppressing Smad3 signaling but stimulating p38 pathway.

    Science.gov (United States)

    Li, Jun; Li, Ping; Zhang, Yan; Li, Gong-Bo; Zhou, Yuan-Guo; Yang, Kang; Dai, Shuang-Shuang

    2013-01-01

    Proliferation of vascular smooth muscle cells (VSMCs) plays key roles in the progression of intimal hyperplasia, but the molecular mechanisms that trigger VSMC proliferation after vascular injury remain unclear. c-Ski, a co-repressor of transforming growth factor β (TGF-β)/Smad signaling, was detected to express in VSMC of rat artery. During the course of arterial VSMC proliferation induced by balloon injury in rat, the endogenous protein expressions of c-Ski decreased markedly in a time-dependent manner. In vivo c-Ski gene delivery was found to significantly suppress balloon injury-induced VSMC proliferation and neointima formation. Further investigation in A10 rat aortic smooth muscle cells demonstrated that overexpression of c-Ski gene inhibited TGF-β1 (1 ng/ml)-induced A10 cell proliferation while knockdown of c-Ski by RNAi enhanced the stimulatory effect of TGF-β1 on A10 cell growth. Western blot for signaling detection showed that suppression of Smad3 phosphorylation while stimulating p38 signaling associated with upregulation of cyclin-dependent kinase inhibitors p21 and p27 was responsible for the inhibitory effect of c-Ski on TGF-β1-induced VSMC proliferation. These data suggest that the decrease of endogenous c-Ski expression is implicated in the progression of VSMC proliferation after arterial injury and c-Ski administration represents a promising role for treating intimal hyperplasia via inhibiting the proliferation of VSMC. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice.

    Science.gov (United States)

    Aroor, Annayya R; Jia, Guanghong; Habibi, Javad; Sun, Zhe; Ramirez-Perez, Francisco I; Brady, Barron; Chen, Dongqing; Martinez-Lemus, Luis A; Manrique, Camila; Nistala, Ravi; Whaley-Connell, Adam T; Demarco, Vincent G; Meininger, Gerald A; Sowers, James R

    2017-09-01

    Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration. Copyright © 2017 Elsevier Inc

  16. Functions of microRNA in response to cocaine stimulation.

    Science.gov (United States)

    Xu, L-F; Wang, J; Lv, F B; Song, Q

    2013-12-04

    MicroRNAs (miRNAs) are a type of non-protein-coding single-stranded RNA, which are typically 20-25 nt in length. miRNAs play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. We aimed to detect the miRNA response to cocaine stimulations and their target genes. Using the miRNA expression data GSE21901 downloaded from the Gene Expression Omnibus database, we screened out the differentially expressed miRNA after short-term (1 h) and longer-term (6 h) cocaine stimulations based on the fold change >1.2. Target genes of differentially expressed miRNAs were retrieved from TargetScan database with the context score -0.3. Functional annotation enrichment analysis was performed for all the target genes with DAVID. A total of 121 differentially expressed miRNAs between the 1-h treatment and the control samples, 58 between the 6-h treatment and the control samples, and 69 between the 1-h and the 6-h treatment samples. Among them, miR-212 results of particular interest, since its expression level was constantly elevated responding to cocaine treatment. After functional and pathway annotations of target genes, we proved that miR-212 was a critical element in cocaine-addiction, because of its involvement in regulating several important cell cycle events. The results may pave the way for further understanding the regulatory mechanisms of cocaine-response in human bodies.

  17. Curcumin prevents human dendritic cell response to immune stimulants

    International Nuclear Information System (INIS)

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2008-01-01

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14 + monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4 + T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant

  18. ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension

    Science.gov (United States)

    Beckers, Cora M.L.; Knezevic, Nebojsa; Valent, Erik T.; Tauseef, Mohammad; Krishnan, Ramaswamy; Rajendran, Kavitha; Hardin, C. Corey; Aman, Jurjan; van Bezu, Jan; Sweetnam, Paul; van Hinsbergh, Victor W.M.; Mehta, Dolly; van Nieuw Amerongen, Geerten P.

    2015-01-01

    Rho kinase mediates the effects of inflammatory permeability factors by increasing actomyosin-generated traction forces on endothelial adherens junctions, resulting in disassembly of intercellular junctions and increased vascular leakage. In vitro, this is accompanied by the Rho kinase-driven formation of prominent radial F-actin fibers, but the in vivo relevance of those F-actin fibers has been debated, suggesting other Rho kinase-mediated events to occur in vascular leak. Here, we delineated the contributions of the highly homologous isoforms of Rho kinase (ROCK1 and ROCK2) to vascular hyperpermeability responses. We show that ROCK2, rather than ROCK1 is the critical Rho kinase for regulation of thrombin receptor-mediated vascular permeability. Novel traction force mapping in endothelial monolayers, however, shows that ROCK2 is not required for the thrombin-induced force enhancements. Rather, ROCK2 is pivotal to baseline junctional tension as a novel mechanism by which Rho kinase primes the endothelium for hyperpermeability responses, independent from subsequent ROCK1-mediated contractile stress-fiber formation during the late phase of the permeability response. PMID:25869521

  19. Thigmotropic responses of Oryza sativa L. to external rubbing stimulation

    Directory of Open Access Journals (Sweden)

    Zhao Benliang

    2018-01-01

    Full Text Available Our aim was to study the morphological and physiological responses of rice to rubbing stimulation. Rice was subjected to rubbing 30 times/day (R30, 60 times/day (R60, 90 times/day (R90 and 0 times/day (control for 35 days. The height, elongation rates and second internode length were significantly decreased by the three treatments, whereas stem width increased significantly. The tiller number and chlorophyll contents of the top third and top fifth of leaves increased significantly after R30 and R60. In R90, the aboveground biomass was significantly decreased and dead leaf biomass was increased. In R30 and R60, the transpiration rates were 16% and 13% higher than in the control, whereas photosynthetic rates increased 25% and 23%, respectively. Root biomass was significantly increased in R30, and root/aboveground was enhanced in R90. Stomatal conductance and root triphenyltetrazolium chloride-deoxidizing ability was significantly increased by the three treatments. The SOD activities in all treatments and the control were similar after stimulation. POD and CAT activities increased significantly in R30 and R60, and malondialdehyde increased by 42% in R90. Membrane permeability in R30 and R60 decreased 26% and 15%, respectively. The calcium content and soluble protein content increased in R30, whereas the magnesium content decreased. The nitrogen content increased significantly in R30 and R60. The silicon content in the whole plant and the size of stomata increased significantly in the three treatments. Thus, rubbing stimulation had complex effects on rice growth.

  20. Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ.

    Science.gov (United States)

    Kırça, M; Oğuz, N; Çetin, A; Uzuner, F; Yeşilkaya, A

    2017-04-01

    Hyperuricemia and angiotensin II (Ang II) may have a pathogenetic role in the development of hypertension and atherosclerosis as well as cardiovascular disease (CVD) and its prognosis. The purpose of this study was to investigate whether uric acid can induce proliferative pathways of vascular smooth muscle cell (VSMC) that are thought to be responsible for the development of CVD. The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and platelet-derived growth factor receptor β (PDGFRβ) was measured by Elisa and Western blot techniques to determine the activation of proliferative pathways in primary cultured VSMCs from rat aorta. Results demonstrated that uric acid can stimulate p38 MAPK, p44/42 MAPK and PDGFRβ phosphorylation in a time- and concentration-dependent manner. Furthermore, treatment of VSMCs with the angiotensin II type I receptor (AT1R) inhibitor losartan suppressed p38 MAPK and p44/42 MAPK induction by uric acid. The stimulatory effect of uric acid on p38 MAPK was higher compared to that of Ang II. The results of this study show for the first time that uric acid-induced PDGFRβ phosphorylation plays a crucial role in the development of CVDs and that elevated uric acid levels could be a potential therapeutical target in CVD patients.

  1. Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo.

    Science.gov (United States)

    Trindade, Alexandre; Djokovic, Dusan; Gigante, Joana; Mendonça, Liliana; Duarte, António

    2017-03-14

    The inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models. We used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas. We found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy. By reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control.

  2. Mn++-stimulated 3H-inositol incorporation in cultured vascular smooth muscle cells: deficiency in cells from spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Buck, S.H.; Nabika, T.; Lovenberg, W.

    1985-01-01

    Incubation of cultured dissociated aortic smooth muscle cells from Wistar-Kyoto rats (WKY) with Mn++ resulted in a 10-fold stimulation of 3 H-myo-inositol incorporation into membrane phospholipids. The stimulation was temperature and energy dependent. The Mn++ EC50 was 1 mM and maximum stimulation occurred at 10 mM Mn++. Other cations were ineffective. In cells from spontaneously hypertensive rats (SHR), the Mn++ EC50 was unchanged whereas the maximum stimulation of 3 H-inositol incorporation was reduced by 50% compared to cells from parallel WKY cultures. These results suggest that in SHR cultured vascular smooth muscle cells there is a deficiency in an enzymatic process mediating exchange of free inositol with the headgroup inositol of membrane phosphatidylinositol

  3. Smart(phone) Learning Experience Among Vascular Trainees Using a Response System Application.

    Science.gov (United States)

    Al-Jundi, Wissam; Kayssi, Ahmed; Papia, Giuseppe; Dueck, Andrew

    Smartphones have become the most important personal technological device. M-learning is learning through mobile device educational technology. We aim to assess the acceptability of a smartphone learning experience among the vascular trainees and determine if results could inform formal teaching efforts. A survey of the vascular trainees at a single center was conducted following a trial of smartphone learning experience. A vascular fellow used a smartphone response system application (Polltogo, Inspirapps Inc.) to send a daily multiple-choice question to the vascular residents for 20 consecutive working days. The application allows for only one attempt from each user, and the answers are registered anonymously. However, each participant receives instant feedback on his/her response by viewing the correct answer after answering each question along with a distribution of answers among other users. A total of 9 trainees participated in the trial, and all of them filled a posttrial survey. All the trainees possessed smartphones. The majority (78%) were not aware of the concept of m-learning. The mobile engagement score (number of answers received divided by total possible answers) was 145/180 (81%). All the trainees were "satisfied" or "very satisfied" with the experience, and the same number stated that they were "likely" or "very likely" to use this technology in the future. The majority (89%) agreed that such an application could assist them in preparing for their board examination. On 3 occasions, 75% or more of the participating trainees answered the multiple-choice question incorrectly, which resulted in addressing the relevant topics in the unit's weekly teaching conference. Using smartphones for education is acceptable among the vascular trainees, and the trial of a response system application with instant written feedback represents a novel method for using smartphones for collaborative learning. Such an application can also inform program directors and

  4. Diverse effects of taurine on vascular response and inflammation in GSH depletion model in rabbits.

    Science.gov (United States)

    Ozsarlak-Sozer, G; Sevin, G; Ozgur, H H; Yetik-Anacak, G; Kerry, Z

    2016-04-01

    A reduction in GSH and an increase in free radicals are observed in inflammatory diseases, indicating oxidative stress. Taurine protects cells from the cytotoxic effects of inflammation. There have been limited studies to date evaluating the effect of taurine in oxidative stress-induced vascular dysfunction and its role in vascular inflammatory diseases. Therefore, we aimed to investigate the effect of taurine on the regulation of vascular tonus and vascular inflammatory markers in rabbit aortae and carotid arteries in oxidative stress-induced by GSH depletion. Rabbits were treated subcutaneously with buthionine sulfoximine (BSO), GSH-depleting compound and/or taurine. Cumulative concentration-response curves for acetylcholine (ACh), phenylephrine and 5-hydroxytriptamine (5-HT) were constructed with or without Nω-nitro-L-arginine (LNA) in the carotid artery and aorta rings. Immunohistochemical staining was performed for TNF-α and IL-1β. BSO increased ACh-induced NO-dependent relaxations, phenylephrine-induced contractions in the carotid artery and 5-HT induced-contractions in both the carotid artery and the aorta. BSO decreased EDHF dependent relaxations only in the aorta. ACh-induced NO-dependent relaxations and augmented contractions were normalized by taurine. BSO increased TNF-α expressions in both carotid arteries and aortas, which were reversed by taurine. The BSO-induced increase in IL-1β was reversed by taurine only in aortae. Treatment with BSO resulted in vascular reactivity changes and increased immunostaining of TNF-α in mainly carotid arteries in this model of oxidative stress. The effect of taurine on BSO-induced vascular reactivity changes varied depending on the vessel. The inhibition of the increase in TNF-α expression by taurine in both carotid arteries and aortae supports the proposal that taurine has a beneficial effect in the treatment of inflammatory diseases such as atherosclerosis.

  5. Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.

    Science.gov (United States)

    Chen, Yu-Ying; Hsu, Ming-Jen; Hsieh, Cheng-Ying; Lee, Lin-Wen; Chen, Zhih-Cherng; Sheu, Joen-Rong

    2014-01-01

    Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  6. Vascular Response of Ruthenium Tetraamines in Aortic Ring from Normotensive Rats

    Directory of Open Access Journals (Sweden)

    Ana Gabriela Conceição-Vertamatti

    2015-03-01

    Full Text Available Background: Ruthenium (Ru tetraamines are being increasingly used as nitric oxide (NO carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved. Objective: To evaluate the vascular response of the tetraamines trans-[RuII(NH34(Py(NO]3+, trans-[RuII(Cl(NO (cyclan](PF62, and trans-[RuII(NH34(4-acPy(NO]3+. Methods: Aortic rings were contracted with noradrenaline (10−6 M. After voltage stabilization, a single concentration (10−6 M of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10−6 M and sodium nitroprusside at 10−6 M as well as by histological examination. Results: Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect. Conclusion: The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10−6 M at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used in the formulation of the compound.

  7. A multifunctional bioactive material that stimulates osteogenesis and promotes the vascularization bone marrow stem cells and their resistance to bacterial infection.

    Directory of Open Access Journals (Sweden)

    Chuang Ma

    Full Text Available The main limitation of tissue engineering lies in the inability to stimulate osteogenesis, angiogenesis of stem cells and broad-spectrum antimicrobial activity. However, the development of multifunctional bioactive materials with these capabilities remains a great challenge. In this study, we prepared mesoporous silica nanoparticles encapsulated with silver nanocrystals (AG-MSN with uniform sphere size and mesopores. Platelet-derived growth factor BB (PDGF-BB was effectively loaded in the AG-MSN mesopores (P-AG-MSN. The silicon ions (Si released by P-AG-MSN stimulate osteogenic differentiation of bone marrow stromal cells (BMSC by activating the alkaline phosphatase (ALP activity of bone-related genes and increasing protein (OCN, RUNX2 and OPN expression. Ag+ ions could be slowly released from the interior of the shell, highlighting their durable antibacterial activity. The sustained release of PDGF-BB from P-AG-MSN stimulated the angiogenic differentiation of BMSC, as indicated by the enhanced secretion of vascular endothelial growth factor (VEGF, HIF-1α, HGF and ANG-1 and protein expression. Our results show that P-AG-MSN can clearly promote BMSC osteostimulation and vascularization. This research serves as a preliminary study of the utilization of this multifunctional mixture to fabricate a new active biological scaffold that integrates BMSC osteostimulation, vascularization and bactericidal effects by 3D printing technology.

  8. Motile Responses of Cochlear Outer Hair Cells Stimulated with an Alternating Electrical Field

    OpenAIRE

    Kitani, Rei; Kakehata, Seiji; Kalinec, Federico

    2011-01-01

    The goal of the present study was to evaluate and characterize the motile responses of guinea pig OHCs, stimulated at frequencies varying from 50 Hz to 4 kHz, using high-definition, high-speed video recording and fully automatic image analysis software. Cells stimulated in continuous, burst and sweeping modes with an external alternating electrical field showed robust fast and slow motility, which were dependent on frequency, mode and intensity of stimulation. In response to continuous stimul...

  9. Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity.

    Science.gov (United States)

    Moran, Fidelma; Leonard, Tracey; Hawthorne, Stephanie; Hughes, Ciara M; McCrum-Gardner, Evie; Johnson, Mark I; Rakel, Barbara A; Sluka, Kathleen A; Walsh, Deirdre M

    2011-08-01

    Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS naïve healthy individuals (18-64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r(2) = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

  10. Inactivation of serum response factor contributes to decrease vascular muscular tone and arterial stiffness in mice.

    Science.gov (United States)

    Galmiche, Guillaume; Labat, Carlos; Mericskay, Mathias; Aissa, Karima Ait; Blanc, Jocelyne; Retailleau, Kevin; Bourhim, Mustapha; Coletti, Dario; Loufrani, Laurent; Gao-Li, Jacqueline; Feil, Robert; Challande, Pascal; Henrion, Daniel; Decaux, Jean-François; Regnault, Véronique; Lacolley, Patrick; Li, Zhenlin

    2013-03-29

    Vascular smooth muscle (SM) cell phenotypic modulation plays an important role in arterial stiffening associated with aging. Serum response factor (SRF) is a major transcription factor regulating SM genes involved in maintenance of the contractile state of vascular SM cells. We investigated whether SRF and its target genes regulate intrinsic SM tone and thereby arterial stiffness. The SRF gene was inactivated SM-specific knockout of SRF (SRF(SMKO)) specifically in vascular SM cells by injection of tamoxifen into adult transgenic mice. Fifteen days later, arterial pressure and carotid thickness were lower in SRF(SMKO) than in control mice. The carotid distensibility/pressure and elastic modulus/wall stress curves showed a greater arterial elasticity in SRF(SMKO) without modification in collagen/elastin ratio. In SRF(SMKO), vasodilation was decreased in aorta and carotid arteries, whereas a decrease in contractile response was found in mesenteric arteries. By contrast, in mice with inducible SRF overexpression, the in vitro contractile response was significantly increased in all arteries. Without endothelium, the contraction was reduced in SRF(SMKO) compared with control aortic rings owing to impairment of the NO pathway. Contractile components (SM-actin and myosin light chain), regulators of the contractile response (myosin light chain kinase, myosin phosphatase target subunit 1, and protein kinase C-potentiated myosin phosphatase inhibitor) and integrins were reduced in SRF(SMKO). SRF controls vasoconstriction in mesenteric arteries via vascular SM cell phenotypic modulation linked to changes in contractile protein gene expression. SRF-related decreases in vasomotor tone and cell-matrix attachment increase arterial elasticity in large arteries.

  11. Mechanisms mediating the coronary vascular response to behavioral stress in the dog.

    Science.gov (United States)

    Billman, G E; Randall, D C

    1981-02-01

    Left circumflex coronary blood flow (CBF) was measured in eight mongrel dogs with 8 MHz continuous wave Doppler flow transducers during classical aversive conditioning. The cardiovascular condition response consisted of significant (P less than 0.01) increases in: (1) mean aortic pressure (16.1%), (2) d(left ventricular pressure)/dt (64.2%), and (3) heart rate (63.2%). The coronary vascular response to behavioral stress consisted of an initial late diastolic decrease in CBF (12.5%) between 5 and 10 seconds after conditional stimulus onset, followed by a significant increase in CBF (96.8%). Concurrently, late diastolic coronary vascular resistance (CVR) first significantly increased (21.9%), then significantly decreased (39.8%). The increase in CVR was attenuated by cardiac pacing and converted into a significant decrease after alpha-receptor blockade. The decrease in CVR was reduced either by cardiac pacing or cardioselective beta-receptor blockage and eliminated by the combination of alpha- and beta-receptor blockade. Thus, these data indicate that the coronary vascular response to stress consisted of two components: an initial alpha-adrenergic coronary vasoconstriction, followed by a more complex vasodilation which was probably mediated by metabolites released secondarily to increases in heart rate and inotropic state.

  12. Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Jiwoo [College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566 (Korea, Republic of); Ku, Sae-Kwang [Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610 (Korea, Republic of); Lee, Suyeon [College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566 (Korea, Republic of); Bae, Jong-Sup, E-mail: baejs@knu.ac.kr [College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566 (Korea, Republic of)

    2016-06-10

    Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.

  13. Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

    International Nuclear Information System (INIS)

    Chung, Jiwoo; Ku, Sae-Kwang; Lee, Suyeon; Bae, Jong-Sup

    2016-01-01

    Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.

  14. Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling.

    Science.gov (United States)

    Wolin, Michael S; Gupte, Sachin A; Neo, Boon Hwa; Gao, Qun; Ahmad, Mansoor

    2010-01-01

    Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension.

  15. Chronic ethanol consumption decreases adrenal responsiveness to adrenocorticotropin (ACTH) stimulation

    International Nuclear Information System (INIS)

    Nolan, C.J.; Bestervelt, L.L.; Cai, Y.; Maimansomsuk, P.; Coleman, L.; Piper, W.N.

    1991-01-01

    Increased alcohol consumption by adolescents and teenagers has heightened awareness of potential endocrine and developmental alterations. The current study was designed to determine whether chronic ethanol intake alters pituitary and adrenal function in the developing rat. One month old male Sprague Dawley rats were administered 6% ethanol in drinking water. After one month of treatment animals were sacrificed and blood, pituitary and adrenal glands collected. Plasma was assayed for ACTH and corticosterone (CS) by radioimmunossay (RIA). Five anterior pituitary glands per group were challenged with 100 μM corticotropin releasing factor (CRF) for 90 min at 37C under 95% air / 5% CO 2 . Media were analyzed for either ACTH (pituitary) or CS (adrenal) by RIA. Plasma ACTH and CS were unaffected by ethanol consumption. Pituitary response to CRF was not altered by ethanol. The lack of difference in ACTH release was not due to differences in pituitary content of ACTH. However, chronic ethanol consumption did decrease adrenal responsiveness to ACTH stimulation. In vitro corticosterone production was 1.21 ± 0.14 μg/adrenal in controls and 0.70 ± 0.06 μg/adrenal in ethanol consuming rats

  16. Single Pulse Electrical Stimulation to identify epileptogenic cortex : Clinical information obtained from early evoked responses

    NARCIS (Netherlands)

    Mouthaan, B.E.; van 't Klooster, M.A.; Keizer, D.; Hebbink, G.J.; Leijten, F.S.S.; Ferrier, C.H.; van Putten, M.J.A.M.; Zijlmans, M.; Huiskamp, G.J.M.

    Objective: Single Pulse Electrical Stimulation (SPES) probes epileptogenic cortex during electrocorticography. Two SPES responses are described: pathological delayed responses (DR, >100 ms) associated with the seizure onset zone (SOZ) and physiological early responses (ER, <100 ms) that map cortical

  17. Tempol improves xanthine oxidoreductase-mediated vascular responses to nitrite in experimental renovascular hypertension

    Directory of Open Access Journals (Sweden)

    Gustavo H. Oliveira-Paula

    2016-08-01

    Full Text Available Upregulation of xanthine oxidoreductase (XOR increases vascular reactive oxygen species (ROS levels and contributes to nitroso-redox imbalance. However, XOR can generate nitric oxide (NO from nitrite, and increased superoxide could inactivate NO formed from nitrite. This study tested the hypothesis that XOR contributes to the cardiovascular effects of nitrite in renovascular hypertension, and that treatment with the antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl improves XOR-mediated effects of nitrite. Blood pressure was assessed weekly in two-kidney one-clip (2K1C and control rats. After six weeks of hypertension, the relaxing responses to nitrite were assessed in aortic rings in the presence of the XOR inhibitor oxypurinol (or vehicle, either in the absence or in the presence of tempol. Moreover, in vivo hypotensive responses to nitrite were also examined in the presence of oxypurinol (or vehicle and tempol (or vehicle. Aortic XOR activity and expression were evaluated by fluorescence and Western blot, respectively. Vascular ROS production was assessed by the dihydroethidium assay. 2K1C hypertensive rats showed increased aortic XOR activity and vascular ROS production compared with control rats. Oxypurinol shifted the nitrite concentration–response curve to the right in aortic rings from 2K1C rats (but not in controls. Oxypurinol also attenuated the hypotensive responses to nitrite in 2K1C rats (but not in controls. These functional findings agree with increased aortic and plasma XOR activity found in 2K1C rats. Tempol treatment enhanced oxypurinol-induced shift of the nitrite concentration–response curve to the right. However, antioxidant treatment did not affect XOR-mediated hypotensive effects of nitrite. Our results show that XOR is important to the cardiovascular responses to nitrite in 2K1C hypertension, and XOR inhibitors commonly used by patients may cancel this effect. This finding suggests that nitrite

  18. Tempol improves xanthine oxidoreductase-mediated vascular responses to nitrite in experimental renovascular hypertension.

    Science.gov (United States)

    Oliveira-Paula, Gustavo H; Pinheiro, Lucas C; Guimaraes, Danielle A; Tella, Sandra O Conde; Blanco, Ana L Furlan; Angelis, Celio D; Schechter, Alan N; Tanus-Santos, Jose E

    2016-08-01

    Upregulation of xanthine oxidoreductase (XOR) increases vascular reactive oxygen species (ROS) levels and contributes to nitroso-redox imbalance. However, XOR can generate nitric oxide (NO) from nitrite, and increased superoxide could inactivate NO formed from nitrite. This study tested the hypothesis that XOR contributes to the cardiovascular effects of nitrite in renovascular hypertension, and that treatment with the antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) improves XOR-mediated effects of nitrite. Blood pressure was assessed weekly in two-kidney one-clip (2K1C) and control rats. After six weeks of hypertension, the relaxing responses to nitrite were assessed in aortic rings in the presence of the XOR inhibitor oxypurinol (or vehicle), either in the absence or in the presence of tempol. Moreover, in vivo hypotensive responses to nitrite were also examined in the presence of oxypurinol (or vehicle) and tempol (or vehicle). Aortic XOR activity and expression were evaluated by fluorescence and Western blot, respectively. Vascular ROS production was assessed by the dihydroethidium assay. 2K1C hypertensive rats showed increased aortic XOR activity and vascular ROS production compared with control rats. Oxypurinol shifted the nitrite concentration-response curve to the right in aortic rings from 2K1C rats (but not in controls). Oxypurinol also attenuated the hypotensive responses to nitrite in 2K1C rats (but not in controls). These functional findings agree with increased aortic and plasma XOR activity found in 2K1C rats. Tempol treatment enhanced oxypurinol-induced shift of the nitrite concentration-response curve to the right. However, antioxidant treatment did not affect XOR-mediated hypotensive effects of nitrite. Our results show that XOR is important to the cardiovascular responses to nitrite in 2K1C hypertension, and XOR inhibitors commonly used by patients may cancel this effect. This finding suggests that nitrite treatment may not be

  19. Characterization of ionizing radiation-induced unfolded protein response in human vascular endothelial cells

    International Nuclear Information System (INIS)

    Kim, Eun Ju; Lee, Yoon Jin; Kang, Seong Man

    2013-01-01

    Misfolded or unfolded proteins within the endoplasmic reticulum (ER stress), viral infection, or amino acid deprivation induce eukaryotic translation initiation factor 2α phosphorylation (eIF2α) in eukaryotic cells, repressing global protein synthesis coincident with preferential translation of activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of genes involved in amino acid metabolism, cellular redox homeostasis, and regulation of apoptosis. When the eIF2α/ATF4 pathway is initiated by ER stress, the pathway is referred toas the unfolded protein response (UPR). In addition to DNA, proteins may be initial and important targets of ionizing radiation (IR), and the damaged protein can trigger ER stress pathway. Recent investigations suggested that IR induces ER stress followed by UPR in various cell types including intestinal epithelial cells. We conducted this study to determine whether IR can activate UPR in human vascular endothelial cells. Our data have shown that IR increased PERK-dependent eIF2α phosphorylation accompanied by induction in ATF4 protein levels in human vascular endothelial cells without alterations in expressions of XBP-1s and GRP78. Based on these data, we suggest that IR selectively activates PERK branch of unfolded protein response in human vascular endothelial cells

  20. Characterization of ionizing radiation-induced unfolded protein response in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ju; Lee, Yoon Jin; Kang, Seong Man [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-04-15

    Misfolded or unfolded proteins within the endoplasmic reticulum (ER stress), viral infection, or amino acid deprivation induce eukaryotic translation initiation factor 2α phosphorylation (eIF2α) in eukaryotic cells, repressing global protein synthesis coincident with preferential translation of activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of genes involved in amino acid metabolism, cellular redox homeostasis, and regulation of apoptosis. When the eIF2α/ATF4 pathway is initiated by ER stress, the pathway is referred toas the unfolded protein response (UPR). In addition to DNA, proteins may be initial and important targets of ionizing radiation (IR), and the damaged protein can trigger ER stress pathway. Recent investigations suggested that IR induces ER stress followed by UPR in various cell types including intestinal epithelial cells. We conducted this study to determine whether IR can activate UPR in human vascular endothelial cells. Our data have shown that IR increased PERK-dependent eIF2α phosphorylation accompanied by induction in ATF4 protein levels in human vascular endothelial cells without alterations in expressions of XBP-1s and GRP78. Based on these data, we suggest that IR selectively activates PERK branch of unfolded protein response in human vascular endothelial cells.

  1. The utility of endovascular simulation to improve technical performance and stimulate continued interest of preclinical medical students in vascular surgery.

    Science.gov (United States)

    Lee, Jason T; Qiu, Mary; Teshome, Mediget; Raghavan, Shyam S; Tedesco, Maureen M; Dalman, Ronald L

    2009-01-01

    New training paradigms in vascular surgery allow for early specialization out of medical school. Surgical simulation has emerged as an educational tool for trainees to practice procedures in a controlled environment allowing interested medical students to perform procedures without compromising patient safety. The purpose of this study is to assess the ability of a simulation-based curriculum to improve the technical performance and interest level of medical students in vascular surgery. Prospective observational cohort study of medical student performance. Academic medical center. Forty-one medical students (23 first year, 15 second year, 3 other) enrolled in a vascular surgery elective course. Students completed a survey of their interests and performed a renal stent procedure on an endovascular simulator (pretest). The curriculum consisted of didactic teaching and weekly mentored simulator sessions and concluded with a final renal stent procedure on the simulator (posttest). Objective procedural measures were determined during the pre- and posttest by the simulator, and subjective performance was graded by expert observers utilizing a structured global assessment scale. After the course, the students were surveyed as to their opinions about vascular surgery as a career option. Finally, 1 year after the course, all students were again surveyed to determine continued interest in vascular surgery. The objective and subjective criteria measured on the simulator and structured global assessment scale significantly improved from pre- to posttest in terms of performer technical skill, patient safety measures, and structured global assessments. Before beginning the course, 8.5% of the students expressed high interest in vascular surgery, and after completing the course 70% were seriously considering vascular surgery as a career option (p = 0.0001). More than 95% of the students responded that endovascular simulation increased their knowledge and interest in vascular

  2. Modified prenatal sensory stimulation influences postnatal behavioral and perceptual responsiveness in bobwhite quail chicks (Colinus virginianus).

    Science.gov (United States)

    Reynolds, Greg D; Lickliter, Robert

    2004-06-01

    Asynchronous bimodal stimulation during prenatal development elicits higher levels of behavioral and physiological arousal in precocial avian embryos than does unimodal sensory stimulation. To investigate whether the increased arousal associated with prenatal bimodal stimulation has enduring effects into postnatal development, bobwhite quail (Colinus virginianus) embryos received no supplemental stimulation, unimodal auditory stimulation, or bimodal (audiovisual) stimulation prior to hatching. Embryos exposed to concurrent bimodal stimulation demonstrated greater levels of behavioral activity and failed to use maternal visual cues to successfully direct species-specific perceptual preferences following hatching. These results provide initial evidence that asynchronous bimodal sensory stimulation during prenatal development can have enduring effects on early postnatal behavioral arousal and perceptual responsiveness and suggest that developmental limitations on prenatal sensory stimulation play an important role in the emergence of species-typical behavior.

  3. Responses to lumbar magnetic stimulation in newborns with spina bifida.

    NARCIS (Netherlands)

    Geerdink, N.; Pasman, J.W.; Roeleveld, N.; Rotteveel, J.J.; Mullaart, R.A.

    2006-01-01

    Searching for a tool to quantify motor impairment in spina bifida, transcranial and lumbar magnetic stimulation were applied in affected newborn infants. Lumbar magnetic stimulation resulted in motor evoked potentials in both the quadriceps muscle and the tibialis anterior muscle in most (11/13)

  4. Exercício físico, receptores β-adrenérgicos e resposta vascular Physical exercise, β-adrenergic receptors, and vascular response

    Directory of Open Access Journals (Sweden)

    Alexandre Sérgio Silva

    2010-06-01

    Full Text Available O exercício aeróbio promove efeitos benéficos na prevenção e tratamento de doenças como hipertensão arterial, aterosclerose, insuficiência venosa e doença arterial periférica. Os receptores β-adrenérgicos estão presentes em várias células. No sistema cardiovascular, promovem inotropismo e cronotropismo positivo cardíaco e relaxamento vascular. Embora os efeitos do exercício tenham sido investigados em receptores cardíacos, estudos focados nos vasos são escassos e controversos. Esta revisão abordará os efeitos do exercício físico sobre os receptores β-adrenérgicos vasculares em modelos animais e humanos e os mecanismos celulares envolvidos na resposta relaxante. Em geral, os estudos mostram resultantes conflitantes, onde observam diminuição, aumento ou nenhum efeito do exercício físico sobre a resposta relaxante. Assim, os efeitos do exercício na sensibilidade β-adrenérgica vascular merecem maior atenção, e os resultados mostram que a área de fisiopatologia vascular é um campo aberto para a descoberta de novos compostos e avanços na prática clínica.Aerobic exercise promotes beneficial effects on the prevention and treatment of diseases such as arterial hypertension, atherosclerosis, venous insufficiency, and peripheral arterial disease. β-adrenergic receptors are present in a variety of cells. In the cardiovascular system, β-adrenergic receptors promote positive inotropic and chronotropic response and vasorelaxation. Although the effect of exercise training has been largely studied in the cardiac tissue, studies focused on the vascular tissue are rare and controversial. This review examines the data from studies using animal and human models to determine the effect of physical exercise on the relaxing response mediated by β-adrenergic receptors as well as the cellular mechanisms involved in this response. Studies have shown reduction, increase, or no effect of physical exercise on the relaxing response

  5. How T-cell-dependent and -independent challenges access the brain: vascular and neural responses to bacterial lipopolysaccharide and staphylococcal enterotoxin B.

    Science.gov (United States)

    Serrats, Jordi; Sawchenko, Paul E

    2009-10-01

    Bacterial lipopolysaccharide (LPS) is widely used to study immune influences on the CNS, and cerebrovascular prostaglandin (PG) synthesis is implicated in mediating LPS influences on some acute phase responses. Other bacterial products, such as staphylococcal enterotoxin B (SEB), impact target tissues differently in that their effects are T-lymphocyte-dependent, yet both LPS and SEB recruit a partially overlapping set of subcortical central autonomic cell groups. We sought to compare neurovascular responses to the two pathogens, and the mechanisms by which they may access the brain. Rats received iv injections of LPS (2 microg/kg), SEB (1mg/kg) or vehicle and were sacrificed 0.5-3h later. Both challenges engaged vascular cells as early 0.5h, as evidenced by induced expression of the vascular early response gene (Verge), and the immediate-early gene, NGFI-B. Cyclooxygenase-2 (COX-2) expression was detected in both endothelial and perivascular cells (PVCs) in response to LPS, but only in PVCs of SEB-challenged animals. The non-selective COX inhibitor, indomethacin (1mg/kg, iv), blocked LPS-induced activation in a subset of central autonomic structures, but failed to alter SEB-driven responses. Liposome mediated ablation of PVCs modulated the CNS response to LPS, did not affect the SEB-induced activational profile. By contrast, disruptions of interoceptive signaling by area postrema lesions or vagotomy (complete or hepatic) markedly attenuated SEB-, but not LPS-, stimulated central activational responses. Despite partial overlap in their neuronal and vascular response profiles, LPS and SEB appear to use distinct mechanisms to access the brain.

  6. The moderate essential amino acid restriction entailed by low-protein vegan diets may promote vascular health by stimulating FGF21 secretion.

    Science.gov (United States)

    McCarty, Mark F

    2016-02-12

    The serum total and LDL cholesterol levels of long-term vegans tend to be very low. The characteristically low ratio of saturated to unsaturated fat in vegan diets, and the absence of cholesterol in such diets, clearly contribute to this effect. But there is reason to suspect that the quantity and composition of dietary protein also play a role in this regard. Vegan diets of moderate protein intake tend to be relatively low in certain essential amino acids, and as a result may increase hepatic activity of the kinase GCN2, which functions as a gauge of amino acid status. GCN2 activation boosts the liver's production of fibroblast growth factor 21 (FGF21), a factor which favorably affects serum lipids and metabolic syndrome. The ability of FGF21 to decrease LDL cholesterol has now been traced to at least two mechanisms: a suppression of hepatocyte expression of sterol response element-binding protein-2 (SREBP-2), which in turn leads to a reduction in cholesterol synthesis; and up-regulated expression of hepatocyte LDL receptors, reflecting inhibition of a mechanism that promotes proteasomal degradation of these receptors. In mice, the vascular benefits of FGF21 are also mediated by favorable effects on adipocyte function - most notably, increased adipocyte secretion of adiponectin, which directly exerts anti-inflammatory effects on the vasculature which complement the concurrent reduction in LDL particles in preventing or reversing atherosclerosis. If, as has been proposed, plant proteins preferentially stimulate glucagon secretion owing to their amino acid composition, this would represent an additional mechanism whereby plant protein promotes FGF21 activity, as glucagon acts on the liver to boost transcription of the FGF21 gene.

  7. Simvastatin attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury.

    Science.gov (United States)

    Wang, Kuo-Wei; Chen, Han-Jung; Lu, Kang; Liliang, Po-Chou; Liang, Cheng-Loong; Tsai, Yu-Duan; Cho, Chung-Lung

    2014-01-01

    Traumatic brain injury (TBI) leads to important and deleterious inflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation and outcome after TBI. It may represent a key cellular target for statin therapy. In our study, cortical contusions were induced, and the effect of continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI was evaluated. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test. The results showed that the non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point as compared to the expression in treatment group. The treatment group had better neurological function as evidenced in a grip test performed from baseline to 72 h. The analysis of a western blot test and pathology also demonstrated reduced ICAM-1 expression and a smaller area of damage and tissue loss. Our findings suggest that simvastatin could attenuate the activation of cerebral vascular endothelial inflammatory response and decrease the loss of neurological function and brain tissue.

  8. Change in the in vivo hyperthermic response resulting from the metabolic effects of temporary vascular occlusion

    International Nuclear Information System (INIS)

    Stewart, J.R.; Gibbs, F.A. Jr.; Lehman, C.M.; Peck, J.W.; Egger, M.J.

    1983-01-01

    Previous workers have reported that clamping of animal tumors in vivo enhanced the effect of hyperthermia; the enhancement has been attributed to pH and nutritional effects of vascular occlusion. It has not been clear, however, the degree to which improved heating patterns or effects on the tumor cells and vasculature from the clamping procedure itself might have contributed to the observed effect. In the experiments herein reported, care was taken to insure comparable heating of C3H mouse mammary tumors transplanted on the flank whether clamped or unclamped. Clamping for one hour with hyperthermia during the final 30 minutes caused a marked thermosensitization as measured by tumor control. The temperature at 30 minutes heating to control 50% of the tumors for 120 days (TCT 50-120) was reduced from 46.8 degrees C in controls to 43.5 degrees C in clamped tumors, a difference of 3.3 +/- 0.09 degrees C. No cytotoxicity from the clamping alone was evident by assessment of subsequent tumor growth and no lasting vascular effects could be detected by 133 Xe washout and tumor growth. Since the techniques used produced essentially identical heating patterns, we conclude that the striking enhancement in hyperthermic response in clamped tumors can be attributed to the metabolic consequences of temporary vascular occlusion

  9. Vascular Response of Ruthenium Tetraamines in Aortic Ring from Normotensive Rats

    Energy Technology Data Exchange (ETDEWEB)

    Conceição-Vertamatti, Ana Gabriela; Ramos, Luiz Alberto Ferreira [Universidade Estadual de Campinas (UNICAMP), São Paulo, SP (Brazil); Calandreli, Ivy; Chiba, Aline Nunes [Universidade de São Paulo (USP), Campus Ribeirão Preto, São Paulo, SP (Brazil); Franco, Douglas Wagner [Universidade de São Paulo (USP), Campus São Carlos, São Paulo, SP (Brazil); Tfouni, Elia [Universidade de São Paulo (USP), Campus Ribeirão Preto, São Paulo, SP (Brazil); Grassi-Kassisse, Dora Maria, E-mail: doramgk@unicamp.br [Universidade Estadual de Campinas (UNICAMP), São Paulo, SP (Brazil)

    2015-03-15

    Ruthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved. To evaluate the vascular response of the tetraamines trans-[Ru{sup II}(NH{sub 3}){sub 4}(Py)(NO)]{sup 3+}, trans-[Ru{sup II}(Cl)(NO) (cyclan)](PF{sub 6}){sub 2}, and trans-[Ru{sup II}(NH{sub 3}){sub 4}(4-acPy)(NO)]{sup 3+}. Aortic rings were contracted with noradrenaline (10{sup −6} M). After voltage stabilization, a single concentration (10{sup −6} M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10{sup −6} M and sodium nitroprusside at 10{sup −6} M as well as by histological examination. Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect. The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10{sup −6} M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used

  10. Contact area affects frequency-dependent responses to vibration in the peripheral vascular and sensorineural systems.

    Science.gov (United States)

    Krajnak, Kristine; Miller, G R; Waugh, Stacey

    2018-01-01

    Repetitive exposure to hand-transmitted vibration is associated with development of peripheral vascular and sensorineural dysfunctions. These disorders and symptoms associated with it are referred to as hand-arm vibration syndrome (HAVS). Although the symptoms of the disorder have been well characterized, the etiology and contribution of various exposure factors to development of the dysfunctions are not well understood. Previous studies performed using a rat-tail model of vibration demonstrated that vascular and peripheral nervous system adverse effects of vibration are frequency-dependent, with vibration frequencies at or near the resonant frequency producing the most severe injury. However, in these investigations, the amplitude of the exposed tissue was greater than amplitude typically noted in human fingers. To determine how contact with vibrating source and amplitude of the biodynamic response of the tissue affects the risk of injury occurring, this study compared the influence of frequency using different levels of restraint to assess how maintaining contact of the tail with vibrating source affects the transmission of vibration. Data demonstrated that for the most part, increasing the contact of the tail with the platform by restraining it with additional straps resulted in an enhancement in transmission of vibration signal and elevation in factors associated with vascular and peripheral nerve injury. In addition, there were also frequency-dependent effects, with exposure at 250 Hz generating greater effects than vibration at 62.5 Hz. These observations are consistent with studies in humans demonstrating that greater contact and exposure to frequencies near the resonant frequency pose the highest risk for generating peripheral vascular and sensorineural dysfunction.

  11. Antioxidative response in variegated Pelargonium zonale leaves and generation of extracellular H2O2 in (peri)vascular tissue induced by sunlight and paraquat.

    Science.gov (United States)

    Vidović, Marija; Morina, Filis; Prokić, Ljiljana; Milić-Komić, Sonja; Živanović, Bojana; Jovanović, Sonja Veljović

    2016-11-01

    In this study we exposed variegated leaves of Pelargonium zonale to strong sunlight (>1100μmolm -2 s -1 of photosynthetically active radiation) with and without paraquat (Pq), with the aim to elucidate the mechanisms of H 2 O 2 regulation in green and white tissues with respect to the photosynthetically-dependent generation of reactive oxygen species (ROS). Sunlight induced marked accumulation of H 2 O 2 in the apoplast of vascular and (peri)vascular tissues only in green sectors. This effect was enhanced by the addition of Pq. In the presence of diphenyl iodide, an NADPH oxidase inhibitor, H 2 O 2 accumulation was abolished. Distinct light-induced responses were observed: in photosynthetic cells, sunlight rapidly provoked ascorbate (Asc) biosynthesis and an increase of glutathione reductase (GR) and catalase activities, while in non-photosynthetic cells, early up-regulation of soluble ascorbate peroxidase, dehydroascorbate reductase (DHAR) and GR activities was observed. Paraquat addition stimulated DHAR and GR activities in green sectors, while in white sectors activities of monodehydroascorbate reductase, DHAR and class III peroxidases, as well as Asc content rapidly increased. Differential antioxidative responses in the two tissues in the frame of their contrasting metabolisms, and the possible role of (peri)vascular H 2 O 2 in signaling were discussed. Copyright © 2016 Elsevier GmbH. All rights reserved.

  12. Nitric oxide and TNFα are critical regulators of reversible lymph node vascular remodeling and adaptive immune response.

    Directory of Open Access Journals (Sweden)

    Stephanie L Sellers

    Full Text Available Lymph node (LN vascular growth, at the level of the main arteriole, was recently characterized for the first time during infection. Arteriole diameter was shown to increase for at least seven days and to occur via a CD4(+ T cell dependent mechanism, with vascular expansion playing a critical role in regulating induction of adaptive immune response. Here, using intravital microscopy of the inguinal LN during herpes simplex type II (HSV-2 infection, the data provides the first studies that demonstrate arteriole expansion during infection is a reversible vascular event that occurs via eutrophic outward remodeling. Furthermore, using genetic ablation models, and pharmacological blockade, we reveal arteriole remodeling and LN hypertrophy to be dependent upon both endothelial nitric oxide synthase (eNOS and TNFα expression. Additionally, we reveal transient changes in nitric oxide (NO levels to be a notable feature of response to viral infection and LN vascular remodeling and provide evidence that mast cells are the critical source of TNFα required to drive arteriole remodeling. Overall, this study is the first to fully characterize LN arteriole vascular changes throughout the course of infection. It effectively reveals a novel role for NO and TNFα in LN cellularity and changes in LN vascularity, which represent key advances in understanding LN vascular physiology and adaptive immune response.

  13. Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Yu-Ying Chen

    2014-01-01

    Full Text Available Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α. Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK, Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  14. Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity

    OpenAIRE

    Christou, Demetra D.; Pierce, Gary L.; Walker, Ashley E.; Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Meade, Thomas H.; English, Mark; Seals, Douglas R.

    2012-01-01

    Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18–79 years; body mass index (BMI), 16.4–42.2 kg/m2], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI...

  15. Visual stimulation facilitates penile responses to vibration in men with and without erectile disorder

    NARCIS (Netherlands)

    Janssen, E.; Everaerd, W.; van Lunsen, R. H.; Oerlemans, S.

    1994-01-01

    This study compared reflexogenic and psychogenic penile responses in men with and without erectile disorder. It was hypothesized that men with psychogenic erectile dysfunction respond minimally to vibrotactile stimulation. An enhancement of penile responses was expected when vibration was combined

  16. Effects of vehicle microdialysis solutions on cutaneous vascular responses to local heating.

    Science.gov (United States)

    Smith, Caroline J; Craighead, Daniel H; Alexander, Lacy M

    2017-12-01

    Microdialysis is a minimally invasive technique often paired with laser Doppler flowmetry to examine cutaneous microvascular function, yet presents with several challenges, including incompatibility with perfusion of highly lipophilic compounds. The present study addresses this methodological concern, with an emphasis on the independent effects of commonly used vehicle dialysis solutions to improve solubility of pharmacological agents with otherwise low aqueous solubility. Four microdialysis fibers were placed in the ventral forearm of eight subjects (4 men, 4 women; 25 ± 1 yr) with sites randomized to serve as 1) control (lactated Ringer's), 2) Sodium carbonate-bicarbonate buffer administered at physiological pH [SCB-HCl; pH 7.4, achieved via addition of hydrochloric acid (HCl)], 3) 0.02% ethanol, and 4) 2% dimethyl sulfoxide (DMSO). After baseline (34°C), vehicle solutions were administered throughout a standardized local heating protocol to 42°C. Laser Doppler flowmetry provided an index of blood flow. Cutaneous vascular conductance was calculated and normalized to maximum (%CVC max , sodium nitroprusside and 43°C local heat). The SCB-HCl solution increased baseline %CVC max (control: 9.7 ± 0.8; SCB-HCl: 21.5 ± 3.5%CVC max ; P = 0.03), but no effects were observed during heating or maximal vasodilation. There were no differences with perfusion of ethanol or DMSO at any stage of the protocol ( P > 0.05). These data demonstrate the potential confounding effects of some vehicle dialysis solutions on cutaneous vascular function. Notably, this study provides evidence that 2% DMSO and 0.02% ethanol are acceptable vehicles with no confounding local vascular effects to a standardized local heating protocol at the concentrations presented. NEW & NOTEWORTHY This study examined the independent effects of common vehicle solutions on cutaneous vascular responses. A basic buffer (SCB-HCl) caused baseline vasodilation; 2% DMSO and 0.02% ethanol had no effects

  17. Prediction of cortical responses to simultaneous electrical stimulation of the retina.

    Science.gov (United States)

    Halupka, Kerry J; Shivdasani, Mohit N; Cloherty, Shaun L; Grayden, David B; Wong, Yan T; Burkitt, Anthony N; Meffin, Hamish

    2017-02-01

    Simultaneous electrical stimulation of multiple electrodes has shown promise in diversifying the responses that can be elicited by retinal prostheses compared to interleaved single electrode stimulation. However, the effects of interactions between electrodes are not well understood and clinical trials with simultaneous stimulation have produced inconsistent results. We investigated the effects of multiple electrode stimulation of the retina by developing a model of cortical responses to retinal stimulation. Electrical stimuli consisting of temporally sparse, biphasic current pulses, with amplitudes sampled from a bi-dimensional Gaussian distribution, were simultaneously delivered to the retina across a 42-channel electrode array implanted in the suprachoroidal space of anesthetized cats. Visual cortex activity was recorded using penetrating microelectrode arrays. These data were used to identify a linear-nonlinear model of cortical responses to retinal stimulation. The ability of the model to generalize was tested by predicting responses to non-white patterned stimuli. The model accurately predicted two cortical activity measures: multi-unit neural responses and evoked potential responses to white noise stimuli. The model also provides information about electrical receptive fields, including the relative effects of each stimulating electrode on every recording site. We have demonstrated a simple model that accurately describes cortical responses to simultaneous stimulation of a suprachoroidal retinal prosthesis. Overall, our results demonstrate that cortical responses to simultaneous multi-electrode stimulation of the retina are repeatable and predictable, and that interactions between electrodes during simultaneous stimulation are predominantly linear. The model shows promise for determining optimal stimulation paradigms for exploiting interactions between electrodes to shape neural activity, thereby improving outcomes for patients with retinal prostheses.

  18. The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias.

    Science.gov (United States)

    Sloop, Gregory D; Weidman, Joseph J; St Cyr, John A

    2015-12-01

    Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing 'anemia of chronic disease or inflammation' or 'hemolytic anemia' both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension. © The Author(s), 2015.

  19. High frequency switched-mode stimulation can evoke postsynaptic responses in cerebellar principal neurons

    Directory of Open Access Journals (Sweden)

    Marijn Van Dongen

    2015-03-01

    Full Text Available This paper investigates the efficacy of high frequency switched-mode neural stimulation. Instead of using a constant stimulation amplitude, the stimulus is switched on and off repeatedly with a high frequency (up to 100kHz duty cycled signal. By means of tissue modeling that includes the dynamic properties of both the tissue material as well as the axon membrane, it is first shown that switched-mode stimulation depolarizes the cell membrane in a similar way as classical constant amplitude stimulation.These findings are subsequently verified using in vitro experiments in which the response of a Purkinje cell is measured due to a stimulation signal in the molecular layer of the cerebellum of a mouse. For this purpose a stimulator circuit is developed that is able to produce a monophasic high frequency switched-mode stimulation signal. The results confirm the modeling by showing that switched-mode stimulation is able to induce similar responses in the Purkinje cell as classical stimulation using a constant current source. This conclusion opens up possibilities for novel stimulation designs that can improve the performance of the stimulator circuitry. Care has to be taken to avoid losses in the system due to the higher operating frequency.

  20. Stimulated mitogen-activated protein kinase is necessary but not sufficient for the mitogenic response to angiotensin II. A role for phospholipase D.

    Science.gov (United States)

    Wilkie, N; Morton, C; Ng, L L; Boarder, M R

    1996-12-13

    Activation of the mitogen-activated protein kinase (MAPK) cascade has been widely associated with cell proliferation; previous studies have shown that angiotensin II (AII), acting on 7-transmembrane G protein-coupled receptors, stimulates the MAPK pathway. In this report we investigate whether the MAPK pathway is required for the mitogenic response to AII stimulation of vascular smooth muscle cells derived from the hypertensive rat (SHR-VSM). AII stimulates the phosphorylation of MAPK, as determined by Western blot specific for the tyrosine 204 phosphorylated form of the protein. This MAPK phosphorylation was inhibited by the presence of the inhibitor of MAPK kinase activation, PD 098059. Using a peptide kinase assay shown to measure the p42 and p44 isoforms of MAPK, the stimulated response to AII was inhibited by PD 098059 with an IC50 of 15.6 +/- 1.6 microM. The AII stimulation of [3H]thymidine incorporation was inhibited by PD 098059 with an IC50 of 17.8 +/- 3.1 microM. PD 098059 had no effect on AII-stimulated phospholipase C or phospholipase D (PLD) activity. When the SHR-VSM cells were stimulated with phorbol ester, there was an activation of MAPK similar in size and duration to the response to AII, but there was no significant enhancement of [3H]thymidine incorporation. There was also no activation of PLD by phorbol ester, while AII produced a robust PLD response. Diversion of the product of the PLD reaction by 1-butanol caused a partial loss of the [3H]thymidine response; this did not occur with tertiary butanol, which did not interfere with the PLD reaction. These results show that in these cells the MAPK cascade is required but not sufficient for the mitogenic response to AII, and suggest that the full mitogenic response requires both MAPK in conjunction with other signaling components, one of which is PLD.

  1. Tumor cells secrete an angiogenic factor that stimulates basic fibroblast growth factor and urokinase expression in vascular endothelial cells

    NARCIS (Netherlands)

    Peverali, F.A.; Mandriota, S.J.; Ciana, P.; Marelli, R.; Quax, P.; Rifkin, D.B.; Della Valle, G.; Mignatti, P.

    1994-01-01

    Culture medium conditioned by human SK-Hep1 hepatoma cells or mouse S180 sarcoma cells rapidly up-regulates endothelial cell expression of basic fibroblast growth factor (bFGF) and induces formation of capillary-like structures by vascular endothelial cells grown on three-dimensional fibrin gels (in

  2. Atorvastatin Protects Vascular Smooth Muscle Cells From TGF-β1-Stimulated Calcification by Inducing Autophagy via Suppression of the β-Catenin Pathway

    Directory of Open Access Journals (Sweden)

    Demin Liu

    2014-01-01

    Full Text Available Background: Arterial calcification is a major event in the progression of atherosclerosis. It is reported that statins exhibit various protective effects against vascular smooth muscle cell (VSMC inflammation and proliferation in cardiovascular remodeling. Although statins counteract atherosclerosis, the molecular mechanisms of statins on the calcium release from VSMCs have not been clearly elucidated. Methods: Calcium content of VSMCs was measured using enzyme-linked immunosorbent assay (ELISA. The expression of proteins involved in cellular transdifferentiation was analyzed by western blot. Cell autophagy was measured by fluorescence microscopic analysis for acridine orange staining and transmission electron microscopy analysis. The autophagic inhibitors (3-MA, chloroquine, NH4Cl and bafilomycin A1 and β-catenin inhibitor JW74 were used to assess the effects of atorvastatin on autophagy and the involvement of β-catenin on cell calcification respectively. Furthermore, cell transfection was performed to overexpress β-catenin. Results: In VSMCs, atorvastatin significantly suppressed transforming growth factor-β1 (TGF-β1-stimulated calcification, accompanied by the induction of autophagy. Downregulation of autophagy with autophagic inhibitors significantly suppressed the inhibitory effect of atorvastatin on cell calcification. Moreover, the beneficial effect of atorvastatin on calcification and autophagy was reversed by β-catenin overexpression. Conversely, JW74 supplement enhanced this effect. Conclusion: These data demonstrated that atorvastatin protect VSMC from TGF-β1-stimulated calcification by inducing autophagy through suppression of the β-catenin pathway, identifying autophagy induction might be a therapeutic strategy for use in vascular calcification.

  3. Vascular Profile Characterization of Liver Tumors by Magnetic Resonance Imaging Using Hemodynamic Response Imaging in Mice

    Directory of Open Access Journals (Sweden)

    Yifat Edrei

    2011-03-01

    Full Text Available Recently, we have demonstrated the feasibility of using hemodynamic response imaging (HRI, a functional magnetic resonance imaging (MRI method combined with hypercapnia and hyperoxia, for monitoring vascular changes during liver pathologies without the need of contrast material. In this study, we evaluated HRI ability to assess changes in liver tumor vasculature during tumor establishment, progression, and antiangiogenic therapy. Colorectal adenocarcinoma cells were injected intrasplenically to model colorectal liver metastasis (CRLM and the Mdr2 knockout mice were used to model primary hepatic tumors. Hepatic perfusion parameters were evaluated using the HRI protocol and were compared with contrast-enhanced (CE MRI. The hypovascularity and the increased arterial blood supply in well-defined CRLM were demonstrated by HRI. In CRLM-bearing mice, the entire liver perfusion was attenuated as the HRI maps were significantly reduced by 35%. This study demonstrates that the HRI method showed enhanced sensitivity for small CRLM (1–2 mm detection compared with CE-MRI (82% versus 38%, respectively. In addition, HRI could demonstrate the vasculature alteration during CRLM progression (arborized vessels, which was further confirmed by histology. Moreover, HRI revealed the vascular changes induced by rapamycin treatment. Finally, HRI facilitates primary hepatic tumor characterization with good correlation to the pathologic differentiation. The HRI method is highly sensitive to subtle hemodynamic changes induced by CRLM and, hence, can function as an imaging tool for understanding the hemodynamic changes occurring during CRLM establishment, progression, and antiangiogenic treatment. In addition, this method facilitated the differentiation between different types of hepatic lesions based on their vascular profile noninvasively.

  4. Early changes in vascular reactivity in response to 56Fe irradiation in ApoE-/- mice

    Science.gov (United States)

    White, C. Roger; Yu, Tao; Gupta, Kiran; Babitz, Stephen K.; Black, Leland L.; Kabarowski, Janusz H.; Kucik, Dennis F.

    2015-03-01

    Epidemiological studies have established that radiation from a number of terrestrial sources increases the risk of atherosclerosis. The accelerated heavy ions in the galacto-cosmic radiation (GCR) that astronauts will encounter on in space, however, interact very differently with tissues than most types of terrestrial radiation, so the health consequences of exposure on deep-space missions are not clear. We demonstrated earlier that 56Fe, an important component of cosmic radiation, accelerates atherosclerotic plaque development. In the present study, we examined an earlier, pro-atherogenic event that might be predictive of later atherosclerotic disease. Decreased endothelium-dependent vasodilation is a prominent manifestation of vascular dysfunction that is thought to predispose humans to the development of structural vascular changes that precede the development of atherosclerotic plaques. To test the effect of heavy-ion radiation on endothelium-dependent vasodilation, we used the same ApoE-/- mouse model in which we previously demonstrated the pro-atherogenic effect of 56Fe on plaque development. Ten week old male ApoE mice (an age at which there is little atherosclerotic plaque in the descending aorta) were exposed to 2.6 Gy 56Fe. The mice were then fed a normal diet and housed under standard conditions. At 4-5 weeks post-irradiation, aortic rings were isolated and endothelial-dependent relaxation was measured. Relaxation in response to acetylcholine was significantly impaired in irradiated mice compared to age-matched, un-irradiated mice. This decrease in vascular reactivity following 56Fe irradiation occurred eight weeks prior to the development of statistically significant exacerbation of aortic plaque formation and may contribute to the formation of later atherosclerotic lesions.

  5. Impairment of microcirculation and vascular responsiveness in adolescents with primary Raynaud phenomenon.

    Science.gov (United States)

    Mosdósi, Bernadett; Bölcskei, Kata; Helyes, Zsuzsanna

    2018-03-23

    Raynaud's phenomenon (RP) is a functional vascular disease, presenting with recurrent episodes of ischemia of extremities in response to cold and emotional stress. Investigating cutaneous microcirculation is an important tool in understanding the complex neuro-immuno-vascular interactions in its pathophysiological mechanisms. Since there is no available data on vascular responsiveness in RP in the paediatric population, we investigated skin perfusion and heat-induced hyperaemia in comparison with clinical severity and laboratory parameters of the disease. Fifty two adolescents (27 patients with primary RP and 25 age-matched healthy controls) were investigated in the study. Patients were divided into two groups according to the symptoms existing within the previous 2 months. Following baseline microcirculation measurement with Laser Doppler flowmetry (Periflux 5000 system), all subjects underwent local heating test at 42 °C and 44 °C. Besides routine laboratory parameters, immune-serological tests and the vasoactive sensory neuropeptides somatostatin and pituitary adenylate-cyclase activating polypeptide (PACAP) were measured. Baseline perfusion measured in perfusion units (PU) at 32 °C was significantly lower in symptomatic RP patients (97.6 ± 22.4 PU) compared with both healthy volunteers (248.3 ± 23.5 PU, p  0.05) when compared with healthy subjects (555.9 ± 28.2 PU). Both the area under the response curve and the latency to reach the maximum flow were significantly increased in both RP groups (symptomatic 164.6 ± 7.4 s, p < 0.001, asymptomatic 236.4 ± 17.4 s, p < 0.001) when compared with the control group (101.9 ± 4.7 s). The heat-induced percentage increase from baseline to maximal blood flow was significantly greater in symptomatic RP adolescents in comparison with healthy ones. Laboratory parameters and neuropeptide plasma levels were not altered in any groups. To our knowledge this is the first study in

  6. Direct Measurement of Bipolar Cell Responses to Electrical Stimulation in Wholemount Mouse Retina.

    Science.gov (United States)

    Walston, Steven T; Chow, Robert H; Weiland, James D

    2018-03-07

    This in vitro investigation examines the response of retinal bipolar cells to extracellular electrical stimulation. Approach: In vitro investigations characterizing the response of retinal neurons to electrical stimulation have primarily focused on retinal ganglion cells because they are the output neurons of the retina and their superficial position in the retina makes them readily accessible to in vitro recording techniques. Thus, the majority of information regarding the response of inner retinal neurons has been inferred from ganglion cell activity. Here we use patch clamp electrophysiology to directly record electrically-evoked activity in bipolar cells within the inner retina of normal Tg(Gng13-EGFP)GI206Gsat and degenerate rd10 Tg(Gng13-EGFP)GI206Gsat mice using a wholemount preparation. Main Results: Bipolar cells respond to electrical stimulation with time-locked depolarizing voltage transients. The latency of the response declines with increases in stimulation amplitude. A desensitizing response is observed during repeated stimulation with 25-ms biphasic current pulses delivered at pulse rates greater than 6 pps. A burst of long-latency (200-1000 ms) inhibitory postsynaptic potentials are evoked by the stimulus and the burst exhibits evidence of a lower and upper stimulation threshold. Significance: These results provide insights into the various types of bipolar cell activity elicited by electrical stimulation and may be useful for future retinal prosthesis stimulation protocols. . © 2018 IOP Publishing Ltd.

  7. Effects of tempol on altered metabolism and renal vascular responsiveness in fructose-fed rats.

    Science.gov (United States)

    Abdulla, Mohammed H; Sattar, Munavvar A; Johns, Edward J

    2016-02-01

    This study investigated the effect of tempol (a superoxide dismutase mimetic) on renal vasoconstrictor responses to angiotensin II (Ang II) and adrenergic agonists in fructose-fed Sprague-Dawley rats (a model of metabolic syndrome). Rats were fed 20% fructose in drinking water (F) for 8 weeks. One fructose-fed group received tempol (FT) at 1 mmol·L(-1) in drinking water for 8 weeks or as an infusion (1.5 mg·kg(-1)·min(-1)) intrarenally. At the end of the treatment regimen, the renal responses to noradrenaline, phenylephrine, methoxamine, and Ang II were determined. F rats exhibited hyperinsulinemia, hyperuricemia, hypertriglyceridemia, and hypertension. Tempol reduced blood glucose and insulin levels (all p tempol infusion blunted responses to noradrenaline, methoxamine, and Ang II in control rats by 32%, 33%, and 62%, while it blunted responses to noradrenaline and Ang II in F rats by 26% and 32%, respectively (all p tempol treatment enhances renal vascular responsiveness in fructose-fed rats.

  8. Metabolomic profiling of cellular responses to carvedilol enantiomers in vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Mingxuan Wang

    Full Text Available Carvedilol is a non-selective β-blocker indicated in the treatment of hypertension and heart failure. Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood. Here we report the use of GC-MS metabolomic profiling to study the effects of Carvedilol enantiomers on vascular smooth muscle cells (A7r5 and to shed new light on molecular events underlying Carvedilol treatment. The metabolic analysis revealed alternations in the levels of 8 intracellular metabolites and 5 secreted metabolites in A7r5 cells incubated separately with S- and R-Carvedilol. Principal component analysis of the metabolite data demonstrated the characteristic metabolic signatures in S- and R-Carvedilol-treated cells. A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction. Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

  9. The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells.

    Science.gov (United States)

    Absi, Mais; Bruce, Jason I; Ward, Donald T

    2014-04-01

    Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.

  10. PPARδ Agonist GW501516 Inhibits PDGF-Stimulated Pulmonary Arterial Smooth Muscle Cell Function Related to Pathological Vascular Remodeling

    Directory of Open Access Journals (Sweden)

    Guangjie Liu

    2013-01-01

    Full Text Available Pulmonary arterial hypertension (PAH is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Growth factors, cytokines, and lipid mediators are involved in this remodeling process. Recent reports suggest that the peroxisome proliferator-activated receptors (PPARs play important roles in the regulation of cell growth and differentiation as well as tissue wounding and repair. In this study, we examined the role of PPARδ in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs. The data showed that PPARδ was the most abundant isoform in HPASMCs. PPARδ was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPARδ by GW501516, a specific PPARδ ligand, significantly inhibited PDGF-induced proliferation in HPASMCs. The inhibitory effect of GW501516 on HPASMCs was associated with decreased expression of cyclin D1, cyclin D3, CDK2, and CDK4 as well as increased expression of the cell cycle inhibitory genes G0S2 and P27kip1. Pretreatment of HPASMCs with GW501516 significantly inhibited PDGF-induced cell migration and collagen synthesis. GW501516 also significantly attenuated TNF-mediated expression of MCP-1. These results suggest that PPARδ may be a potential therapeutic target against the progression of vascular remodeling in PAH.

  11. A model of auditory nerve responses to electrical stimulation

    DEFF Research Database (Denmark)

    Joshi, Suyash Narendra; Dau, Torsten; Epp, Bastian

    peripheral for the cathodic phase. This results in an average difference of 200 μs in spike latency for AP generated by anodic vs cathodic pulses. It is hypothesized here that this difference is large enough to corrupt the temporal coding in the AN. To quantify effects of pulse polarity on auditory...... as a framework to test various stimulation strategies and to quantify their effect on the performance of CI listeners in psychophysical tasks....

  12. Separability of neural responses to standardised mechanical stimulation of limbs

    OpenAIRE

    Brunton, Emma; Blau, Christoph W.; Nazarpour, Kianoush

    2017-01-01

    Considerable scientific and technological efforts are currently being made towards the development of neural prostheses. Understanding how the peripheral nervous system responds to electro-mechanical stimulation of the limb, will help to inform the design of prostheses that can restore function or accelerate recovery from injury to the sensory motor system. However, due to differences in experimental protocols, it is difficult, if not impossible, to make meaningful comparisons between differe...

  13. Angiogenesis for tumor vascular normalization of Endostar on hepatoma 22 tumor-bearing mice is involved in the immune response.

    Science.gov (United States)

    Xu, Qingyu; Gu, Junfei; Lv, You; Yuan, Jiarui; Yang, Nan; Chen, Juan; Wang, Chunfei; Hou, Xuefeng; Jia, Xiaobin; Feng, Liang; Yin, Guowen

    2018-03-01

    Tumor vascular normalization involved in immune response is beneficial to the chemotherapy of tumors. Recombinant human endostatin (Endostar), an angiogenesis inhibitor, has been demonstrated to be effective in hepatocellular cancer (HCC). However, its vascular normalization in HCC and the role of the immune response in angiogenesis were unclear. In the present study, effects of Endostar on tumor vascular normalization were evaluated in hepatoma 22 (H22) tumor-bearing mice. Endostar was able to inhibit the proliferation and infiltration of tumor cells and improve α-fetoprotein, tumor necrosis factor-α and cyclic adenosine 5'-phosphate levels in the serum of H22-bearing mice, as well as the protein expression levels of the immune factors interferon-γ and cluster of differentiation (CD)86 in liver tissue. Endostar also exhibited more marked downregulation of the levels of vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, MMP-9 and interleukin-17 during day 3-9 treatment, resulting in short-term normalization of tumor blood vessels. The period of vascular normalization was 3-9 days. The results of the present study demonstrated that Endostar was able to induce the period of vascular normalization, contributing to a more efficacious means of HCC treatment combined with other chemotherapy, and this effect was associated with the immune response. It may be concluded that Endostar inhibited immunity-associated angiogenesis behaviors of vascular endothelial cells in response to HCC. The results of the present study provided more reasonable possibility for the combination therapy of Endostar for the treatment of HCC.

  14. Epilepsia partialis continua responsive to neocortical electrical stimulation.

    Science.gov (United States)

    Valentin, Antonio; Ughratdar, Ismail; Cheserem, Beverly; Morris, Robert; Selway, Richard; Alarcon, Gonzalo

    2015-08-01

    Epilepsia partialis continua (EPC), defined as a syndrome of continuous focal jerking, is a rare form of focal status epilepticus that usually affects a distal limb, and when prolonged, can produce long-lasting deficits in limb function. Substantial electrophysiologic evidence links the origin of EPC to the motor cortex; thus surgical resection carries the risk of significant handicap. We present two patients with focal, drug-resistant EPC, who were admitted for intracranial video-electroencephalography monitoring to elucidate the location of the epileptogenic focus and identification of eloquent motor cortex with functional mapping. In both cases, the focus resided at or near eloquent motor cortex and therefore precluded resective surgery. Chronic cortical stimulation delivered through subdural strips at the seizure focus (continuous stimulation at 60-130 Hz, 2-3 mA) resulted in >90% reduction in seizures and abolition of the EPC after a follow-up of 22 months in both patients. Following permanent implantation of cortical stimulators, no adverse effects were noted. EPC restarted when intensity was reduced or batteries depleted. Battery replacement restored previous improvement. This two-case report opens up avenues for the treatment of this debilitating condition. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

  15. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Jeongyeon; Ryoo, Sungwoo, E-mail: ryoosw08@kangwon.ac.kr

    2013-06-07

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.

  16. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    International Nuclear Information System (INIS)

    Yoon, Jeongyeon; Ryoo, Sungwoo

    2013-01-01

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner

  17. Effect of healthy aging on renal vascular responses to local cooling and apnea.

    Science.gov (United States)

    Patel, Hardikkumar M; Mast, Jessica L; Sinoway, Lawrence I; Muller, Matthew D

    2013-07-01

    Sympathetically mediated renal vasoconstriction may contribute to the pathogenesis of hypertension in older adults, but empirical data in support of this concept are lacking. In 10 young (26 ± 1 yr) and 11 older (67 ± 2 yr) subjects, we quantified acute hemodynamic responses to three sympathoexcitatory stimuli: local cooling of the forehead, cold pressor test (CPT), and voluntary apnea. We hypothesized that all stimuli would increase mean arterial blood pressure (MAP) and renal vascular resistance index (RVRI) and that aging would augment these effects. Beat-by-beat MAP, heart rate (HR), and renal blood flow velocity (from Doppler) were measured in the supine posture, and changes from baseline were compared between groups. In response to 1°C forehead cooling, aging was associated with an augmented MAP (20 ± 3 vs. 6 ± 2 mmHg) and RVRI (35 ± 6 vs. 16 ± 9%) but not HR. In older adults, there was a positive correlation between the cold-induced pressor response and forehead pain (R = 0.726), but this effect was not observed in young subjects. The CPT raised RVRI in both young (56 ± 13%) and older (45 ± 8%) subjects, but this was not different between groups. Relative to baseline, end-expiratory apnea increased RVRI to a similar extent in both young (46 ± 14%) and older (41 ± 9%) subjects. During sympathetic activation, renal vasoconstriction occurred in both groups. Forehead cooling caused an augmented pressor response in older adults that was related to pain perception.

  18. A Simple and Accurate Model to Predict Responses to Multi-electrode Stimulation in the Retina.

    Science.gov (United States)

    Maturana, Matias I; Apollo, Nicholas V; Hadjinicolaou, Alex E; Garrett, David J; Cloherty, Shaun L; Kameneva, Tatiana; Grayden, David B; Ibbotson, Michael R; Meffin, Hamish

    2016-04-01

    Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants). Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time) despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs) stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron's electrical receptive field (ERF), i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

  19. A Simple and Accurate Model to Predict Responses to Multi-electrode Stimulation in the Retina.

    Directory of Open Access Journals (Sweden)

    Matias I Maturana

    2016-04-01

    Full Text Available Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants. Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron's electrical receptive field (ERF, i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

  20. Referred pain and cutaneous responses from deep tissue electrical pain stimulation in the groin

    DEFF Research Database (Denmark)

    Aasvang, E K; Werner, M U; Kehlet, H

    2015-01-01

    outside the stimulation area was reported, with 90-100% having the same response on both days, depending on the location. Deep pain stimulation significantly increased the cutaneous HPT (P...>0.474, P≤0.040) at the two test days for the majority of test areas. CONCLUSION: Our results corroborate a systematic relationship between deep pain and changes in cutaneous nociception. The individual referred/projected pain patterns and cutaneous responses are variable, but reproducible...

  1. Vascular Endothelium as a Target of Immune Response in Renal Transplant Rejection

    Science.gov (United States)

    Piotti, Giovanni; Palmisano, Alessandra; Maggiore, Umberto; Buzio, Carlo

    2014-01-01

    This review of clinical and experimental studies aims at analyzing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularized solid transplants. Endothelial cells (EC) express all the major sets of antigens (Ag) that elicit host immune response, and therefore represent a preferential target in organ rejection. Some of the Ag expressed by EC are target of the antibody-mediated response, such as the AB0 blood group system, the human leukocyte antigens (HLA), and MHC class I related chain A antigens (MICA) systems, and the endothelial cell-restricted Ag; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover, the rejection process can force injured EC to expose cryptic self-Ag, toward which an autoimmune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are EC a passive target of the host immune response but also an active player in lymphocyte activation; therefore, their interaction with allogenic T-cells is analyzed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells. Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of EC to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ regulatory T-cells, that are crucial mediators of tolerance. PMID

  2. Electrically responsive microstructured polypyrrole-polyurethane composites for stimulated osteogenesis

    Science.gov (United States)

    Luculescu, Catalin Romeo; Acasandrei, Adriana Maria; Mustaciosu, Cosmin Catalin; Zamfirescu, Marian; Dinescu, Maria; Calin, Bogdan Stefanita; Popescu, Andrei; Chioibasu, Diana; Cristian, Dan; Paun, Irina Alexandra

    2018-03-01

    In this work, we demonstrate the efficiency of substrate-mediated electrical stimulation of micropatterned polypyrrole/polyurethane (PPy/PU) composites for enhancing the osteogenesis in osteoblast-like cells. The PPy/PU substrates were obtained by dispersing electrically conductive PPy nanograins within a mechanically resistant PU matrix. Spin-coated PPy/PU layers were micropatterned with predefined 3D geometries by ultrashort laser ablation. Then they were conformally coated by Matrix Assisted Pulsed Laser Evaporation, in order to restore their chemical and electrical integrity. The chemical structure of the laser-processed PPy/PU substrates was investigated by 2D and 3D mapping of the laser-processed areas, via Raman microspectroscopy. In vitro studies revealed that the micropatterned PPy/PU substrates facilitated the topological and electrical communication of the seeded osteoblasts. Specifically, we demonstrated the cells attachment on the predefined 3D micropatterns. More importantly, we found evidence about the cells mineralization inside the 3D micropatterns by investigating the calcium deposits by Energy-Dispersive X-Ray Spectroscopy (EDS) and Alizarin Red staining. We found that the substrate-mediated electrical stimulation of the PPy/PU substrates induced a twofold increase of the Ca deposits in the cultured cells.

  3. Dynamic properties of sensory stimulation evoked responses in mouse cerebellar granule cell layer and molecular layer.

    Science.gov (United States)

    Bing, Yan-Hua; Zhang, Guang-Jian; Sun, Lei; Chu, Chun-Ping; Qiu, De-Lai

    2015-01-12

    Sensory information coming from climbing fiber and mossy fiber-granule cell pathways, generates motor-related outputs according to internal rules of integration and computation in the cerebellar cortex. However, the dynamic properties of sensory information processing in mouse cerebellar cortex are less understood. Here, we studied the dynamic properties of sensory stimulation-evoked responses in the cerebellar granule cell layer (GCL) and molecular layer (ML) by electrophysiological recordings method. Our data showed that air-puff stimulation (5-10 ms in duration) of the ipsilateral whisker pad evoked single-peak responses in the GCL and ML; whereas a duration of stimulation ≥30 ms in GCL and ≥60 ms in ML, evoked double-peak responses that corresponded with stimulation-on and -off responses via mossy fiber pathway. The highest frequency of stimulation train for evoking GCL responses was 33 Hz. In contrast, the highest frequency of stimulation train for evoking ML responses was 4 Hz. These results indicate that the cerebellar granule cells transfer the high-fidelity sensory information from mossy fibers, which is cut-off by molecular layer interneurons (MLIs). Our results suggest that the MLIs network acts as a low-pass filter during the processing of high-frequency sensory information. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Mapping of the brain hemodynamic responses to sensorimotor stimulation in a rodent model: A BOLD fMRI study.

    Directory of Open Access Journals (Sweden)

    Salem Boussida

    Full Text Available Blood Oxygenation Level Dependent functional MRI (BOLD fMRI during electrical paw stimulation has been widely used in studies aimed at the understanding of the somatosensory network in rats. However, despite the well-established anatomical connections between cortical and subcortical structures of the sensorimotor system, most of these functional studies have been concentrated on the cortical effects of sensory electrical stimulation. BOLD fMRI study of the integration of a sensorimotor input across the sensorimotor network requires an appropriate methodology to elicit functional activation in cortical and subcortical areas owing to the regional differences in both neuronal and vascular architectures between these brain regions. Here, using a combination of low level anesthesia, long pulse duration of the electrical stimulation along with improved spatial and temporal signal to noise ratios, we provide a functional description of the main cortical and subcortical structures of the sensorimotor rat brain. With this calibrated fMRI protocol, unilateral non-noxious sensorimotor electrical hindpaw stimulation resulted in robust positive activations in the contralateral sensorimotor cortex and bilaterally in the sensorimotor thalamus nuclei, whereas negative activations were observed bilaterally in the dorsolateral caudate-putamen. These results demonstrate that, once the experimental setup allowing necessary spatial and temporal signal to noise ratios is reached, hemodynamic changes related to neuronal activity, as preserved by the combination of a soft anesthesia with a soft muscle relaxation, can be measured within the sensorimotor network. Moreover, the observed responses suggest that increasing pulse duration of the electrical stimulus adds a proprioceptive component to the sensory input that activates sensorimotor network in the brain, and that these activation patterns are similar to those induced by digits paw's movements. These findings may

  5. Ovarian response to recombinant human follicle-stimulating hormone

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; Andersen, Anders Nyboe; Fernández-Sánchez, Manuel

    2014-01-01

    OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrat......OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH...

  6. Intrinsic optical imaging study on cortical responses to electrical stimulation in ventral posterior medial nucleus of thalamus.

    Science.gov (United States)

    Zhang, Jiacheng; Zhang, Shaomin; Yu, Chaonan; Zheng, Xiaoxiang; Xu, Kedi

    2018-04-01

    Intracortical electrical micro-stimulation has been applied widely for the attempts on reconstruction of sensory functions. More recently, thalamic electrical stimulation has been proposed as a promising target for somatosensory stimulation. However, the cortical activations and mechanisms evoked by VPM stimulation remained unclear. In this report, the cortical neural responses to electrical stimulations were recorded by optical imaging of intrinsic signals. The impact of stimulation parameters was characterized to illustrate how the VPM stimulation alter cortical activities. Significant increases were found in cortical responses with increased stimulation amplitude or pulse width. However, frequency modulation exhibited significant inhibition with higher frequency stimulation. Our results suggest that optical imaging of intrinsic signals is sensitive and reliable to deep brain stimulations. These results may not only help to understand the modulation effects through thalamocortical pathway, but also show the possibility to use VPM stimulation to evoke frequency-tuned tactile sensations in rats. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Calcineurin /NFAT activation-dependence of leptin synthesis and vascular growth in response to mechanical stretch

    Directory of Open Access Journals (Sweden)

    Nadia Soudani

    2016-09-01

    Full Text Available Background and Aims- Hypertension and obesity are important risk factors of cardiovascular disease. They are both associated with high leptin levels and have been shown to promote vascular hypertrophy, through the RhoA/ROCK and ERK1/2 phosphorylation. Calcineurin/NFAT activation also induces vascular hypertrophy by upregulating various genes. This study aimed to decipher whether a crosstalk exists between the RhoA/ROCK pathway, Ca+2/calcineurin/NFAT pathway, and ERK1/2 phosphorylation in the process of mechanical stretch-induced vascular smooth muscle cell (VSMC hypertrophy and leptin synthesis. Methods and Results- Rat portal vein (RPV organ culture was used to investigate the effect of mechanical stretch and exogenous leptin (3.1 nM on VSMC hypertrophy and leptin synthesis. Results showed that stretching the RPV significantly upregulated leptin secretion, mRNA and protein expression, which were inhibited by the calcium channel blocker nifedipine (10 μM, the selective calcineurin inhibitor FK506 (1 nM and the ERK1/2 inhibitor PD98059 (1 μM. The transcription inhibitor actinomycin D (0.1M and the translation inhibitor cycloheximide (1 mM significantly decreased stretch-induced leptin protein expression. Mechanical stretch or leptin caused an increase in wet weight changes and protein synthesis, considered as hypertrophic markers, while they were inhibited by FK506 (0.1 nM; 1 nM. In addition, stretch or exogenous leptin significantly increased calcineurin activity and MCIP1 expression whereas leptin induced NFAT nuclear translocation in VSMCs. Moreover, in response to stretch or exogenous leptin, the Rho inhibitor C3 exoenzyme (30 ng/mL, the ROCK inhibitor Y-27632 (10 μM, and the actin depolymerization agents Latrunculin B (50 nM and cytochalasin D (1 μM reduced calcineurin activation and NFAT nuclear translocation. ERK1/2 phosphorylation was inhibited by FK506 and C3. Conclusions- Mechanical stretch-induced VSMC hypertrophy and leptin

  8. Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release.

    Science.gov (United States)

    Dautova, Yana; Kapustin, Alexander N; Pappert, Kevin; Epple, Matthias; Okkenhaug, Hanneke; Cook, Simon J; Shanahan, Catherine M; Bootman, Martin D; Proudfoot, Diane

    2018-02-01

    Calcium phosphate (CaP) particle deposits are found in several inflammatory diseases including atherosclerosis and osteoarthritis. CaP, and other forms of crystals and particles, can promote inflammasome formation in macrophages leading to caspase-1 activation and secretion of mature interleukin-1β (IL-1β). Given the close association of small CaP particles with vascular smooth muscle cells (VSMCs) in atherosclerotic fibrous caps, we aimed to determine if CaP particles affected pro-inflammatory signalling in human VSMCs. Using ELISA to measure IL-1β release from VSMCs, we demonstrated that CaP particles stimulated IL-1β release from proliferating and senescent human VSMCs, but with substantially greater IL-1β release from senescent cells; this required caspase-1 activity but not LPS-priming of cells. Potential inflammasome agonists including ATP, nigericin and monosodium urate crystals did not stimulate IL-1β release from VSMCs. Western blot analysis demonstrated that CaP particles induced rapid activation of spleen tyrosine kinase (SYK) (increased phospho-Y525/526). The SYK inhibitor R406 reduced IL-1β release and caspase-1 activation in CaP particle-treated VSMCs, indicating that SYK activation occurs upstream of and is required for caspase-1 activation. In addition, IL-1β and caspase-1 colocalised in intracellular endosome-like vesicles and we detected IL-1β in exosomes isolated from VSMC media. Furthermore, CaP particle treatment stimulated exosome secretion by VSMCs in a SYK-dependent manner, while the exosome-release inhibitor spiroepoxide reduced IL-1β release. CaP particles stimulate SYK and caspase-1 activation in VSMCs, leading to the release of IL-1β, at least in part via exosomes. These novel findings in human VSMCs highlight the pro-inflammatory and pro-calcific potential of microcalcification. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Molecular Ultrasound Imaging of Early Vascular Response in Prostate Tumors Irradiated with Carbon Ions

    Directory of Open Access Journals (Sweden)

    Moritz Palmowski

    2009-09-01

    Full Text Available Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1 and of αvβ3-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of αvβ3-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of αvβ3-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and αvβ3-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

  10. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

    DEFF Research Database (Denmark)

    Christensen, Louise Wulff; Kuhre, Rune Ehrenreich; Janus, Charlotte

    2015-01-01

    -protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam....../L LA, all significantly increased GLP-1 secretion compared to basal levels (Pagonists was ineffective. Thus, both natural and small-mole- cule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion......Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G...

  11. Forearm vascular response to nitric oxide and calcitonin gene-related peptide: comparison between migraine patients and control subjects.

    NARCIS (Netherlands)

    Hoon, J.N. de; Smits, P.; Troost, J.; Struijker-Boudier, H.A.; Bortel, L.M. van

    2006-01-01

    The forearm vascular response to nitric oxide (NO) and calcitonin gene-related peptide (CGRP) was investigated in 10 migraine patients and 10 matched control subjects. Changes in forearm blood flow (FBF) during intrabrachial infusion of: (i) serotonin (releasing endogenous NO), (ii) sodium

  12. Differential responsiveness of the right parahippocampal region to electrical stimulation in fixed human brains: Implications for historical surgical stimulation studies?

    Science.gov (United States)

    Rouleau, Nicolas; Persinger, Michael A

    2016-07-01

    If structure dictates function within the living human brain, then the persistence of specific responses to weak electric currents in fixed, deceased brains could reflect "hardwired" properties. Different key structures from the left and right hemispheres of brains that had been fixed for over 20years with ethanol-formalin-acetic acid were stimulated with either 1-Hz, 7-Hz, 10-Hz, 20-Hz, or 30-Hz, sine-wave, square-wave, or pulsed currents while needle-recorded quantitative electroencephalographic responses were obtained. Differential responses occurred only within the right hippocampus and parahippocampal gyrus. The right hippocampus displayed frequency-independent increases in gamma power relative to the left hemispheric homologue. The parahippocampal region responded exclusively to 7-Hz pulsed currents with wideband (8-30Hz) power. These profiles are consistent with dynamic connections associated with memory and consciousness and may partially explain the interactions resultant of pulse type and hemisphere for experiential elicitations during the golden age of surgical stimulations. The results also indicate that there may be an essential "hardwiring" within the human brain that is maintained for decades when it is fixed appropriately. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress.

    Science.gov (United States)

    Hammadah, Muhammad; Alkhoder, Ayman; Al Mheid, Ibhar; Wilmot, Kobina; Isakadze, Nino; Abdulhadi, Naser; Chou, Danielle; Obideen, Malik; O'Neal, Wesley T; Sullivan, Samaah; Tahhan, Ayman Samman; Kelli, Heval Mohamed; Ramadan, Ronnie; Pimple, Pratik; Sandesara, Pratik; Shah, Amit J; Ward, Laura; Ko, Yi-An; Sun, Yan; Uphoff, Irina; Pearce, Brad; Garcia, Ernest V; Kutner, Michael; Bremner, J Douglas; Esteves, Fabio; Sheps, David S; Raggi, Paolo; Vaccarino, Viola; Quyyumi, Arshed A

    2017-09-15

    Mental stress-induced myocardial ischemia (MSIMI) in patients with coronary artery disease (CAD) is associated with adverse cardiovascular outcomes. We aim to assess hemodynamic, neuro-hormonal, endothelial, vasomotor and vascular predictors of MSIMI. We subjected 660 patients with stable CAD to 99mTc sestamibi myocardial perfusion imaging at rest, with mental (speech task) and with conventional (exercise/pharmacological) stress. Endothelium-dependent flow-mediated dilation (FMD), microvascular reactivity [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] were measured at rest and 30-min after mental stress. The digital microvascular vasomotor response during mental stress was assessed using peripheral arterial tonometry (PAT). A total of 106(16.1%) patients had MSIMI. Mental stress was accompanied by significant increases in rate-pressure-product (heart rate x systolic blood pressure; RPP), epinephrine levels and PWV, and significant decreases in FMD and PAT ratio denoting microvascular constriction. In comparison to those with no MSIMI, patients with MSIMI had higher hemodynamic and digital vasoconstrictive responses (pmental stress can help predict subjects with CAD at greater risk of developing MSIMI. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Hemodynamic and vascular response to resistance exercise with L-arginine.

    Science.gov (United States)

    Fahs, Christopher A; Heffernan, Kevin S; Fernhall, Bo

    2009-04-01

    L-arginine, the precursor to nitric oxide (NO), has been shown to improve endothelial function in patients with endothelial dysfunction. Resistance exercise has been shown to increase arterial stiffness acutely with no definitive cause. It is possible that a reduction in NO bioavailability is responsible for this. The purpose of this study was to examine the effect of acute L-arginine supplementation and resistance exercise on arterial function. Eighteen (N = 18) young men (24.2 +/- 0.7 yr) volunteered for this study. In a crossover design, subjects underwent body composition testing, 1-repetition maximum testing for the bench press and the biceps curls and performed two acute bouts of resistance exercise in which they consumed either placebo or 7 g L-arginine before each resistance exercise bout. Anthropometric measures, augmentation index (AIx), arterial stiffness, and forearm blood flow (FBF) were assessed before and after each treatment condition. There were significant (P L-arginine; furthermore, blood flow was not augmented with supplementation. On the basis of these data, l-arginine does not appear to change the hemodynamic and vascular responses to resistance exercise.

  15. MMP-sensitive PEG diacrylate hydrogels with spatial variations in matrix properties stimulate directional vascular sprout formation.

    Directory of Open Access Journals (Sweden)

    Michael V Turturro

    Full Text Available The spatial presentation of immobilized extracellular matrix (ECM cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The goal of this work was to explore whether gradients of elastic modulus, immobilized matrix metalloproteinase (MMP-sensitivity, and YRGDS cell adhesion ligands are capable of directing 3D vascular sprout formation in tissue engineered scaffolds. PEGDA hydrogels were engineered with mechanical and biofunctional gradients using perfusion-based frontal photopolymerization (PBFP. Bulk photopolymerized hydrogels with uniform mechanical properties, degradation, and immobilized biofunctionality served as controls. Gradient hydrogels exhibited an 80.4% decrease in elastic modulus and a 56.2% decrease in immobilized YRGDS. PBFP hydrogels also demonstrated gradients in hydrogel degradation with degradation times ranging from 10-12 hours in the more crosslinked regions to 4-6 hours in less crosslinked regions. An in vitro model of neovascularization, composed of co-culture aggregates of endothelial and smooth muscle cells, was used to evaluate the effect of these gradients on vascular sprout formation. Aggregate invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, aggregate sprout length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked MMP-sensitive peptide presentation, and immobilized YRGDS concentration.

  16. Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury.

    Science.gov (United States)

    Wagenaar, Gerry T M; Laghmani, El Houari; de Visser, Yvonne P; Sengers, Rozemarijn M A; Steendijk, Paul; Baelde, Hans J; Walther, Frans J

    2013-02-15

    Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.

  17. DIVERSITY OF VASCULAR REACTIVITY AND THE TREATMENT RESPONSE IN DIABETIC, HYPERTENSIVE, HYPERLIPIDEMIC, AND HEALTHY RATS SUBJECTED TO HEMORRHAGIC SHOCK.

    Science.gov (United States)

    Wu, Yue; Zhu, Yu; Chen, Xiang-Yun; Liu, Liang-Ming; Li, Tao

    2016-02-01

    The current diagnosis and treatment guidelines for severe trauma and shock are all for healthy population. Few studies focused on the pathophysiological features and treatments in metabolic diseases after severe trauma and shock. Vascular reactivity is significantly decreased after severe trauma and shock. Improving the vascular reactivity with arginine vasopressin (AVP) and phorbol-12 myristate-13-acetate (PMA) is beneficial to trauma and shock. Whether the cardiovascular function and treatment responses have the own features in hypertensive, diabetic, and hyperlipidemic patients after traumatic hemorrhagic shock is not known. Using hypertensive, diabetic, and hyperlipidemic and healthy rats, we compared the change patterns in cardiovascular function including vascular reactivity, tissue perfusion, and the hemodynamics after hemorrhagic shock and their responses to AVP, PMA, and common antishock agents including dopamine and norepinephrine. A same degree of hemorrhagic shock (40% hemorrhage or mean arterial pressure maintained at 40 mm Hg for 2 h) resulted in a more obvious decrease in vascular reactivity, hemodynamics, tissue perfusion, and mitochondrial function of liver and kidney in hypertensive, diabetic, and hyperlipidemic rats, and a more rapidly natural death than in healthy rats. The effectiveness of AVP and PMA in these diseased rats was lower than in healthy rats. The effective dosage of common antishock agents including norepinephrine, dopamine, and AVP in healthy rats was wider than that in these diseased rats. Among the antishock agents used in the current study, AVP had the best effect in improving animal survival and vascular reactivity both in healthy and in diseased rats. These findings suggest that hypertensive, diabetic, and hyperlipidemic rats have a worse vascular reactivity and organ function than the healthy rats after traumatic hemorrhagic shock, which result in the worse treatment responses and effects to vasoactive agents. Lower dose

  18. The response of retinal neurons to high-frequency stimulation

    Science.gov (United States)

    Cai, Changsi; Twyford, Perry; Fried, Shelley

    2013-06-01

    Objective. High-rate pulse trains have proven to be effective in cochlear prosthetics and, more recently, have been shown to elicit a wide range of interesting response properties in axons of the peripheral nervous system. Surprisingly, the effectiveness of such trains for use in retinal prostheses has not been explored. Approach. Using cell-attached patch clamp methods, we measured the in vitro response of two rabbit retinal ganglion cell types, OFF-brisk transient (OFF-BT) and ON-OFF directionally selective (DS), to trains of biphasic pulses delivered at 2000 pulses per second (PPS). Main Results. For OFF-BT cells, response onset occurred at ˜20 µA, and maximum response occurred at ˜40 µA. Interestingly, spiking levels decreased for further increases in amplitude. In contrast, DS cells had a spiking onset at ˜25 µA and maintained strong spiking as stimulus amplitude was increased, even at the highest levels tested. Thus, a low-amplitude stimulus train at 2000 PPS (˜25 µA) will activate OFF-BT cells strongly, while simultaneously activating DS cells only weakly. In contrast, a high amplitude train (˜75 µA) will activate DS cells strongly while suppressing responses in OFF-BT cells. Significance. The response differences between cell types suggest some forms of preferential activation may be possible, and further testing is warranted. Further, the scope of the response differences found here suggests activation mechanisms that are more complex than those described in previous studies.

  19. Brain stimulation-induced neuroplasticity underlying therapeutic response in phantom sounds.

    Science.gov (United States)

    Poeppl, Timm B; Langguth, Berthold; Lehner, Astrid; Frodl, Thomas; Rupprecht, Rainer; Kreuzer, Peter M; Landgrebe, Michael; Schecklmann, Martin

    2018-01-01

    Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (P neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554-562, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  20. Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin.

    Science.gov (United States)

    Williams, Diana L; Baskin, Denis G; Schwartz, Michael W

    2009-11-01

    Leptin is thought to reduce food intake, in part, by increasing sensitivity to satiation signals, including CCK. Leptin action in both forebrain and hindbrain reduces food intake, and forebrain leptin action augments both the anorexic and neuronal activation responses to CCK. Here, we asked whether leptin signaling in hindbrain also enhances these responses to CCK. We found that food intake was strongly inhibited at 30 min after a combination of 4th-intracerebroventricular (4th-icv) leptin injection and intraperitoneal CCK administration, whereas neither hormone affected intake during this period when given alone. Leptin injections targeted directly at the dorsal vagal complex (DVC) similarly enhanced the anorexic response to intraperitoneal CCK. Intra-DVC leptin injection also robustly increased the number of neurons positive for phospho-STAT3 staining in the area surrounding the site of injection, confirming local leptin receptor activation. Conversely, the anorexic response to 4th-icv leptin was completely blocked by IP devazepide, a CCKA-R antagonist, suggesting that hindbrain leptin reduces intake via a mechanism requiring endogenous CCK signaling. We then asked whether hindbrain leptin treatment enhances the dorsomedial hindbrain, hypothalamus, or amygdala c-Fos responses to IP CCK. We found that, in contrast to the effects of forebrain leptin administration, 4th-icv leptin injection had no effect on CCK-induced c-Fos in any structures examined. We conclude that leptin signaling in either forebrain or hindbrain areas can enhance the response to satiation signals and that multiple distinct neural circuits likely contribute to this interaction.

  1. Nitrate decreases xanthine oxidoreductase-mediated nitrite reductase activity and attenuates vascular and blood pressure responses to nitrite

    Directory of Open Access Journals (Sweden)

    Célio Damacena-Angelis

    2017-08-01

    Full Text Available Nitrite and nitrate restore deficient endogenous nitric oxide (NO production as they are converted back to NO, and therefore complement the classic enzymatic NO synthesis. Circulating nitrate and nitrite must cross membrane barriers to produce their effects and increased nitrate concentrations may attenuate the nitrite influx into cells, decreasing NO generation from nitrite. Moreover, xanthine oxidoreductase (XOR mediates NO formation from nitrite and nitrate. However, no study has examined whether nitrate attenuates XOR-mediated NO generation from nitrite. We hypothesized that nitrate attenuates the vascular and blood pressure responses to nitrite either by interfering with nitrite influx into vascular tissue, or by competing with nitrite for XOR, thus inhibiting XOR-mediated NO generation. We used two independent vascular function assays in rats (aortic ring preparations and isolated mesenteric arterial bed perfusion to examine the effects of sodium nitrate on the concentration-dependent responses to sodium nitrite. Both assays showed that nitrate attenuated the vascular responses to nitrite. Conversely, the aortic responses to the NO donor DETANONOate were not affected by sodium nitrate. Further confirming these results, we found that nitrate attenuated the acute blood pressure lowering effects of increasing doses of nitrite infused intravenously in freely moving rats. The possibility that nitrate could compete with nitrite and decrease nitrite influx into cells was tested by measuring the accumulation of nitrogen-15-labeled nitrite (15N-nitrite by aortic rings using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS. Nitrate exerted no effect on aortic accumulation of 15N-nitrite. Next, we used chemiluminescence-based NO detection to examine whether nitrate attenuates XOR-mediated nitrite reductase activity. Nitrate significantly shifted the Michaelis Menten saturation curve to the right, with a 3-fold increase in

  2. Conceptual approaches to the formation the mechanism of enterprises social responsibility stimulation

    OpenAIRE

    Ohorodnikova, Natalia

    2014-01-01

    The article defines the economic content of the enterprise social responsibility incentive mechanism, the concept of its perfection. There are formulated the purpose and objectives of the proposed mechanisms, sounded principles of its formation. As tools of the enterprise social responsibility incentive mechanism, it is advised to use: methods of corporate social responsibility stimulating, a model of corporate strategy in the context of implementing the practice of social responsibility in t...

  3. Suppressive effect of formononetin on platelet-derived growth factor-BB-stimulated proliferation and migration of vascular smooth muscle cells.

    Science.gov (United States)

    Chen, Zhuo; Liu, Suixin; Cai, Ying; Xie, Kangling; Zhang, Wenliang; Dong, Lei; Liu, Yuan; Zheng, Fan; Dun, Yaoshan; Li, Ning

    2016-09-01

    Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) has been implicated in intimal hyperplasia, atherosclerosis and restenosis following percutaneous coronary intervention. Formononetin, a phytoestrogen extracted from the root of Astragalus membranaceus , has been widely used in Chinese tradition medicine due to its protective effects against certain symptoms of cancer, hypertension, inflammation, hypoxia-induced cytotoxicity and ovariectomy-induced bone loss. However, the effect of formononetin on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of VSMCs, as well as the underlying molecular mechanism, remains largely unclear. In the present study, treatment with formononetin significantly inhibited PDGF-BB-induced proliferation and migration of human VSMCs. Investigation into the underlying molecular mechanism revealed that the administration of formononetin suppressed PDGF-BB-stimulated switch of VSMCs to a proliferative phenotype. Furthermore, treatment with formononetin inhibited the PDGF-BB-induced upregulation of cell cycle-related proteins, matrix metalloproteinase (MMP2) and MMP9. In addition, the that administration of formononetin inhibited the phosphorylation of AKT induced by PDGF-BB in VSMCs. The present results suggest that formononetin has a suppressive effect on PDGF-BB-stimulated VSMCs proliferation and migration, which may occur partly via the inhibition of AKT signaling pathway. Therefore, formononetin may be useful for the treatment of intimal hyperplasia, atherosclerosis and restenosis.

  4. Variations in Responses of Vascular Smooth Muscles to Na-K Pump ...

    African Journals Online (AJOL)

    There is a paucity of information concerning the variability of Na+-K+-ATPase activity in various vascular preparations. In this study, we have investigated, comparatively, K+-induced relaxation in different vascular tissues, to establish the heterogeneity of the activity of this enzyme. Isometric contractions of ring preparations ...

  5. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-01-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID:28854172

  6. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K.; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-09-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

  7. Multicompartment retinal ganglion cells response to high frequency bi-phasic pulse train stimulation: Simulation results.

    Science.gov (United States)

    Maturana, Matias I; Grayden, David B; Burkitt, Anthony N; Meffin, Hamish; Kameneva, Tatiana

    2013-01-01

    Retinal ganglion cells (RGCs) are the sole output neurons of the retina that carry information about a visual scene to the brain. By stimulating RGCs with electrical stimulation, it is possible to elicit a sensation of light for people with macular degeneration or retinitis pigmentosa. To investigate the responses of RGCs to high frequency bi-phasic pulse train stimulation, we use previously constrained models of multi-compartment OFF RGCs. The morphologies of mouse RGCs are taken from the Chalupa set of the NeuroMorpho database. The cell models are divided into compartments representing the dendrites, soma and axon that vary between the cells. A total of 132 cells are simulated in the NEURON environment. Results show that the cell morphology plays an important role in the response characteristics of the cell to high frequency bi-phasic pulse train stimulation.

  8. Response to thyrotropin-releasing hormone stimulation tests in preterm infants with transient hypothyroxinemia of prematurity.

    Science.gov (United States)

    Yamamoto, A; Kawai, M; Iwanaga, K; Matsukura, T; Niwa, F; Hasegawa, T; Heike, T

    2015-09-01

    Whether hormone supplementation is necessary for infants with transient hypothyroxinemia of prematurity (THOP) remains controversial, and further analysis of the hypothalamus-pituitary-thyroid axis of infants with THOP is necessary. Thyrotropin-releasing hormone (TRH) stimulation tests were performed at 2 weeks of age in 50 infants with a gestational age of 30 weeks or less, and the data were analyzed retrospectively. Subjects were divided into three groups; group A consisted of euthyroid infants, group B consisted of infants with THOP and group C consisted of hypothyroid infants. The basal and peak thyroid-stimulating hormone level of group C in response to TRH stimulation tests was significantly higher than the others, but no differences were observed between groups A and B. The response of infants with THOP to the TRH stimulation test was not different from that of euthyroid infants, which suggested that their hypothalamic-pituitary-thyroid axis was appropriately regulated in infants with THOP.

  9. Infrared neural stimulation (INS) inhibits electrically evoked neural responses in the deaf white cat

    Science.gov (United States)

    Richter, Claus-Peter; Rajguru, Suhrud M.; Robinson, Alan; Young, Hunter K.

    2014-03-01

    Infrared neural stimulation (INS) has been used in the past to evoke neural activity from hearing and partially deaf animals. All the responses were excitatory. In Aplysia californica, Duke and coworkers demonstrated that INS also inhibits neural responses [1], which similar observations were made in the vestibular system [2, 3]. In deaf white cats that have cochleae with largely reduced spiral ganglion neuron counts and a significant degeneration of the organ of Corti, no cochlear compound action potentials could be observed during INS alone. However, the combined electrical and optical stimulation demonstrated inhibitory responses during irradiation with infrared light.

  10. The effects of temperature changes on retinal ganglion cell responses to electrical stimulation.

    Science.gov (United States)

    Maturana, Matias I; Apollo, Nicholas V; Garrett, David J; Kameneva, Tatiana; Meffin, Hamish; Ibbotson, Michael R; Cloherty, Shaun L; Grayden, David B

    2015-01-01

    Little is known about how the retina's response to electrical stimulation is modified by temperatures. In vitro experiments are often used to inform in vivo studies, hence it is important to understand what changes occur at physiological temperature. To investigate this, we recorded from eight RGCs in vitro at three temperatures; room temperature (24°C), 30°C and 34°C. Results show that response latencies and thresholds are reduced, bursting spike rates in response to stimulation increases, and the spiking becomes more consistently locked to the stimulus at higher temperatures.

  11. Stimulation of the subthalamic region facilitates the selection and inhibition of motor responses in Parkinson's disease

    NARCIS (Netherlands)

    van den Wildenberg, Wery P. M.; van Boxtel, Geert J. M.; van der Molen, Maurits W.; Bosch, D. Andries; Speelman, Johannes D.; Brunia, Cornelis H. M.

    2006-01-01

    The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinson's disease (PD) who received deep-brain stimulation (DBS) of the subthalamic

  12. Rhythmic entrainment source separation: Optimizing analyses of neural responses to rhythmic sensory stimulation

    NARCIS (Netherlands)

    Cohen, M.S.; Gulbinaite, R.

    2017-01-01

    Steady-state evoked potentials (SSEPs) are rhythmic brain responses to rhythmic sensory stimulation, and are often used to study perceptual and attentional processes. We present a data analysis method for maximizing the signal-to-noise ratio of the narrow-band steady-state response in the frequency

  13. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Yuece, Ulkue Rabia, E-mail: ulkuyuce@hotmail.co [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Meric, Niyazi, E-mail: meric@ankara.edu.t [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Atakol, Orhan, E-mail: atakol@science.ankara.edu.t [Ankara University, Science Faculty, Department of Chemistry, 06100, Tandogan - Ankara (Turkey); Yasar, Fusun, E-mail: ab121310@adalet.gov.t [Council of Forensic Medicine, Ankara Branch, Ankara (Turkey)

    2010-08-15

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  14. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    International Nuclear Information System (INIS)

    Yuece, Ulkue Rabia; Meric, Niyazi; Atakol, Orhan; Yasar, Fusun

    2010-01-01

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  15. Cochlear Implant Stimulation of a Hearing Ear Generates Separate Electrophonic and Electroneural Responses.

    Science.gov (United States)

    Sato, Mika; Baumhoff, Peter; Kral, Andrej

    2016-01-06

    Electroacoustic stimulation in subjects with residual hearing is becoming more widely used in clinical practice. However, little is known about the properties of electrically induced responses in the hearing cochlea. In the present study, normal-hearing guinea pig cochleae underwent cochlear implantation through a cochleostomy without significant loss of hearing. Using recordings of unit activity in the midbrain, we were able to investigate the excitation patterns throughout the tonotopic field determined by acoustic stimulation. With the cochlear implant and the midbrain multielectrode arrays left in place, the ears were pharmacologically deafened and electrical stimulation was repeated in the deafened condition. The results demonstrate that, in addition to direct neuronal (electroneuronal) stimulation, in the hearing cochlea excitation of the hair cells occurs ("electrophonic responses") at the cochlear site corresponding to the dominant temporal frequency components of the electrical stimulus, provided these are cochlear implants and hearing aids is becoming more widely clinically used in subjects with residual hearing. The neurophysiological characteristics underlying electroacoustic stimulation and the mechanism of its benefit remain unclear. The present study directly demonstrates that cochlear implantation does not interfere with the normal mechanical and physiological function of the cochlea. For the first time, it double-dissociates the electrical responses of hair cells (electrophonic responses) from responses of the auditory nerve fibers (electroneural responses), with separate excited cochlear locations in the same animals. We describe the condition in which these two responses spatially overlap. Finally, the study implicates that using the clinical characteristics of stimulation makes electrophonic responses unlikely in implanted subjects. Copyright © 2016 the authors 0270-6474/16/360054-11$15.00/0.

  16. Lateral cord stimulation decreases spastic electromyographic spreading: responses in a brain-damaged pig preparation.

    Science.gov (United States)

    Andreani, Juan Carlos M; Guma, Cristina

    2008-07-01

    Objective.  The aim of our work was to investigate whether lateral stimulation of the spinal cord, lateral cord stimulation (LCS), results in inhibition of the spastic phenomena of upper motor lesions in an animal model. Methods.  This study was conducted using an animal model consisting of surgically brain damaged pigs subjected to unilateral cortical and subcortical brain lesions. A double laminectomy at cervical (C3-C4) and lumbar (L3-L6) was performed, and spastic thresholds of abnormal electromyographic responses, disseminated to adjacent segments, facilitated by spinal liberation, and produced by extradural electrical stimulation of the fourth lumbar root, were measured before and after cervical stimulation of the LCS. The variable studied was the minimal amount of current of LCS necessary to abolish electromyographic responses in the L7 myotome, away from the stimulated L4 nerve root. Results.  Experiments in 12 animals showed a significant increase of threshold after LCS, with a marked posteffect, signaling a less abnormal threshold. Conclusions.  This experiment demonstrated that LCS produces threshold increases to abolish abnormally propagated electromyographic evoked responses induced by the electrical stimulation of the fourth lumbar root in pigs with experimental cortical and subcortical brain lesions. © 2008 International Neuromodulation Society.

  17. Optical spectroscopy of radiotherapy and photodynamic therapy responses in normal rat skin shows vascular breakdown products

    Science.gov (United States)

    Teles de Andrade, Cintia; Nogueira, Marcelo S.; Kanick, Stephen C.; Marra, Kayla; Gunn, Jason; Andreozzi, Jacqueline; Samkoe, Kimberley S.; Kurachi, Cristina; Pogue, Brian W.

    2016-03-01

    Photodynamic therapy (PDT) and radiotherapy are non-systemic cancer treatment options with different mechanisms of damage. So combining these techniques has been shown to have some synergy, and can mitigate their limitations such as low PDT light penetration or radiotherapy side effects. The present study monitored the induced tissue changes after PDT, radiotherapy, and a combination protocol in normal rat skin, using an optical spectroscopy system to track the observed biophysical changes. The Wistar rats were treated with one of the protocols: PDT followed by radiotherapy, PDT, radiotherapy and radiotherapy followed by PDT. Reflectance spectra were collected in order to observe the effects of these combined therapies, especially targeting vascular response. From the reflectance, information about oxygen saturation, met-hemoglobin and bilirubin concentration, blood volume fraction (BVF) and vessel radius were extracted from model fitting of the spectra. The rats were monitored for 24 hours after treatment. Results showed that there was no significant variation in the vessel size or BVF after the treatments. However, the PDT caused a significant increase in the met-hemoglobin and bilirubin concentrations, indicating an important blood breakdown. These results may provide an important clue on how the damage establishment takes place, helping to understand the effect of the combination of those techniques in order to verify the existence of a known synergistic effect.

  18. Effect of preceding exercise on cerebral and splanchnic vascular responses to mental task

    Directory of Open Access Journals (Sweden)

    Someya Nami

    2012-06-01

    Full Text Available Abstract Background To investigate the effect of preceding acute exercise on the peripheral vascular response to a mental task, we measured splanchnic and cerebral blood flow responses to performing a mental task after exercise and resting. Methods In the exercise trial, 11 males exercised for 30 min on a cycle ergometer with a workload set at 70% of the age-predicted maximal heart rate for each individual. After a 15-min recovery period, the subjects rested for 5 min for pre-task baseline measurement and then performed mental arithmetic for 5 min followed by 5 min of post-task measurement. In the resting trial, they rested for 45 min and pre-task baseline data was obtained for 5 min. Then mental arithmetic was performed for 5 min followed by post-task measurement. We measured the mean blood velocity in the middle cerebral artery and superior mesenteric artery and the mean arterial pressure. Results Mean arterial pressure and mean blood velocity in the middle cerebral artery were significantly higher than the baseline during mental arithmetic in both exercise and resting trials. Mean blood velocity in the middle cerebral artery during mental arithmetic was greater in the control trial than the exercise trial. Mean blood velocity in the superior mesenteric artery showed no significant change during mental arithmetic from baseline in both trials. Conclusion These results suggest that acute exercise can moderate the increase in cerebral blood flow induced by a mental task.

  19. Granulocyte-colony stimulating factor (G-CSF in stroke patients with concomitant vascular disease--a randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Agnes Floel

    Full Text Available G-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke.Here, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day, or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study.Adverse events (AEs were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl, and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function.These results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits.ClinicalTrials.gov NCT00298597.

  20. Abscisic acid released by human monocytes activates monocytes and vascular smooth muscle cell responses involved in atherogenesis.

    Science.gov (United States)

    Magnone, Mirko; Bruzzone, Santina; Guida, Lucrezia; Damonte, Gianluca; Millo, Enrico; Scarfì, Sonia; Usai, Cesare; Sturla, Laura; Palombo, Domenico; De Flora, Antonio; Zocchi, Elena

    2009-06-26

    Abscisic acid (ABA) is a phytohormone recently identified as a new endogenous pro-inflammatory hormone in human granulocytes. Here we report the functional activation of human monocytes and vascular smooth muscle cells by ABA. Incubation of monocytes with ABA evokes an intracellular Ca2+ rise through the second messenger cyclic ADP-ribose, leading to NF-kappaB activation and consequent increase of cyclooxygenase-2 expression and prostaglandin E2 production and enhanced release of MCP-1 (monocyte chemoattractant protein-1) and of metalloprotease-9, all events reportedly involved in atherogenesis. Moreover, monocytes release ABA when exposed to thrombin-activated platelets, a condition occurring at the injured vascular endothelium; monocyte-derived ABA behaves as an autocrine and paracrine pro-inflammatory hormone-stimulating monocyte migration and MCP-1 release, as well as vascular smooth muscle cells migration and proliferation. These results, and the presence of ABA in human arterial plaques at a 10-fold higher concentration compared with normal arterial tissue, identify ABA as a new signal molecule involved in the development of atherosclerosis and suggest a possible new target for anti-atherosclerotic therapy.

  1. Abscisic Acid Released by Human Monocytes Activates Monocytes and Vascular Smooth Muscle Cell Responses Involved in Atherogenesis*

    Science.gov (United States)

    Magnone, Mirko; Bruzzone, Santina; Guida, Lucrezia; Damonte, Gianluca; Millo, Enrico; Scarfì, Sonia; Usai, Cesare; Sturla, Laura; Palombo, Domenico; De Flora, Antonio; Zocchi, Elena

    2009-01-01

    Abscisic acid (ABA) is a phytohormone recently identified as a new endogenous pro-inflammatory hormone in human granulocytes. Here we report the functional activation of human monocytes and vascular smooth muscle cells by ABA. Incubation of monocytes with ABA evokes an intracellular Ca2+ rise through the second messenger cyclic ADP-ribose, leading to NF-κB activation and consequent increase of cyclooxygenase-2 expression and prostaglandin E2 production and enhanced release of MCP-1 (monocyte chemoattractant protein-1) and of metalloprotease-9, all events reportedly involved in atherogenesis. Moreover, monocytes release ABA when exposed to thrombin-activated platelets, a condition occurring at the injured vascular endothelium; monocyte-derived ABA behaves as an autocrine and paracrine pro-inflammatory hormone-stimulating monocyte migration and MCP-1 release, as well as vascular smooth muscle cells migration and proliferation. These results, and the presence of ABA in human arterial plaques at a 10-fold higher concentration compared with normal arterial tissue, identify ABA as a new signal molecule involved in the development of atherosclerosis and suggest a possible new target for anti-atherosclerotic therapy. PMID:19332545

  2. Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.

    Science.gov (United States)

    López-Solà, Marina; Pujol, Jesus; Wager, Tor D; Garcia-Fontanals, Alba; Blanco-Hinojo, Laura; Garcia-Blanco, Susana; Poca-Dias, Violant; Harrison, Ben J; Contreras-Rodríguez, Oren; Monfort, Jordi; Garcia-Fructuoso, Ferran; Deus, Joan

    2014-11-01

    Fibromyalgia (FM) is a disorder characterized by chronic pain and enhanced responses to acute noxious events. However, the sensory systems affected in FM may extend beyond pain itself, as FM patients show reduced tolerance to non-nociceptive sensory stimulation. Characterizing the neural substrates of multisensory hypersensitivity in FM may thus provide important clues about the underlying pathophysiology of the disorder. The aim of this study was to characterize brain responses to non-nociceptive sensory stimulation in FM patients and their relationship to subjective sensory sensitivity and clinical pain severity. Functional magnetic resonance imaging (MRI) was used to assess brain response to auditory, visual, and tactile motor stimulation in 35 women with FM and 25 matched controls. Correlation and mediation analyses were performed to establish the relationship between brain responses and 3 types of outcomes: subjective hypersensitivity to daily sensory stimulation, spontaneous pain, and functional disability. Patients reported increased subjective sensitivity (increased unpleasantness) in response to multisensory stimulation in daily life. Functional MRI revealed that patients showed reduced task-evoked activation in primary/secondary visual and auditory areas and augmented responses in the insula and anterior lingual gyrus. Reduced responses in visual and auditory areas were correlated with subjective sensory hypersensitivity and clinical severity measures. FM patients showed strong attenuation of brain responses to nonpainful events in early sensory cortices, accompanied by an amplified response at later stages of sensory integration in the insula. These abnormalities are associated with core FM symptoms, suggesting that they may be part of the pathophysiology of the disease. Copyright © 2014 by the American College of Rheumatology.

  3. No maternal effects after stimulation of the melanization response in the yellow fever mosquito Aedes aegypti

    OpenAIRE

    Voordouw, M. J.; Lambrechts, Louis; Koella, J.

    2008-01-01

    The costs and benefits of activating the immune system can reach across generations. Thus, in vertebrates and in several invertebrates, stimulating the immune system of a female can enhance immunity of her offspring or decrease offspring fitness. We evaluated the potential maternally transmitted costs and benefits of the melanization response, an innate immune response of insects that helps to protect mosquitoes from malaria parasites. We manipulated the maternal melanization response of the ...

  4. Effect of gabazine on sensory stimulation train evoked response in mouse cerebellar Purkinje cells.

    Science.gov (United States)

    Bing, Yan-Hua; Jin, Wen-Zhe; Sun, Lei; Chu, Chun-Ping; Qiu, De-Lai

    2015-02-01

    Cerebellar Purkinje cells (PCs) respond to sensory stimulation via climbing fiber and mossy fiber-granule cell pathways, and generate motor-related outputs according to internal rules of integration and computation. However, the dynamic properties of sensory information processed by PC in mouse cerebellar cortex are currently unclear. In the present study, we examined the effects of the gamma-aminobutyric acid receptor A (GABA(A)) antagonist, gabazine, on the stimulation train on the simple spike firing of PCs by electrophysiological recordings method. Our data showed that the output of cerebellar PCs could be significantly affected by all pulses of the low-frequency (0.25 -2 Hz) sensory stimulation train, but only by the 1st and 2nd pulses of the high-frequency (≥ 4 Hz) sensory stimulation train. In the presence of gabazine (20 μM), each pulse of 1 Hz facial stimulation evoked simple spike firing in the PCs, but only the 1st and 2nd pulses of 4 Hz stimulation induced an increase in simple spike firing of the PCs. These results indicated that GABAA receptor-mediated inhibition did not significantly affect the frequency properties of sensory stimulation evoked responses in the mouse cerebellar PCs.

  5. The Effects of Endurance Exercise Training on the Coronary Vascular Responsiveness to Intracoronary Acetylcholine in Swine

    Science.gov (United States)

    1993-04-09

    physica l training in patients with ischaemic heart disease . Sf. Heart J. 48:33-38, 1982. Vanhoutte, P.M., and RA. Cohen. Effects of ace tlycholine...vascular disease . Examination of these regulatory mechanisms aft er physical conditioning may permit ext rapolation to other altered coronary vascular...an increase in cont ract il ity. This produces an increase in stroke volume (Barnard , 1975; Blomqvist, 1983; Dowell, 1983; Nadel, 1985) due to enha

  6. Multi-scale simulations predict responses to non-invasive nerve root stimulation

    Science.gov (United States)

    Laakso, Ilkka; Matsumoto, Hideyuki; Hirata, Akimasa; Terao, Yasuo; Hanajima, Ritsuko; Ugawa, Yoshikazu

    2014-10-01

    Objective. Established biophysical neurone models have achieved limited success in reproducing electrophysiological responses to non-invasive stimulation of the human nervous system. This is related to our insufficient knowledge of the induced electric currents inside the human body. Despite the numerous research and clinical applications of non-invasive stimulation, it is still unclear which internal sites are actually affected by it. Approach. We performed multi-scale computer simulations that, by making use of advances in computing power and numerical algorithms, combine a microscopic model of electrical excitation of neurones with a macroscopic electromagnetic model of the realistic whole-body anatomy. Main results. The simulations yield responses consistent with those experimentally recorded following magnetic and electrical motor root stimulation in human subjects, and reproduce the observed amplitudes and latencies for a wide variety of stimulation parameters. Significance. Our findings demonstrate that modern computational techniques can produce detailed predictions about which and where neurones are activated, leading to improved understanding of the physics and basic mechanisms of non-invasive stimulation and enabling potential new applications that make use of improved targeting of stimulation.

  7. Estudo da reatividade vascular induzida pelo estresse mental na gravidez de mulheres portadoras de estenose mitral Vascular reactivity response to mental stress in pregnant women with mitral stenosis

    Directory of Open Access Journals (Sweden)

    Walkiria Samuel Avila

    2006-08-01

    mitral stenosis. METHODS: Twenty two women with mitral stenosis, 13 of whom were pregnant (PS and 9 were non-pregnant (MIS, and 9 healthy pregnant women (NP were studied. During gestation, 9 out of the 13 patients of the PS group required a beta-blocker (PSB and the remaining 4 progressed without medication (PSWB. Plethysmography at rest and during mental stress analyzed muscle blood flow, peripheral vascular resistance (PVR, mean arterial pressure (MAP and heart rate (HR during gestation and puerperium. RESULTS: During gestation of PSWB, muscle blood flow and HR were higher in 1.6% and 20.5% (p = 0.05, and PVR and MAP were lower in 19.3% and 4.4%, respectively, in comparison to the puerperium; during mental stress, the muscle blood flow increased by 55.9%, HR decreased by 30.2% and PVR and MAP were similar. In PSB, muscle blood muscle blood flow and HR were greater in 5.9% and 14.9% (p= 0.001 and MAP and PVR were lower in 10.3% and 9.1%, respectively, when compared to the puerperium. During mental stress, muscle blood flow and MAP increased by 69.8% and 174.1%, respectively. HR was similar and PVR decreased by 53.7%. The comparative study showed that in the NP group the muscle blood flow was higher, PVR was lower, and MAP and HR were similar in relation to the PS group, and that the PS, NP, MIS groups had a similar response to mental stress. CONCLUSIONS: Vascular reactivity in pregnant women with mitral stenosis was preserved and the analysis of measurements showed lower values of muscle blood flow and higher values of PVR when compared to those of healthy pregnant women.

  8. Post-treatment vascular leakage and inflammatory responses around brain cysts in porcine neurocysticercosis.

    Directory of Open Access Journals (Sweden)

    Siddhartha Mahanty

    2015-03-01

    Full Text Available Cysticidal treatment of neurocysticercosis, an infection of humans and pig brains with Taenia solium, results in an early inflammatory response directed to cysts causing seizures and focal neurological manifestations. Treatment-induced pericystic inflammation and its association with blood brain barrier (BBB dysfunction, as determined by Evans blue (EB extravasation, was studied in infected untreated and anthelmintic-treated pigs. We compared the magnitude and extent of the pericystic inflammation, presence of EB-stained capsules, the level of damage to the parasite, expression of genes for proinflammatory and regulatory cytokines, chemokines, and tissue remodeling by quantitative PCR assays between treated and untreated infected pigs and between EB-stained (blue and non stained (clear cysts. Inflammatory scores were higher in pericystic tissues from EB-stained cysts compared to clear cysts from untreated pigs and also from anthelmintic-treated pigs 48 hr and 120 hr after treatment. The degree of inflammation correlated with the severity of cyst wall damage and both increased significantly at 120 hours. Expression levels of the proinflammatory genes for IL-6, IFN-γ, TNF-α were higher in EB-stained cysts compared to clear cysts and unaffected brain tissues, and were generally highest at 120 hr. Additionally, expression of some markers of immunoregulatory activity (IL-10, IL-2Rα were decreased in EB-stained capsules. An increase in other markers for regulatory T cells (CTLA4, FoxP3 was found, as well as significant increases in expression of two metalloproteases, MMP1 and MMP2 at 48 hr and 120 hr post-treatment. We conclude that the increase in severity of the inflammation caused by treatment is accompanied by both a proinflammatory and a complex regulatory response, largely limited to pericystic tissues with compromised vascular integrity. Because treatment induced inflammation occurs in porcine NCC similar to that in human cases, this model

  9. Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans

    Science.gov (United States)

    Cui, Jian; Blaha, Cheryl

    2016-01-01

    The effects of whole body heat stress on sympathetic and cardiovascular responses to stimulation of muscle metaboreceptors and mechanoreceptors remains unclear. We examined the muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate in 14 young healthy subjects during fatiguing isometric handgrip exercise, postexercise circulatory occlusion (PECO), and passive muscle stretch during PECO. The protocol was performed under normothermic and whole body heat stress (increase internal temperature ~0.6°C via a heating suit) conditions. Heat stress increased the resting MSNA and heart rate. Heat stress did not alter the mean blood pressure (MAP), heart rate, and MSNA responses (i.e., changes) to fatiguing exercise. During PECO, whole body heat stress accentuated the heart rate response [change (Δ) of 5.8 ± 1.5 to Δ10.0 ± 2.1 beats/min, P = 0.03], did not alter the MSNA response (Δ16.4 ± 2.8 to Δ17.3 ± 3.8 bursts/min, P = 0.74), and lowered the MAP response (Δ20 ± 2 to Δ12 ± 1 mmHg, P heat stress prevented the MAP and MSNA responses to stretch during PECO (both P > 0.05). These data suggest that whole body heat stress attenuates the pressor response due to metaboreceptor stimulation, and the sympathetic nerve response due to mechanoreceptor stimulation. PMID:27763873

  10. Asymmetry of balance responses to monaural galvanic vestibular stimulation in subjects with vestibular schwannoma.

    Science.gov (United States)

    Welgampola, Miriam S; Ramsay, Elijane; Gleeson, Michael J; Day, Brian L

    2013-09-01

    We investigated the potential of galvanic vestibular stimulation (GVS) to quantify lateralised asymmetry of the vestibulospinal pathways by measuring balance responses to monaural GVS in 10 subjects with vestibular schwannoma and 22 healthy control subjects. Subjects standing without vision were stimulated with 3 s, 1 mA direct current stimuli delivered monaurally. The mean magnitude and direction of the evoked balance responses in the horizontal plane were measured from ground-reaction forces and from displacement and velocity of the trunk. Vestibular-evoked myogenic potentials (VEMPs) to 500 Hz air and bone-conducted tones were also recorded. In healthy subjects, the magnitudes of the force, velocity and displacement responses were not significantly different for left compared to right ear stimulation. Their individual asymmetry ratios were always vestibular schwannoma had significantly smaller force, velocity and displacement responses to stimulation of the affected compared with non-affected ear. Their mean asymmetry ratios were significantly elevated for all three measures (41.2 ± 10.3%, 40.3 ± 15.1% and 21.9 ± 14.6%). Asymmetry ratios of balance responses to monaural GVS provide a quantitative and clinically applicable lateralising test of the vestibulospinal pathways. This method offers a more clinically relevant measure of standing balance than existing vestibular function tests which assess only vestibuloocular and vestibulocollic pathways. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  11. Reevaluation of reflex responses of the human masseter muscle to electrical lip stimulation.

    Science.gov (United States)

    Uginčius, Paulius; Yilmaz, Gizem; Sebik, Oğuz; Türker, Kemal S

    2017-08-01

    We examined the reflex response of the human masseter muscle to electrical stimulation of the lip using both single motor unit and surface electromyogram based methods. Using the classical analysis methods, reflex response to mild electrical stimuli generated two distinct short-lasting inhibitions. This pattern may reflect the development of combinations of short- and long-latency inhibitory postsynaptic potentials as a result of the mildly painful electrical lip stimulation. However, this pattern appearing in the classical analysis methods may have developed as a consequence of earlier responses and may not be genuine. This study examined the genuineness of these responses using both the classical analysis methods and the discharge rate method to uncover the realistic postsynaptic potentials in human trigeminal motor nucleus. Using the discharge rate method, we found that the electrical lip stimulation only generated a long-lasting single or compound inhibitory response that is followed by late, long-lasting excitation. These findings have important implications on the redrawing of the neuronal pathways of the trigeminal nerve that are frequently used to judge neuromuscular disorders of the trigeminal region. NEW & NOTEWORTHY We examined the human masseter reflex response to electrical stimulation of lower lip to uncover realistic postsynaptic potentials in the trigeminal motor nucleus. We found that the stimulation generates a long-lasting single or compound inhibitory response that is followed by a late, long-lasting excitation. These findings have important implications on the redrawing of the neuronal pathways of the trigeminal nerve that are frequently used to judge neuromuscular disorders of the trigeminal region. Copyright © 2017 the American Physiological Society.

  12. Motile responses of cochlear outer hair cells stimulated with an alternating electrical field.

    Science.gov (United States)

    Kitani, Rei; Kakehata, Seiji; Kalinec, Federico

    2011-10-01

    The goal of the present study was to evaluate and characterize the motile responses of guinea pig OHCs, stimulated at frequencies varying from 50 Hz to 4 kHz, using high-definition, high-speed video recording and fully automatic image analysis software. Cells stimulated in continuous, burst and sweeping modes with an external alternating electrical field showed robust fast and slow motility, which were dependent on frequency, mode and intensity of stimulation. In response to continuous stimulation, electromotile amplitude ranged from 0.3% to 3.2% of total cell length, whereas cell length usually decreased in amounts varying from 0.1% to 4.3%. Electromotile amplitude in OHCs stimulated with square wave's sweeps was near constant up to 200 Hz, progressively decreased between 200 Hz and 2 kHz, and then remained constant up to 4 kHz. In continuous and burst modes electromotility followed cycle-by-cycle the electrical stimulus, but it required 1-2 s to fully develop and reach maximal amplitude. Instead, slow cell length changes started about 0.6 s after the beginning and continuously developed up to 3 s after the end of electrical stimulation. Incubation of OHCs with 10 mM salicylate affected electromotility but not slow motility, whereas incubation with 3 mM gadolinium affected both. Thus, combination of external electrical stimulation, high-speed video recording and advanced image analysis software provides information about OHC motile responses at acoustic frequencies with an unprecedented detail, opening new areas of research in the field of OHC mechanics. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. The initial course of in-stent restenosis influences the response to vascular brachytherapy

    International Nuclear Information System (INIS)

    Cheneau, Edouard; Leborgne, Laurent; Wolfram, Roswitha; Dilcher, Christian; Pakala, Rajbabu; Pichard, Augusto D.; Satler, Lowell F.; Canos, Daniel; Lindsay, Joseph; Waksman, Ron

    2002-01-01

    Background: Vascular brachytherapy (VBT) reduces the rate of recurrence of in-stent restenosis (ISR) by inhibiting intimal proliferation. However, the rate of cell proliferation, reflected by the speed of ISR development, is variable in ISR lesions and might influence the responsiveness of ISR to radiation. The aim of this study was to determine the influence of the initial ISR course on the clinical outcome of patients undergoing VBT. Methods: In 1165 patients treated for ISR with VBT in the WRIST studies, we determined the time for ISR (time between initial stent implantation and restenosis), the time for VBT treatment (time between stent implantation and VBT), and previous ISR treatment with conventional strategies. Target lesion revascularization (TLR) at 6 months was available in all patients. Results: Previous ISR treatment did not influence the result of VBT (TLR was 17% vs. 16% without previous angioplasty). Time to ISR influences the outcome of patients undergoing VBT; TLR decreased when ISR occurred later. TLR was 18.2%, 16.7%, and 11.1% when time to ISR was 270 days, respectively, P=.03. Early ISR (time for ISR <90 days) is a factor for radiation failure (OR=2.1, P<.05). In patients with early ISR, TLR is lower when VBT is delayed; TLR was 11% if performed 90 days after stent implantation as compared to 22% if VBT is performed early (<90 days), P<.05. Conclusion: The course of ISR development affects the long-term efficacy of VBT. Early restenosis remains a factor of treatment failure in the VBT era. Delaying VBT beyond 90 days after stent implantation reduces the rate of subsequent revascularization in these patients

  14. Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity.

    Science.gov (United States)

    Christou, Demetra D; Pierce, Gary L; Walker, Ashley E; Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Meade, Thomas H; English, Mark; Seals, Douglas R

    2012-09-15

    Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4-42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = -0.30; all P ≤ 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors.

  15. Retinal Vascular and Oxygen Temporal Dynamic Responses to Light Flicker in Humans.

    Science.gov (United States)

    Felder, Anthony E; Wanek, Justin; Blair, Norman P; Shahidi, Mahnaz

    2017-11-01

    To mathematically model the temporal dynamic responses of retinal vessel diameter (D), oxygen saturation (SO2), and inner retinal oxygen extraction fraction (OEF) to light flicker and to describe their responses to its cessation in humans. In 16 healthy subjects (age: 60 ± 12 years), retinal oximetry was performed before, during, and after light flicker stimulation. At each time point, five metrics were measured: retinal arterial and venous D (DA, DV) and SO2 (SO2A, SO2V), and OEF. Intra- and intersubject variability of metrics was assessed by coefficient of variation of measurements before flicker within and among subjects, respectively. Metrics during flicker were modeled by exponential functions to determine the flicker-induced steady state metric values and the time constants of changes. Metrics after the cessation of flicker were compared to those before flicker. Intra- and intersubject variability for all metrics were less than 6% and 16%, respectively. At the flicker-induced steady state, DA and DV increased by 5%, SO2V increased by 7%, and OEF decreased by 13%. The time constants of DA and DV (14, 15 seconds) were twofold smaller than those of SO2V and OEF (39, 34 seconds). Within 26 seconds after the cessation of flicker, all metrics were not significantly different from before flicker values (P ≥ 0.07). Mathematical modeling revealed considerable differences in the time courses of changes among metrics during flicker, indicating flicker duration should be considered separately for each metric. Future application of this method may be useful to elucidate alterations in temporal dynamic responses to light flicker due to retinal diseases.

  16. Vascular development of the grapevine (Vitis vinifera L.) inflorescence rachis in response to flower number, plant growth regulators and defoliation.

    Science.gov (United States)

    Gourieroux, Aude M; Holzapfel, Bruno P; McCully, Margaret E; Scollary, Geoffrey R; Rogiers, Suzy Y

    2017-09-01

    The grapevine inflorescence is a determinate panicle and as buds emerge, shoot, flower and rachis development occur simultaneously. The growth and architecture of the rachis is determined by genetic and environmental factors but here we examined the role of flower and leaf number as well as hormones on its elongation and vascular development. The consequences of rachis morphology and vascular area on berry size and composition were also assessed. One week prior to anthesis, Merlot and Cabernet Sauvignon field vines were exposed to manual flower removal, exogenous plant growth regulators or pre-bloom leaf removal. Manual removal of half the flowers along the vertical axis of the inflorescence resulted in a shorter rachis in both cultivars. Conversely, inflorescences treated with gibberellic acid (GA 3 ) and the synthetic cytokinin, 6-benzylaminopurine (BAP) resulted in a longer rachis while pre-bloom removal of all leaves on the inflorescence-bearing shoot did not alter rachis length relative to untreated inflorescences. Across the treatments, the cross-sectional areas of the conducting xylem and phloem in the rachis were positively correlated to rachis girth, flower number at anthesis, bunch berry number, bunch berry fresh mass and bunch sugar content at harvest. Conversely, average berry size and sugar content were not linked to rachis vascular area. These data indicate that the morphological and vascular development of the rachis was more responsive to flower number and plant growth regulators than to leaf removal.

  17. Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation

    DEFF Research Database (Denmark)

    Nissen, T N; Birk, N M; Blok, B A

    2018-01-01

    mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG...

  18.  Evaluation of the humoral and cellular immune responses after implantation of a PTFE vascular prosthesis.

    Science.gov (United States)

    Skóra, Jan; Pupka, Artur; Dorobisz, Andrzej; Barć, Piotr; Korta, Krzysztof; Dawiskiba, Tomasz

    2012-07-02

    The experiment was designed in order to determine the immunological processes that occur during the healing in synthetic vascular grafts, especially to establish the differences in the location of the complement system proteins between the proximal and distal anastomosis and the differences in the arrangement of inflammatory cells in those anastomoses. The understanding of those processes will provide a true basis for determining risk factors for complications after arterial repair procedures. The experiment was carried out on 16 dogs that underwent implantation of unilateral aorto-femoral bypass with expanded polytetrafluoroethylene (ePTFE). After 6 months all animals were euthanized to dissect the vascular grafts. Immunohistochemical assays and electron microscopic examinations were performed. Immunohistochemical findings in the structure of neointima between anastomoses of vascular prostheses demonstrated significant differences between humoral and cellular responses. The area of proximal anastomosis revealed the presence of fibroblasts, but no macrophages were detected. The histological structure of the proximal anastomosis indicates that inflammatory processes were ended during the prosthesis healing. The immunological response obtained in the distal anastomosis corresponded to the chronic inflammatory reaction with the presence of macrophages, myofibroblasts and deposits of complement C3. The identification of differences in the presence of macrophages and myofibroblasts and the presence of the C3 component between the anastomoses is the original achievement of the present study. In the available literature, no such significant differences have been shown so far in the humoral and cellular immune response caused by the presence of an artificial vessel in the arterial system.

  19. Differential responses to high-frequency electrical stimulation in ON and OFF retinal ganglion cells

    Science.gov (United States)

    Twyford, Perry; Cai, Changsi; Fried, Shelley

    2014-04-01

    Objective. The field of retinal prosthetics for artificial vision has advanced considerably in recent years, however clinical outcomes remain inconsistent. The performance of retinal prostheses is likely limited by the inability of electrical stimuli to preferentially activate different types of retinal ganglion cell (RGC). Approach. Here we examine the response of rabbit RGCs to high-frequency stimulation, using biphasic pulses applied at 2000 pulses per second. Responses were recorded using cell-attached patch clamp methods, and stimulation was applied epiretinally via a small cone electrode. Main results. When prolonged stimulus trains were applied to OFF-brisk transient (BT) RGCs, the cells exhibited a non-monotonic relationship between response strength and stimulus amplitude; this response pattern was different from those elicited previously by other electrical stimuli. When the amplitude of the stimulus was modulated transiently from a non-zero baseline amplitude, ON-BT and OFF-BT cells exhibited different activity patterns: ON cells showed an increase in activity while OFF cells exhibited a decrease in activity. Using a different envelope to modulate the amplitude of the stimulus, we observed the opposite effect: ON cells exhibited a decrease in activity while OFF cells show an increase in activity. Significance. As ON and OFF RGCs often exhibit opposing activity patterns in response to light stimulation, this work suggests that high-frequency electrical stimulation of RGCs may be able to elicit responses that are more physiological than traditional pulsatile stimuli. Additionally, the prospect of an electrical stimulus capable of cell-type specific selective activation has broad applications throughout the fields of neural stimulation and neuroprostheses.

  20. Diagnostic Power of Vascular Endothelial Growth Factor and Macrophage Colony-Stimulating Factor in Breast Cancer Patients Based on ROC Analysis

    Directory of Open Access Journals (Sweden)

    Monika Zajkowska

    2016-01-01

    Full Text Available Breast cancer (BC is the most common malignancy in women. Vascular endothelial growth factor (VEGF has been described as an important regulator of angiogenesis which plays a vital role in the progression of tumor. Macrophage colony-stimulating factor (M-CSF is a cytokine whose functions include regulation of hematopoietic lineages cells growth, proliferation, and differentiation. We investigated the diagnostic significance of these parameters in comparison to CA15-3 in BC patients and in relation to the control group (benign breast tumor and healthy women. Plasma levels of the tested parameters were determined by ELISA and CA15-3 was determined by CMIA. VEGF was shown to be comparable to CA15-3 values of sensitivity in BC group and, what is more important, higher values in early stages of BC. VEGF was also the only parameter which has statistically significant AUC in all stages of cancer. M-CSF has been shown to be comparable to CA15-3 and VEGF, specificity, and AUC values only in stages III and IV of BC. These results indicate the usefulness and high diagnostic power of VEGF in the detection of BC. Also, it occurred to be the best candidate for cancer diagnostics in stages I and II of BC and in the differentiation between BC and benign cases.

  1. Crucial role of Toll-like receptors in the zinc/nickel-induced inflammatory response in vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan (China); Liou, Saou-Hsing; Yeh, Szu-Ching; Tsai, Feng-Yuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan (China); Chao, How-Ran [Emerging Compounds Research Center, Department of Environmental Science and Engineering, National Pingtung University and Science and Technology, Neipu, Pingtung 912, Taiwan (China)

    2013-12-15

    Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs in the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause

  2. Cost effectiveness of responsive stimulation and nutrition interventions on early child development outcomes in Pakistan.

    Science.gov (United States)

    Gowani, Saima; Yousafzai, Aisha K; Armstrong, Robert; Bhutta, Zulfiqar A

    2014-01-01

    Early childhood programs are heralded as a way to improve children's health and educational outcomes. However, few studies in developing countries calculate the effectiveness of quality early childhood interventions. Even fewer estimate the associated costs of such interventions. The study here looks at the costs and effectiveness of a cluster-randomized effectiveness trial on children from birth to 24 months in rural Sindh, Pakistan. Responsive stimulation and/or enhanced nutrition interventions were integrated in the Lady Health Worker program in Pakistan. Outcomes suggest that children who receive responsive stimulation had significantly better development outcomes at 24 months than those who only received enhanced nutrition intervention. A cost-effectiveness analysis of the results verifies that early childhood interventions that include responsive stimulation are more cost effective than a nutrition intervention alone in promoting children's early development. Costs of a responsive stimulation intervention integrated in an existing community-based service providing basic health and nutrition care is approximately US$4 per month per child. We discuss these findings and make recommendations about scaling up and costs for future early child development programs. © 2014 New York Academy of Sciences.

  3. Respiratory Responses to Stimulation of Branchial Vagus Nerve Ganglia of a Teleost Fish

    NARCIS (Netherlands)

    Ballintijn, C.M.; Luiten, P.G.M.

    1983-01-01

    The effects of electrical stimulation of epibranchial vagus ganglia upon respiration of the carp were investigated. Single shocks evoked fast twitch responses in a number of respiratory muscles with latencies around 18 msec to the beginning and 30-35 msec to the peak of activity. Shocks given during

  4. Multimodal stimulation of Colorado potato beetle reveals modulation of pheromone response by yellow light.

    Directory of Open Access Journals (Sweden)

    Fernando Otálora-Luna

    Full Text Available Orientation of insects to host plants and conspecifics is the result of detection and integration of chemical and physical cues present in the environment. Sensory organs have evolved to be sensitive to important signals, providing neural input for higher order multimodal processing and behavioral output. Here we report experiments to determine decisions made by Colorado potato beetle (CPB, Leptinotarsa decemlineata, in response to isolated stimuli and multimodal combinations of signals on a locomotion compensator. Our results show that in complete darkness and in the absence of other stimuli, pheromonal stimulation increases attraction behavior of CPB as measured in oriented displacement and walking speed. However, orientation to the pheromone is abolished when presented with the alternative stimulation of a low intensity yellow light in a dark environment. The ability of the pheromone to stimulate these diurnal beetles in the dark in the absence of other stimuli is an unexpected but interesting observation. The predominance of the phototactic response over that to pheromone when low intensity lights were offered as choices seems to confirm the diurnal nature of the insect. The biological significance of the response to pheromone in the dark is unclear. The phototactic response will play a key role in elucidating multimodal stimulation in the host-finding process of CPB, and perhaps other insects. Such information might be exploited in the design of applications to attract and trap CPB for survey or control purposes and other insect pests using similar orientation mechanisms.

  5. Effect of ischemia and cooling on the response to high frequency stimulation in rat tail nerves

    DEFF Research Database (Denmark)

    Andersen, Henning; Feldbæk Nielsen, Jørgen; Sørensen, Bodil

    2000-01-01

    In normal rat tail nerves the effect of temperature and ischemia on the response to long-term high frequency stimulation (HFS) (143 Hz) was studied. The effect of temperature was studied in two consecutive tests at 14 degrees C and 35 degrees C. Prior to the HFS the peak-to-peak amplitude (PP...

  6. Visual cortex responses reflect temporal structure of continuous quasi-rhythmic sensory stimulation.

    Science.gov (United States)

    Keitel, Christian; Thut, Gregor; Gross, Joachim

    2017-02-01

    Neural processing of dynamic continuous visual input, and cognitive influences thereon, are frequently studied in paradigms employing strictly rhythmic stimulation. However, the temporal structure of natural stimuli is hardly ever fully rhythmic but possesses certain spectral bandwidths (e.g. lip movements in speech, gestures). Examining periodic brain responses elicited by strictly rhythmic stimulation might thus represent ideal, yet isolated cases. Here, we tested how the visual system reflects quasi-rhythmic stimulation with frequencies continuously varying within ranges of classical theta (4-7Hz), alpha (8-13Hz) and beta bands (14-20Hz) using EEG. Our findings substantiate a systematic and sustained neural phase-locking to stimulation in all three frequency ranges. Further, we found that allocation of spatial attention enhances EEG-stimulus locking to theta- and alpha-band stimulation. Our results bridge recent findings regarding phase locking ("entrainment") to quasi-rhythmic visual input and "frequency-tagging" experiments employing strictly rhythmic stimulation. We propose that sustained EEG-stimulus locking can be considered as a continuous neural signature of processing dynamic sensory input in early visual cortices. Accordingly, EEG-stimulus locking serves to trace the temporal evolution of rhythmic as well as quasi-rhythmic visual input and is subject to attentional bias. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Reducing aggressive responses to social exclusion using transcranial direct current stimulation.

    Science.gov (United States)

    Riva, Paolo; Romero Lauro, Leonor J; DeWall, C Nathan; Chester, David S; Bushman, Brad J

    2015-03-01

    A vast body of research showed that social exclusion can trigger aggression. However, the neural mechanisms involved in regulating aggressive responses to social exclusion are still largely unknown. Transcranial direct current stimulation (tDCS) modulates the excitability of a target region. Building on studies suggesting that activity in the right ventrolateral pre-frontal cortex (rVLPFC) might aid the regulation or inhibition of social exclusion-related distress, we hypothesized that non-invasive brain polarization through tDCS over the rVLPFC would reduce behavioral aggression following social exclusion. Participants were socially excluded or included while they received tDCS or sham stimulation to the rVLPFC. Next, they received an opportunity to aggress. Excluded participants demonstrated cognitive awareness of their inclusionary status, yet tDCS (but not sham stimulation) reduced their behavioral aggression. Excluded participants who received tDCS stimulation were no more aggressive than included participants. tDCS stimulation did not influence socially included participants' aggression. Our findings provide the first causal test for the role of rVLPFC in modulating aggressive responses to social exclusion. Our findings suggest that modulating activity in a brain area (i.e. the rVLPFC) implicated in self-control and emotion regulation can break the link between social exclusion and aggression. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  8. Redox Signaling and Its Impact on Skeletal and Vascular Responses to Spaceflight

    Science.gov (United States)

    Tahimic, Candice; Globus, Ruth K.

    2018-01-01

    Spaceflight entails exposure to numerous environmental challenges with the potential to contribute to both musculoskeletal and vascular dysfunction. The purpose of this review is to describe current understanding of microgravity and radiation impacts on the mammalian skeleton and associated vasculature at the level of the whole organism. Recent experiments from spaceflight and groundbased models have provided fresh insights into how these environmental stresses influence mechanisms that are related to redox signaling, oxidative stress, and tissue dysfunction. Emerging mechanistic knowledge on cellular defenses to radiation and other environmental stressors, including microgravity, are useful for both screening and developing interventions against spaceflight-induced deficits in bone and vascular function.

  9. Redox Signaling and Its Impact on Skeletal and Vascular Responses to Spaceflight

    Directory of Open Access Journals (Sweden)

    Candice G. T. Tahimic

    2017-10-01

    Full Text Available Spaceflight entails exposure to numerous environmental challenges with the potential to contribute to both musculoskeletal and vascular dysfunction. The purpose of this review is to describe current understanding of microgravity and radiation impacts on the mammalian skeleton and associated vasculature at the level of the whole organism. Recent experiments from spaceflight and ground-based models have provided fresh insights into how these environmental stresses influence mechanisms that are related to redox signaling, oxidative stress, and tissue dysfunction. Emerging mechanistic knowledge on cellular defenses to radiation and other environmental stressors, including microgravity, are useful for both screening and developing interventions against spaceflight-induced deficits in bone and vascular function.

  10. Spatially divergent cardiac responses to nicotinic stimulation of ganglionated plexus neurons in the canine heart.

    Science.gov (United States)

    Cardinal, René; Pagé, Pierre; Vermeulen, Michel; Ardell, Jeffrey L; Armour, J Andrew

    2009-01-28

    Ganglionated plexuses (GPs) are major constituents of the intrinsic cardiac nervous system, the final common integrator of regional cardiac control. We hypothesized that nicotinic stimulation of individual GPs exerts divergent regional influences, affecting atrial as well as ventricular functions. In 22 anesthetized canines, unipolar electrograms were recorded from 127 atrial and 127 ventricular epicardial loci during nicotine injection (100 mcg in 0.1 ml) into either the 1) right atrial (RA), 2) dorsal atrial, 3) left atrial, 4) inferior vena cava-inferior left atrial, 5) right ventricular, 6) ventral septal ventricular or 7) cranial medial ventricular (CMV) GP. In addition to sinus and AV nodal function, neural effects on atrial and ventricular repolarization were identified as changes in the area subtended by unipolar recordings under basal conditions and at maximum neurally-induced effects. Animals were studied with intact AV node or following ablation to achieve ventricular rate control. Atrial rate was affected in response to stimulation of all 7 GPs with an incidence of 50-95% of the animals among the different GPs. AV conduction was affected following stimulation of 6/7 GP with an incidence of 22-75% among GPs. Atrial and ventricular repolarization properties were affected by atrial as well as ventricular GP stimulation. Distinct regional patterns of repolarization changes were identified in response to stimulation of individual GPs. RAGP predominantly affected the RA and posterior right ventricular walls whereas CMVGP elicited biatrial and biventricular repolarization changes. Spatially divergent and overlapping cardiac regions are affected in response to nicotinic stimulation of neurons in individual GPs.

  11. Auditory steady-state responses in cochlear implant users: Effect of modulation frequency and stimulation artifacts.

    Science.gov (United States)

    Gransier, Robin; Deprez, Hanne; Hofmann, Michael; Moonen, Marc; van Wieringen, Astrid; Wouters, Jan

    2016-05-01

    Previous studies have shown that objective measures based on stimulation with low-rate pulse trains fail to predict the threshold levels of cochlear implant (CI) users for high-rate pulse trains, as used in clinical devices. Electrically evoked auditory steady-state responses (EASSRs) can be elicited by modulated high-rate pulse trains, and can potentially be used to objectively determine threshold levels of CI users. The responsiveness of the auditory pathway of profoundly hearing-impaired CI users to modulation frequencies is, however, not known. In the present study we investigated the responsiveness of the auditory pathway of CI users to a monopolar 500 pulses per second (pps) pulse train modulated between 1 and 100 Hz. EASSRs to forty-three modulation frequencies, elicited at the subject's maximum comfort level, were recorded by means of electroencephalography. Stimulation artifacts were removed by a linear interpolation between a pre- and post-stimulus sample (i.e., blanking). The phase delay across modulation frequencies was used to differentiate between the neural response and a possible residual stimulation artifact after blanking. Stimulation artifacts were longer than the inter-pulse interval of the 500pps pulse train for recording electrodes ipsilateral to the CI. As a result the stimulation artifacts could not be removed by artifact removal on the bases of linear interpolation for recording electrodes ipsilateral to the CI. However, artifact-free responses could be obtained in all subjects from recording electrodes contralateral to the CI, when subject specific reference electrodes (Cz or Fpz) were used. EASSRs to modulation frequencies within the 30-50 Hz range resulted in significant responses in all subjects. Only a small number of significant responses could be obtained, during a measurement period of 5 min, that originate from the brain stem (i.e., modulation frequencies in the 80-100 Hz range). This reduced synchronized activity of brain stem

  12. Stimulation of 5-HT2A receptors recovers sensory responsiveness in acute spinal neonatal rats.

    Science.gov (United States)

    Swann, Hillary E; Kauer, Sierra D; Allmond, Jacob T; Brumley, Michele R

    2017-02-01

    Quipazine is a 5-HT 2A -receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. Vascular biomarkers to predict response to exercise in Alzheimer's disease: the study protocol

    Science.gov (United States)

    Li, Danni; Thomas, Robin; Tsai, Michael Y; Li, Ling; Vock, David M; Greimel, Susan; Yu, Fang

    2016-01-01

    Introduction Exercise interventions are a promising treatment for improving cognition in persons with Alzheimer's disease. This is similar to Alzheimer's disease pharmacotherapies in which only 18–48% of treated patients demonstrate improvement in cognition. Aerobic exercise interventions positively affect brain structure and function through biologically sound pathways. However, an under-studied mechanism of aerobic exercise's effects is n-3 fatty acids in plasma. The objective of this pilot study is to inform a future large-scale study to develop n-3 fatty acids-based prediction of cognitive responses to aerobic exercise treatment in Alzheimer's disease. Methods and analysis This study will recruit and follow a cohort of 25 subjects enrolled in the FIT-AD Trial, an ongoing randomised controlled trial that investigates the effects of a 6-month moderate-intensity cycling intervention on cognition and hippocampal volume in older adults with mild to moderate Alzheimer's disease over a year. This study will collect blood from subjects at baseline and at 3 and 6 months to assay vascular biomarkers (ie, plasma fatty acids). Global cognition as measured by the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) at baseline, 3, 6, 9 and 12 months will be used as the main outcome. A multiple linear-regression model will be used with 12-month change in cognition as the outcome and baseline measure of n-3 fatty acids or changes in the ratio of n-3 to n-6 fatty-acid levels in plasma at 3 and/or 6 months, randomised treatment group, and their interaction as predictors. Ethics and dissemination We have obtained Institutional Review Board approval for our study. We obtain consent or assent/surrogate consent from all subjects depending on their consenting capacity assessment. Data of this study are/will be stored in the Research Electronic Data Capture (REDCap). We plan to present and publish our study findings through presentations and manuscripts. Trial

  14. Vascular biomarkers to predict response to exercise in Alzheimer's disease: the study protocol.

    Science.gov (United States)

    Li, Danni; Thomas, Robin; Tsai, Michael Y; Li, Ling; Vock, David M; Greimel, Susan; Yu, Fang

    2016-12-30

    Exercise interventions are a promising treatment for improving cognition in persons with Alzheimer's disease. This is similar to Alzheimer's disease pharmacotherapies in which only 18-48% of treated patients demonstrate improvement in cognition. Aerobic exercise interventions positively affect brain structure and function through biologically sound pathways. However, an under-studied mechanism of aerobic exercise's effects is n-3 fatty acids in plasma. The objective of this pilot study is to inform a future large-scale study to develop n-3 fatty acids-based prediction of cognitive responses to aerobic exercise treatment in Alzheimer's disease. This study will recruit and follow a cohort of 25 subjects enrolled in the FIT-AD Trial, an ongoing randomised controlled trial that investigates the effects of a 6-month moderate-intensity cycling intervention on cognition and hippocampal volume in older adults with mild to moderate Alzheimer's disease over a year. This study will collect blood from subjects at baseline and at 3 and 6 months to assay vascular biomarkers (ie, plasma fatty acids). Global cognition as measured by the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) at baseline, 3, 6, 9 and 12 months will be used as the main outcome. A multiple linear-regression model will be used with 12-month change in cognition as the outcome and baseline measure of n-3 fatty acids or changes in the ratio of n-3 to n-6 fatty-acid levels in plasma at 3 and/or 6 months, randomised treatment group, and their interaction as predictors. We have obtained Institutional Review Board approval for our study. We obtain consent or assent/surrogate consent from all subjects depending on their consenting capacity assessment. Data of this study are/will be stored in the Research Electronic Data Capture (REDCap). We plan to present and publish our study findings through presentations and manuscripts. NCT01954550. Published by the BMJ Publishing Group Limited. For permission to

  15. No effect of melatonin to modify surgical-stress response after major vascular surgery

    DEFF Research Database (Denmark)

    Kücükakin, B.; Wilhelmsen, M.; Lykkesfeldt, Jens

    2010-01-01

    A possible mechanism underlying cardiovascular morbidity after major vascular surgery may be the perioperative ischaemia-reperfusion with excessive oxygen-derived free-radical production and increased levels of circulating inflammatory mediators. We examined the effect of melatonin infusion during...... surgery and oral melatonin treatment for 3 days after surgery on biochemical markers of oxidative and inflammatory stress....

  16. The Sheer Stress of Shear Stress: Responses of the Vascular Wall to a Haemodynamic Force

    NARCIS (Netherlands)

    C. Cheng (Caroline (Ka Lai))

    2006-01-01

    textabstractStudies in the hemodynamic field point to a strong relation between shear stress and the onset to vascular diseases such as atherosclerosis. Data from in vitro studies using sheared endothelial cells have provided insight into the possible mechanisms involved. However, the lack of an

  17. Short-term bryoid and vascular vegetation response to reforestation alternatives following wildfire in conifer plantations

    Science.gov (United States)

    Lori J. Kayes; Klaus J. Puettmann; Paul D. Anderson

    2011-01-01

    How are dynamics of early-seral post-fire vascular plant and bryoid (terrestrial mosses, lichens, and fungi) vegetation impacted by reforestation activities, particularly manual vegetation removal and planting density? Does the relationship between vegetation dynamics and vegetation removal differ between harsh (west-facing) and moderate (east-facing) aspects?...

  18. Responses of starburst amacrine cells to prosthetic stimulation of the retina.

    Science.gov (United States)

    Tsai, D; Morley, J W; Suaning, G J; Lovell, N H

    2011-01-01

    Recent advances in the design and development of retinal implants have made these devices a promising therapeutic strategy for restoring sight to the blind. Over the last decade a plethora of studies have investigated the responses of the retinal ganglion cells (RGCs) to electrical stimulation under a variety of stimulus configurations. Similar to the RGCs, the amacrine cells also survive in large numbers following retinal neural degeneration. However, with the exception of two previous reports, where the responses of the amacrine cells were measured indirectly, these cells have thus far received little attention in the context of prosthetic stimulation. In this study we focused on the starburst amacrine cells (SACs), a particularly well-characterized amacrine cell among the approximately two-dozen types known to exist in the retina. Using whole-cell patch clamp recordings in the whole-mount rabbit retina, we investigated the temporal responses of the SACs following subretinal biphasic pulse stimulation. These cells responded to the stimuli with oscillatory membrane potentials that lasted for tens to hundreds of milliseconds, with the response amplitude increasing as a function of stimulus strength. Furthermore, the SAC responses originated primarily from the presynaptic inputs they receive, rather than through direct activation of these cells by the electrical stimuli.

  19. Learning in clinical practice: Stimulating and discouraging response to social comparison.

    Science.gov (United States)

    Raat, Janet; Kuks, Jan; Cohen-Schotanus, Janke

    2010-01-01

    Social comparison theory is relevant for learning in general. In a clinical context, we examined four hypotheses concerning: preferred other to compare with, preferred direction of comparison, response to social comparison and influence of personal social comparison orientation (SCO). To investigate the relevance of social comparison for clinical workplace learning. Students (n = 437) from nine different hospitals completed two questionnaires measuring their SCO and the direction of and response to their comparisons. t-tests were used to analyse the data. Students substantially did compare. They preferred to compare with peer students more than with residents or staff, and with peers doing better more than with peers doing worse. Their response to social comparison was more often stimulating for learning than discouraging. Students high in SCO reported a stronger stimulating and discouraging response to their comparisons than students low in SCO. Social comparison does play a role in clinical workplace learning. The mainly stimulating response to social comparison indicates a positive learning influence. The preferred comparison with peers emphasizes the role of peers in the learning process. Further research should focus on student comparison behaviour and on situations that strengthen the positive effects of social comparison and reduce the negative or obstructing ones.

  20. Differential vascular dysfunction in response to diets of differing macronutrient composition: a phenomenonological study

    Directory of Open Access Journals (Sweden)

    Cassidy Roslyn

    2007-06-01

    Full Text Available Abstract Background Vascular dysfunction can develop from consumption of an energy-rich diet, even prior to the onset of obesity. However, the roles played by different dietary components remain uncertain. While attempting to develop models of obesity in a separate study, we observed that two high-energy diets of differing macronutrient compositions affected vascular function differently in overweight rats. Methods Male Wistar rats (n = 6/group were fed diets providing varying percentages of energy from fat and carbohydrate (CHO. For 10 weeks, they were fed either chow, as control diet (10% of energy from fat; 63% from CHO, chow supplemented with chocolate biscuit (30% fat; 56% CHO or a high-fat diet (45% fat; 35% CHO. Blood concentrations of biochemical markers of obesity were measured, and epididymal fat pads weighed as a measure of adiposity. Mesenteric arteries were dissected and their contractile and relaxant properties analysed myographically. Data were tested by analysis of variance (ANOVA. Results Weight gain and plasma concentrations of glucose, insulin and leptin were similar in all groups. However, biscuit-fed animals showed increased food intake (+27%; p p p p p Conclusion Vascular dysfunction resulting from consumption of a high-fat or combined relatively high-fat/high-CHO diet occurs through different physiological processes, which may be attributable to their differing macronutrient compositions. Combining potentially atherogenic macronutrients induces more extensive vascular impairment than that of high-fat alone, and may be attributable to the more marked dyslipidaemia observed with such a diet. Thus, these findings help clarify the role of dietary components in vascular impairment, which has implications for clinical approaches to preventing cardiovascular disease.

  1. Synchronized Firings in Retinal Ganglion Cells in Response to Natural Stimulation

    International Nuclear Information System (INIS)

    Zhang Ying-Ying; Xiao Lei; Liu Wen-Zhong; Gong Hai-Qing; Liang Pei-Ji

    2011-01-01

    The response of synchronously firing groups of population retinal ganglion cells (RGCs) to natural movies (NMs) and pseudo-random white-noise checker-board flickering (CB, as control) are investigated using an information-theoretic algorithm. The main results are: (1) the population RGCs tend to fire in synchrony far more frequently than expected by chance during both NM and CB stimulation; (2) more synchronous groups could be formed and each group contains more neurons under NM than CB stimulation; (3) the individual neurons also participate in more groups and have more distinct partners in NM than CB stimulation. All these results suggest that the synchronized firings in RGCs are more extensive and diverse, which may account for more effective information processing in representing the natural visual environment. (cross-disciplinary physics and related areas of science and technology)

  2. Gold nanoparticle-mediated laser stimulation induces a complex stress response in neuronal cells.

    Science.gov (United States)

    Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Kalies, Stefan; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

    2018-04-25

    Stimulation of neuronal cells generally resorts to electric signals. Recent advances in laser-based stimulation methods could present an alternative with superior spatiotemporal resolution. The avoidance of electronic crosstalk makes these methods attractive for in vivo therapeutic application. In particular, nano-mediators, such as gold nanoparticles, can be used to transfer the energy from a laser pulse to the cell membrane and subsequently activate excitable cells. Although the underlying mechanisms of neuronal activation have been widely unraveled, the overall effect on the targeted cell is not understood. Little is known about the physiological and pathophysiological impact of a laser pulse targeted onto nanoabsorbers on the cell membrane. Here, we analyzed the reaction of the neuronal murine cell line Neuro-2A and murine primary cortical neurons to gold nanoparticle mediated laser stimulation. Our study reveals a severe, complex and cell-type independent stress response after laser irradiation, emphasizing the need for a thorough assessment of this approach's efficacy and safety.

  3. Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    1999-01-01

    Ageing is associated with decreased resistance to bacterial infections and concomitant increased circulating levels of inflammatory cytokines. The purpose of the present study was to research age-related changes in levels of early mediators of the acute-phase response in whole blood supernatants...... following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91...... of proinflammatory cytokines compared with young men, but this difference was blurred by ageing. No relation was found between circulating plasma levels of TNF-alpha and levels after in vitro LPS stimulation. In conclusion, decreased production of TNF-alpha and IL-1 beta after exposure to LPS may reflect impaired...

  4. Spatiotemporal dynamics of cortical perfusion in response to thalamic deep brain stimulation.

    Science.gov (United States)

    Noor, M Sohail; Murari, Kartikeya; McCracken, Clinton B; Kiss, Zelma H T

    2016-02-01

    Deep brain stimulation (DBS) has revolutionized the treatment of movement disorders. The parameters of electrical stimulation are important to its therapeutic effect and remain a source of clinical controversy. DBS exerts its actions not only locally at the site of stimulation but also remotely through afferent and efferent connections, which are vital to its clinical effects. Yet, only a few studies have examined how cortical activity changes in response to various electrical parameters. Here, we investigated how the parameters of thalamic DBS alter cortical perfusion in rats using intrinsic optical imaging. We hypothesized that thalamic DBS will increase perfusion in primary motor cortex (M1), proportional to amplitude, pulse width, or frequency of the stimulation applied. We applied 45 different combinations of amplitude, pulse width and frequency in the ventro-lateral (VL) nucleus of the thalamus in anesthetized rats while measuring perfusion in M1. VL thalamic DBS reduced cortical reflectance, which corresponds to an increase in cortical perfusion. We computed the maximum change in reflectance (MCR) as well as the spatial spread of MCR in each trial. Both MCR and spatial spread increased linearly with increases in current amplitude or pulse width of stimulation; however, the effect of frequency was non-linear. Stimulation at 20 Hz was significantly different from that at higher frequencies while stimulation at higher frequencies did not differ significantly from each other. Moreover, the effect of pulse width on MCR was larger than the effect of amplitude. The proportional increase in M1 perfusion due to increase in amplitude or pulse width suggests that both activate more neural elements and increase the volume of tissue activated. These results should help clinicians set parameters of DBS. The use of optical imaging to monitor effects of DBS on M1 may not only help understand DBS mechanisms, but may also provide feedback for closed loop DBS devices

  5. Multimodal responses induced by cortical stimulation of the parietal lobe: a stereo-electroencephalography study.

    Science.gov (United States)

    Balestrini, Simona; Francione, Stefano; Mai, Roberto; Castana, Laura; Casaceli, Giuseppe; Marino, Daniela; Provinciali, Leandro; Cardinale, Francesco; Tassi, Laura

    2015-09-01

    The functional complexity of the parietal lobe still represents a challenge for neurophysiological and functional neuroimaging studies. While the somatosensory functions of the anterior parietal cortex are well established, the posterior parietal cortex has a relevant role in processing the sensory information, including visuo-spatial perception, visual attention, visuo-motor transformations and other complex and not completely understood functions. We retrospectively analysed all the clinical manifestations induced by intracerebral bipolar electrical stimulation in 172 patients suffering from drug-resistant focal epilepsy (mean age 25.6, standard deviation 11.6; 44% females and 56% males) with at least one electrode stereotactically implanted in the parietal cortex. A total of 1186 electrical stimulations were included in the analysis, of which 88 were subsequently excluded because of eliciting pathological electric activity or inducing ictal symptomatology. In the dominant parietal lobe, clinical responses were observed for 56 (25%) of the low-frequency stimulations and for 76 (50%) of the high-frequency stimulations. In the non-dominant parietal lobe, 111 (27%) low-frequency and 176 (55%) high-frequency stimulations were associated with a clinical response. Body scheme alteration was the only clinical effect showing a lateralization, as they were evoked only in the non-dominant hemisphere. The occurrence of somatosensory sensations, motor symptoms, dysarthria and multimodal responses were significantly associated with stimulation of the postcentral gyrus (odds ratio: 5.83, P < 0.001; odds ratio: 8.77, P < 0.001; odds ratio: 5.44, P = 0.011; odds ratio: 8.33, P = 0.006; respectively). Stimulation of the intraparietal sulcus was associated with the occurrence of sensory illusions or hallucinations (odds ratio: 8.68, P < 0.001) and eyeball/eyelid movements or sensations (odds ratio: 4.35, P = 0.047). To our knowledge, this is the only currently available complete

  6. Rac1 protein signaling is required for DNA damage response stimulated by topoisomerase II poisons.

    Science.gov (United States)

    Huelsenbeck, Stefanie C; Schorr, Anne; Roos, Wynand P; Huelsenbeck, Johannes; Henninger, Christian; Kaina, Bernd; Fritz, Gerhard

    2012-11-09

    To investigate the potency of the topoisomerase II (topo II) poisons doxorubicin and etoposide to stimulate the DNA damage response (DDR), S139 phosphorylation of histone H2AX (γH2AX) was analyzed using rat cardiomyoblast cells (H9c2). Etoposide caused a dose-dependent increase in the γH2AX level as shown by Western blotting. By contrast, the doxorubicin response was bell-shaped with high doses failing to increase H2AX phosphorylation. Identical results were obtained by immunohistochemical analysis of γH2AX focus formation, comet assay-based DNA strand break analysis, and measuring the formation of the topo II-DNA cleavable complex. At low dose, doxorubicin activated ataxia telangiectasia mutated (ATM) but not ATM and Rad3-related (ATR). Both the lipid-lowering drug lovastatin and the Rac1-specific inhibitor NSC23766 attenuated doxorubicin- and etoposide-stimulated H2AX phosphorylation, induction of DNA strand breaks, and topo II-DNA complex formation. Lovastatin and NSC23766 acted in an additive manner. They did not attenuate doxorubicin-induced increase in p-ATM and p-Chk2 levels. DDR stimulated by topo II poisons was partially blocked by inhibition of type I p21-associated kinases. DDR evoked by the topoisomerase I poison topotecan remained unaffected by lovastatin. The data show that the mechanisms involved in DDR stimulated by topo II poisons are agent-specific with anthracyclines lacking DDR-stimulating activity at high doses. Pharmacological inhibition of Rac1 signaling counteracts doxorubicin- and etoposide-stimulated DDR by disabling the formation of the topo II-DNA cleavable complex. Based on the data we suggest that Rac1-regulated mechanisms are required for DNA damage induction and subsequent activation of the DDR following treatment with topo II but not topo I poisons.

  7. Rac1 Protein Signaling Is Required for DNA Damage Response Stimulated by Topoisomerase II Poisons*

    Science.gov (United States)

    Huelsenbeck, Stefanie C.; Schorr, Anne; Roos, Wynand P.; Huelsenbeck, Johannes; Henninger, Christian; Kaina, Bernd; Fritz, Gerhard

    2012-01-01

    To investigate the potency of the topoisomerase II (topo II) poisons doxorubicin and etoposide to stimulate the DNA damage response (DDR), S139 phosphorylation of histone H2AX (γH2AX) was analyzed using rat cardiomyoblast cells (H9c2). Etoposide caused a dose-dependent increase in the γH2AX level as shown by Western blotting. By contrast, the doxorubicin response was bell-shaped with high doses failing to increase H2AX phosphorylation. Identical results were obtained by immunohistochemical analysis of γH2AX focus formation, comet assay-based DNA strand break analysis, and measuring the formation of the topo II-DNA cleavable complex. At low dose, doxorubicin activated ataxia telangiectasia mutated (ATM) but not ATM and Rad3-related (ATR). Both the lipid-lowering drug lovastatin and the Rac1-specific inhibitor NSC23766 attenuated doxorubicin- and etoposide-stimulated H2AX phosphorylation, induction of DNA strand breaks, and topo II-DNA complex formation. Lovastatin and NSC23766 acted in an additive manner. They did not attenuate doxorubicin-induced increase in p-ATM and p-Chk2 levels. DDR stimulated by topo II poisons was partially blocked by inhibition of type I p21-associated kinases. DDR evoked by the topoisomerase I poison topotecan remained unaffected by lovastatin. The data show that the mechanisms involved in DDR stimulated by topo II poisons are agent-specific with anthracyclines lacking DDR-stimulating activity at high doses. Pharmacological inhibition of Rac1 signaling counteracts doxorubicin- and etoposide-stimulated DDR by disabling the formation of the topo II-DNA cleavable complex. Based on the data we suggest that Rac1-regulated mechanisms are required for DNA damage induction and subsequent activation of the DDR following treatment with topo II but not topo I poisons. PMID:23012366

  8. Testing a linear time invariant model for skin conductance responses by intraneural recording and stimulation.

    Science.gov (United States)

    Gerster, Samuel; Namer, Barbara; Elam, Mikael; Bach, Dominik R

    2018-02-01

    Skin conductance responses (SCR) are increasingly analyzed with model-based approaches that assume a linear and time-invariant (LTI) mapping from sudomotor nerve (SN) activity to observed SCR. These LTI assumptions have previously been validated indirectly, by quantifying how much variance in SCR elicited by sensory stimulation is explained under an LTI model. This approach, however, collapses sources of variability in the nervous and effector organ systems. Here, we directly focus on the SN/SCR mapping by harnessing two invasive methods. In an intraneural recording experiment, we simultaneously track SN activity and SCR. This allows assessing the SN/SCR relationship but possibly suffers from interfering activity of non-SN sympathetic fibers. In an intraneural stimulation experiment under regional anesthesia, such influences are removed. In this stimulation experiment, about 95% of SCR variance is explained under LTI assumptions when stimulation frequency is below 0.6 Hz. At higher frequencies, nonlinearities occur. In the intraneural recording experiment, explained SCR variance is lower, possibly indicating interference from non-SN fibers, but higher than in our previous indirect tests. We conclude that LTI systems may not only be a useful approximation but in fact a rather accurate description of biophysical reality in the SN/SCR system, under conditions of low baseline activity and sporadic external stimuli. Intraneural stimulation under regional anesthesia is the most sensitive method to address this question. © 2017 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

  9. Dose-response of seeds of the parasitic weeds Striga and Orobanche toward the synthetic germination stimulants GR24.

    NARCIS (Netherlands)

    Wigchert, S.C.M.; Kuiper, E.; Boelhouwer, G.J.; Nefkens, G.H.L.; Verkley, J.A.C.; Zwanenburg, B.

    1999-01-01

    Striga and Orobanche seeds germinate in response to a host-derived germination stimulant. Dose-response curves of the synthetic strigolactone analogues GR 24 and Nijmegen 1 were determined, and their activities were compared to that of the naturally occurring stimulant sorgolactone. Typical

  10. A neuroanatomical correlate of sensorimotor recovery in response to repeated vaginocervical stimulation in rats.

    Directory of Open Access Journals (Sweden)

    Barry R Komisaruk

    2012-04-01

    Full Text Available Gentle probing against the cervix via the vagina (VCS increases tail flick latency (TFL to radiant heat; greater force totally abolishes the tail flick response and other withdrawal responses. This effect occurs in spinal cord-transected rats and in intact rats. On the basis of our earlier finding that vaginocervical stimulation (VCS releases vasoactive intestinal peptide (VIP into the spinal cord, and others’ reports of neurotrophic effects of VIP in vitro, we hypothesized that repeated VCS would stimulate sprouting and sensorimotor function of terminals of genital nerve primary afferents in the sacral spinal cord. To test this hypothesis, in the present study, we denervated the genital tract only unilaterally, which significantly reduced the TFL-elevating effect of VCS. Then we applied repeated daily VCS for one week and compared the subsequent effectiveness of acute VCS in elevating TFL. The rats that received the repeated daily VCS showed a significantly greater elevation in TFL in response to acute VCS than control rats that did not receive the repeated stimulation. Then, to test whether daily repeated VCS stimulates sprouting of genital primary afferents in such unilaterally genital tract-denervated rats, we transected the contralateral remaining intact pelvic nerve, applied horseradish peroxidase (HRP to its proximal cut end for 1-2h, and 2-3d later counted HRP particles in its terminal zone (S1 in the spinal cord. There were significantly more HRP particles in the rats that received the daily repeated VCS than in the control rats. In the context of these findings, we conclude that vaginocervical stimulation in rats can produce a functional sensorimotor recovery via a neurotrophic effect on compromised primary afferents in the spinal cord. Based on our previous research, we speculate that a similar functional sprouting antinociceptive process could occur supraspinally, after spinal cord injury, via an alternative vaginocervical sensory

  11. Temporal code in the vibrissal system - Part I: Vibrissa response to passive stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Farfan, F D [Departamento de BioingenierIa, FACET, Universidad Nacional de Tucuman, INSIBIO - CONICET, CC 327, Postal Code CP, 4000 (Argentina); AlbarracIn, A L [Catedra de Neurociencias, Facultad de Medicina, Universidad Nacional de Tucuman (Argentina); Felice, C J [Departamento de BioingenierIa, FACET, Universidad Nacional de Tucuman, INSIBIO - CONICET, CC 327, Postal Code CP, 4000 (Argentina)

    2007-11-15

    In this paper we analyzed the afferent discharges of two nerves: one innervating three vibrissae (N1) and another one innervating the DELTA vibrissa (N2). Sustained mechanical stimulations were applied to the hair shaft of a whisker innervated by N1 in three different directions. The vibrissa selected for stimulation was the one that produced the higher electrical activity in the N1. The vibrissa was bent 1, 2 and 3 mm in each direction. The manual stimulation was applied to DELTA vibrissa and its electrical activity was registered. A custom-made photoresistive sensor registered the vibrissa displacements. We analyzed the multifiber discharge with a spike detection algorithm using the continuous wavelet transform (CWT). Directional sensibility in afferent responses was observed. RMS values had higher sensibility to deflection intensity in direction 1, while the responses in direction 2 and 3 were different. Median and dispersion of the inter-event times were decreased during different levels of the bent (events of 0.2 msec). The statistical analysis of the inter-event times showed significant differences among different stimulation levels. The inter-event times are decreased during passive movement with bent quantity induced to DELTA vibrissa. In this case the events duration was 0.6 ms.

  12. Hemodynamic response to visual stimulation in newborn infants using functional near-infrared spectroscopy.

    Science.gov (United States)

    Karen, Tanja; Morren, Geert; Haensse, Daniel; Bauschatz, Andrea S; Bucher, Hans Ulrich; Wolf, Martin

    2008-04-01

    Brain activity is associated with physiological changes, which alter the optical properties of tissue. These changes can be detected by near-infrared spectroscopy (NIRS). Aim of the study was to determine changes in cerebral oxygenation in response to stimulation in the visual cortex in newborn infants during spontaneous sleep in the first days of life. We used an in-house developed multichannel NIRS imaging instrument, the MCP-II, to measure changes in concentration of oxyhemoglobin (O(2)Hb) and deoxyhemoglobin (HHb) in specific brain areas. In 10 out of 15 subjects, a significant increase in O(2)Hb and/or a significant decrease in HHb were found in one or more channels over the occipital cortex. During stimulation, O(2)Hb increased by a mean of 0.98 mumol/l, HHb decreased by a mean 0.17 mumol/l, and total-Hb increased by a mean of 0.81 mumol/l. The hemodynamic response to visual stimulation in the occipital cortex in newborn infants is similar to adults. The increase in O(2)Hb and the simultaneous decrease in HHb during stimulation suggest an increase in cerebral blood flow (CBF) that overcompensates for the increased oxygen consumption (CMRO(2)) in the activated cortical area. (c) 2007 Wiley-Liss, Inc.

  13. Delay-Dependent Response in Weakly Electric Fish under Closed-Loop Pulse Stimulation.

    Directory of Open Access Journals (Sweden)

    Caroline Garcia Forlim

    Full Text Available In this paper, we apply a real time activity-dependent protocol to study how freely swimming weakly electric fish produce and process the timing of their own electric signals. Specifically, we address this study in the elephant fish, Gnathonemus petersii, an animal that uses weak discharges to locate obstacles or food while navigating, as well as for electro-communication with conspecifics. To investigate how the inter pulse intervals vary in response to external stimuli, we compare the response to a simple closed-loop stimulation protocol and the signals generated without electrical stimulation. The activity-dependent stimulation protocol explores different stimulus delivery delays relative to the fish's own electric discharges. We show that there is a critical time delay in this closed-loop interaction, as the largest changes in inter pulse intervals occur when the stimulation delay is below 100 ms. We also discuss the implications of these findings in the context of information processing in weakly electric fish.

  14. Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits.

    Science.gov (United States)

    Scholtzova, Henrieta; Do, Eileen; Dhakal, Shleshma; Sun, Yanjie; Liu, Shan; Mehta, Pankaj D; Wisniewski, Thomas

    2017-01-25

    Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-β (Aβ) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-β-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD

  15. Population response characteristics of intrinsic signals in the cat somatosensory cortex following canine mechanical stimulation.

    Science.gov (United States)

    Tao, Jianxiang; Wang, Jian; Li, Zhong; Meng, Jianjun; Yu, Hongbo

    2016-08-04

    Intrinsic signal optical imaging has been widely used to measure functional maps in various sensory cortices due to better spatial resolution and sensitivity for detecting cortical neuroplasticity. However, application of this technique in dentistry has not been reported. In this study, intrinsic signal optical imaging was used to investigate mechanically driven responses in the cat somatosensory cortex, when punctate mechanical stimuli were applied to maxillary canines. The global signal and its spatial organization pattern were obtained. Global signal strength gradually increased with stimulus strength. There was no significant difference in response strength between contralateral and ipsilateral mechanical stimulation. A slightly greater response was recorded in the sigmoidal gyrus than in the coronal gyrus. The cat somatosensory cortex activated by sensory inputs from mechanical stimulation of canines lacks both topographical and functional organization. It is not organized into columns that represent sensory input from each tooth or direction of stimulation. These results demonstrate that intrinsic signal optical imaging is a valid tool for investigating neural responses and neuroplasticity in the somatosensory cortex that represents teeth. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation

    Directory of Open Access Journals (Sweden)

    Kingsley David M

    2008-04-01

    Full Text Available Abstract Background Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear. Results Here, we identify a novel germline mutation at the mouse Bone morphogenetic protein 5 (Bmp5 locus. Genetic analysis shows that the mutation occurs at a site encoding the proteolytic processing sequence of the BMP5 protein and blocks proper processing of BMP5. Anatomic studies reveal that this mutation affects the formation of multiple skeletal features including several muscle-induced skeletal sites in vivo. Biomechanical studies of osteoblasts from these anatomic sites show that the mutation inhibits the proper response of bone cells to mechanical stimulation. Conclusion The results from these genetic, biochemical, and biomechanical studies suggest that BMPs are required not only for skeletal patterning during embryonic development, but also for bone response and remodeling to mechanical stimulation at specific anatomic sites in the skeleton.

  17. Reservoir response to thermal and high-pressure well stimulation efforts at Raft River, Idaho

    Energy Technology Data Exchange (ETDEWEB)

    Plummer, Mitchell [Idaho National Lab. (INL), Idaho Falls, ID (United States); Bradford, Jacob [Energy & Geoscience Institute at the Univ. of Utah, Salt Lake City, UT (United States); Moore, Joseph [Energy & Geoscience Institute at the Univ. of Utah, Salt Lake City, UT (United States); Podgorney, Robert [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-08-01

    An injection stimulation test begun at the Raft River geothermal reservoir in June, 2013 has produced a wealth of data describing well and reservoir response via high-resolution temperature logging and distributed temperature sensing, seismic monitoring, periodic borehole televiewer logging, periodic stepped flow rate tests and tracer injections before and after stimulation efforts. One of the primary measures of response to the stimulation is the relationship between fluid pressure and flow rate, short-term during forced flow rate changes and the long-term change in injectivity. In this paper we examine that hydraulic response using standard pumping test analysis methods, largely because pressure response to the stimulation was not detected, or measurable, in other wells. Analysis of stepped rate flow tests supports the inference from other data that a large fracture, with a radial extent of one to several meters, intersects the well in the target reservoir, suggests that the flow regime is radial to a distance of only several meters and demonstrates that the pressure build-up cone reaches an effective constant head at that distance. The well’s longer term hydraulic response demonstrated continually increasing injectivity but at a dramatically faster rate later from ~2 years out and continuing to the present. The net change in injectivity is significantly greater than observed in other longterm injectivity monitoring studies, with an approximately 150–fold increase occurring over ~2.5 years. While gradually increasing injectivity is a likely consequence of slow migration of a cooling front, and consequent dilation of fractures, the steady, ongoing, rate of increase is contrary to what would be expected in a radial or linear flow regime, where the cooling front would slow with time. As a result, occasional step-like changes in injectivity, immediately following high-flow rate tests suggest that hydro shearing during high-pressure testing altered the near

  18. Changes in Ultrasonographic Vascularity Upon Initiation of Adalimumab Combination Therapy in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.

    Science.gov (United States)

    Kaeley, Gurjit S; Nishio, Midori J; Goyal, Janak R; MacCarter, Daryl K; Wells, Alvin F; Chen, Su; Kupper, Hartmut; Kalabic, Jasmina

    2016-11-01

    To assess joint disease activity by ultrasound (US) in patients with rheumatoid arthritis (RA) initiating treatment with adalimumab (ADA) plus methotrexate (MTX). Data for this post hoc analysis originated from the MUSICA trial (ClinicalTrials.gov identifier: NCT01185288), which evaluated the efficacy of initiating ADA (40 mg every other week) plus 7.5 or 20 mg/week MTX in 309 patients with RA with an inadequate response to MTX. Synovial vascularization over 24 weeks was assessed bilaterally at metacarpophalangeal joint 2 (MCP2), MCP3, MCP5, metatarsophalangeal joint 5, and the wrists by power Doppler US (PDUS). A semiquantitative 4-grade scale was used. Disease activity was assessed using the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and Simplified Disease Activity Index (SDAI). The correlation between continuous variables was assessed using Pearson's correlation coefficient. After 24 weeks of treatment with ADA plus MTX, rapid improvements in the mean synovial vascularity score were observed; the greatest improvements were in MCP2 (-0.5), MCP3 (-0.4), and the wrist (-0.4). At week 24, patients with the lowest DAS28-CRP ( 0.9). Synovial vascularity scores correlated poorly with DAS28, swollen joint count in 66 joints (SJC66), SJC28, tender joint count in 68 joints (TJC68), TJC28, Clinical Disease Activity Index (CDAI), SDAI, physician's global assessment, patient's global assessment of pain, and disease duration (ρ < 0.2). Thirty-two (70%) of 46 patients with a DAS28-CRP of <2.6, and 11 (58%) of 19 patients with an SDAI indicating remission had at least 1 joint with a synovial vascularity score of ≥1. PDUS detects changes in synovial vascularity in RA patients treated with ADA plus MTX, and residual synovial vascularity in patients in whom clinical disease control has been achieved. © 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

  19. Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1α and inhibits stromal cell-derived factor-1 in human endometrial stromal cells.

    Science.gov (United States)

    Tsuzuki, Tomoko; Okada, Hidetaka; Cho, Hisayuu; Tsuji, Shoko; Nishigaki, Akemi; Yasuda, Katsuhiko; Kanzaki, Hideharu

    2012-02-01

    Hypoxia of the human endometrium is a physiologic event occurring during the perimenstrual period and the local stimulus for angiogenesis. The aim of this study was to investigate the effects of hypoxic stress on the regulation of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1/CXCL12), and the potential role of hypoxia-inducible factor-1α (HIF-1α) in the endometrium. Human endometrial stromal cells (ESCs, n= 22 samples) were studied in vitro. ESCs were cultured under hypoxic and normoxic conditions and treated with cobalt chloride (CoCl₂; a hypoxia-mimicking agent) and/or echinomycin, a small-molecule inhibitor of HIF-1α activity. The mRNA levels and production of VEGF and SDF-1 were assessed by real-time PCR and ELISA, respectively. The HIF-1α protein levels were measured using western blot analysis. Hypoxia simultaneously induced the expression of mRNA and production of VEGF and attenuated the expression and production of SDF-1 from ESCs in a time-dependent manner. Similar changes were observed in the ESCs after stimulation with CoCl₂ in a dose-dependent manner. CoCl₂ significantly induced the expression of HIF-1α protein, and its highest expression was observed at 6 h. Echinomycin inhibited hypoxia-induced VEGF production without affecting the HIF-1α protein level and cell toxicity and had no effect on SDF-1 secretion (P hypoxic conditions that could influence angiogenesis in the human endometrium.

  20. [Effects of two methods of heat therapy on the acute vascular response and hemodynamics in healthy subjects].

    Science.gov (United States)

    Ramírez-Vélez, R; García Sánchez, A; Martínez Betancourt, C J; Parra Galeano, C A; Ortega, J G; López Alban, C A; Agredo Zúñiga, R A

    2012-01-01

    Recently, non-pharmacological resources to relieve pain like hot packs and ultrasound (US) have become common in clinical practice. However, little experimental evidence is available about the possible mechanisms through which these methods bring about pain relief. We aimed to determine the effects of hot packs and US on the acute vascular response and on hemodynamic parameters in healthy subjects. We conducted an experimental study in 20 healthy subjects (10 men and 10 women; mean age, 22.54±1.70 years). The two interventions were randomly applied: a) hot packs (n=10): 15min at 60°C and b) US (n=10): 15min at 1Mhz. Before and after each intervention, the following vascular parameters were measured in the brachial artery using Doppler ultrasonography with a 7MHz probe: arterial compliance, elastic modulus, beta stiffness index, systolic and diastolic arterial diameters, systolic flow velocity and diastolic flow velocity, systolic/diastolic ratio, resistance index, and pulsatility index. The following hemodynamic parameters were monitored: heart rate and blood pressure (systolic, diastolic, and mean). After the application of hot packs, we observed changes in diastolic flow velocity and in the pulsatility index (Phot packs or US modifies the physiology of the vascular system but does not affect hemodynamic parameters in healthy subjects. Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.

  1. Effect of diesel exhaust particles on renal vascular responses in rats with chronic kidney disease.

    Science.gov (United States)

    Al Suleimani, Y M; Al Mahruqi, A S; Al Za'abi, M; Shalaby, A; Ashique, M; Nemmar, A; Ali, B H

    2017-02-01

    Several recent studies have indicated the possible association between exposure to particulate air pollution and the increased rate of morbidity and mortality in patients with kidney diseases. The link of this observation to vascular damage has not been adequately addressed. Therefore, this study aims to investigate possible vascular damage that might be associated with exposure to diesel exhaust particles (DP) in adenine (AD)-induced chronic kidney disease (CKD) in rats, and the possible ameliorative effect of gum acacia (GA). CKD was induced by feeding AD (0.75%, w/w), and DP (0.5 mg/kg) was instilled intratracheally every second day and GA was given concomitantly in the drinking water at a dose of 15% w/v. All treatments were given concomitantly for 28 days. Changes in renal blood flow (RBF) and systolic and diastolic blood pressure were monitored in these animals after anesthesia, together with several other endpoints. Exposure to DP significantly reduced RBF and this was significantly potentiated in AD-treated rats. Phenylephrine-induced decreases in RBF and increases in systolic and diastolic blood pressure were severely potentiated in rats exposed to DP, and these actions were significantly augmented in AD-treated rats. GA did not significantly affect the vascular impairment induced by AD and DP given together. This study provides experimental evidence that exposure to particulate air pollution can exacerbate the vascular damage seen in patients with CKD. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 541-549, 2017. © 2016 Wiley Periodicals, Inc.

  2. Head Stabilization Reflex in Patients with Brain Stem Vascular Lesions

    Directory of Open Access Journals (Sweden)

    Ferah Kızılay

    2009-03-01

    Full Text Available OBJECTIVE: The head stabilization reflex (HSR elicited by stimulating the accessory nerve is an oligo-polysynaptic/plurisegmental flexor reflex, which brings the head back to its previous position in response to a variety of sudden head position changes. This reflex was studied in numerous diseases and was inhibited in patients with cerebellar lesions. The present study aimed to investigate how HSR is affected in patients with brain stem vascular lesions. METHODS: The study included 18 patients with brain stem vascular lesions and 18 normal control subjects. Concentric needle electrodes were inserted into the belly of both the sternocleidomastoid muscle and the accessory nerve, and were stimulated separately from the posterior triangle. In all, 8 HSR responses were recorded and mean onset latencies were measured. RESULTS: By stimulating the left accessory nerve in patients with brain stem vascular lesions, contralateral HSR could not be elicited. Similarly, by stimulating the right accessory nerve, contralateral HSR response was elicited only in 3 of the 18 patients. In contrast, stimulation of both the left and right accessory nerves elicited contralateral HSR in all the controls. CONCLUSION: HSR was inhibited in patients with brain stem vascular lesions. This observation shows that the descending pathways in the brain stem facilitate HSR in a similar fashion as the cerebellum was shown to do in a previous study

  3. Time and Antigen-Stimulation History Influence Memory CD8 T Cell Bystander Responses.

    Science.gov (United States)

    Martin, Matthew D; Shan, Qiang; Xue, Hai-Hui; Badovinac, Vladimir P

    2017-01-01

    Memory CD8 T cells can be activated and induced to produce cytokines and increase stores of cytolytic proteins not only in response to cognate antigen (Ag) but also in response to inflammatory cytokines (bystander responses). Importantly, bystander memory CD8 T cell functions have been shown to be dependent upon memory CD8 T cell fitness, since exhausted CD8 T cells have diminished capacity to respond to inflammatory cues. While it is known that memory CD8 T cell functional abilities, including ability to produce cytokines in response to cognate Ag, change with time after initial Ag encounter and upon multiple Ag stimulations (e.g., primary vs. tertiary CD8 T cell responses), it is unknown if bystander memory CD8 T cell responses are influenced by time or by Ag-exposure history. Here, we examined time and Ag-stimulation history-dependent alterations in virus-specific memory CD8 T cell bystander functions in response to inflammatory cytokines and unrelated bacterial infection. We found that expression of cytokine receptors and ability to produce IFN-γ following heterologous infection or incubation with inflammatory cytokines decreases with time following initial Ag encounter and increases with additional Ag encounters, suggesting that the ability to sense inflammation and respond with bystander cytokine production is dependent on age and Ag-stimulation history of memory CD8 T cells. These data shed further light on the regulation of memory CD8 T cell effector functions and have important implications for the development of vaccines designed to elicit protective memory CD8 T cells.

  4. Near-infrared spectroscopy can detect differences in vascular responsiveness to a hyperglycaemic challenge in individuals with obesity compared to normal-weight individuals.

    Science.gov (United States)

    Soares, Rogério Nogueira; Reimer, Raylene A; Alenezi, Zaid; Doyle-Baker, Patricia K; Murias, Juan Manuel

    2018-01-01

    To examine whether the near-infrared spectroscopy combined with vascular occlusion test technique could detect differences in vascular responsiveness during hyperglycaemia between normal-weight individuals and individuals with obesity. A total of 16 normal-weight individuals (body mass index, 21.3 ± 1.7 kg/m 2 ) and 13 individuals with obesity (body mass index, 34.4 ± 2.0 kg/m 2 ) were submitted to five vascular occlusion tests (Pre, 30, 60, 90 and 120 min after glucose challenge). Vascular responsiveness was determined by the Slope 2 (Slope 2 StO 2 ) and the area under the curve (StO 2AUC ) of oxygen saturation derived from near-infrared spectroscopy-vascular occlusion test. The Slope 2 StO 2 increased from 1.07 ± 0.16%/s (Pre) to 1.53 ± 0.21%/s at 90 min ( p obese it increased from 0.71 ± 0.09%/s (Pre) to 0.92 ± 0.14%/s at 60 min ( p obesity. Near-infrared spectroscopy-vascular occlusion test technique was capable of detecting differences in vascular responsiveness during hyperglycaemia between normal-weight individuals and individuals with obesity.

  5. Near-infrared spectroscopy assessment of microvasculature detects difference in lower limb vascular responsiveness in obese compared to lean individuals.

    Science.gov (United States)

    Soares, Rogério Nogueira; Murias, Juan M

    2018-02-03

    Microvascular dysfunction is an early complication in obesity-related cardiovascular disease (CVD) that can lead to changes in hemodynamic function and endothelial cell expression throughout the vasculature that is vessel specific. This study aimed to evaluate whether the near-infrared spectroscopy (NIRS) combined with a vascular occlusion (VOT) assessment was capable of detecting differences in vascular responsiveness within the microvasculature of the lower limb between lean and obese individuals. Twenty lean (BMI = 21.6 ± 1.3) and 17 obese individuals (BMI = 33.9 ± 1.1) participated in the study. Individuals underwent a VOT (5 min of baseline, 5 min of occlusion, and 8 min following cuff release) and vascular responsiveness was evaluated by the Slope 2 (Slope 2 StO 2 ) and the area under the curve (StO 2AUC ) of oxygen saturation (StO 2 ) signal during reperfusion. The difference between the minimal and the maximal value of StO 2 was calculated as the Amplitude of the StO 2 response. The Slope 2 StO 2 of the obese individuals was smaller (0.68 ± 0.07%·s -1 ) than the Slope 2 StO 2 of the lean individuals (1.08 ± 0.13%·s -1 ;P lean individuals (1708 ± 168%·s -1 ; P lean ones (30.4 ± 2.9 vs 21.6 ± 1.3 StO 2 (%), respectively; P lean individuals (r = 0.745; P lean and obese individuals. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Interactive effects of music and prefrontal cortex stimulation in modulating response inhibition

    OpenAIRE

    Mansouri, Farshad Alizadeh; Acevedo, Nicola; Illipparampil, Rosin; Fehring, Daniel J.; Fitzgerald, Paul B.; Jaberzadeh, Shapour

    2017-01-01

    Influential hypotheses propose that alterations in emotional state influence decision processes and executive control of behavior. Both music and transcranial direct current stimulation (tDCS) of prefrontal cortex affect emotional state, however interactive effects of music and tDCS on executive functions remain unknown. Learning to inhibit inappropriate responses is an important aspect of executive control which is guided by assessing the decision outcomes such as errors. We found that high-...

  7. Vascular insulin response is preserved in non-diabetic patients with coronary artery disease, despite endothelial dysfunction

    DEFF Research Database (Denmark)

    Ihlemann, Nikolaj; Rask-Madsen, Christian; Køber, Lars

    2004-01-01

    BACKGROUND--Patients with coronary artery disease (CAD) are often insulin resistant, a state that predisposes to increased atherosclerosis. Recently, it was suggested that a "vascular insulin resistance" could explain this association, causing endothelial dysfunction and hence atherosclerosis. We...... nitroprusside (SNP) elicited endothelium-dependent and -independent vasodilation and were repeated during intra-arterial insulin infusion. RESULTS--Patients were insulin resistant as determined by HOMA index. Insulin infusion resulted in high physiological levels of insulin in the forearm without systemic...... response is intact in non-diabetic CAD patients in spite of insulin resistance and endothelial dysfunction....

  8. Investigation of electrical responses to acupuncture stimulation: the effect of electrical grounding and insulation conditions.

    Science.gov (United States)

    Lee, Yong-Heum; Ryu, Yeon-Hang; Jung, Byungjo

    2009-03-01

    Acupuncture in Oriental medicine has been widely used as a core therapeutic method due to its minimal side-effects and therapeutic efficacy. However, the electrical response to acupuncture stimulation (ERAS) has not been clearly studied under acupuncture conditions that might affect the efficacy of acupuncture therapy. In this study, the ERAS was objectively investigated by measuring meridian electric potentials (MEPs) when the electrical grounding conditions of the operator and subject were varied, and when the insulation conditions of acupuncture needle were varied. MEPs between Sang-geoheo (ST37) and Ha-geoheo (ST39) of the Stomach Meridian (ST) were measured by stimulating Jok-samni (ST36) with an acupuncture needle. For non-insulated acupuncture stimulation (NIAS), the average MEP peak was 148.6 +/- 20.6 when neither the operator nor the subject were electrically grounded, 23.1 +/- 8.8 when the subject only was electrically grounded, 348 +/- 76.8 when the operator only was electrically grounded, and 19.9 +/- 4.7 when both the operator and the subject were electrically grounded. The MEPs presented various magnitudes and patterns depending on the electrical grounding conditions. The MEP pattern was very similar to that of the charge and discharge of a capacitor. For insulated acupuncture stimulation (IAS), the average MEP peak was 20 +/- 4 in all electrical grounding conditions, which is not a significant electric response for acupuncture stimulation. In terms of electricity, this study verified that acupuncture therapy might be affected by acupuncture conditions such as (1) the electrical grounding condition of the operator and the subject and (2) the insulation condition of the acupuncture needle.

  9. Simultaneous recording of electroretinogram and visual evoked response. Focal stimulation under direct observation.

    Science.gov (United States)

    Hirose, T; Miyake, Y; Hara, A

    1977-07-01

    A system has been tested that allows simultaneous recording of the retinal response (electroretinogram [ERG]) and the occipital response (visual evoked response [VER]) with focal photic stimulation of the retina under direct observation of the fundus. A helium-neon gas laser is used as a stimulus source. The laser is chopped either by a pen motor or a rotating disc. The laser is attached to a biomicroscope through which the examiner can observe the fundus of the subject during the entire recording session. The optically clear contact lens is made with a flat surface that neutralizes refraction due to the cornea, thereby allowing fundus observation by microscope. Two metal wires mounted inside and outside of the lens serve as the electrode for the ERG. Graticules consisting of concentric circles and radial lines are projected onto the subject's fundus, providing a pattern that the examiner can use to determine the exact location to be stimulated in the fundus. With proper adjustment of stimulus and background illumination, local ERG and VER can be recorded simultaneously by stimulating the macula.

  10. Effects of cyclopiazonic acid and dexamethasone on serotonin-induced calcium responses in vascular smooth muscle cells.

    Science.gov (United States)

    Selli, Cigdem; Tosun, Metiner

    2016-06-01

    We previously observed that sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) blockade by cyclopiazonic acid (CPA) significantly potentiates serotonin (5-hydroxytryptamine (5-HT))-induced vascular contractions. Furthermore, 5-HT receptor antagonist methysergide partially inhibited CPA-potentiated 5-HT contractions. In the present study, we further investigated whether SERCA inhibition potentiates 5-HT-induced Ca(2+) responses along with attenuating the receptor antagonism by store-operated Ca(2+) (SOC) entry and protein kinase C (PKC)-mediated mechanisms. The effects of dexamethasone that was previously shown to induce SOC entry and enhance 5-HT responses were also tested. For this purpose, intracellular Ca(2+) levels were monitored in A7r5 embryonic rat vascular smooth muscle cells by spectrofluorometry using the fluorescent indicator fura-2. The results showed that CPA, although not dexamethasone, significantly potentiated 5-HT-induced Ca(2+) elevations. Ketanserin partially decreased 5-HT-induced and CPA-potentiated Ca(2+) elevations whereas both PKC inhibitor D-sphingosine and SOC entry blocker 2-aminoethoxydiphenyl borate (2-APB) abolished the remaining responses. The data suggests that diminished antagonistic effect on 5-HT-induced Ca(2+) elevations in the presence of SERCA inhibition is induced by SOC entry and PKC activation.

  11. Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2017-01-01

    INTRODUCTION: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant...... normal tissues. MATERIAL AND METHODS: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed......% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p 4P. The radiation...

  12. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org [Department of Radiological Sciences, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu Shengjie [Department of Biostatistics, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Chemaitilly, Wassim [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Lukose, Renin C.; Merchant, Thomas E. [Department of Radiological Sciences, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  13. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    International Nuclear Information System (INIS)

    Hua Chiaho; Wu Shengjie; Chemaitilly, Wassim; Lukose, Renin C.; Merchant, Thomas E.

    2012-01-01

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test ≥7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  14. Transcriptional and temporal response of Populus stems to gravi-stimulation.

    Science.gov (United States)

    Zinkgraf, Matthew; Gerttula, Suzanne; Zhao, Shutang; Filkov, Vladimir; Groover, AndrewLi

    2018-02-26

    Plants modify development in response to external stimuli, to produce new growth that is appropriate for environmental conditions. For example, gravi-stimulation of leaning branches in angiosperm trees results in modifications of wood development, to produce tension wood that pulls leaning stems upright. Here, we use gravi-stimulation and tension wood response to dissect the temporal changes in gene expression underlying wood formation in Populus stems. Using time-series analysis of 7 time points over a 14-day experiment, we identified 8919 genes that were differentially expressed between tension wood (upper) and opposite wood (lower) sides of leaning stems. Clustering of differentially expressed genes showed four major transcriptional responses, including gene clusters whose transcript levels were associated with two types of tissue-specific impulse responses that peaked at about 24 - 48 hours, and gene clusters with sustained changes in transcript levels that persisted until the end of the 14-day experiment. Functional enrichment analysis of those clusters suggests they reflect temporal changes in pathways associated with hormone regulation, protein localization, cell wall biosynthesis and epigenetic processes. Time-series analysis of gene expression is an underutilized approach for dissecting complex developmental responses in plants, and can reveal gene clusters and mechanisms influencing development. This article is protected by copyright. All rights reserved.

  15. GPCR responses in vascular smooth muscle can occur predominantly through dual transactivation of kinase receptors and not classical Gαq protein signalling pathways.

    Science.gov (United States)

    Little, Peter J

    2013-05-30

    GPCR signalling is well known to proceed through several linear pathways involving activation of G proteins and their downstream signalling pathways such as activation of phospholipase C. In addition, GPCRs signal via transactivation of Protein Tyrosine Kinase receptors such as that for Epidermal Growth Factor (EGF) and Platelet-Derived Growth Factor (PDGF) where GPCR agonists mediate increase levels of phosphorylated Erk (pErk) the immediate downstream product of the activation of EGF receptor. It has recently been shown that this paradigm can be extended to include the GPCR transactivation of a Protein Serine/Threonine Kinase receptor, specifically the Transforming Growth Factor β Type I receptor (also known as Alk V) (TβRI) in which case GPCR activation leads to the formation of carboxy terminal polyphosphorylated Smad2 (phosphoSmad2) being the immediate downstream product of the activation of TβRI. Growth factor and hormone regulation of proteoglycan synthesis in vascular smooth muscle cells represent one component of an in vitro model of atherosclerosis because modified proteoglycans show enhanced binding to lipoproteins as the initiating step in atherosclerosis. In the example of proteoglycan synthesis stimulated by GPCR agonists such as thrombin and endothelin-1, the transactivation pathways for the EGF receptor and TβRI are both active and together account for essentially all of the response to the GPCRs. In contrast, signalling downstream of GPCRs such as increased inositol 1,4,5 trisphosphate (IP3) and intracellular calcium do not have any effect on GPCR stimulated proteoglycan synthesis. These data lead to the conclusion that dual transactivation pathways for protein tyrosine and serine/threonine kinase receptors may play a far greater role in GPCR signalling than currently recognised. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Which limb is it? Responses to vibrotactile stimulation in early infancy.

    Science.gov (United States)

    Somogyi, Eszter; Jacquey, Lisa; Heed, Tobias; Hoffmann, Matej; Lockman, Jeffrey J; Granjon, Lionel; Fagard, Jacqueline; O'Regan, J Kevin

    2017-12-11

    This study focuses on how the body schema develops during the first months of life, by investigating infants' motor responses to localized vibrotactile stimulation on their limbs. Vibrotactile stimulation was provided by small buzzers that were attached to the infants' four limbs one at a time. Four age groups were compared cross-sectionally (3-, 4-, 5-, and 6-month-olds). We show that before they actually reach for the buzzer, which, according to previous studies, occurs around 7-8 months of age, infants demonstrate emerging knowledge about their body's configuration by producing specific movement patterns associated with the stimulated body area. At 3 months, infants responded with an increase in general activity when the buzzer was placed on the body, independently of the vibrator's location. Differentiated topographical awareness of the body seemed to appear around 5 months, with specific responses resulting from stimulation of the hands emerging first, followed by the differentiation of movement patterns associated with the stimulation of the feet. Qualitative analyses revealed specific movement types reliably associated with each stimulated location by 6 months of age, possibly preparing infants' ability to actually reach for the vibrating target. We discuss this result in relation to newborns' ability to learn specific movement patterns through intersensory contingency. Statement of contribution what is already known on infants' sensorimotor knowledge about their own bodies 3-month-olds readily learn to produce specific limb movements to obtain a desired effect (movement of a mobile). infants detect temporal and spatial correspondences between events involving their own body and visual events. what the present study adds until 4-5 months of age, infants mostly produce general motor responses to localized touch. this is because in the present study, infants could not rely on immediate contingent feedback. we propose a cephalocaudal developmental trend of

  17. Multiple blocks of intermittent and continuous theta-burst stimulation applied via transcranial magnetic stimulation differently affect sensory responses in rat barrel cortex.

    Science.gov (United States)

    Thimm, Andreas; Funke, Klaus

    2015-02-15

    Theta-burst stimulation (TBS) applied via transcranial magnetic stimulation is able to modulate human cortical excitability. Here we investigated in a rat model how two different forms of TBS, intermittent (iTBS) and continuous (cTBS), affect sensory responses in rat barrel cortex. We found that iTBS but less cTBS promoted late (>18 ms) sensory response components while not affecting the earliest response (8-18 ms). The effect increased with each of the five iTBS blocks applied. cTBS somewhat reduced the early response component after the first block but had a similar effect as iTBS after four to five blocks. We conclude that iTBS primarly modulates the activity of (inhibitory) cortical interneurons while cTBS may first reduce general neuronal excitability with a single block but reverse to iTBS-like effects with application of several blocks. Cortical sensory processing varies with cortical state and the balance of inhibition to excitation. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate human cortical excitability. In a rat model, we recently showed that intermittent theta-burst stimulation (iTBS) applied to the corpus callosum, to activate primarily supragranular cortical pyramidal cells but fewer subcortical neurons, strongly reduced the cortical expression of parvalbumin (PV), indicating reduced activity of fast-spiking interneurons. Here, we used the well-studied rodent barrel cortex system to test how iTBS and continuous TBS (cTBS) modulate sensory responses evoked by either single or double stimuli applied to the principal (PW) and/or adjacent whisker (AW) in urethane-anaesthetized rats. Compared to sham stimulation, iTBS but not cTBS particularly enhanced late (>18 ms) response components of multi-unit spiking and local field potential responses in layer 4 but not the very early response (stimulation at 20 ms intervals. The effects increased with each of the five iTBS blocks applied. With cTBS a mild effect similar to

  18. Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography.

    Science.gov (United States)

    Willmann, Jürgen K; Chen, Kai; Wang, Hui; Paulmurugan, Ramasamy; Rollins, Mark; Cai, Weibo; Wang, David S; Chen, Ian Y; Gheysens, Olivier; Rodriguez-Porcel, Martin; Chen, Xiaoyuan; Gambhir, Sanjiv S

    2008-02-19

    Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training. 64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P angiogenesis stimulated by treadmill exercise training.

  19. Retinal ganglion cells: mechanisms underlying depolarization block and differential responses to high frequency electrical stimulation of ON and OFF cells

    Science.gov (United States)

    Kameneva, T.; Maturana, M. I.; Hadjinicolaou, A. E.; Cloherty, S. L.; Ibbotson, M. R.; Grayden, D. B.; Burkitt, A. N.; Meffin, H.

    2016-02-01

    Objective. ON and OFF retinal ganglion cells (RGCs) are known to have non-monotonic responses to increasing amplitudes of high frequency (2 kHz) biphasic electrical stimulation. That is, an increase in stimulation amplitude causes an increase in the cell’s spike rate up to a peak value above which further increases in stimulation amplitude cause the cell to decrease its activity. The peak response for ON and OFF cells occurs at different stimulation amplitudes, which allows differential stimulation of these functional cell types. In this study, we investigate the mechanisms underlying the non-monotonic responses of ON and OFF brisk-transient RGCs and the mechanisms underlying their differential responses. Approach. Using in vitro patch-clamp recordings from rat RGCs, together with simulations of single and multiple compartment Hodgkin-Huxley models, we show that the non-monotonic response to increasing amplitudes of stimulation is due to depolarization block, a change in the membrane potential that prevents the cell from generating action potentials. Main results. We show that the onset for depolarization block depends on the amplitude and frequency of stimulation and reveal the biophysical mechanisms that lead to depolarization block during high frequency stimulation. Our results indicate that differences in transmembrane potassium conductance lead to shifts of the stimulus currents that generate peak spike rates, suggesting that the differential responses of ON and OFF cells may be due to differences in the expression of this current type. We also show that the length of the axon’s high sodium channel band (SOCB) affects non-monotonic responses and the stimulation amplitude that leads to the peak spike rate, suggesting that the length of the SOCB is shorter in ON cells. Significance. This may have important implications for stimulation strategies in visual prostheses.

  20. Response of Merkel cells in the palatal rugae to the continuous mechanical stimulation by palatal plate.

    Science.gov (United States)

    Ishizaki, Ken; Sakurai, Kaoru; Tazaki, Masakazu; Inoue, Takashi

    2006-01-01

    The aim of the present study was to investigate the responses of Merkel cells that are numerous in the palatine rugae, due to the continuous mechanical stimulation exerted by the palatal plate. Forty golden hamsters were used in this experiment. The palatal plate was made of adhesive resin and it was set on the palate of the animal. To exert a continuous pressure, a 0.8 mm elevation on the internal surface of the palatal plate was created at the middle portion of the fourth palatine ruga. Thereafter, the number of Merkel cells in the mucosa was calculated by immunohistochemical observation. Morphological changes of Merkel cells were examined by electron microscopy. There was significant difference among the control and any of the treated groups on the number of CK20 positive Merkel cells (p < 0.05) and that numbers were decreased at the sites where continuous mechanical stimulation was exerted. Degeneration of the cytoplasm mitochondria and nerve endings, and a decrease in both the number of neurosecretory granules and cytoplasmic processes were observed. Furthermore, the presence of nuclear chromatin aggregation and fragmentation was recognized. The continuous mechanical stimulation by the palatal plate affected the responses of Merkel cells and nerve endings, thus inducing a decrease in the number of Merkel cells. A portion of these changes was also associated with the expression of apoptosis.

  1. Differential effects of culture senescence and mechanical stimulation on the proliferation and leiomyogenic differentiation of MSC from different sources: implications for engineering vascular grafts.

    Science.gov (United States)

    Koobatian, Maxwell T; Liang, Mao-Shih; Swartz, Daniel D; Andreadis, Stelios T

    2015-04-01

    We examined the effects of senescence on the proliferation and leiomyogenic differentiation potential of mesenchymal stem cells (MSCs) isolated from bone marrow (BM-MSCs) or hair follicles (HF-MSCs). To this end, we compared ovine HF-MSCs and BM-MSCs in terms of their proliferation and differentiation potential to the smooth muscle cell lineage. We discovered that HF-MSCs are less susceptible to culture senescence compared with BM-MSCs. We hypothesized that application of mechanical forces may enhance the contractility and mechanical properties of vascular constructs prepared from senescent MSCs. Interestingly, HF-MSCs and BM-MSCs responded differently to changes in the mechanical microenvironment, suggesting that despite phenotypic similarities, MSCs from different anatomic locations may activate different pathways in response to the same microenvironmental factors. In turn, this may also suggest that cell-based tissue regeneration approaches may need to be tailored to the stem cell origin, donor age, and culture time for optimal results.

  2. Prediction of heat-illness symptoms with the prediction of human vascular response in hot environment under resting condition.

    Science.gov (United States)

    Aggarwal, Yogender; Karan, Bhuwan Mohan; Das, Barsa Nand; Sinha, Rakesh Kumar

    2008-04-01

    The thermoregulatory control of human skin blood flow is vital to maintain the body heat storage during challenges of thermal homeostasis under heat stress. Whenever thermal homeostasis disturbed, the heat load exceeds heat dissipation capacity, which alters the cutaneous vascular responses along with other body physiological variables. Whole body skin blood flow has been calculated from the forearm blood flow. Present model has been designed using electronics circuit simulator (Multisim 8.0, National Instruments, USA), is to execute a series of predictive equations for early prediction of physiological parameters of young nude subjects during resting condition at various level of dry heat stress under almost still air to avoid causalities associated with hot environmental. The users can execute the model by changing the environmental temperature in degrees C and exposure time in minutes. The model would be able to predict and detect the changes in human vascular responses along with other physiological parameters and from this predicted values heat related-illness symptoms can be inferred.

  3. Prenatal features of Pena-Shokeir sequence with atypical response to acoustic stimulation.

    Science.gov (United States)

    Pittyanont, Sirida; Jatavan, Phudit; Suwansirikul, Songkiat; Tongsong, Theera

    2016-09-01

    A fetal sonographic screening examination performed at 23 weeks showed polyhydramnios, micrognathia, fixed postures of all long bones, but no movement and no breathing. The fetus showed fetal heart rate acceleration but no movement when acoustic stimulation was applied with artificial larynx. All these findings persisted on serial examinations. The neonate was stillborn at 37 weeks and a final diagnosis of Pena-Shokeir sequence was made. In addition to typical sonographic features of Pena-Shokeir sequence, fetal heart rate accelerations with no movement in response to acoustic stimulation suggests that peripheral myopathy may possibly play an important role in the pathogenesis of the disease. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:459-462, 2016. © 2016 Wiley Periodicals, Inc.

  4. Local electric stimulation causes conducted calcium response in rat interlobular arteries

    DEFF Research Database (Denmark)

    Salomonsson, Max; Gustafsson, Finn; Andreasen, Ditte

    2002-01-01

    microscope. Local electrical pulse stimulation (200 ms, 100 V) was administered by means of an NaCl-filled microelectrode (0.7-1 M(Omega)) juxtaposed to one end of the vessel. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured with an image system at a site approximately 500 microm from...... the location of the electrode. The expression of mRNA for pore-forming units Ca(V)3.1 and Ca(V)3.2 of voltage-sensitive T-type channels was investigated by using RT-PCR. Current stimulation elicited a conducted [Ca(2+)](i) response. A positive electrode (relative to ground) increased [Ca(2+)](i) to 145 +/- 7...

  5. Dynamical mechanisms for sensitive response of aperiodic firing cells to external stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Xie Yong E-mail: xie813@263.net; Xu Jianxue; Hu Sanjue; Kang Yanmei; Yang Hongjun; Duan Yubin

    2004-10-01

    An interesting phenomenon that aperiodic firing neurons have a higher sensitivity to drugs than periodic firing neurons have been reported for the chronically compressed dorsal root ganglion neurons in rats. In this study, the dynamical mechanisms for such a phenomenon are uncovered from the viewpoint of dynamical systems theory. We use the Rose-Hindmarsh neuron model to illustrate our opinions. Periodic orbit theory is introduced to characterize the dynamical behavior of aperiodic firing neurons. It is considered that bifurcations, crises and sensitive dependence of chaotic motions on control parameters can be the underlying mechanisms. And then, a similar analysis is applied to the modified Chay model describing the firing behavior of pancreatic beta cells. The same dynamical mechanisms can be obtained underlying that aperiodic firing cells are more sensitive to external stimulation than periodic firing ones. As a result, we conjecture that sensitive response of aperiodic firing cells to external stimulation is a universal property of excitable cells.

  6. Very low dose gamma irradiation stimulates gaseous exchange and carboxylation efficiency, but inhibits vascular sap flow in groundnut (Arachis hypogaea L.).

    Science.gov (United States)

    Ahuja, Sumedha; Singh, Bhupinder; Gupta, Vijay Kumar; Singhal, R K; Venu Babu, P

    2014-02-01

    An experiment was carried out to determine the effect of low dose gamma radiation on germination, plant growth, nitrogen and carbon fixation and carbon flow and release characteristics of groundnut. Dry seeds of groundnut variety Trombay groundnut 37A (TG 37A), a radio mutant type developed by Bhabha Atomic Research Centre (BARC), Mumbai, India, were subjected to the pre-sowing treatment of gamma radiation within low to high dose physiological range, i.e., 0.0, 0.0082, 0.0164. 0.0328, 0.0656, 0.1312, 5, 25, 100, 500 Gray (Gy) from a cobalt source ((60)Co). Observations were recorded for the radiation effect on percentage germination, vigour, gas exchange attributes such as photosynthetic rate, stomatal conductance and transpiration rate, chlorophyll content, root exudation in terms of (14)C release, vascular sap flow rate and activities of rate defining carbon and nitrogen assimilating enzymes such as ribulose-1,5-bisphosphate carboxylase (rubisco) and nitrate reductase (NR). Seed germination was increased by 10-25% at the lower doses up to 5 Gy while the improvement in plant vigour in the same dose range was much higher (22-84%) than the unirradiated control. For radiation exposure above 5 Gy, a dose-dependent decline in germination and plant vigour was measured. No significant effect was observed on the photosynthesis at radiation exposure below 5 Gy but above 5 Gy dose there was a decline in the photosynthetic rate. Stomatal conductance and transpiration rate, however, were only inhibited at a high dose of 500 Gy. Leaf rubisco activity and NR activities remained unaffected at all the investigated doses of gamma irradiation. Mean root exudation and sap flow rate of the irradiated plants, irrespective of the dose, was reduced over the unirradiated control more so in a dose-dependent manner. Results indicated that a very low dose of gamma radiation, in centigray to gray range, did not pose any threat and in fact stimulated metabolic functions in such a way to aid

  7. Hemispheric differences in electrical and hemodynamic responses during hemifield visual stimulation with graded contrasts.

    Science.gov (United States)

    Si, Juanning; Zhang, Xin; Zhang, Yujin; Jiang, Tianzi

    2017-04-01

    A multimodal neuroimaging technique based on electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) was used with horizontal hemifield visual stimuli with graded contrasts to investigate the retinotopic mapping more fully as well as to explore hemispheric differences in neuronal activity, the hemodynamic response, and the neurovascular coupling relationship in the visual cortex. The fNIRS results showed the expected activation over the contralateral hemisphere for both the left and right hemifield visual stimulations. However, the EEG results presented a paradoxical lateralization, with the maximal response located over the ipsilateral hemisphere but with the polarity inversed components located over the contralateral hemisphere. Our results suggest that the polarity inversion as well as the latency advantage over the contralateral hemisphere cause the amplitude of the VEP over the contralateral hemisphere to be smaller than that over the ipsilateral hemisphere. Both the neuronal and hemodynamic responses changed logarithmically with the level of contrast in the hemifield visual stimulations. Moreover, the amplitudes and latencies of the visual evoked potentials (VEPs) were linearly correlated with the hemodynamic responses despite differences in the slopes.

  8. Spatiotemporal characteristics of retinal response to network-mediated photovoltaic stimulation.

    Science.gov (United States)

    Ho, Elton; Smith, Richard; Goetz, Georges; Lei, Xin; Galambos, Ludwig; Kamins, Theodore I; Harris, James; Mathieson, Keith; Palanker, Daniel; Sher, Alexander

    2018-02-01

    Subretinal prostheses aim at restoring sight to patients blinded by photoreceptor degeneration using electrical activation of the surviving inner retinal neurons. Today, such implants deliver visual information with low-frequency stimulation, resulting in discontinuous visual percepts. We measured retinal responses to complex visual stimuli delivered at video rate via a photovoltaic subretinal implant and by visible light. Using a multielectrode array to record from retinal ganglion cells (RGCs) in the healthy and degenerated rat retina ex vivo, we estimated their spatiotemporal properties from the spike-triggered average responses to photovoltaic binary white noise stimulus with 70-μm pixel size at 20-Hz frame rate. The average photovoltaic receptive field size was 194 ± 3 μm (mean ± SE), similar to that of visual responses (221 ± 4 μm), but response latency was significantly shorter with photovoltaic stimulation. Both visual and photovoltaic receptive fields had an opposing center-surround structure. In the healthy retina, ON RGCs had photovoltaic OFF responses, and vice versa. This reversal is consistent with depolarization of photoreceptors by electrical pulses, as opposed to their hyperpolarization under increasing light, although alternative mechanisms cannot be excluded. In degenerate retina, both ON and OFF photovoltaic responses were observed, but in the absence of visual responses, it is not clear what functional RGC types they correspond to. Degenerate retina maintained the antagonistic center-surround organization of receptive fields. These fast and spatially localized network-mediated ON and OFF responses to subretinal stimulation via photovoltaic pixels with local return electrodes raise confidence in the possibility of providing more functional prosthetic vision. NEW & NOTEWORTHY Retinal prostheses currently in clinical use have struggled to deliver visual information at naturalistic frequencies, resulting in discontinuous percepts. We

  9. Conflicts during response selection affect response programming: reactions toward the source of stimulation.

    Science.gov (United States)

    Buetti, Simona; Kerzel, Dirk

    2009-06-01

    In the Simon effect, participants make a left or right keypress in response to a nonspatial attribute (e.g., color) that is presented on the left or right. Reaction times (RTs) increase when the response activated by the irrelevant stimulus location and the response retrieved by instruction are in conflict. The authors measured RTs and movement parameters (MPs) of pointing responses in a typical Simon task. Their results show that the trajectories veer toward the imperative stimulus. This bias decreased as RTs increased. The authors suggest that the time course of trajectory deviations reflects the resolution of the response conflict over time. Further, time pressure did not affect the size of the Simon effect in MPs or its time course, but strongly reduced the Simon effect in RTs. In contrast, response selection before the onset of a go signal on the left or right did not affect the Simon effect in RTs, but reduced the Simon effect in MPs and reversed the time course. The authors speculate about independent Simon effects associated with response selection and programming. (c) 2009 APA, all rights reserved.

  10. Brain responses to mechanical rectal stimulation in patients with faecal incontinence: an fMRI study.

    Science.gov (United States)

    Mirbagheri, N; Hatton, S; Ng, K-S; Lagopoulos, J; Gladman, M A

    2017-10-01

    Continence is dependent on anorectal-brain interactions. Consequently, aberrations of the brain-gut axis may be important in the pathophysiology of faecal incontinence (FI) in certain patients. The aim of this study was to assess the feasibility of recording brain responses to rectal mechanical stimulation in patients with FI using functional magnetic resonance imaging (fMRI). A prospective, cohort pilot study was performed to assess brain responses during rectal stimulation in 14 patients [four men, mean (SD) age 62 (15) years]. Blood oxygen level dependent (BOLD) signals were measured by fMRI during rest and mechanical distension, involving random repetitions of isobaric phasic rectal distensions at fixed (15 and 45 mmHg) and variable (10% above sensory perception threshold) pressures. Increases in BOLD signals in response to high pressure rectal distension (45 mmHg) and maximum toleration were observed in the cingulate gyrus, thalamus, insular cortex, inferior frontal gyrus, cerebellum, caudate nucleus, supramarginal gyrus, putamen and amygdala. Additionally, activation of the supplementary motor cortex and caudate nucleus with inconsistent activity in the frontal lobe was observed. This study has demonstrated the feasibility of recording brain responses to rectal mechanical stimulation using fMRI in patients with FI, revealing activity in widespread areas of the brain involved in visceral sensory processing. The observed activity in the supplementary motor cortex and caudate nucleus, with relative paucity of activity in the frontal lobes, warrants investigation in future studies to determine whether aberrations in cerebral processing of rectal stimuli play a role in the pathogenesis of FI. Colorectal Disease © 2017 The Association of Coloproctology of Great Britain and Ireland.

  11. Treatment of ADHD with Stimulant Medications: Response to Nissen Perspective in the New England Journal of Medicine

    Science.gov (United States)

    Biederman, Joseph; Spencer, Thomas J.; Wilens, Timothy E.; Prince, Jefferson B.; Faraone, Stephen V.

    2006-01-01

    This article is a response to Dr. Steven E. Nissen's comments (Nissen, 2006) about attention deficit/hyperactivity disorder (ADHD) and its treatment with stimulant medications. In this article, the authors refute his arguments and provide accurate information. Here, they answer the questions, such as: (1) Do stimulants increase the risk for sudden…

  12. Effects of stimulus mode and ambient temperature on cerebral responses to local thermal stimulation: An EEG study.

    Science.gov (United States)

    Lv, Bin; Su, Chang; Yang, Lei; Wu, Tongning

    2017-03-01

    The physiological responses to human thermal stimulation have been widely investigated, but most of them are mainly concerned about the whole body thermal stimulation. In this study, we investigated the effects of stimulus mode and ambient temperature on cerebral responses during local thermal stimulation on hand. The left hands were stimulated by metal thermostat based and thermostatic water based stimulators at different stimulated temperatures (38°C, 40°C, 42°C and 44°C) and different ambient temperatures (25°C and 32°C). EEG data were recorded over the whole brain during the experiments. Then the statistical comparisons were conducted on the EEG relative power among different experimental sessions. We observed that EEG activities were alternated between thermal stimulated periods and the baseline in all four frequency bands. And there was a higher percentage of delta band power in the right temporal and parietal regions under the ambient temperature of 32°C while compared to 25°C. In addition, the theta band activity under the metal based stimulation showed significantly higher EEG relative power than that under the water based stimulation over the whole brain. Compared with the water based stimulation, there was a lower EEG relative power of the beta band activity during the metal based stimulation in the bilateral frontal and right temporal regions. The experimental results suggested that the neural physiological responses in different EEG frequency bands were sensitive to different influence factors during the local hand thermal stimulation. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.

    Science.gov (United States)

    Zhang, Tianhe C; Janik, John J; Peters, Ryan V; Chen, Gang; Ji, Ru-Rong; Grill, Warren M

    2015-07-01

    Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry. Copyright © 2015 the American Physiological Society.

  14. Vascular remodeling in response to 12 wk of upper arm unilateral resistance training.

    Science.gov (United States)

    Zoeller, Robert F; Angelopoulos, Theodore J; Thompson, Benjamin C; Wenta, Marlene R; Price, Thomas B; Thompson, Paul D; Moyna, Niall M; Seip, Richard L; Clarkson, Priscilla M; Gordon, Paul M; Pescatello, Linda S; Devaney, Joseph M; Gordish-Dressman, Heather; Hoffman, Eric P; Visich, Paul S

    2009-11-01

    Participation in regular aerobic exercise has been shown to increase arterial size and that exercise-induced vascular remodeling may be regional rather than systemic. However, these issues have been minimally investigated concerning resistance training. To determine whether 1) resistance training of the nondominant arm elicits an increase in diameter of the brachial artery and 2) unilateral training induces arterial remodeling in the contralateral arm. Twenty-four previously untrained participants, consisting of 18 females (aged 22.3 +/- 5.1 yr) and 6 males (aged 21.7 +/- 1.8 yr), participated in unilateral strength training of the biceps and triceps for 12 wk using their nondominant arm. Isotonic (one-repetition maximum, 1RM) and isometric (ISO) strength of the biceps were assessed before and after training on both arms. Brachial artery diameter and biceps muscle cross-sectional area (CSA) of both arms were also measured before and after training using magnetic resonance imaging (MRI). Brachial artery diameter increased 5.47% (P change observed in the dominant untrained arm. Biceps CSA increased 18.3% (P change (P > 0.05) in the untrained limb. Nondominant 1RM and ISO strength increased by 35.1% and 16.8%, respectively (P changes (P > 0.05) in the contralateral arm. A modest correlation was found between the increases in CSA and in brachial artery diameter (r2 = 0.19, P = 0.039). These results indicate that upper arm vascular remodeling, manifesting as increased brachial artery diameter, can result from resistance training and that these changes are localized to the trained limb and associated with increases in CSA.

  15. Influence of progestin bioactivity on cutaneous vascular responses to passive heating.

    Science.gov (United States)

    Houghton, Belinda L; Holowatz, Lacy A; Minson, Christopher T

    2005-01-01

    Oral contraceptives influence the regulation of cutaneous vascular tone, and both estrogen and progesterone have been shown to affect nitric oxide (NO)-mediated vasodilation. We tested the hypothesis that cutaneous vascular conductance (CVC) during passive heating would be lower in women taking oral contraceptives with higher progestational bioactivity compared with those taking oral contraceptives with lower progestational bioactivity. We further hypothesized that this difference could be attributed to the relative degree of NO-dependent vasodilation. Fourteen women (20.3 +/- 0.3 yr) taking combined oral contraceptives (low progestin: 6 subjects, high progestin: 8 subjects) participated in a whole-body heating protocol and were tested during the end of active and placebo pill phases. Red blood cell (RBC) flux was measured by laser-Doppler flowmetry at a control microdialysis site (Ringer's solution) and an experimental site where NO-synthase (NOS) was inhibited (10 mM L-NAME). CVC was calculated as RBC flux/MAP. Baseline oral temperature (Tor) was significantly higher during the active pill phase for all subjects (active: 36.8 +/- 0.1 degrees C; placebo: 36.6 +/- 0.1 degrees C) (P = 0.02) but was not affected by progestational bioactivity. CVC at the control site during heating did not differ between low and high progestin users during either phase of oral contraceptive use. However, CVC in the NOS inhibited site was diminished during both phases of oral contraceptive use in the low progestin group at a given change in Tor (active: DeltaT(or) of 0.6-1.0 degrees C, placebo: DeltaT(or) of 0.8-1.0 degrees C) (P heating via NO-dependent cutaneous active vasodilation.

  16. Mobilization of Circulating Vascular Progenitors in Cancer Patients Receiving External Beam Radiation in Response to Tissue Injury

    International Nuclear Information System (INIS)

    Allan, David S.; Morgan, Scott C.; Birch, Paul E.; Yang, Lin; Halpenny, Michael J.; Gunanayagam, Angelo; Li Yuhua; Eapen, Libni

    2009-01-01

    Purpose: Endothelial-like vascular progenitor cells (VPCs) are associated with the repair of ischemic tissue injury in several clinical settings. Because the endothelium is a principal target of radiation injury, VPCs may be important in limiting toxicity associated with radiotherapy (RT) in patients with cancer. Methods and Materials: We studied 30 patients undergoing RT for skin cancer (n = 5), head-and-neck cancer (n = 15), and prostate cancer (n = 10) prospectively, representing a wide range of irradiated mucosal volumes. Vascular progenitor cell levels were enumerated from peripheral blood at baseline, midway through RT, at the end of treatment, and 4 weeks after radiation. Acute toxicity was graded at each time point by use of the National Cancer Institute's Common Toxicity Criteria, version 3.0. Results: Significant increases in the proportion of CD34 + /CD133 + VPCs were observed after completion of RT, from 0.012% at baseline to 0.048% (p = 0.029), and the increase in this subpopulation was most marked in patients with Grade 2 peak toxicity or greater after RT (p = 0.034). Similarly, CD34 + /vascular endothelial growth factor receptor 2-positive VPCs were increased after the completion of radiation therapy in comparison to baseline (from 0.014% to 0.027%, p = 0.043), and there was a trend toward greater mobilization in patients with more significant toxicity (p = 0.08). The mobilization of CD34 + hematopoietic stem cells did not increase after treatment (p = 0.58), and there was no relationship with toxicity. Conclusions: We suggest that VPCs may play an important role in reducing radiation-induced tissue damage. Interventions that increase baseline VPC levels or enhance their mobilization and recruitment in response to RT may prove useful in facilitating more rapid and complete tissue healing.

  17. Seeds of Brassicaceae weeds have an inherent or inducible response to the germination stimulant karrikinolide.

    Science.gov (United States)

    Long, Rowena L; Stevens, Jason C; Griffiths, Erin M; Adamek, Markus; Gorecki, Marta J; Powles, Stephen B; Merritt, David J

    2011-10-01

    Karrikinolide (KAR(1)) is a smoke-derived chemical that can trigger seeds to germinate. A potential application for KAR(1) is for synchronizing the germination of weed seeds, thereby enhancing the efficiency of weed control efforts. Yet not all species germinate readily with KAR(1), and it is not known whether seemingly non-responsive species can be induced to respond. Here a major agronomic weed family, the Brassicaceae, is used to test the hypothesis that a stimulatory response to KAR(1) may be present in physiologically dormant seeds but may not be expressed under all circumstances. Seeds of eight Brassicaceae weed species (Brassica tournefortii, Raphanus raphanistrum, Sisymbrium orientale, S. erysimoides, Rapistrum rugosum, Lepidium africanum, Heliophila pusilla and Carrichtera annua) were tested for their response to 1 µm KAR(1) when freshly collected and following simulated and natural dormancy alleviation, which included wet-dry cycling, dry after-ripening, cold and warm stratification and a 2 year seed burial trial. Seven of the eight Brassicaceae species tested were stimulated to germinate with KAR(1) when the seeds were fresh, and the remaining species became responsive to KAR(1) following wet-dry cycling and dry after-ripening. Light influenced the germination response of seeds to KAR(1), with the majority of species germinating better in darkness. Germination with and without KAR(1) fluctuated seasonally throughout the seed burial trial. KAR(1) responses are more complex than simply stating whether a species is responsive or non-responsive; light and temperature conditions, dormancy state and seed lot all influence the sensitivity of seeds to KAR(1), and a response to KAR(1) can be induced. Three response types for generalizing KAR(1) responses are proposed, namely inherent, inducible and undetected. Given that responses to KAR(1) were either inherent or inducible in all 15 seed lots included in this study, the Brassicaceae may be an ideal target for

  18. Photodynamic therapy stimulates anti-tumor immune response in mouse models: the role of regulatory Tcells, anti-tumor antibodies, and immune attacks on brain metastases

    Science.gov (United States)

    Vatansever, Fatma; Kawakubo, Masayoshi; Chung, Hoon; Hamblin, Michael R.

    2013-02-01

    We have previously shown that photodynamic therapy mediated by a vascular regimen of benzoporphyrin derivative and 690nm light is capable of inducing a robust immune response in the mouse CT26.CL25 tumor model that contains a tumor-rejection antigen, beta-galactosidase (β-gal). For the first time we show that PDT can stimulate the production of serum IgG antibodies against the β-gal antigen. It is known that a common cause of death from cancer, particularly lung cancer, is brain metastases; especially the inoperable ones that do not respond to traditional cytotoxic therapies either. We asked whether PDT of a primary tumor could stimulate immune response that could attack the distant brain metastases. We have developed a mouse model of generating brain metastases by injecting CT26.CL25 tumor cells into the brain as well as injecting the same cancer cells under the skin at the same time. When the subcutaneous tumor was treated with PDT, we observed a survival advantage compared to mice that had untreated brain metastases alone.

  19. Radiation dose response correlation between thermoluminescence and optically stimulated luminescence in quartz

    International Nuclear Information System (INIS)

    Oniya, E.O.; Polymeris, G.S.; Tsirliganis, N.C.; Kitis, G.

    2012-01-01

    The fast, linearly modulated optically stimulated luminescence (LM-OSL) component in quartz is the main dosimetric signal used for the dating applications of this material. Since the blue light stimulation (470 nm, 40 mW cm −2 ) time needed to obtain the fast LM-OSL component is less than 50 s the electron trapping levels responsible for it are still highly populated. In this way an active radiation history is created which could play an important role in the dosimetric characteristics of the fast OSL signal. In the present work the dose response behavior of the fast OSL signal is investigated in quartz samples with an annealed radiation history and quartz samples possessing an artificial radiation history. A computerized curve de-convolution analysis of the LM-OSL curves for 50 s stimulation time showed that it consists of three individual OSL components. The faster component C 1 with peak maximum time around 5 s has a linear dose response in virgin samples, which turns to a slight superlinearity as a function of the artificial radiation history. On the other hand the component C 2 with peak maximum time at 12 s is slightly superlinear which turns into strong superlinearity as a function of artificial radiation history. Finally, component C 3 with peak maximum time at about 45 s is strongly superlinear for both virgin samples and as a function of artificial radiation history. The implications to practical application are discussed. - Highlights: ► The fast OSL component consists of three components. ► The linearity of first fast component does not depend on radiation history. ► The linearity of second and third components depend on radiation history. ► The TL between 180 and 300 °C is the major source of OSL.

  20. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

    Science.gov (United States)

    Perez-Caballero, L; Pérez-Egea, R; Romero-Grimaldi, C; Puigdemont, D; Molet, J; Caso, J-R; Mico, J-A; Pérez, V; Leza, J-C; Berrocoso, E

    2014-05-01

    Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

  1. Single Pulse Electrical Stimulation to identify epileptogenic cortex: Clinical information obtained from early evoked responses.

    Science.gov (United States)

    Mouthaan, B E; van 't Klooster, M A; Keizer, D; Hebbink, G J; Leijten, F S S; Ferrier, C H; van Putten, M J A M; Zijlmans, M; Huiskamp, G J M

    2016-02-01

    Single Pulse Electrical Stimulation (SPES) probes epileptogenic cortex during electrocorticography. Two SPES responses are described: pathological delayed responses (DR, >100 ms) associated with the seizure onset zone (SOZ) and physiological early responses (ER, 80 Hz, in the SOZ and seizure propagation areas. We used data from 12 refractory epilepsy patients. SPES consisted of 10 pulses of 1 ms, 4-8 mA and 5s interval on adjacent electrodes pairs. Data were available at 2048 samples/s for six and 512 samples/s (22 bits) for eight patients and analyzed in the time-frequency (TF) and time-domain (TD). Electrodes with ERs were stronger associated with SOZ than non-SOZ electrodes. ERs with frequency content >80 Hz exist and are specific for SOZ channels. ERs evoked by stimulation of seizure onset electrodes were associated with electrodes involved in seizure propagation. Analysis of ERs can reveal aspects of pathology, manifested by association with seizure propagation and areas with high ER numbers that coincide with the SOZ. Not only DRs, but also ERs could have clinical value for mapping epileptogenic cortex and help to unravel aspects of the epileptic network. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  2. Clay Nanoparticles Elicit Long-Term Immune Responses by Forming Biodegradable Depots for Sustained Antigen Stimulation.

    Science.gov (United States)

    Chen, Weiyu; Zuo, Huali; Li, Bei; Duan, Chengcheng; Rolfe, Barbara; Zhang, Bing; Mahony, Timothy J; Xu, Zhi Ping

    2018-04-14

    Nanomaterials have been widely tested as new generation vaccine adjuvants, but few evoke efficient immunoreactions. Clay nanoparticles, for example, layered double hydroxide (LDH) and hectorite (HEC) nanoparticles, have shown their potent adjuvanticity in generating effective and durable immune responses. However, the mechanism by which clay nanoadjuvants stimulate the immune system is not well understood. Here, it is demonstrated that LDH and HEC-antigen complexes form loose agglomerates in culture medium/serum. They also form nodules with loose structures in tissue after subcutaneous injection, where they act as a depot for up to 35 d. More importantly, clay nanoparticles actively and continuously recruit immune cells into the depot for up to one month, and stimulate stronger immune responses than FDA-approved adjuvants, Alum and QuilA. Sustained antigen release is also observed in clay nanoparticle depots, with 50-60% antigen released after 35 d. In contrast, Alum-antigen complexes show minimal antigen release from the depot. Importantly, LDH and HEC are more effective than QuilA and Alum in promoting memory T-cell proliferation. These findings suggest that both clay nanoadjuvants can serve as active vaccine platforms for sustained and potent immune responses. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Sensory handedness is not reflected in cortical responses after basic nerve stimulation: a MEG study.

    Science.gov (United States)

    Chen, Andrew C N; Theuvenet, Peter J; de Munck, Jan C; Peters, Maria J; van Ree, Jan M; Lopes da Silva, Fernando L

    2012-04-01

    Motor dominance is well established, but sensory dominance is much less clear. We therefore studied the cortical evoked magnetic fields using magnetoencephalography (MEG) in a group of 20 healthy right handed subjects in order to examine whether standard electrical stimulation of the median and ulnar nerve demonstrated sensory lateralization. The global field power (GFP) curves, as an indication of cortical activation, did not depict sensory lateralization to the dominant left hemisphere. Comparison of the M20, M30, and M70 peak latencies and GFP values exhibited no statistical differences between the hemispheres, indicating no sensory hemispherical dominance at these latencies for each nerve. Field maps at these latencies presented a first and second polarity reversal for both median and ulnar stimulation. Spatial dipole position parameters did not reveal statistical left-right differences at the M20, M30 and M70 peaks for both nerves. Neither did the dipolar strengths at M20, M30 and M70 show a statistical left-right difference for both nerves. Finally, the Laterality Indices of the M20, M30 and M70 strengths did not indicate complete lateralization to one of the hemispheres. After electrical median and ulnar nerve stimulation no evidence was found for sensory hand dominance in brain responses of either hand, as measured by MEG. The results can provide a new assessment of patients with sensory dysfunctions or perceptual distortion when sensory dominance occurs way beyond the estimated norm.

  4. Synthesis of nitric oxide in human osteoblasts in response to physiologic stimulation of electrotherapy.

    Science.gov (United States)

    Hamed, Ayman; Kim, Paul; Cho, Michael

    2006-12-01

    Electrotherapy for bone healing, remodeling and wound healing may be mediated by modulation of nitric oxide (NO). Using NO-specific fluorophore (DAF-2), we report here that application of non-invasive, physiologic electrical stimulation induces NO synthesis in human osteoblasts, and that such NO generation is comparable to that induced by estrogen treatment. For example, application of a sinusoidal 1 Hz, 2 V/cm (peak to peak) electrical stimulation (ES) increases NO-bound DAF-2 fluorescence intensity by a 2-fold within 60 min exposure by activating nitric oxide synthase (NOS). Increase in the NO level is found to depend critically on the frequency and strength of ES. While the frequency of 1 Hz ES seems optimal, the ES strength >0.5 V/cm is required to induce significant NO increase, however. Nitric oxide synthesis in response to ES is completely prevented by blocking estrogen receptors using a competitive inhibitor, suggesting that NO generation is likely initiated by activation of estrogen receptors at the cell surface. Based on these findings, physiologic stimulation of electrotherapy appears to represent a potential non-invasive, non-genomic, and novel physical technique that could be used to regulate NO-mediated bone density and facilitate bone remodeling without adverse effects associated with hormone therapy.

  5. Gamma response characterizations of optically stimulated luminescence (OSL) affects personal dosimetry

    Science.gov (United States)

    Monthonwattana, S.; Esor, J.; Rungseesumran, T.; Intang, A.

    2017-06-01

    Optically Stimulated Luminescence (OSL) is the current technique of personal dosimetry changed by Nuclear Technology Service Center instead of Thermoluminescence dosimetry (TLD) because OSL has more advantages, such as repeat reading and elimination of heating process. In this study, OSL was used to test the gamma response characterizations. Detailed OSL investigation on personal dosimetry was carried out in the dose range of 0.2 - 3.0 mSv. The batch homogeneity was 7.66%. R2 value of the linear regression was 0.9997. The difference ratio of angular dependence at ± 60° was 8.7%. Fading of the reading was about 3%.

  6. Tendon response to pharmaco-mechanical stimulation of the chronically retracted rotator cuff in sheep.

    Science.gov (United States)

    Wieser, Karl; Farshad, Mazda; Meyer, Dominik C; Conze, Philipp; von Rechenberg, Brigitte; Gerber, Christian

    2015-02-01

    Chronic tearing of tendons is associated with molecular and structural alterations causing biomechanical changes, which compromise musculotendinous function and become limiting factors for tendon repair. This study investigated the histological response of chronically retracted sheep rotator cuff tendons to mechanical and pharmacological stimulation in view of tendon repair. Sixteen weeks after experimental release of the infraspinatus tendon in 20 sheep, the retracted musculotendinous unit was subjected to continuous traction either with [anabolic steroids (nandrolone) group/insulin-like growth factor (IGF) group] or without (control group) additional pharmacological treatment during 6 weeks. A new degeneration score for tendinous tissues (DSTT), based on established knowledge on histological changes associated with tendon degeneration, was used for histological analysis at the time of tendon release, at the beginning of continuous re-lengthening and at repair in all animals. The DSTT score (inter-observer correlation: r = 0.83), quantifiably representing tendon degeneration, improved from 15.5 (SD 1.3) points before to 9.8 (SD 3.8) points after re-lengthening. It improved in a qualitatively and quantitatively similar fashion if pharmacological stimulation was added. The nandrolone group improved from 13.7 (SD 1.6) to 9.8 (SD 1.9) and the IGF group from 13.3 (SD 3.6) to 8.8 (SD 1.8) points. Mechanical stimulation significantly reduced tissue degeneration. However, the addition of a pharmacological stimulation with anabolic steroids or IGF had neither a measurable positive nor negative effect on the degenerative process. Therefore, this investigation does neither support the additional pharmacological use of the anabolic steroid nandrolone or of IGF decanoate for restoration of tendon degeneration, nor otherwise provide evidence for additional tendon damage, if those substances are used to alter the muscular metabolism.

  7. Two Persons with Multiple Disabilities Use Camera-Based Microswitch Technology to Control Stimulation with Small Mouth and Eyelid Responses

    Science.gov (United States)

    Lancioni, Giulio E.; Bellini, Domenico; Oliva, Doretta; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Lang, Russell

    2012-01-01

    Background: A camera-based microswitch technology was recently developed to monitor small facial responses of persons with multiple disabilities and allow those responses to control environmental stimulation. This study assessed such a technology with 2 new participants using slight variations of previous responses. Method: The technology involved…

  8. Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Rosch, Keri S.; Fosco, Whitney D.; Pelham, William E.; Waxmonsky, James G.; Bubnik, Michelle G.; Hawk, Larry W.

    2015-01-01

    This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n=111, 25 girls) and typically-developing (TD) controls (n=33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

  9. Effects of Insufficient Sleep on Pituitary-Adrenocortical Response to CRH Stimulation in Healthy Men.

    Science.gov (United States)

    Guyon, Aurore; Morselli, Lisa L; Balbo, Marcella L; Tasali, Esra; Leproult, Rachel; L'Hermite-Balériaux, Mireille; Van Cauter, Eve; Spiegel, Karine

    2017-06-01

    Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  10. Specific response of mouse tumor-feeding arterioles to stimulation by 5-HT1 agonists

    International Nuclear Information System (INIS)

    Stuecker, Olivier; Laemmel, Elisabeth; Teisseire, Bernard; Vicaut, Eric

    1997-01-01

    Using intravital microscopy, we compared the responses to 5-HT 1 receptor stimulation by the host-modified arterioles feeding a Meth-A tumor implanted in the flank of female Balb/c mice with the responses of tumor-independent arterioles (TIA) and those of control arterioles from mice without tumor. Topical administration of 5 x 10 -5 M serotonin in the presence of 10 -4 M ketanserin (5-HT 2 receptors inhibitor) induced arteriolar vasodilation in TIA (+13%) and in the control arterioles (+19%), but induced constriction (-14%) in the tumor-feeding arterioles (TFA). Topical administration of the general 5-HT 1 agonist 5-carboxamidotryptamine maleate (10 -6 to 10 -4 M) or the 5-HT 1A agonist buspirone (2 x 10 -6 to 2 x 10 -4 M) induced vasoconstriction that was dramatically higher in TFA than in TIA or control arterioles (p 1B agonist M-trifluoromethylphenylpiperazine (2 x 10 -6 to 2 x 10 -4 M) produced opposite responses, i.e., dose-dependent vasodilation in TIA and control arterioles, and dose-dependent constriction in TFA. Since we observed the same degree of vasodilation in response to 10 -4 M acetylcholine in all three groups of arterioles, the differences between the responses to 5-HT 1 receptor stimulation were not due to the absence of endothelial-dependent dilatory mechanisms in the tumor-feeding arterioles. We conclude that 5-HT 1 agonists are interesting pharmacologic tools for the modulation of tumoral blood flow, since they more dramatically constrict the microvasculature feeding the tumors than that feeding normal tissue

  11. The influence of prenatal tactile and vestibular stimulation on auditory and visual responsiveness in bobwhite quail: A matter of timing.

    Science.gov (United States)

    Honeycutt, Hunter; Lickliter, Robert

    2003-09-01

    The fact that the sensory systems do not become functional at the same time during prenatal development raises the question of how experience in a given modality can influence functioning in other sensory modalities. The present study exposed groups of bobwhite quail embryos to augmented tactile and vestibular stimulation at times that either coincided with or followed the period of onset of function in the later-developing auditory and visual modalities. Differences in the timing of augmented prenatal stimulation led to different patterns of subsequent auditory and visual responsiveness following hatching. No effect on normal visual responsiveness to species-typical maternal cues was found when exposure to tactile and vestibular stimulation coincided with the emergence of visual function (Days 14-19), but when exposure took place after the onset of visual functioning (Days 17-22), chicks displayed enhanced responsiveness to the same maternal visual cues. When augmented tactile and vestibular stimulation coincided with the onset of auditory function (Days 9-14), embryos subsequently failed to learn a species-typical maternal call prior to hatching. However, when given exposure to the same type and amount of augmented stimulation following the onset of auditory function (Days 14-19), embryos did learn the maternal call. These findings demonstrate that augmented stimulation to earlier-emerging sensory modalities can either facilitate or interfere with perceptual responsiveness in later-developing modalities, depending on when that stimulation takes place. Copyright 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 71-81, 2003.

  12. Vascular plant one-zinc-finger protein 1/2 transcription factors regulate abiotic and biotic stress responses in Arabidopsis.

    Science.gov (United States)

    Nakai, Yusuke; Nakahira, Yoichi; Sumida, Hiroki; Takebayashi, Kosuke; Nagasawa, Yumiko; Yamasaki, Kanako; Akiyama, Masako; Ohme-Takagi, Masaru; Fujiwara, Sumire; Shiina, Takashi; Mitsuda, Nobutaka; Fukusaki, Eiichiro; Kubo, Yasuyuki; Sato, Masa H

    2013-03-01

    Plants adapt to abiotic and biotic stresses by activating abscisic acid-mediated (ABA) abiotic stress-responsive and salicylic acid-(SA) or jasmonic acid-mediated (JA) biotic stress-responsive pathways, respectively. Although the abiotic stress-responsive pathway interacts antagonistically with the biotic stress-responsive pathways, the mechanisms that regulate these pathways remain largely unknown. In this study, we provide insight into the function of vascular plant one-zinc-finger proteins (VOZs) that modulate various stress responses in Arabidopsis. The expression of many stress-responsive genes was changed in the voz1voz2 double mutant under normal growth conditions. Consistent with altered stress-responsive gene expression, freezing- and drought-stress tolerances were increased in the voz1voz2 double mutant. In contrast, resistance to a fungal pathogen, Colletotrichum higginsianum, and to a bacterial pathogen, Pseudomonas syringae, was severely impaired. Thus, impairing VOZ function simultaneously conferred increased abiotic tolerance and biotic stress susceptibility. In a chilling stress condition, both the VOZ1 and VOZ2 mRNA expression levels and the VOZ2 protein level gradually decreased. VOZ2 degradation during cold exposure was completely inhibited by the addition of the 26S proteasome inhibitor, MG132, a finding that suggested that VOZ2 degradation is dependent on the ubiquitin/26S proteasome system. In voz1voz2, ABA-inducible transcription factor CBF4 expression was enhanced significantly even under normal growth conditions, despite an unchanged endogenous ABA content. A finding that suggested that VOZs negatively affect CBF4 expression in an ABA-independent manner. These results suggest that VOZs function as both negative and positive regulators of the abiotic and biotic stress-responsive pathways, and control Arabidopsis adaptation to various stress conditions. © 2012 The Authors The Plant Journal © 2012 Blackwell Publishing Ltd.

  13. Deep brain stimulation and responsiveness of the Persian version of Parkinson's disease questionnaire with 39-items.

    Science.gov (United States)

    Shahidi, Gholam Ali; Ghaempanah, Zeinab; Khalili, Yasaman; Nojomi, Marzieh

    2014-10-06

    Assessment of quality-of-life (QOF) as an outcome measure after deep brain stimulation (DBS) surgery in patients with Parkinson's disease (PD) need a valid, reliable and responsive instrument. The aim of the current study was to determine responsiveness of validated Persian version of PD questionnaire with 39-items (PDQ-39) after DBS surgery in patients with PD. Eleven patients with PD, who were candidate for DBS operation between May 2012 and June 2013 were assessed. PDQ-39 and short-form questionnaire with 36-items (SF-36) were used. To assess responsiveness of PDQ-39 standardized response mean (SRM) was used. Mean age was 51.8 (8.8) and all of the patients, but just one were male (10 patients). Mean duration of the disease was 8.7 (2.1) years. Eight patients were categorized as moderate using Hoehn and Yahr (H and Y) classification. All patients had a better H and Y score compared with the baseline evaluation (3.09 vs. 0.79). The amount of SRM was above 0.70 for all domains means a large responsiveness for PDQ-39. Persian version of PDQ-39 has an acceptable responsiveness and could be used to assess as an outcome measure to evaluate the effect of therapies on PD.

  14. Vascular changes in the developing rat retina in response to hypoxia.

    Science.gov (United States)

    Rathnasamy, Gurugirijha; Sivakumar, Viswanathan; Foulds, Wallace S; Ling, Eng Ang; Kaur, Charanjit

    2015-01-01

    This study was carried out to investigate the roles of tight junction (TJ) proteins and other factors in the increased permeability of the blood retinal barrier (BRB) affecting the immature neonatal retina following a hypoxic insult. The expression of endothelial TJ proteins such as claudin-5, occludin and zonula occludens-1 (ZO-1) and endothelial cell specific molecule-1 (ESM-1), and associated structural changes in the blood vessels were analyzed in the retinas of 1-day-old Wistar rats subjected to hypoxia for 2 h and subsequently sacrificed at different time points ranging from 3 h to 14 d. The mRNA and protein expression of claudin-5, occludin & ZO-1 was found to be reduced in the hypoxic retina, although, at the ultrastructural level, the TJ between the endothelial cells and retinal pigment epithelial cells appeared to be intact. Following the hypoxic insult vascular endothelial cells frequently showed presence of cytoplasmic vacuoles, vacuolated mitochondria and multivesicular aggregations projecting into the lumen of the capillaries. The expression of ESM-1 in the immature retinas was found to be increased following hypoxic exposure. The structural and molecular changes in the hypoxic neonatal retinas were consistent with a hypoxia induced impairment of the BRB. Hypoxia reduced the expression of TJ proteins in the neonatal retina, but the role of increased ESM-1 expression in this process warrants further investigation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation.

    Science.gov (United States)

    de Zambotti, Massimiliano; Pizza, Fabio; Covassin, Naima; Vandi, Stefano; Cellini, Nicola; Stegagno, Luciano; Plazzi, Giuseppe

    2014-08-01

    Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed strongly linked with emotions that usually trigger the episodes. Our study aimed to investigate haemodynamic and behavioural responses during emotional stimulation in narco-cataplexy. Twelve adult drug-naive narcoleptic patients (five males; age: 33.3 ± 9.4 years) and 12 healthy controls (five males; age: 30.9 ± 9.5 years) were exposed to emotional stimuli (pleasant, unpleasant and neutral pictures). Heart rate, arterial blood pressure and mean cerebral blood flow velocity of the middle cerebral arteries were continuously recorded using photoplethysmography and Doppler ultrasound. Ratings of valence and arousal and coping strategies were scored by the Self-Assessment Manikin and by questionnaires, respectively. Narcoleptic patients' haemodynamic responses to pictures overlapped with the data obtained from controls: decrease of heart rate and increase of mean cerebral blood flow velocity regardless of pictures' content, increase of systolic blood pressure during the pleasant condition, and relative reduction of heart rate during pleasant and unpleasant conditions. However, when compared with controls, narcoleptic patients reported lower arousal scores during the pleasant and neutral stimulation, and lower valence scores during the pleasant condition, respectively, and also a lower score at the 'focus on and venting of emotions' dimensions of coping. Our results suggested that adult narcoleptic patients, compared with healthy controls, inhibited their emotion-expressive behaviour to emotional stimulation, and that may be related to the development of adaptive cognitive strategies to face emotions avoiding cataplexy. © 2014 European Sleep Research Society.

  16. Differentiation-Dependent Motility-Responses of Developing Neural Progenitors to Optogenetic Stimulation

    Directory of Open Access Journals (Sweden)

    Tímea Köhidi

    2017-12-01

    Full Text Available During neural tissue genesis, neural stem/progenitor cells are exposed to bioelectric stimuli well before synaptogenesis and neural circuit formation. Fluctuations in the electrochemical potential in the vicinity of developing cells influence the genesis, migration and maturation of neuronal precursors. The complexity of the in vivo environment and the coexistence of various progenitor populations hinder the understanding of the significance of ionic/bioelectric stimuli in the early phases of neuronal differentiation. Using optogenetic stimulation, we investigated the in vitro motility responses of radial glia-like neural stem/progenitor populations to ionic stimuli. Radial glia-like neural stem cells were isolated from CAGloxpStoploxpChR2(H134-eYFP transgenic mouse embryos. After transfection with Cre-recombinase, ChR2(channelrhodopsin-2-expressing and non-expressing cells were separated by eYFP fluorescence. Expression of light-gated ion channels were checked by patch clamp and fluorescence intensity assays. Neurogenesis by ChR2-expressing and non-expressing cells was induced by withdrawal of EGF from the medium. Cells in different (stem cell, migrating progenitor and maturing precursor stages of development were illuminated with laser light (λ = 488 nm; 1.3 mW/mm2; 300 ms in every 5 min for 12 h. The displacement of the cells was analyzed on images taken at the end of each light pulse. Results demonstrated that the migratory activity decreased with the advancement of neuronal differentiation regardless of stimulation. Light-sensitive cells, however, responded on a differentiation-dependent way. In non-differentiated ChR2-expressing stem cell populations, the motility did not change significantly in response to light-stimulation. The displacement activity of migrating progenitors was enhanced, while the motility of differentiating neuronal precursors was markedly reduced by illumination.

  17. Response of cardiac autonomic modulation after a single exposure to musical auditory stimulation.

    Science.gov (United States)

    Ferreira, Lucas L; Vanderlei, Luiz Carlos M; Guida, Heraldo L; de Abreu, Luiz Carlos; Garner, David M; Vanderlei, Franciele M; Ferreira, Celso; Valenti, Vitor E

    2015-01-01

    The acute effects after exposure to different styles of music on cardiac autonomic modulation assessed through heart rate variability (HRV) analysis have not yet been well elucidated. We aimed to investigate the recovery response of cardiac autonomic modulation in women after exposure to musical auditory stimulation of different styles. The study was conducted on 30 healthy women aged between 18 years and 30 years. We did not include subjects having previous experience with musical instruments and those who had an affinity for music styles. The volunteers remained at rest for 10 min and were exposed to classical baroque (64-84 dB) and heavy metal (75-84 dB) music for 10 min, and their HRV was evaluated for 30 min after music cessation. We analyzed the following HRV indices: Standard deviation of normal-to-normal (SDNN) intervals, root mean square of successive differences (RMSSD), percentage of normal-to-normal 50 (pNN50), low frequency (LF), high frequency (HF), and LF/HF ratio. SDNN, LF in absolute units (ms 2 ) and normalized (nu), and LF/HF ratio increased while HF index (nu) decreased after exposure to classical baroque music. Regarding the heavy metal music style, it was observed that there were increases in SDNN, RMSSD, pNN50, and LF (ms 2 ) after the musical stimulation. In conclusion, the recovery response of cardiac autonomic modulation after exposure to auditory stimulation with music featured an increased global activity of both systems for the two musical styles, with a cardiac sympathetic modulation for classical baroque music and a cardiac vagal tone for the heavy metal style.

  18. Molecular mechanisms underlying antiproliferative and differentiating responses of hepatocarcinoma cells to subthermal electric stimulation.

    Directory of Open Access Journals (Sweden)

    María Luisa Hernández-Bule

    Full Text Available Capacitive Resistive Electric Transfer (CRET therapy applies currents of 0.4-0.6 MHz to treatment of inflammatory and musculoskeletal injuries. Previous studies have shown that intermittent exposure to CRET currents at subthermal doses exert cytotoxic or antiproliferative effects in human neuroblastoma or hepatocarcinoma cells, respectively. It has been proposed that such effects would be mediated by cell cycle arrest and by changes in the expression of cyclins and cyclin-dependent kinase inhibitors. The present work focuses on the study of the molecular mechanisms involved in CRET-induced cytostasis and investigates the possibility that the cellular response to the treatment extends to other phenomena, including induction of apoptosis and/or of changes in the differentiation stage of hepatocarcinoma cells. The obtained results show that the reported antiproliferative action of intermittent stimulation (5 m On/4 h Off with 0.57 MHz, sine wave signal at a current density of 50 µA/mm(2, could be mediated by significant increase of the apoptotic rate as well as significant changes in the expression of proteins p53 and Bcl-2. The results also revealed a significantly decreased expression of alpha-fetoprotein in the treated samples, which, together with an increased concentration of albumin released into the medium by the stimulated cells, can be interpreted as evidence of a transient cytodifferentiating response elicited by the current. The fact that this type of electrical stimulation is capable of promoting both, differentiation and cell cycle arrest in human cancer cells, is of potential interest for a possible extension of the applications of CRET therapy towards the field of oncology.

  19. Vascular response to ischemia in the feet of falanga torture victims and normal controls--color and spectral Doppler findings

    DEFF Research Database (Denmark)

    Torp-Pedersen, Søren; Amris, Kirstine; Holm, Christian Cato

    2009-01-01

    OBJECTIVE: To investigate whether signs of chronic compartment syndrome could be found in plantar muscles of falanga torture victims with painful feet and impaired gait. The hypothesis was that the muscular vascular response to two minutes ischemia would be decreased in torture victims compared...... to controls. On color Doppler this would be seen as less color after ischemia and on spectral Doppler as elevated resistive index (RI). METHODS: Ten male torture victims from the Middle East and nine age, sex and ethnically matched controls underwent Doppler examination of the abductor hallucis and flexor...... ischemia. RESULTS: Both torture victims and controls responded to ischemia with an increased CF. There was no difference between torture victims and controls. With spectral Doppler all subjects had an RI of 1.0 before ischemia. After ischemia, in nearly all subjects and all muscles the first RI was lowest...

  20. Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics.

    Science.gov (United States)

    Farzam, Parisa; Johansson, Johannes; Mireles, Miguel; Jiménez-Valerio, Gabriela; Martínez-Lozano, Mar; Choe, Regine; Casanovas, Oriol; Durduran, Turgut

    2017-05-01

    The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the therapy effect twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point.

  1. [Inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide-stimulated human mast cells].

    Science.gov (United States)

    Zhou, Yun-jiang; Wang, Hu; Li, Li; Sui, He-huan; Huang, Jia-jun

    2015-06-01

    This study is to investigate the inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide(LPS)-stimulated HMC-1 mast cells. The cytotoxicity of kaempferol to HMC-1 mast cells were analyzed by using MTT assay and then the administration concentrations of kaempferol were established. Histamine, IL-6, IL-8, IL-1β and TNF-α were measured using ELISA assay in activated HMC-1 mast cells after incubation with various concentrations of kaempferol (10, 20 and 40 µmol.L-1). Western blot was used to test the protein expression of p-IKKβ, IκBα, p-IκBα and nucleus NF-κB of LPS-induced HMC-1 mast cells after incubation with different concentrations of kaempferol. The optimal concentrations of kaempferol were defined as the range from 5 µmol.L-1 to 40 µmol.L-1. Kaempferol significantly decreased the release of histamine, IL-6, IL-8, IL-1β and TNF-α of activated HMC-1 mast cells (Pkaempferol, the protein expression of p-IKKβ, p-IKBa and nucleus NF-κB (p65) markedly reduced in LPS-stimulated HMC-1 mast cells (Pkaempferol markedly inhibit mast cell-mediated inflammatory response. At the same time, kaempferol can inhibit the activation of IKKβ, block the phosphorylation of IκBα, prevent NF-KB entering into the nucleus, and then decrease the release of inflammatory mediators.

  2. Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation

    DEFF Research Database (Denmark)

    Durnerin, Cedrin I; Erb, K; Fleming, R

    2008-01-01

    BACKGROUND: The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored...... in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high......-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured...

  3. Aluminum hydroxide nanoparticles show strong activity to stimulate Th-1 immune response against tuberculosis.

    Science.gov (United States)

    Amini, Yousef; Moradi, Bagher; Fasihi-Ramandi, Mahdi

    2017-11-01

    Many materials such as aluminum hydroxide have been tried as adjuvants to compensate low inherent immunogenicity of subunit vaccines. The aim of this study was to evaluate the specific immune response following the administration of aluminum hydroxide nanoparticles with EsxV antigen. The physiochemical properties of the nanoparticle were characterized in vitro. After subcutaneous immunization, cytokine secretion patterns including IFN-gama,IL-4, and TGF-beta levels were measured by indirect enzyme linked immunosorbent assay (ELISA). Aluminum hydroxide-NPs were demonstrated excellent effects to raise of IFN-γ secretion in compare to EsxV alone. Administration of aluminum hydroxide nanoparticles stimulates strong cellular immune response and could be considered as appropriate adjuvant against TB infection.

  4. Prediction of postoperative pain by preoperative pain response to heat stimulation in total knee arthroplasty

    DEFF Research Database (Denmark)

    Lunn, Troels H; Gaarn-Larsen, Lissi; Kehlet, Henrik

    2013-01-01

    postoperative pain after total knee arthroplasty (TKA). Patients scheduled for elective, unilateral, primary TKA under spinal anesthesia were consecutively included in this prospective, observational study. Perioperative analgesia was standardized for all patients. Outcomes were postoperative pain during walk......It has been estimated that up to 54% of the variance in postoperative pain experience may be predicted with preoperative pain responses to experimental stimuli, with suprathreshold heat pain as the most consistent test modality. We aimed to explore if 2 heat test paradigms could predict......: From 6-24hrs (primary), from postoperative day (POD) 1-7 (secondary), and from POD14-30 (tertiary). Two preoperative tonic heat stimuli with 47°C were used; short (5sec) and long (7min) stimulation upon which patients rated their pain response on an electronic VAS. Multivariate stepwise linear...

  5. The response to repetitive stimulation of human motor cortex is influenced by the history of synaptic activity.

    Science.gov (United States)

    Todd, G; Ridding, M C

    2010-01-01

    Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter-subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques.

  6. Molecular Mechanisms of Glucose-Stimulated GLP-1 Secretion From Perfused Rat Small Intestine

    DEFF Research Database (Denmark)

    Kuhre, Rune E.; Frost, Charlotte R.; Svendsen, Berit

    2015-01-01

    /v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration...... not stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal α-MGP in matched concentrations...

  7. Dorsal vagal preganglionic neurons: differential responses to CCK1 and 5-HT3 receptor stimulation.

    Science.gov (United States)

    Mussa, Bashair M; Sartor, Daniela M; Verberne, Anthony J M

    2010-08-25

    The dorsal motor nucleus of the vagus (DMV) is the main source of the vagal innervation of the pancreas. Several studies in vitro have demonstrated that the DMV consists of a heterogeneous population of preganglionic neurons but little is known about their electrophysiological characteristics in vivo. The aims of this study were to (i) identify DMV preganglionic neurons in vivo with axons in the pancreatic vagus and (ii) characterize their responses to stimulation of cholecystokinin (CCK(1)) and serotonin (5-HT(3)) receptors which are major regulators of pancreatic secretion. Male Sprague Dawley rats anaesthetised with isoflurane (1.5%/100% O(2)) were used throughout. Dorsal vagal preganglionic neurons were identified by antidromic activation in response to stimulation of the pancreatic vagus. Dorsal vagal preganglionic neurons had axonal conduction velocities in the C-fibre range (0.7+/-0.03 m/s). Forty-four neurons were identified within the rostral, intermediate and caudal DMV and thirty-eight were tested for responsiveness to CCK-8S (CCK(1) agonist) and phenylbiguanide (PBG; 5-HT(3) receptor agonist). CCK-8S and PBG (0.1-10 microg/kg, i.v.) produced three types of response: (i) preganglionic neurons in the intermediate DMV were inhibited by CCK-8S (n=18) and PBG (n=10), (ii) neurons in the caudal DMV were activated by CCK (n=5) and PBG (n=2) and (iii) CCK-8S (n=9) and PBG (n=7) had no effect on preganglionic neurons in the rostral DMV. CCK-8S and PBG have complex actions on preganglionic neurons in the DMV that may be related to their effects on pancreatic secretion. Copyright 2010 Elsevier B.V. All rights reserved.

  8. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

    Science.gov (United States)

    Bergey, Gregory K; Morrell, Martha J; Mizrahi, Eli M; Goldman, Alica; King-Stephens, David; Nair, Dileep; Srinivasan, Shraddha; Jobst, Barbara; Gross, Robert E; Shields, Donald C; Barkley, Gregory; Salanova, Vicenta; Olejniczak, Piotr; Cole, Andrew; Cash, Sydney S; Noe, Katherine; Wharen, Robert; Worrell, Gregory; Murro, Anthony M; Edwards, Jonathan; Duchowny, Michael; Spencer, David; Smith, Michael; Geller, Eric; Gwinn, Ryder; Skidmore, Christopher; Eisenschenk, Stephan; Berg, Michel; Heck, Christianne; Van Ness, Paul; Fountain, Nathan; Rutecki, Paul; Massey, Andrew; O'Donovan, Cormac; Labar, Douglas; Duckrow, Robert B; Hirsch, Lawrence J; Courtney, Tracy; Sun, Felice T; Seale, Cairn G

    2015-02-24

    The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years. © 2015 American Academy of Neurology.

  9. A novel technique for quantifying changes in vascular density, endothelial cell proliferation and protein expression in response to modulators of angiogenesis using the chick chorioallantoic membrane (CAM assay

    Directory of Open Access Journals (Sweden)

    Kohn Elise

    2004-01-01

    Full Text Available Abstract Reliable quantitative evaluation of molecular pathways is critical for both drug discovery and treatment monitoring. We have modified the CAM assay to quantitatively measure vascular density, endothelial proliferation, and changes in protein expression in response to anti-angiogenic and pro-angiogenic agents. This improved CAM assay can correlate changes in vascular density with changes seen on a molecular level. We expect that these described modifications will result in a single in vivo assay system, which will improve the ability to investigate molecular mechanisms underlying the angiogenic response.

  10. Decremental responses to repetitive nerve stimulation in x-linked bulbospinal muscular atrophy.

    Science.gov (United States)

    Kim, Jee Young; Park, Kee Duk; Kim, Seung-Min; Sunwoo, Il Nam

    2013-01-01

    X-linked bulbospinal muscular atrophy (X-BSMA) is characterized by bulbar and spinal muscular weakness and fasciculations. Although X-BSMA is a motor neuronopathy, there are several reports of myasthenic symptoms or decremental responses to repetitive nerve stimulation (RNS). We report the results of applying the RNS test to 15 patients among 41 with genetically confirmed X-BSMA; these 15 patients complained of fatigue, ease of becoming tired, or early muscular exhaustion. The 3-Hz RNS test was performed on the trapezius, nasalis, orbicularis oculi, flexor carpi ulnaris, and abductor digiti quinti muscles. A decrement greater than 10% was considered abnormal. Additionally, a pharmacologic response to neostigmine was identified in three patients. A significant decrement was observed in 67% of patients, and was most common in the trapezius muscle (nine cases). The decrement of the trapezius muscle response ranged from 15.9% to 36.9%. The decrement was inversely correlated with the amplitude of compound muscle action potentials at rest. Neostigmine injection markedly improved the decrement in three patients, who showed noticeable decremental responses to 3-Hz RNS. This study shows that myasthenic symptoms and abnormal decremental responses to low-rate RNS are common in X-BSMA.

  11. Interactive effects of music and prefrontal cortex stimulation in modulating response inhibition.

    Science.gov (United States)

    Mansouri, Farshad Alizadeh; Acevedo, Nicola; Illipparampil, Rosin; Fehring, Daniel J; Fitzgerald, Paul B; Jaberzadeh, Shapour

    2017-12-22

    Influential hypotheses propose that alterations in emotional state influence decision processes and executive control of behavior. Both music and transcranial direct current stimulation (tDCS) of prefrontal cortex affect emotional state, however interactive effects of music and tDCS on executive functions remain unknown. Learning to inhibit inappropriate responses is an important aspect of executive control which is guided by assessing the decision outcomes such as errors. We found that high-tempo music, but not low-tempo music or low-level noise, significantly influenced learning and implementation of inhibitory control. In addition, a brief period of tDCS over prefrontal cortex specifically interacted with high-tempo music and altered its effects on executive functions. Measuring event-related autonomic and arousal response of participants indicated that exposure to task demands and practice led to a decline in arousal response to the decision outcome and high-tempo music enhanced such practice-related processes. However, tDCS specifically moderated the high-tempo music effect on the arousal response to errors and concomitantly restored learning and improvement in executive functions. Here, we show that tDCS and music interactively influence the learning and implementation of inhibitory control. Our findings indicate that alterations in the arousal-emotional response to the decision outcome might underlie these interactive effects.

  12. Effects of cyclosporine, tacrolimus and sirolimus on vascular changes related to immune response.

    Science.gov (United States)

    Rigol, Montserrat; Solanes, Núria; Sionis, Alessandro; Gálvez, Carolina; Martorell, Jaume; Rojo, Isabel; Brunet, Mercè; Ramírez, José; Roqué, Mercè; Roig, Eulàlia; Pérez-Villa, Fèlix; Barquín, Leire; Pomar, José Luís; Sanz, Ginés; Heras, Magda

    2008-04-01

    Despite the use of newer immunosuppressors such as sirolimus (SRL) and tacrolimus (TRL) in heart transplantation, the rate of humoral rejection has remained unchanged. The aim of this study was to analyze the immunologic and histologic effects of cyclosporine (CsA), SRL, and TRL in a porcine model of arterial transplantation. Each transplant recipient animal (n = 49) received an autograft and an allograft and was then allocated to one of four treatment groups and a 7- or 30-day follow-up period, as follows: a WOT group (without immunosuppressor treatment), 7 days (n = 6) and 30 days (n = 5); a CsA group, 7 days (n = 5) and 30 days (n = 6); an SRL group, 7 days (n = 7) and 30 days (n = 8); and a TRL group, 7 days (n = 6) and 30 days (n = 6). The presence of donor-specific antibodies (DSA) was tested at the end of the follow-up period. Morphometric parameters and inflammatory infiltration were analyzed in the explanted grafts. At 30-day follow-up, SRL was the only treatment capable of suppressing DSA formation (0 of 7 vs 4 of 5 in the WOT group; p < 0.05). SRL completely prevented aneurismal dilation and reduced the number of macrophages in the allografts. TRL treatment achieved a greater reduction of T lymphocytes. CsA did not prevent the reduction in total vascular area at 7 days that was achieved with the SRL and TRL groups. Animals treated with CsA had the largest number of T lymphocytes and macrophages in both follow-up periods. SRL prevented DSA formation and reduced the number of macrophages as compared with TRL and CsA.

  13. Phagocytic response to fully controlled plural stimulation of antigens on macrophage using on-chip microcultivation system

    Directory of Open Access Journals (Sweden)

    Wakamoto Yuichi

    2006-08-01

    Full Text Available Abstract To understand the control mechanism of innate immune response in macrophages, a series of phagocytic responses to plural stimulation of antigens on identical cells was observed. Two zymosan particles, which were used as antigens, were put on different surfaces of a macrophage using optical tweezers in an on-chip single-cell cultivation system, which maintains isolated conditions of each macrophage during their cultivation. When the two zymosan particles were attached to the macrophage simultaneously, the macrophage responded and phagocytosed both of the antigens simultaneously. In contrast, when the second antigen was attached to the surface after the first phagocytosis had started, the macrophage did not respond to the second stimulation during the first phagocytosis; the second phagocytosis started only after the first process had finished. These results indicate that (i phagocytosis in a macrophage is not an independent process when there are plural stimulations; (ii the response of the macrophage to the second stimulation is related to the time" delay from the first stimulation. Stimulations that occur at short time intervals resulted in simultaneous phagocytosis, while a second stimulation that is delayed long enough might be neglected until the completion of the first phagocytic process.

  14. The "brittle response" to Parkinson's disease medications: characterization and response to deep brain stimulation.

    Directory of Open Access Journals (Sweden)

    Daniel Martinez-Ramirez

    Full Text Available Formulate a definition and describe the clinical characteristics of PD patients with a "brittle response" (BR to medications versus a "non-brittle response" (NBR, and characterize the use of DBS for this population.An UF IRB approved protocol used a retrospective chart review of 400 consecutive PD patients presenting to the UF Center for Movement Disorders and Neurorestoration. Patient records were anonymized and de-identified prior to analysis. SPSS statistics were used to analyze data.Of 345 included patients, 19 (5.5% met criteria for BR PD. The BR group was comprised of 58% females, compared to 29% in the NBR group (P = .008. The former had a mean age of 63.4 compared to 68.1 in the latter. BR patients had lower mean weight (63.5 vs. 79.6, P = <.001, longer mean disease duration (12.6 vs. 8.9 years, P = .003, and had been on LD for more years compared to NBR patients (9.8 vs. 5.9, P = .001. UPDRS motor scores were higher (40.4 vs. 30.0, P = .001 in BR patients. No differences were observed regarding the Schwab and England scale, PDQ-39, and BDI-II. Sixty-three percent of the BR group had undergone DBS surgery compared to 18% (P = .001. Dyskinesias were more common, severe, and more often painful (P = <.001 in the BR group. There was an overall positive benefit from DBS.BR PD occurred more commonly in female patients with a low body weight. Patients with longer disease duration and longer duration of LD therapy were also at risk. The BR group responded well to DBS.

  15. The Effect of Acutely Elevated Intraocular Pressure on the Functional and Blood Flow Responses of the Rat Retina to Flicker Stimulation.

    Science.gov (United States)

    Tan, Bingyao; MacLellan, Benjamin; Mason, Erik; Bizheva, Kostadinka K

    2017-10-01

    To evaluate the effect of acutely elevated intraocular pressure (IOP) on the functional and blood flow responses of the rat retina to flicker stimulation. Brown Norway (n = 15) rats were dark-adapted before ketamine/xylazine anesthesia. IOP was raised acutely in one eye to ∼45 mm Hg with a vascular loop. In 11 rats, white light flicker stimulus (10 Hz, 2 seconds duration, 0.80 log scotopic cd·s/m2) was applied before and during IOP elevation, and 10 minutes after loop removal. Changes in the total retinal blood flow (TRBF) and retinal function induced by the visual stimulus were measured simultaneously with a combined optical coherence tomography (OCT) + electroretinography (ERG) system. Systemic blood pressure was measured in the remaining four rats frequently from 10 to 90 minutes post anesthesia injection. The systemic blood pressure remained at 99 ± 4 mm Hg throughout the measurements (n = 4). Under normal IOP, the TRBF was 5.6 ± 1.9 μL/min, and the average retinal blood vessel size (BVS) in the vicinity of the optic nerve head (ONH) was 44.1 ± 4.5 μm. During IOP elevation, the TRBF was significantly lower (3.8 ± 1.2 μL/min, P flicker-induced TRBF change measured under normal IOP (6.0 ± 3.3%) was reduced significantly to 0.1 ± 0.3% (P flicker stimulation.

  16. The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis.

    Science.gov (United States)

    Smith, Gina A; Fearnley, Gareth W; Tomlinson, Darren C; Harrison, Michael A; Ponnambalam, Sreenivasan

    2015-08-18

    VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments. © 2015 Authors.

  17. Cutaneous stimulation of the digits and lips evokes responses with different adaptation patterns in primary somatosensory cortex.

    Science.gov (United States)

    Popescu, Mihai; Barlow, Steven; Popescu, Elena-Anda; Estep, Meredith E; Venkatesan, Lalit; Auer, Edward T; Brooks, William M

    2010-10-01

    Neuromagnetic evoked fields were recorded to compare the adaptation of the primary somatosensory cortex (SI) response to tactile stimuli delivered to the glabrous skin at the fingertips of the first three digits (condition 1) and between midline upper and lower lips (condition 2). The stimulation paradigm allowed to characterize the response adaptation in the presence of functional integration of tactile stimuli from adjacent skin areas in each condition. At each stimulation site, cutaneous stimuli (50 ms duration) were delivered in three runs, using trains of 6 pulses with regular stimulus onset asynchrony (SOA). The pulses were separated by SOAs of 500 ms, 250 ms or 125 ms in each run, respectively, while the inter-train interval was fixed (5s) across runs. The evoked activity in SI (contralateral to the stimulated hand, and bilaterally for lips stimulation) was characterized from the best-fit dipoles of the response component peaking around 70 ms for the hand stimulation, and 8 ms earlier (on average) for the lips stimulation. The SOA-dependent long-term adaptation effects were assessed from the change in the amplitude of the responses to the first stimulus in each train. The short-term adaptation was characterized by the lifetime of an exponentially saturating model function fitted to the set of suppression ratios of the second relative to the first SI response in each train. Our results indicate: 1) the presence of a rate-dependent long-term adaptation effect induced only by the tactile stimulation of the digits; and 2) shorter recovery lifetimes for the digits compared with the lips stimulation. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Bioengineered vascular access maintains structural integrity in response to arteriovenous flow and repeated needle puncture.

    Science.gov (United States)

    Tillman, Bryan W; Yazdani, Saami K; Neff, Lucas P; Corriere, Matthew A; Christ, George J; Soker, Shay; Atala, Anthony; Geary, Randolph L; Yoo, James J

    2012-09-01

    were created within a clinically relevant time frame and demonstrated stable wall geometry despite high flow and repeated puncture. Cellular ingrowth and puncture site healing may improve wall durability, but venous outflow stenosis remains the primary mode of TEBV graft failure in the ovine model. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  19. Development of Fetal Movement between 26 and 36 Weeks’ Gestation in Response to Vibro-acoustic Stimulation

    Directory of Open Access Journals (Sweden)

    Marybeth eGrant-Beuttler

    2011-12-01

    Full Text Available Background: Ultrasound observation of fetal movement has documented general trends in motor development and fetal age when motor response to stimulation is observed. Evaluation of fetal movement quality, in addition to specific motor activity, may improve documentation of motor development and highlight specific motor responses to stimulation. Aims: The aim of this investigation was to assess fetal movement at 26 and 36 weeks gestation during three conditions (baseline, immediate response to vibro-acoustic stimulation (VAS, and post-response. Design: A prospective, longitudinal design was utilized. Subjects: Twelve normally developing fetuses, 8 females and 4 males, were examined with continuous ultrasound imaging. Outcome measures: The Fetal Neurobehavioral Coding System (FENS was used to evaluate the quality of motor activity during 10-second epochs over the three conditions. Results: Seventy-five percent of the fetuses at the 26 week assessment and 100% of the fetuses at the 36 week assessment responded with movement immediately following stimulation. Significant differences in head, fetal breathing, general, limb, and mouthing movements were detected between the 26 week and 36 week assessments. Movement differences between conditions were detected in head, fetal breathing, limb, and mouthing movements. Conclusions: Smoother and more complex movement was observed with fetal maturation. Following VAS stimulation, an immediate increase of large, jerky movements suggest instability in fetal capabilities. Fetal movement quality changes over gestation may reflect sensorimotor synaptogenesis in the central nervous system, while observation of immature movement patterns following VAS stimulation may reflect movement pattern instability.

  20. Abnormal response to photic stimulation in juvenile myoclonic epilepsy: an EEG-fMRI study.

    Science.gov (United States)

    Bartolini, Emanuele; Pesaresi, Ilaria; Fabbri, Serena; Cecchi, Paolo; Giorgi, Filippo Sean; Sartucci, Ferdinando; Bonuccelli, Ubaldo; Cosottini, Mirco

    2014-07-01

    Juvenile myoclonic epilepsy (JME) is a young-onset electroclinical syndrome, characterized by myoclonic, generalized tonic-clonic, and possibly typical absence seizures. Interictal electroencephalography (EEG) displays 3-6 Hz spike/polyspike and wave pattern. Photosensitivity is common. Our aim was to explore the blood oxygen level-dependent (BOLD) response evoked by a highly provocative photic stimulus in a cohort of people with JME compared to a group of nonphotosensitive healthy controls, and to investigate the hemodynamic phenomena seen in patients with photosensitive JME. We studied 13 JME patients and 18 healthy controls using EEG-functional magnetic resonance imaging (fMRI) performed during low luminance intermittent photic stimulation (IPS). The BOLD response to IPS was investigated both in JME and control groups. In photosensitive JME subjects, we also performed a dynamic evaluation of BOLD signal changes evoked by the photoparoxysmal response (PPR) in a time frame ranging from 10 s before the onset of the EEG paroxysm up until 10 s afterward. The IPS evoked a positive BOLD response in striate and extrastriate visual areas, which was less in JME patients than in controls. Moreover, people with JME had a reduced positive BOLD response in the frontoparietal areas and putamen but a stronger negative BOLD response in the primary sensorimotor cortex (SM1) and in cortical regions belonging to the default mode network (DMN). In JME, the dynamic evaluation of BOLD signal changes related to PPR revealed an early positive response in the putamen and SM1, followed by BOLD signal decrements in the putamen, caudate nuclei, thalami, and SM1. Our results confirm the hypothesis that people with JME might have an altered interaction between the motor circuit and other neuronal networks, with prominent involvement of basal ganglia circuitry. The PPR could be a final expression of pathogenic phenomena occurring in the striato-thalamocortical system, possibly a core feature

  1. Effects of age and caloric restriction in the vascular response of renal arteries to endothelin-1 in rats.

    Science.gov (United States)

    Amor, Sara; García-Villalón, Angel Luis; Rubio, Carmen; Carrascosa, Jose Ma; Monge, Luis; Fernández, Nuria; Martín-Carro, Beatriz; Granado, Miriam

    2017-02-01

    Cardiovascular alterations are the most prevalent cause of impaired physiological function in aged individuals with kidney being one the most affected organs. Aging-induced alterations in renal circulation are associated with a decrease in endothelium-derived relaxing factors such as nitric oxide (NO) and with an increase in contracting factors such as endothelin-1(ET-1). As caloric restriction (CR) exerts beneficial effects preventing some of the aging-induced alterations in cardiovascular system, the aim of this study was to analyze the effects of age and caloric restriction in the vascular response of renal arteries to ET-1 in aged rats. Vascular function was studied in renal arteries from 3-month-old Wistar rats fed ad libitum (3m) and in renal arteries from 8-and 24-month-old Wistar rats fed ad libitum (8m and 24m), or subjected to 20% caloric restriction during their three last months of life (8m-CR and 24m-CR). The contractile response to ET-1 was increased in renal arteries from 8m and 24m compared to 3m rats. ET-1-induced contraction was mediated by ET-A receptors in all experimental groups and also by ET-B receptors in 24m rats. Caloric restriction attenuated the increased contraction to ET-1 in renal arteries from 8m but not from 24m rats possibly through NO release proceeding from ET-B endothelial receptors. In 24m rats, CR did not attenuate the aging-increased response of renal arteries to ET-1, but it prevented the aging-induced increase in iNOS mRNA levels and the aging-induced decrease in eNOS mRNA levels in arterial tissue. In conclusion, aging is associated with an increased response to ET-1 in renal arteries that is prevented by CR in 8m but not in 24m rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Acute effect of Vagus nerve stimulation parameters on cardiac chronotropic, inotropic, and dromotropic responses

    Science.gov (United States)

    Ojeda, David; Le Rolle, Virginie; Romero-Ugalde, Hector M.; Gallet, Clément; Bonnet, Jean-Luc; Henry, Christine; Bel, Alain; Mabo, Philippe; Carrault, Guy; Hernández, Alfredo I.

    2017-11-01

    Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy and depression, and is considered as a potential therapy for other pathologies, including Heart Failure (HF) or inflammatory diseases. In the case of HF, several experimental studies on animals have shown an improvement in the cardiac function and a reverse remodeling of the cardiac cavity when VNS is applied. However, recent clinical trials have not been able to reproduce the same response in humans. One of the hypothesis to explain this lack of response is related to the way in which stimulation parameters are defined. The combined effect of VNS parameters is still poorly-known, especially in the case of VNS synchronously delivered with cardiac activity. In this paper, we propose a methodology to analyze the acute cardiovascular effects of VNS parameters individually, as well as their interactive effects. A Latin hypercube sampling method was applied to design a uniform experimental plan. Data gathered from this experimental plan was used to produce a Gaussian process regression (GPR) model in order to estimate unobserved VNS sequences. Finally, a Morris screening sensitivity analysis method was applied to each obtained GPR model. Results highlight dominant effects of pulse current, pulse width and number of pulses over frequency and delay and, more importantly, the degree of interactions between these parameters on the most important acute cardiovascular responses. In particular, high interacting effects between current and pulse width were found. Similar sensitivity profiles were observed for chronotropic, dromotropic and inotropic effects. These findings are of primary importance for the future development of closed-loop, personalized neuromodulator technologies.

  3. Salivary alpha-amylase and cortisol responsiveness following electrically stimulated physical stress in bipolar disorder patients

    Directory of Open Access Journals (Sweden)

    Tanaka Y

    2013-12-01

    Full Text Available Yoshihiro Tanaka, Yoshihiro Maruyama, Yoshinobu Ishitobi, Aimi Kawano, Tomoko Ando, Rie Ikeda, Ayako Inoue, Junko Imanaga, Shizuko Okamoto, Masayuki Kanehisa, Taiga Ninomiya, Jusen Tsuru, Jotaro Akiyoshi Department of Neuropsychiatry, Faculty of Medicine, Oita University, Hasama-Machi, Oita, Japan Background: Bipolar disorder (BP is often associated with a change in hypothalamus–pituitary–adrenal axis function change due to chronic stress. Salivary α-amylase (sAA levels increase in response to psychosocial stress and thus function as a marker of sympathoadrenal medullary system activity. However, sAA has been studied less often than salivary cortisol in BP patients. Method: We measured Profile of Mood States and State-Trait Anxiety Inventory scores, heart rate variability, and salivary cortisol levels during electrical stimulation stress in 25 BP patients and 22 healthy volunteers. Results: Tension–anxiety, depression–dejection, anger–hostility, fatigue, and confusion scores in BP patients significantly increased compared with those of the healthy controls. In contrast, the vigor scores of BP patients significantly decreased compared with those of the healthy controls. Significant difference in the sAA levels was observed between BP patients and healthy controls. sAA of female patients was significantly higher than that of female healthy controls, and sAA in male patients tended to be higher than that of male healthy controls. No difference in salivary cortisol was observed between BP patients and the healthy controls. Only three time points were measured before and after the electrical stimulation stress. Furthermore, sAA secretion by BP patients increased before and after electrical stimulation. Conclusion: These preliminary results suggest that sAA may be a useful biological marker for BP patients. Keywords: HPA axis, bipolar disorder, α-amylase, cortisol, SAM activity

  4. Functional response of cerebral blood flow induced by somatosensory stimulation in rats with subarachnoid hemorrhage

    Science.gov (United States)

    Li, Zhiguo; Huang, Qin; Liu, Peng; Li, Pengcheng; Ma, Lianting; Lu, Jinling

    2015-09-01

    Subarachnoid hemorrhage (SAH) is often accompanied by cerebral vasospasm (CVS), which is the phenomenon of narrowing of large cerebral arteries, and then can produce delayed ischemic neurological deficit (DIND) such as lateralized sensory dysfunction. CVS was regarded as a major contributor to DIND in patients with SAH. However, therapy for preventing vasospasm after SAH to improve the outcomes may not work all the time. It is important to find answers to the relationship between CVS and DIND after SAH. How local cerebral blood flow (CBF) is regulated during functional activation after SAH still remains poorly understood, whereas, the regulation of CBF may play an important role in weakening the impact of CVS on cortex function. Therefore, it is worthwhile to evaluate the functional response of CBF in the activated cortex in an SAH animal model. Most evaluation of the effect of SAH is presently carried out by neurological behavioral scales. The functional imaging of cortical activation during sensory stimulation may help to reflect the function of the somatosensory cortex more locally than the behavioral scales do. We investigated the functional response of CBF in the somatosensory cortex induced by an electrical stimulation to contralateral forepaw via laser speckle imaging in a rat SAH model. Nineteen Sprague-Dawley rats from two groups (control group, n=10 and SAH group, n=9) were studied. SAH was induced in rats by double injection of autologous blood into the cisterna magna after CSF aspiration. The same surgical procedure was applied in the control group without CSF aspiration or blood injection. Significant CVS was found in the SAH group. Meanwhile, we observed a delayed peak of CBF response in rats with SAH compared with those in the control group, whereas no significant difference was found in magnitude, duration, and areas under curve of relative CBF changes between the two groups. The results suggest that the regulation function of local CBF during

  5. MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

    DEFF Research Database (Denmark)

    Schlosser, Anders; Pilecki, Bartosz; Hemstra, Line E

    2016-01-01

    OBJECTIVE: Arterial injury stimulates remodeling responses that, when excessive, lead to stenosis. These responses are influenced by integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand localized to extracellular matrix fibers...

  6. Human cutaneous vascular responses to whole-body tilting, Gz centrifugation, and LBNP

    Science.gov (United States)

    Watenpaugh, Donald E.; Breit, Gregory A.; Buckley, Theresa M.; Ballard, Richard E.; Murthy, Gita; Hargens, Alan R.

    2004-01-01

    We hypothesized that gravitational stimuli elicit cardiovascular responses in the following order with gravitational stress equalized at the level of the feet, from lowest to highest response: short-(SAC) and long-arm centrifugation (LAC), tilt, and lower body negative pressure (LBNP). Up to 15 healthy subjects underwent graded application of the four stimuli. Laser-Doppler flowmetry measured regional skin blood flow. At 0.6 G(z) (60 mmHg LBNP), tilt and LBNP similarly reduced leg skin blood flow to approximately 36% of supine baseline levels. Flow increased back toward baseline levels at 80-100 mmHg LBNP yet remained stable during 0.8-1.0 G(z) tilt. Centrifugation usually produced less leg vasoconstriction than tilt or LBNP. Surprisingly, SAC and LAC did not differ significantly. Thigh responses were less definitive than leg responses. No gravitational vasoconstriction occurred in the neck. All conditions except SAC increased heart rate, according to our hypothesized order. LBNP may be a more effective and practical means of simulating cardiovascular effects of gravity than centrifugation.

  7. Cerebral blood flow and vascular response to hypercapnia in hypertensive patients with leukoaraiosis

    International Nuclear Information System (INIS)

    Kuwabara, Yasuo; Ichiya, Yuichi; Sasaki, Masayuki; Yoshida, Tsuyoshi; Fukumura, Toshimitsu; Masuda, Kouji; Ibayashi, Setsuro; Fujishima, Masatoshi

    1996-01-01

    Both arteriosclerosis and leukoaraiosis have a close relationship with hypertension, but the relationship between cerebral hemodynamics and leukoaraiosis in hypertensive patients has not been fully examined. To clarify this issue, we measured the regional cerebral blood flow (rCBF) and cerebrovascular response to hypercapnia in hypertensive patients with various degrees of leukoaraiosis. The subjects consisted of 7 normotensive normal controls and 17 hypertensive patients. The hypertensive patients were divided into three groups according to the severity of white matter lesions (leukoaraiosis) on MRI and the presence of dementia, namely, negative or mild leukoaraiosis without dementia, moderate to severe leukoaraiosis without dementia and severe leukoaraiosis with dementia. Both the rCBF and the cerebrovascular response to hypercapnia were measured by the O-15 H 2 O bolus-injection method and positron emission tomography. The rCBF in hypertensive patients without dementia did not decrease when compared with the normotensive controls, but the rCBF in hypertensive patients with dementia markedly decreased in the cerebral cortices and white matter. On the other hand, the cerebrovascular response to hypercapnia declined with the severity of leukoaraiosis, and it decreased most severely in patients with severe leukoaraiosis and dementia. Our results indicate that the reduction in the cerebral hemodynamic reserve capacity has a close relationship with the severity of leukoaraiosis in hypertensive patients, although the rCBF is maintained in hypertensive patients without dementia, and suggest that arteriosclerotic change reduces cerebrovascular CO 2 response and causes a leukoaraiosis in hypertensive patients. (author)

  8. The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies

    Directory of Open Access Journals (Sweden)

    Lucia M Li

    2015-05-01

    Full Text Available There has been an explosion of research using transcranial direct current stimulation (tDCS for investigating and modulating human cognitive and motor function in healthy populations. It has also been used in many studies seeking to improve deficits in disease populations. With the slew of studies reporting ‘promising results’ for everything from motor recovery after stroke to boosting memory function, one could be easily seduced by the idea of tDCS being the next panacea for all neurological ills. However, huge variability exists in the reported effects of tDCS, with great variability in the effect sizes and even contradictory results reported. In this review, we consider the interindividual factors that may contribute to this variability. In particular, we discuss the importance of baseline neuronal state and features, anatomy, age and the inherent variability in the injured brain. We additionally consider how interindividual variability affects the results of motor evoked potential (MEP testing with transcranial magnetic stimulation (TMS, which, in turn, can lead to apparent variability in response to tDCS in motor studies.

  9. A Novel Approach for Responsive Neural Stimulator Implantation With Infraclavicular Placement of the Internal Pulse Generator.

    Science.gov (United States)

    Philipp, Lucas R; Witcher, Mark R; Gross, Robert E

    2018-03-14

    The Responsive Neurostimulation System (RNS, Neuropace, Mountain View, California) has been proven to be effective at reducing seizures in patients with partial-onset epilepsy. The system incorporates a skull-mounted neurostimulator that requires a cranial incision for replacement. Although integral to the functioning of the system, in some circumstances, such as in the setting of infection, this can be disadvantageous. At present, there are no alternatives to cranial implantation of the RNS System. We describe a novel procedure enabling implantation of the neurostimulator within the chest wall, using components from a peripheral nerve stimulator. In a patient who achieved complete seizure freedom with the use of the RNS System, distant site implantation provided a viable means of continuing therapy in a setting where device explantation would have otherwise been inevitable as a result of cranial infection. We present continuous electrocorticographic data recorded from the device documenting the performance of the system with the subclavicular neurostimulator. Band pass detection rates increased by 50%, while line length detection rates decreased by 50%. The number of detections decreased from 1046 to 846, with a resultant decrease in stimulations. Although there was some compromise of function due to the elevated noise floor, more than 2 yr following the procedure the patient remains free of seizures and infection. The salvage procedure we describe offered an alternative therapeutic option in a patient with a complicated cranial wound issue, using heterogeneous components with marginal compromises in device functionality and no sacrifice in patient outcome.

  10. Erythropoiesis in the aged mouse. II. Response to stimulation in vitro

    International Nuclear Information System (INIS)

    Udupa, K.B.; Lipschitz, D.A.

    1984-01-01

    In this study, in vitro evidence is presented that erythropoietic precursors in aged mice respond less to stimulation by erythropoietin than do precursors in young mice. The effect of age on proliferation of differentiated erythroid cells from the marrow of young and old mice was examined in liquid culture to which increasing concentrations of erythropoietin were added. Cellular proliferation was measured indirectly by 59 Fe incorporation into heme and directly as tritiated thymidine incorporation into DNA. The number of normoblasts remaining in culture with and without the addition of erythropoietin was also measured. In each case, cellular proliferation was significantly lower in marrow in old than in young mice. In contrast, CFU-E colonies cultured with increasing doses of erythropoietin were similar in young and old animals. These findings indicate that aging causes a reduction in the proliferative response of differentiated erythroid cells. Failure of these cells to respond to stimulation is the likely mechanism for the reduced erythropoietic proliferative capacity found in aged animals

  11. The Role of Erbin in GTS-21 Regulating Inflammtory Responses in MDP-Stimulated Macrophages.

    Science.gov (United States)

    Wu, Xiao-Jing; Yang, Xu-Ming; Song, Xue-Min; Xu, Yang; Li, Jian-Guo; Wang, Yan-Lin; Zhang, Zong-Ze; Le, Lin-Li; Liang, Hui; Zhang, Yin

    2017-05-01

    To explore the role of Erbin protein and nucleotide-binding oligomerization domain 2/receptor-interacting serine/threonine protein kinases (NOD2/RICK) in GTS-21 activating cholinergic anti-inflammatory pathway. Experiments were randomly divided into four groups: normal control (NC) group, muramyl dipeptide (MDP) group, 10 μg/mL MDP, GTS-21 (GTS) group, 10 μg/mL MDP plus 50 μg/mL GTS-21 (α7 nAChRs agonist), Erbin shRNA interference (sh-Erbin) group: sh-Erbin RNA plus 10 μg/mL MDP and 50 μg/mL GTS-21. We extract specimens at the point of 1, 6, and 24 h after stimulation of MDP in Raw264.7 macrophages. After stimulation of MDP, the NLR2 mRNA, RICK and Erbin protein, nuclear factor (NF)-κB activity, the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and HMGB1 were significantly increased in MDP group (P MDP group, the NLR2 mRNA, RICK, NF-κB, TNF-α, and HMGB1 were significantly decreased, but the Erbin was increased in GTS group (P MDP-induced pro-inflammatory cytokines responses via activating cholinergic anti-inflammatory pathway, and the Erbin might be the key negative regulatory protein in NLR2/RICK signal transduction.

  12. Differences in salivary alpha-amylase and cortisol responsiveness following exposure to electrical stimulation versus the Trier Social Stress Tests.

    Directory of Open Access Journals (Sweden)

    Yoshihiro Maruyama

    Full Text Available BACKGROUND: Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM system. PRINCIPAL FINDINGS: We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S and Trait (STAI-T versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations, while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation. CONCLUSIONS: These preliminary results suggest that the HPA axis (but not the SAM

  13. Vascular Cures

    Science.gov (United States)

    ... vascular disease, such as stroke, aneurysm and pulmonary artery disease. Each one has their own unique story about their battle with vascular disease and their road to recovery. SEE PATIENT STORIES Our Supporters Caring ...

  14. Network effects of subthalamic deep brain stimulation drive a unique mixture of responses in basal ganglia output

    OpenAIRE

    Humphries, Mark D.; Gurney, Kevin

    2012-01-01

    Deep brain stimulation (DBS) is a remarkably successful treatment for the motor symptoms of Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN) within the basal ganglia is a main clinical target, but the physiological mechanisms of therapeutic STN DBS at the cellular and network level are unclear. We set out to begin to address the hypothesis that a mixture of responses in the basal ganglia output nuclei, combining regularized firing and inhibition, is a key contr...

  15. Dynamic stereotypic responses of basal ganglia neurons to subthalamic nucleus high frequency stimulation in the parkinsonian primate

    Directory of Open Access Journals (Sweden)

    Anan eMoran

    2011-04-01

    Full Text Available Deep brain stimulation in the subthalamic nucleus (STN is a well-established therapy for patients with severe Parkinson‟s disease (PD; however, its mechanism of action is still unclear. In this study we explored static and dynamic activation patterns in the basal ganglia during high frequency macro-stimulation of the STN. Extracellular multi-electrode recordings were performed in primates rendered parkinsonian using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Recordings were preformed simultaneously in the STN and the globus pallidus externus and internus. Single units were recorded preceding and during the stimulation. During the stimulation, STN mean firing rate dropped significantly, while pallidal mean firing rates did not change significantly. The vast majority of neurons across all three nuclei displayed stimulation driven modulations, which were stereotypic within each nucleus but differed across nuclei. The predominant response pattern of STN neurons was somatic inhibition. However, most pallidal neurons demonstrated synaptic activation patterns. A minority of neurons across all nuclei displayed axonal activation. Temporal dynamics were observed in the response to stimulation over the first 10 seconds in the STN and over the first 30 seconds in the pallidum. In both pallidal segments, the synaptic activation response patterns underwent delay and decay of the magnitude of the peak response due to short term synaptic depression. We suggest that during STN macro stimulation the STN goes through a functional ablation as its upper bound on information transmission drops significantly. This notion is further supported by the evident dissociation between the stimulation driven pre-synaptic STN somatic inhibition and the post-synaptic axonal activation of its downstream targets. Thus, basal ganglia output maintains its firing rate while losing the deleterious effect of the STN. This may be a part of the mechanism leading to the beneficial

  16. Reproductive organ and vascular specific promoter of the rice plasma membrane Ca2+ATPase mediates environmental stress responses in plants.

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    Kazi Md Kamrul Huda

    Full Text Available Plasma membrane Ca(2+ATPase is a transport protein in the plasma membrane of cells and helps in removal of calcium (Ca(2+ from the cell, hence regulating Ca(2+ level within cells. Though plant Ca(2+ATPases have been shown to be involved in plant stress responses but their promoter regions have not been well studied.The 1478 bp promoter sequence of rice plasma membrane Ca(2+ATPase contains cis-acting elements responsive to stresses and plant hormones. To identify the functional region, serial deletions of the promoter were fused with the GUS sequence and four constructs were obtained. These were differentially activated under NaCl, PEG cold, methyl viologen, abscisic acid and methyl jasmonate treatments. We demonstrated that the rice plasma membrane Ca(2+ATPase promoter is responsible for vascular-specific and multiple stress-inducible gene expression. Only full-length promoter showed specific GUS expression under stress conditions in floral parts. High GUS activity was observed in roots with all the promoter constructs. The -1478 to -886 bp flanking region responded well upon treatment with salt and drought. Only the full-length promoter presented cold-induced GUS expression in leaves, while in shoots slight expression was observed for -1210 and -886 bp flanking region. The -1210 bp deletion significantly responded to exogenous methyl viologen and abscisic acid induction. The -1210 and -886 bp flanking region resulted in increased GUS activity in leaves under methyl jasmonate treatments, whereas in shoots the -886 bp and -519 bp deletion gave higher expression. Salicylic acid failed to induce GUS activities in leaves for all the constructs.The rice plasma membrane Ca(2+ATPase promoter is a reproductive organ-specific as well as vascular-specific. This promoter contains drought, salt, cold, methyl viologen, abscisic acid and methyl jasmonate related cis-elements, which regulated gene expression. Overall, the tissue-specificity and inducible

  17. An LPS based method to stimulate the inflammatory response in growing rabbits

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    C. Knudsen

    2016-03-01

    Full Text Available Reliable indicators are needed to study the relationship between the inflammatory response of the growing rabbit and breeding factors such as feeding practices. A lipopolysaccharide (LPS stimulation of the inflammatory response is a valid model of bacterial infection in laboratory animals, but no data on the growing rabbit has yet been obtained. The aim of our study was to determine an adequate dose of LPS to inject in growing rabbits in order to elicit a measurable inflammatory response in terms of plasmatic TNF-α and rise in rectal temperature. Three trials were carried out in this study: 2 development trials, the first (n=18 testing 3 doses of LPS (2, 10, 50 μg/kg on the plasmatic TNF-α concentration at 90 and 180 min post injection, and the second trial (n=36 testing 4 doses of LPS (50, 75, 100 and 150 μg/kg on the TNF-α concentration 90 min post injection and the rectal temperature. The third trial was designed as an application of the method in a large number of animals (n=32 to study the effect of feed restriction and dietary increase in digestible fibre to starch ratio on the LPS inflammatory challenge response of growing rabbits. In development trials 1 and 2, animals had measurable TNF-α responses for doses higher than 10 μg/kg at 90 min post injection, with an increase in the number of responsive animals along with the dose. High variability was observed in TNF-α concentrations in responsive animals (coefficient of variation from 44 to 94%. Animals demonstrated an increase in rectal temperature for all doses injected in the range of 50-150 μg/kg from 90 min post injection with a peak at 180 min (ΔTr =1.9±0.7°C. Our observations led us to choose a dose of 100 μg/kg of LPS for our following studies, as the responses in terms of temperature and TNF-α were the most satisfactory. The application of our LPS injection protocol to our nutritional study enabled us to validate our protocol (ΔTr =1.1±0.7°C at 180 min and 15

  18. Effects of chloride channel blockers on rat renal vascular responses to angiotensin II and norepinephrine

    DEFF Research Database (Denmark)

    Steendahl, Joen; Sørensen, Charlotte Mehlin; Salomonsson, Max

    2003-01-01

    -[(2-cyclopentenyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid (IAA-94; 0.045 and 0.09 micromol/min) did not affect the vasoconstrictive responses of these compounds. Pretreatment with niflumic acid (50 microM) or IAA-94 (30 microM) for 2 min decreased baseline [Ca2+]i but did not change...

  19. Evasion of Cytosolic DNA-Stimulated Innate Immune Responses by Herpes Simplex Virus 1.

    Science.gov (United States)

    Zheng, Chunfu

    2018-03-15

    Recognition of virus-derived nucleic acids by host pattern recognition receptors (PRRs) is crucial for early defense against viral infections. Recent studies revealed that PRRs also include several newly identified DNA sensors, most of which could activate the downstream adaptor stimulator of interferon genes (STING) and lead to the production of host antiviral factors. Herpes simplex virus 1 (HSV-1) is extremely successful in establishing effective infections, due to its capacity to counteract host innate antiviral responses. In this Gem, I summarize the most recent findings on the molecular mechanisms utilized by HSV-1 to target different steps of the cellular DNA-sensor-mediated antiviral signal pathway. Copyright © 2018 American Society for Microbiology.

  20. Cerebral Asymmetry of fMRI-BOLD Responses to Visual Stimulation

    DEFF Research Database (Denmark)

    Hougaard, Anders; Jensen, Bettina Hagström; Amin, Faisal Mohammad

    2015-01-01

    was correlated with subject age, suggesting a shift towards the left hemisphere with increasing age. Our findings suggest a right-hemispheric dominance of these areas, which could lend support to the generally observed leftward visual attentional bias and to the left hemifield advantage for some visual......Hemispheric asymmetry of a wide range of functions is a hallmark of the human brain. The visual system has traditionally been thought of as symmetrically distributed in the brain, but a growing body of evidence has challenged this view. Some highly specific visual tasks have been shown to depend...... on hemispheric specialization. However, the possible lateralization of cerebral responses to a simple checkerboard visual stimulation has not been a focus of previous studies. To investigate this, we performed two sessions of blood-oxygenation level dependent (BOLD) functional magnetic resonance imaging (f...

  1. Evaluation of laser treatment response of vascular skin disorders in relation to skin properties using multi-spectral imaging

    Science.gov (United States)

    de Roode, Rowland; Noordmans, Herke Jan; Rem, Alex; Couwenberg, Sharon; Verdaasdonk, Rudolf

    2008-02-01

    There can be a large variation in response between laser treatments of vascular malformations like port-wine stains even in one patient. This could be ascribed to variations in the skin properties like tint (melanin) and perfusion (redness) which will influence the effectiveness of the laser dosimetry. To obtain a better understanding of the relation between skin properties just before treatment, laser dosimetry and clinical response, a multi-spectral dermatoscope is applied. A sequence of calibrated images is captured from 400 to 720 nm. Images at the treatment laser wavelength (532 nm) show the absorbing structures during laser exposure. Images of different treatment sessions of one patient were matched with dedicated registration software to quantify the results of the laser treatment (change in blood vessels structure, effect on pigment). For feasibility, images were collected from 5 patients and used to determine the optimal wavelength combination strategies. The image matching software gives an objective impression of the improvement, e.g. the clearing of the port-wine stain over time or pigment reactions, which will facilitate the discussion with the patient about the end point of treatment. The multi-spectral dermatoscope and software developed enables the evaluation of large patient series which will result in objective data to advise the dermatologist on the optimal laser dosimetry in future in relation to the skin properties.

  2. Cytoprotective response induced by electromagnetic stimulation on SH-SY5Y human neuroblastoma cell line.

    Science.gov (United States)

    Osera, Cecilia; Fassina, Lorenzo; Amadio, Marialaura; Venturini, Letizia; Buoso, Erica; Magenes, Giovanni; Govoni, Stefano; Ricevuti, Giovanni; Pascale, Alessia

    2011-10-01

    It is well known that physiological functions and pathological conditions of cells and tissues can be influenced not only by chemical molecules, but also by physical stimuli such as electromagnetic waves. In particular, epidemiological studies suggest possible associations between exposure to electromagnetic fields and an increased risk of tumors and neurodegenerative disorders, such as Alzheimer's disease. However, depending on the dose and on the length of treatment, the electromagnetic stimuli can be harmful or induce a cytoprotective cellular response, suggesting a possible application in medical therapy. In this study, under a tissue engineering viewpoint, we investigated the effects of an electromagnetic wave (magnetic field intensity, 2 mT; frequency, 75 Hz) on a neuronal cellular model characterized by the overexpression of the amyloid precursor protein (APP). After a prolonged electromagnetic treatment, lower mitochondrial activity and proliferation rate, resulting in a higher cellular quiescence, were observed. Focusing on the stress and oxidative pathways, we detected an overall increase of two fundamental proteins, the chaperone heat shock protein HSP70 and the free radical scavenger superoxide dismutase-1 enzyme (SOD-1). Interestingly, we found that the electromagnetic stimulation promotes the nonamyloidogenic processing of APP through an increased expression of the α-secretase ADAM10 and an enhanced release of the soluble neurotrophic factor sAPPα (a product of the ADAM10-mediated cleavage of APP). In conclusion, these findings suggest that the electromagnetic stimulus, if properly administered in terms of dose and timing, is able to induce a cytoprotective response in the cell. Moreover, these results suggest a possible use of this particular physical stimulation to improve the functional capability of the cells to face noxae. © Mary Ann Liebert, Inc.

  3. Effects of cranial electrotherapy stimulation on preoperative anxiety, pain and endocrine response.

    Science.gov (United States)

    Lee, Se-Hwa; Kim, Woon-Young; Lee, Chang-Hyung; Min, Too-Jae; Lee, Yoon-Sook; Kim, Jae-Hwan; Park, Young-Cheol

    2013-12-01

    Cranial electrotherapy stimulation (CES) is used as a treatment for depression and anxiety, and as an adjunctive intervention for pain management. This prospective study investigated whether CES could decrease preoperative anxiety, the injection pain of rocuronium, postoperative pain and stress hormone levels. Female patients undergoing thyroidectomy were randomly assigned to two groups, to receive either no pretreatment (control group) or CES pretreatment. Anxiety score, withdrawal response on rocuronium injection, and pain scores at 1, 4, 12 and 24 h post surgery were evaluated. Adrenocorticotrophic hormone (ACTH), cortisol and glucose levels were measured. Patients were blinded to the treatment condition. Fifty patients entered the study (n = 25 per group). Anxiety score and withdrawal responses during rocuronium injection were significantly reduced in the CES group compared with the control group. Pain score was significantly lower in the CES group than in the control group, 1 h and 4 h post surgery. There were no significant differences in ACTH, cortisol and glucose levels. CES pretreatment appears to reduce the level of preoperative anxiety, injection pain of rocuronium and postoperative pain. However, CES pretreatment did not affect stress hormone responses.

  4. Photoreactions in Phycomyces. Responses to the stimulation of narrow test areas with ultraviolet light.

    Science.gov (United States)

    DELBRUECK, M; VARJU, D

    1961-07-01

    Equipment has been developed for ultraviolet illumination of sharply bounded test areas of the growing zone of sporangiophores of Phycomyces. The growing zone is opaque for this light and the tropic responses are negative. Periodic short narrow stimuli on alternating sides produce periodic tropic responses when applied at x > 0.5 mm, but none for x 0.1 mm. The lag between stimulus and response is 3.3 min. for any x > 0.5 mm. For smaller x the lag increases progressively. In all cases the tropic bend occurs at values of x > 0.5 mm. Sustained tropic stimuli, applied at constant height relative to ground, produce relatively sharp tropic bends. The center of the bend is at all times close to the simultaneous position of the stimulated area. The boundaries of a light-adapted zone move less than 0.1 mm in 10 min. relative to the sporangium. It is concluded that the receiving and adapting structures do not move relative to the sporangium, and that the responding system does not move relative to ground. The two systems move relative to each other with the speed of growth. The responding system does not extend above x = 0.5 mm.

  5. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y [University of Michigan, Ann Arbor, MI (United States)

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  6. Individual differences in the effects of music engagement on responses to painful stimulation.

    Science.gov (United States)

    Bradshaw, David H; Donaldson, Gary W; Jacobson, Robert C; Nakamura, Yoshio; Chapman, C Richard

    2011-12-01

    Engaged attention, including music listening, has shown mixed results when used as a method for reducing pain. Applying the framework of constructivism, we extend the concept of engagement beyond attention/distraction to include all cognitive and emotional/motivational processes that may be recruited in order to construct an alternative experience to pain and thus reduce pain. Using a music-listening task varying in task demand, we collected stimulus-evoked potentials, pupil dilation, and skin conductance responses to noxious electrocutaneous stimulations as indicators of central and peripheral arousal, respectively. Trait anxiety (Spielberger State-Trait Anxiety Inventory) and absorption (Tellegen Absorption Scale) provided indicators of individual differences. One hundred and fifty-three healthy, normal volunteers participated in a test session in which they received 3 stimulus intensity levels while listening to background tones (No Task) or performing a music-listening task. Linear slopes indicating net engagement (change in stimulus arousal relative to task performance) decreased with increasing task demand and stimulus level for stimulus-evoked potentials. Slopes for pupil dilation response and skin conductance response varied with task demand, anxiety, and absorption, with the largest engagement effect occurring for high anxiety/high absorption participants. Music engagement reduces pain responses, but personality factors like anxiety and absorption modulate the magnitude of effect. Engaging in music listening can reduce responses to pain, depending on the person: people who are anxious and can become absorbed in activities easily may find music listening especially effective for relieving pain. Clinicians should consider patients' personality characteristics when recommending behavioral interventions like music listening for pain relief. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

  7. Rate of rise in diastolic blood pressure influences vascular sympathetic response to mental stress

    Science.gov (United States)

    El Sayed, Khadigeh; Macefield, Vaughan G.; Hissen, Sarah L.; Joyner, Michael J.

    2016-01-01

    Key points Research indicates that individuals may experience a rise (positive responders) or fall (negative responders) in muscle sympathetic nerve activity (MSNA) during mental stress.In this study, we examined the early blood pressure responses (including the peak, time of peak and rate of rise in blood pressure) to mental stress in positive and negative responders.Negative MSNA responders to mental stress exhibit a more rapid rise in diastolic pressure at the onset of the stressor, suggesting a baroreflex‐mediated suppression of MSNA. In positive responders there is a more sluggish rise in blood pressure during mental stress, which appears to be MSNA‐driven.This study suggests that whether MSNA has a role in the pressor response is dependent upon the reactivity of blood pressure early in the task. Abstract Research indicates that individuals may experience a rise (positive responders) or fall (negative responders) in muscle sympathetic nerve activity (MSNA) during mental stress. The aim was to examine the early blood pressure response to stress in positive and negative responders and thus its influence on the direction of change in MSNA. Blood pressure and MSNA were recorded continuously in 21 healthy young males during 2 min mental stressors (mental arithmetic, Stroop test) and physical stressors (cold pressor, handgrip exercise, post‐exercise ischaemia). Participants were classified as negative or positive responders according to the direction of the mean change in MSNA during the stressor tasks. The peak changes, time of peak and rate of changes in blood pressure were compared between groups. During mental arithmetic negative responders experienced a significantly greater rate of rise in diastolic blood pressure in the first minute of the task (1.3 ± 0.5 mmHg s−1) compared with positive responders (0.4 ± 0.1 mmHg s−1; P = 0.03). Similar results were found for the Stroop test. Physical tasks elicited robust parallel increases in blood

  8. Cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus in the rat: role of the hypothalamic paraventricular nucleus.

    Directory of Open Access Journals (Sweden)

    Tetsuya Kawabe

    Full Text Available The mechanism of cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus (ARCN was studied in urethane-anesthetized adult male Wistar rats. At the baseline mean arterial pressure (BLMAP close to normal, ARCN stimulation elicited decreases in MAP and sympathetic nerve activity (SNA. The decreases in MAP elicited by ARCN stimulation were attenuated by either gamma-aminobutyric acid (GABA, neuropeptide Y (NPY, or beta-endorphin receptor blockade in the ipsilateral hypothalamic paraventricular nucleus (PVN. Combined blockade of GABA-A, NPY1 and opioid receptors in the ipsilateral PVN converted the decreases in MAP and SNA to increases in these variables. Conversion of inhibitory effects on the MAP and SNA to excitatory effects following ARCN stimulation was also observed when the BLMAP was decreased to below normal levels by an infusion of sodium nitroprusside. The pressor and tachycardic responses to ARCN stimulation at below normal BLMAP were attenuated by blockade of melanocortin 3/4 (MC3/4 receptors in the ipsilateral PVN. Unilateral blockade of GABA-A receptors in the ARCN increased the BLMAP and heart rate (HR revealing tonic inhibition of the excitatory neurons in the ARCN. ARCN stimulation elicited tachycardia regardless of the level of BLMAP. ARCN neurons projecting to the PVN were immunoreactive for glutamic acid decarboxylase 67 (GAD67, NPY, and beta-endorphin. These results indicated that: 1 at normal BLMAP, decreases in MAP and SNA induced by ARCN stimulation were mediated via GABA-A, NPY1 and opioid receptors in the PVN, 2 lowering of BLMAP converted decreases in MAP following ARCN stimulation to increases in MAP, and 3 at below normal BLMAP, increases in MAP and HR induced by ARCN stimulation were mediated via MC3/4 receptors in the PVN. These results provide a base for future studies to explore the role of ARCN in cardiovascular diseases.

  9. Caffeine's Vascular Mechanisms of Action

    Directory of Open Access Journals (Sweden)

    Darío Echeverri

    2010-01-01

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

  10. Cortisol Response to Low-Dose (1 μg ACTH Stimulation for the Prediction of Outcome in Patients with Systemic Inflammatory Response Syndrome

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    Bjekić-Macut Jelica

    2016-10-01

    Full Text Available Background: Systemic inflammatory response syndrome (SIRS changes cortisol dynamics and indicates dissociation between the adrenal cortex and the hypothalamo-pituitary unit. The aim of this study was to assess the cortisol response after stimulation with ACTH1-24 in patients with SIRS at admission to the Respiratory Intensive Care Unit (RICU and seven days later.

  11. No maternal effects after stimulation of the melanization response in the yellow fever mosquito Aedes aegypti

    OpenAIRE

    Voordouw, Maarten J.; Lambrechts, Louis; Koella, Jacob

    2011-01-01

    The costs and benefits of activating the immune system can reach across generations. Thus, in vertebrates and in several invertebrates, stimulating the immune system of a female can enhance immunity of her offspring or decrease offspring fitness. We evaluated the potential maternally transmitted costs and benefits of the melanization response, an innate immune response of insects that helps to protect mosquitoes from malaria parasites. We manipulated the maternal melanization response of the ...

  12. Efficient generation of smooth muscle cells from adipose-derived stromal cells by 3D mechanical stimulation can substitute the use of growth factors in vascular tissue engineering.

    Science.gov (United States)

    Parvizi, Mojtaba; Bolhuis-Versteeg, Lydia A M; Poot, André A; Harmsen, Martin C

    2016-07-01

    Occluding artery disease causes a high demand for bioartificial replacement vessels. We investigated the combined use of biodegradable and creep-free poly (1,3-trimethylene carbonate) (PTMC) with smooth muscle cells (SMC) derived by biochemical or mechanical stimulation of adipose tissue-derived stromal cells (ASC) to engineer bioartificial arteries. Biochemical induction of cultured ASC to SMC was done with TGF-β1 for 7d. Phenotype and function were assessed by qRT-PCR, immunodetection and collagen contraction assays. The influence of mechanical stimulation on non-differentiated and pre-differentiated ASC, loaded in porous tubular PTMC scaffolds, was assessed after culturing under pulsatile flow for 14d. Assays included qRT-PCR, production of extracellular matrix and scanning electron microscopy. ASC adhesion and TGF-β1-driven differentiation to contractile SMC on PTMC did not differ from tissue culture polystyrene controls. Mesenchymal and SMC markers were increased compared to controls. Interestingly, pre-differentiated ASC had only marginal higher contractility than controls. Moreover, in 3D PTMC scaffolds, mechanical stimulation yielded well-aligned ASC-derived SMC which deposited ECM. Under the same conditions, pre-differentiated ASC-derived SMC maintained their SMC phenotype. Our results show that mechanical stimulation can replace TGF-β1 pre-stimulation to generate SMC from ASC and that pre-differentiated ASC keep their SMC phenotype with increased expression of SMC markers. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Vascular response to ischemia in the feet of falanga torture victims and normal controls--color and spectral Doppler findings.

    Science.gov (United States)

    Torp-Pedersen, Søren; Amris, Kirstine; Holm, Christian Cato; Kønig, Merete; Prip, Karen; Danneskiold-Samsøe, Bente

    2009-01-01

    To investigate whether signs of chronic compartment syndrome could be found in plantar muscles of falanga torture victims with painful feet and impaired gait. The hypothesis was that the muscular vascular response to two minutes ischemia would be decreased in torture victims compared to controls. On color Doppler this would be seen as less color after ischemia and on spectral Doppler as elevated resistive index (RI). Ten male torture victims from the Middle East and nine age, sex and ethnically matched controls underwent Doppler examination of the abductor hallucis and flexor digitorum brevis muscles before and after two minutes ischemia induced with a pressure cuff over the malleoli. The color Doppler findings were quantified with the color fraction (CF) before and after ischemia. On spectral Doppler the resistive index was measured once before and three consecutive times after ischemia. Both torture victims and controls responded to ischemia with an increased CF. There was no difference between torture victims and controls. With spectral Doppler all subjects had an RI of 1.0 before ischemia. After ischemia, in nearly all subjects and all muscles the first RI was lowest, the second was higher and the third was highest indicating that the response to ischemia was disappearing as measurements were made. There was a trend that the first RI was higher in torture victims than in controls. The study was not able to confirm the presence of chronic compartment syndrome. However, the trend in RI still supports the hypothesis. The negative findings may be due to inadequate design where the CF and RI were measured in one setting, perhaps resulting in both methods being applied imperfectly. The response to ischemia seems short-lived and we suggest that the Doppler methods may be re-evaluated with separate ischemic phases for CF and RI.

  14. Preclinical Evaluation of Radioiodinated Hoechst 33258 for Early Prediction of Tumor Response to Treatment of Vascular-Disrupting Agents

    Directory of Open Access Journals (Sweden)

    Dongjian Zhang

    2018-01-01

    Full Text Available This study aimed to explore the use of 131I-Hoechst 33258 (131I-H33258 for early prediction of tumor response to vascular-disrupting agents (VDAs with combretastatin-A4 phosphate (CA4P as a representative. Necrosis avidity of 131I-H33258 was evaluated in mouse models with muscle necrosis and blocking was used to confirm the tracer specificity. Therapy response was evaluated by 131I-H33258 SPECT/CT imaging 24 h after CA4P therapy in W256 tumor-bearing rats. Radiotracer uptake in tumors was validated ex vivo using γ-counting, autoradiography, and histopathological staining. Results showed that 131I-H33258 had predominant necrosis avidity and could specifically bind to necrotic tissue. SPECT/CT imaging demonstrated that an obvious “hot spot” could be observed in the CA4P-treated tumor. Ex vivo γ-counting revealed 131I-H33258 uptake in tumors was increased 2.8-fold in rats treated with CA4P relative to rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that 131I-H33258 was mainly localized in necrotic tumor area and the higher overall uptake in the treated tumors was attributed to the increased necrosis. These results suggest that 131I-H33258 can be used to image induction of cell necrosis 24 h after CA4P therapy, which support further molecular design of probes based on scaffold H33258 for monitoring of tumor response to VDAs treatment.

  15. Physiological responses to brain stimulation during limbic surgery: further evidence of anterior cingulate modulation of autonomic arousal.

    Science.gov (United States)

    Gentil, André Felix; Eskandar, Emad N; Marci, Carl David; Evans, Karleyton Conroy; Dougherty, Darin Dean

    2009-10-01

    In view of conflicting neuroimaging results regarding autonomic-specific activity within the anterior cingulate cortex (ACC), we investigated autonomic responses to direct brain stimulation during stereotactic limbic surgery. Skin conductance activity and accelerative heart rate responses to multi-voltage stimulation of the ACC (n = 7) and paralimbic subcaudate (n = 5) regions were recorded during bilateral anterior cingulotomy and bilateral subcaudate tractotomy (in patients that had previously received an adequate lesion in the ACC), respectively. Stimulations in both groups were accompanied by increased autonomic arousal. Skin conductance activity was significantly increased during ACC stimulations compared with paralimbic targets at 2 V (2.34 +/- .68 [score in microSiemens +/- SE] vs. .34 +/- .09, p = .013) and 3 V (3.52 +/- .86 vs. 1.12 +/- .37, p = .036), exhibiting a strong "voltage-response" relationship between stimulus magnitude and response amplitude (difference from 1 to 3 V = 1.15 +/- .90 vs. 3.52 +/- .86, p = .041). Heart rate response was less indicative of between-group differences. This is the first study of its kind aiming at seeking novel insights into the mechanisms responsible for central autonomic modulation. It supports a concept that interregional interactions account for the coordination of autonomic arousal.

  16. Repeated chlorpromazine administration increases a behavioural response of rats to 5-hydroxytryptamine receptor stimulation.

    Science.gov (United States)

    Green, A R

    1977-01-01

    1 The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by L-tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5-hydroxytryptamine (5-HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and L-tryptophan administration 24 h after the final dose of chlorpromazine. 2 One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/L-tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and L-tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose. 3 Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioral responses to the suggested 5-HT agonist 5-methoxy N,N-dimethyltryptamine (2 mg/kg) on day 5. 4 Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5-hydroxytryptamine (5-HT) concentration on day 5, but no difference in the rate of brain 5-HT synthesis or the rate of 5-HT accumulation after tranylcypromine and L-tryptophan administration. 5. There is some evidence that chlorpromazine blocks 5-HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5-HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5-HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5-HT receptors. PMID:264797

  17. The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses

    Science.gov (United States)

    Khan, Shaniya H.; Martin, Matthew D.; Starbeck-Miller, Gabriel R.; Xue, Hai-Hui; Harty, John T.; Badovinac, Vladimir P.

    2015-01-01

    Abstract Memory CD8 T cells provide protection to immune hosts by eliminating pathogen-infected cells during re-infection. While parameters influencing the generation of primary (1°) CD8 T cells are well established, the factors controlling the development of secondary (2°) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2° memory (M) CD8 T cells. We observed that the time at which 1° M CD8 T cells enter into immune response impacts their fate and differentiation into 2° M CD8 T cells. Late-entry of 1° M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2° effector CD8 T cells, but also influenced the ability of 2° M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1° M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2° effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2° CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2° CD8 T cell responses. Thus, our data suggest that the process of 1° M to 2° M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches. PMID:26431533

  18. Influence of vascular endothelial growth factor stimulation and serum deprivation on gene activation patterns of human adipose tissue-derived stromal cells

    DEFF Research Database (Denmark)

    Tratwal, Josefine; Mathiasen, Anders Bruun; Juhl, Morten

    2015-01-01

    stimulation is usually performed under serum deprivation. Potential regenerative molecular mechanisms are numerous and the role of contributing factors is uncertain. The aim of the current study was to investigate the effect of in vitro serum deprivation and VEGF stimulation on gene expression patterns......: Compared to ASCs in complete medium, 190 and 108 genes were significantly altered by serum deprivation and serum deprivation combined with VEGF, respectively. No significant differences in gene expression patterns between serum-deprived ASCs and serum-deprived ASCs combined with VEGF stimulation were found......, matricellular proteins and matrix metalloproteinases in concert, diverge from direct pro-angiogenic paracrine mechanisms as a primary consequence of the used protocol. In vitro serum starvation (with or without VEGF present) appears to favour cardioprotection, extracellular matrix remodelling and blood vessel...

  19. Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex.

    Science.gov (United States)

    Litvak, Vladimir; Komssi, Soile; Scherg, Michael; Hoechstetter, Karsten; Classen, Joseph; Zaaroor, Menashe; Pratt, Hillel; Kahkonen, Seppo

    2007-08-01

    Analyzing the brain responses to transcranial magnetic stimulation (TMS) using electroencephalography (EEG) is a promising method for the assessment of functional cortical connectivity and excitability of areas accessible to this stimulation. However, until now it has been difficult to analyze the EEG responses during the several tens of milliseconds immediately following the stimulus due to TMS-induced artifacts. In the present study we show that by combining a specially adapted recording system with software artifact correction it is possible to remove a major part of the artifact and analyze the cortical responses as early as 10 ms after TMS. We used this methodology to examine responses of left and right primary motor cortex (M1) to TMS at different intensities. Based on the artifact-corrected data we propose a model for the cortical activation following M1 stimulation. The model revealed the same basic response sequence for both hemispheres. A large part of the response could be accounted for by two sources: a source close to the stimulation site (peaking approximately 15 ms after the stimulus) and a midline frontal source ipsilateral to the stimulus (peaking approximately 25 ms). In addition the model suggests responses in ipsilateral temporo-parietal junction areas (approximately 35 ms) and ipsilateral (approximately 30 ms) and middle (approximately 50 ms) cerebellum. Statistical analysis revealed significant dependence on stimulation intensity for the ipsilateral midline frontal source. The methodology developed in the present study paves the way for the detailed study of early responses to TMS in a wide variety of brain areas.

  20. Mild salinity stimulates a stress-induced morphogenic response in Arabidopsis thaliana roots.

    Science.gov (United States)

    Zolla, Gaston; Heimer, Yair M; Barak, Simon

    2010-01-01

    Plant roots exhibit remarkable developmental plasticity in response to local soil conditions. It is shown here that mild salt stress stimulates a stress-induced morphogenic response (SIMR) in Arabidopsis thaliana roots characteristic of several other abiotic stresses: the proliferation of lateral roots (LRs) with a concomitant reduction in LR and primary root length. The LR proliferation component of the salt SIMR is dramatically enhanced by the transfer of seedlings from a low to a high NO3- medium, thereby compensating for the decreased LR length and maintaining overall LR surface area. Increased LR proliferation is specific to salt stress (osmotic stress alone has no stimulatory effect) and is due to the progression of more LR primordia from the pre-emergence to the emergence stage, in salt-stressed plants. In salt-stressed seedlings, greater numbers of LR primordia exhibit expression of a reporter gene driven by the auxin-sensitive DR5 promoter than in unstressed seedlings. Moreover, in the auxin transporter mutant aux1-7, the LR proliferation component of the salt SIMR is completely abrogated. The results suggest that salt stress promotes auxin accumulation in developing primordia thereby preventing their developmental arrest at the pre-emergence stage. Examination of ABA and ethylene mutants revealed that ABA synthesis and a factor involved in the ethylene signalling network also regulate the LR proliferation component of the salt SIMR.

  1. Pharmacological stimulation of nuclear factor (erythroid-derived 2)-like 2 translation activates antioxidant responses.

    Science.gov (United States)

    Perez-Leal, Oscar; Barrero, Carlos Alberto; Merali, Salim

    2017-08-25

    Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and post-translational levels. It is well-known that Nrf2 is regulated at the protein level by proteasomal degradation via Kelch-like ECH-associated protein 1 (Keap1), but how Nrf2 is regulated at the translational level is less clear. Here, we show that pharmacological stimulation increases Nrf2 levels by overcoming basal translational repression. We developed a novel reporter assay that enabled identification of natural compounds that induce Nrf2 translation by a mechanism independent of Keap1-mediated degradation. Apigenin, resveratrol, and piceatannol all induced Nrf2 translation. More importantly, the pharmacologically induced Nrf2 overcomes Keap1 regulation, translocates to the nucleus, and activates the antioxidant response. We conclude that translational regulation controls physiological levels of Nrf2, and this can be modulated by apigenin, resveratrol, and piceatannol. Also, targeting this mechanism with novel compounds could provide new insights into prevention and treatment of multiple diseases in which oxidative stress plays a significant role. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Brucella melitensis infection stimulates an immune response leading to Kikuchi-Fujimoto disease.

    Science.gov (United States)

    Charalabopoulos, Konstantin; Papalimneou, Vicky; Charalabopoulos, Alexander; Bai, Maria; Agnantis, Niki

    2003-01-01

    A 43-year-old Greek cattler with a history of brucellosis three months previously for which he was treated with sulfonamides for three weeks, was admitted to the hospital complaining of fever, arthralgias, night sweats, painful cervical and axillary lymph nodes as well as a weight loss of 8 kg in the previous four months. Since microbiological and serological studies did not give a specific diagnosis, an open cervical lymph node biopsy was performed. The histological examination revealed Kikuchi-Fujimoto disease. The etiology of the disease is unknown but viral, bacterial, protozoal and neoplastic as well as physicochemical agents may stimulate a particular immune response leading to Kikuchi-Fujimoto disease. Hereby, we present a case in which Kikuchi-Fujimoto disease followed brucella melitensis infection. This association permits us to hypothesize that the initial brucella melitensis infection three months previously triggered an immune response leading to Kikuchi-Fujimoto disease. The association of the disease with brucellosis is very important since these two entities share some similar characteristics, with brucellosis being relatively common in Europe. To our best knowledge, in the English language bibliography, this is the first reported case worldwide, though another similar case was described in the Spanish literature ten years ago.

  3. Response of optically stimulated luminescence dosimeters subjected to X-rays in diagnostic energy range

    International Nuclear Information System (INIS)

    Musa, Y; Hashim, S; Karim, M K A; Ang, W C; Salehhon, N; Bakar, K A

    2017-01-01

    The use of optically stimulated luminescence (OSL) for dosimetry applications has recently increased considerably due to availability of commercial OSL dosimeters (nanoDots) for clinical use. The OSL dosimeter has a great potential to be used in clinical dosimetry because of its prevailing advantages in both handling and application. However, utilising nanoDot OSLDs for dose measurement in diagnostic radiology can only be guaranteed when the performance and characteristics of the dosimeters are apposite. In the present work, we examined the response of commercially available nanoDot OSLD (Al 2 O 3 :C) subjected to X-rays in general radiography. The nanoDots response with respect to reproducibility, dose linearity and signal depletion were analysed using microStar reader (Landauer, Inc., Glenwood, IL). Irradiations were performed free-in-air using 70, 80 and 120 kV tube voltages and tube currents ranging from 10 – 100 mAs. The results showed that the nanoDots exhibit good linearity and reproducibility when subjected to diagnostic X-rays, with coefficient of variations (CV) ranging between 2.3% to 3.5% representing a good reproducibility. The results also indicated average of 1% signal reduction per readout. Hence, the nanoDots showed a promising potential for dose measurement in general X-ray procedure. (paper)

  4. Cardiovascular and metabolic responses during functional electric stimulation cycling at different cadences.

    Science.gov (United States)

    Fornusek, Ché; Davis, Glen M

    2008-04-01

    To determine the influence of pedaling cadence on cardiorespiratory responses and muscle oxygenation during functional electric stimulation (FES) leg cycling. Repeated measures. Laboratory. Nine subjects with T4 through T10 spinal cord injury (SCI) (American Spinal Injury Association grade A). FES cycling was performed at pedaling cadences of 15, 30, and 50 revolutions per minute (rpm). At each cadence, heart rate, oxygen uptake, and cardiac output were recorded during 35 minutes of cycling. Near infrared spectroscopy was used to quantify quadriceps muscle oxygenation. All pedaling cadences induced similar elevations in cardiorespiratory metabolism, compared with resting values. Higher average power output was produced at 30rpm (8.2+/-0.7W, P30 and 50rpm than at 15rpm. Quadriceps muscle oxygenation did not differ with pedaling cadences. Cardiorespiratory responses and muscle metabolism adjustments during FES leg cycling were independent of pedal cadence. FES cycling at a cadence of 50rpm may not confer any advantages over 30 or 15rpm for cardiovascular fitness promotion in persons with SCI.

  5. Amplitude-dependency of response of SI cortex to flutter stimulation

    Directory of Open Access Journals (Sweden)

    Whitsel Barry L

    2005-06-01

    Full Text Available Abstract Background It is established that increasing the amplitude of a flutter stimulus increases its perceived intensity. Although many studies have examined this phenomenon with regard to the responding afferent population, the way in which the intensity of a stimulus is coded in primary somatosensory cortex (SI remains unclear. Results Optical intrinsic signal (OIS imaging was used to study the evoked responses in SI of anesthetized squirrel monkeys by 25 Hz sinusoidal vertical skin displacement stimulation. Stimuli were 10 sec duration with a 50 sec inter-stimulus interval. Stimulus amplitude ranged from 50 to 400 microns and different amplitudes were interleaved. Control levels of activity were measured in the absence of stimulation, and used to compare with activation levels evoked by the different stimulus amplitudes. Stimulation of a discrete skin site on the forelimb evoked a prominent increase in absorbance within the forelimb representational region in cytoarchitectonic areas 3b and 1 of the contralateral hemisphere. An increase in stimulus amplitude led to a proportional increase in the magnitude of the absorbance increase in this region of areas 3b and 1 while surrounding cortex underwent a decrease in absorbance. Correlation maps revealed that as stimulus amplitude is increased, the spatial extent of the activated region in SI remains relatively constant, and the activity within this region increases progressively. Additionally, as stimulus amplitude is increased to suprathreshold levels, activity in the surround of the activated SI territory decreases, suggesting an increase in inhibition of neuronal activity within these regions. Conclusion Increasing the amplitude of a flutter stimulus leads to a proportional increase in absorbance within the forelimb representational region of SI. This most likely reflects an increase in the firing rate of neurons in this region of SI. The relatively constant spatial extent of this stimulus

  6. Effects of stimulation of muscarinic acetylcholine receptors in medial septum on some immune responses in rats.

    Science.gov (United States)

    Dutta, Goutam; Ghosh, Tusharkanti

    2016-04-21

    Though the immunomodulatory role of medial septum (MS) has been indicated, but the contribution of the muscarinic acetylcholine (mAch) receptors presented in the internal network of the neurons of MS in this regard is not known. The aim of the present study is to assess the contribution of mAch receptors of MS on some immunological parameters. Different immunological parameters i.e. phagocytic activity of peripheral leukocytes, adhesibility and cytotoxicity of splenic mononuclear cells (MNC), delayed type of hypersensitivity (DTH) responses, Total Count (TC) and Differential Count (DC) of WBC with serum corticosterone (CORT) concentration have been measured after stimulation and blocking of mAch receptors of MS in rats. Ach or atropine has been micro infused into MS of separate groups of rats for stimulating or blocking of the mAch receptors respectively. In Ach or atropine microinfused rats, the TC of WBC remained unaltered in the present study. The percentage of neutrophil has increased and the percentage of lymphocyte has decreased in Ach microinfused rats, but these parameters remain unaltered in atropine microinfused rats. The observed immunological parameters have increased after microinfusion of 0.60μM and 0.12μM of Ach and serum CORT concentration has decreased in those animals. These immunological parameters have decreased and serum CORT has increased after microinfusion of atropine (2 and 4mM) in MS of rats. It appears that the Ach receptors in MS can modulate the observed immunological parameters, and serum CORT plays an important role for these immune changes. Copyright © 2016. Published by Elsevier Ireland Ltd.

  7. Gastric Electrical Stimulation for Refractory Gastroparesis: Predictors of Response and Redefining a Successful Outcome

    Science.gov (United States)

    Richmond, Bryan; Chong, Benny; Modak, Asmita; Emmett, Mary; Knackstedt, Kimball; Dyer, Benjamin; Aburahma, Zachary

    2015-01-01

    Predictors of a favorable response and measures of success with gastric electrical stimulation (GES) for gastroparesis remain elusive. Published results remain inconsistent with respect to patient perceived benefit, despite statistical improvements in objective measures of symptom severity. We performed a retrospective analysis of 56 patients with gastroparesis who underwent insertion of a gastric electrical stimulator during the study period. Data included demographics, symptoms, total symptom severity score (TSS, range 0–24, initial and most recent), and gastric emptying times. TSS were grouped into four severity categories (0–10, 11–14, 15–18, 19–24). TSS improvement was defined as movement to a lower severity category. Perception of improvement was compared with that of TSS score improvement using χ2 test. Etiology as a predictor of improvement was measured using logistic regression. Initial mean TSS was 21, and post-treatment TSS was 13.5. Improvement was significant for individual symptoms and in reduction of TSS for both diabetic/idiopathic etiologies (P ≤ 0.001). No correlation was noted between likelihood of success/failure and gastric emptying times (P = 0.32). Thirty-eight improved (moved to lower TSS category), whereas 18 failed (remained in same category) (P ≤ 0.001), which correlated with perception of improvement. Of 18 failures, 14 (77.7%) were idiopathic. On logistic regression, diabetics were more likely than idiopathic patients to move to a lower TSS category (odds ratio 14, P = 0.003) and even more likely to improve based on patient perception (odds ratio 45, P = 0.005). GES produces far more consistent improvement in diabetics. Further study of GES in idiopathic gastroparesis is needed. Application of the proposed TSS severity categories allowed differentiation of small, statistically significant (but clinically insignificant) reductions in TSS from larger, clinically significant reductions, thereby permitting more reliable

  8. Activity-Dependent Calcium, Oxygen, and Vascular Responses in a Mouse Model of Familial Hemiplegic Migraine Type 1

    DEFF Research Database (Denmark)

    Khennouf, Lila; Gesslein, Bodil; Lind, Barbara Lykke

    2016-01-01

    it with assessment of local field potentials by electrophysiological recordings, cerebral blood flow by laser Doppler flowmetry, and oxygen consumption with measurement of the oxygen tissue tension. Results: During spreading depression, the evoked increase in cytosolic Ca2+ was larger and faster in FHM1 mice than...... wild-type (WT) mice. It was accompanied by larger increases in oxygen consumption in FHM1 mice, leading to tissue anoxia, but moderate hypoxia, in WT mice. In comparison, before CSD, Ca2+ and hemodynamic responses to somatosensory stimulations were smaller in FHM1 mice than WT mice and almost abolished...... after CSD. The CSD-induced Ca2+ changes were mitigated by the CaV2.1 gating modifier, tert-butyl dihydroquinone. Interpretation: Our findings suggest that tissue anoxia might be a mechanism for prolonged aura in FHM1. Reduced Ca2+ signals during normal network activity in FHM1 as compared to WT mice may...

  9. Abnormal retinal vascular oxygen tension response to light flicker in diabetic rats.

    Science.gov (United States)

    Blair, Norman P; Wanek, Justin M; Mori, Marek; Shahidi, Mahnaz

    2009-11-01

    To test the hypothesis that the intravascular oxygen response to light flicker is abnormal in diabetes. Ten eyes of normal rats and 10 eyes of rats made diabetic with streptozotocin were examined. Oxygen tension (PO(2)) was measured noninvasively in the retinal arteries and veins on optical section retinal images. PO(2) was estimated based on the quenching by oxygen of the phosphorescence of an intravenously injected palladium porphyrin molecular probe. Measurements were conducted with and without light flicker at 10 Hz. Oxygen saturation (SO(2)) was calculated with adjustment for the arterial pH. In the normal rats flicker induced an increase in arterial PO(2) and in the difference in arterial and venous (A-V difference) PO(2) from 51 +/- 5 (mean and SD) to 55 +/- 7 mm Hg and from 22 +/- 3 to 26 +/- 5 mm Hg, respectively (P Flicker induced an increase of arterial SO(2) and A-V SO(2) difference from 64% +/- 8% to 68% +/- 7% and from 34% +/- 4% to 38% +/- 6%, respectively (P flicker in the veins. In the diabetic rats, no significant flicker-induced changes were seen in PO(2) or SO(2) in the retinal arteries, veins, or A-V differences. The diabetic rats lacked the flicker induced increase in arterial PO(2) and SO(2) and also the A-V difference in PO(2) and SO(2) observed in the normal rats. The best explanation appeared to be that diabetes impairs the increase in oxygen consumption normally provoked by light flicker.

  10. Modification of vascular responsiveness to angiotensin II in pregnant women by intravenously infused 5alpha-dihydroprogesterone.

    Science.gov (United States)

    Everett, R B; Worley, R J; MacDonald, P C; Gant, N F

    1978-06-15

    In gravid women who are destined to develop pregnancy-induced hypertension (PIH), normal pregnancy-associated refractoriness to the pressor effects of administered angiotensin II (A-II) is lost several weeks before the onset of hypertension. From a study of the determinants of A-II pressor responsiveness in normal gravid women, it appears likely that the loss of resistance to A-II is principally unrelated to plasma renin activity or to plasma A-II levels. However, it recently has been shown that the vascular refractoriness to A-II in normal women can be reduced significantly by the administration of the prostaglandin synthetase inhibitors, indomethacin or aspirin. In seven women who had developed PIH and who had lost their refractoriness to A-II, the infusion of 5alpha-pregnan-3,20-dione (5alpha-DHP) was associated with restoration of refractoriness to the pressor effects of A-II. Moreover, in five normotensive gravid women beyond 28 weeks' gestation in whom the refractoriness to A-II was reduced by the administration of indomethacin, the intravenous infusion of 5alpha-DPH was associated with restoration of refractoriness to the pressor effects of A-II. These observations are consistent with the view that a progesterone metabolite(s) may be important in the maintenance of normal blood pressure during human pregnancy.

  11. Depressão vascular no idoso: resposta ao tratamento antidepressivo associado a inibidor das colinesterases Vascular depression in elderly: response to treatment with antidepressant associated to cholinesterase inhibitor

    Directory of Open Access Journals (Sweden)

    Ricardo Barcelos

    2007-01-01

    Full Text Available CONTEXTO: Entre os transtornos neuropsiquiátricos ocasionados por eventos cerebrovasculares, a depressão vascular é pouco diagnosticada por médicos não especialistas, causando aumento da morbimortalidade de pacientes idosos. CASO CLÍNICO: Trata-se de um paciente com 67 anos que apresentou resposta parcial a tratamento com inibidores da recaptura de serotonina e efeitos adversos autonômicos graves com outros antidepressivos. A adição de rivastigmina ao citalopram promoveu sucesso terapêutico, com redução de 23 para 7 pontos, na escala de Hamilton para depressão. DISCUSSÃO: O resultado obtido traz novas perspectivas para o tratamento da depressão vascular, sendo necessários ensaios clínicos controlados que evidenciem o benefício da adição dos inibidores das colinesterases aos antidepressivos no tratamento destes pacientes.CONTEXT: Among neuropsychiatric disorders caused by cerebrovascular factors, vascular depression is diagnosed in a small degree by general practitioners, causing morbid-mortality increase in elderly. CASE REPORT: That is a case of a 67 year-old-man with partial response after treatment with a Selective Serotonin Receptors Inhibitor, and severe autonomic adverse effects with other antidepressants. The addition of rivastigmine to citalopram resulted in a therapeutic success, with a reduction of 23 to 7 points on the Hamilton Depressive Scale (HAM-D. DISCUSSION: The result obtained brings new perspectives to the treatment of vascular depression, providing that randomized controlled trials with larger sample sizes confirm the positive effect of the addition of a cholinesterase inhibitor to antidepressants in the treatment of these patients.

  12. Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation.

    Science.gov (United States)

    Stobart, Jillian L; Ferrari, Kim David; Barrett, Matthew J P; Stobart, Michael J; Looser, Zoe J; Saab, Aiman S; Weber, Bruno

    2018-01-01

    Localized, heterogeneous calcium transients occur throughout astrocytes, but the characteristics and long-term stability of these signals, particularly in response to sensory stimulation, remain unknown. Here, we used a genetically encoded calcium indicator and an activity-based image analysis scheme to monitor astrocyte calcium activity in vivo. We found that different subcellular compartments (processes, somata, and endfeet) displayed distinct signaling characteristics. Closer examination of individual signals showed that sensory stimulation elevated the number of specific types of calcium peaks within astrocyte processes and somata, in a cortical layer-dependent manner, and that the signals became more synchronous upon sensory stimulation. Although mice genetically lacking astrocytic IP3R-dependent calcium signaling (Ip3r2-/-) had fewer signal peaks, the response to sensory stimulation was sustained, suggesting other calcium pathways are also involved. Long-term imaging of astrocyte populations revealed that all compartments reliably responded to stimulation over several months, but that the location of the response within processes may vary. These previously unknown characteristics of subcellular astrocyte calcium signals provide new insights into how astrocytes may encode local neuronal circuit activity. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Propranolol modulates the collateral vascular responsiveness to vasopressin via a G(α)-mediated pathway in portal hypertensive rats.

    Science.gov (United States)

    Lee, Jing-Yi; Huo, Teh-Ia; Huang, Hui-Chun; Lee, Fa-Yauh; Lin, Han-Chieh; Chuang, Chiao-Lin; Chang, Ching-Chih; Wang, Sun-Sang; Lee, Shou-Dong

    2011-12-01

    Gastro-oesophageal variceal haemorrhage is one of the most dreadful complications of portal hypertension and can be controlled with vasoconstrictors. Nevertheless, sympathetic tone abnormality and vascular hyporesponsiveness in portal hypertension may impede the haemostatic effects of vasoconstrictors. Propranolol, a β-blocker binding the G-protein-coupled adrenoceptor, is a portal hypotensive agent. However, whether propranolol influences the collateral vasoresponse is unknown. Portal hypertension was induced by PVL (portal vein ligation) in Sprague-Dawley rats. In an acute study with an in situ perfusion model, the collateral responsiveness to AVP (arginine vasopressin) was evaluated with vehicle, propranolol (10 μmol/l), propranolol plus suramin (100 μmol/l, a G(α) inhibitor) or suramin pre-incubation. G(α) mRNA expression in the splenorenal shunt, the most prominent intra-abdominal collateral vessel, was measured. In the chronic study, rats received DW (distilled water) or propranolol (10 mg x kg(-1) of body weight x day(-1)) for 9 days. Then the concentration-response relationship of AVP and G(α) mRNA expression were assessed. Propranolol pre-incubation elevated the perfusion pressure changes of collaterals in response to AVP, which was inhibited by suramin. The splenorenal shunt G(αq) and G(α11) mRNA expression were enhanced by propranolol. The group treated with propranolol plus suramin had a down-regulation of G(α11) as compared with the propranolol group. Chronic propranolol treatment reduced mean arterial pressure, PP (portal pressure) and the perfusion pressure changes of collaterals to AVP. G(αs) expression was up-regulated. In conclusion, propranolol pre-incubation enhanced the portal-systemic collateral AVP responsiveness in portal hypertensive rats, which was related to G(αq) and G(α11) up-regulation. In contrast, the attenuated AVP responsiveness by chronic propranolol treatment was related to G(αs) up-regulation. The G(α) signalling

  14. Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation.

    Science.gov (United States)

    Spary, Lisa K; Al-Taei, Saly; Salimu, Josephine; Cook, Alexander D; Ager, Ann; Watson, H Angharad; Clayton, Aled; Staffurth, John; Mason, Malcolm D; Tabi, Zsuzsanna

    2014-04-01

    As a side effect of cancer radiotherapy, immune cells receive varying doses of radiation. Whereas high doses of radiation (>10 Gy) can lead to lymphopenia, lower radiation doses (2-4 Gy) represent a valid treatment option in some hematological cancers, triggering clinically relevant immunological changes. Based on our earlier observations, we hypothesized that lower radiation doses have a direct positive effect on T cells. In this study, we show that 0.6-2.4 Gy radiation enhances proliferation and IFN-γ production of PBMC or purified T cells induced by stimulation via the TCR. Radiation with 1.2 Gy also lowered T cell activation threshold and broadened the Th1 cytokine profile. Although radiation alone did not activate T cells, when followed by TCR stimulation, ERK1/2 and Akt phosphorylation increased above that induced by stimulation alone. These changes were followed by an early increase in glucose uptake. Naive (CD45RA(+)) or memory (CD45RA(-)) T cell responses to stimulation were boosted at similar rates by radiation. Whereas increased Ag-specific cytotoxic activity of a CD8(+) T cell line manifested in a 4-h assay (10-20% increase), highly significant (5- to 10-fold) differences in cytokine production were detected in 6-d Ag-stimulation assays of PBMC, probably as a net outcome of death of nonstimulated and enhanced response of Ag-stimulated T cells. T cells from patients receiving pelvic radiation (2.2-2.75 Gy) also displayed increased cytokine production when stimulated in vitro. We report in this study enhanced T cell function induced by synergistic radiation treatment, with potential physiological significance in a wide range of T cell responses.

  15. Efficient generation of smooth muscle cells from adipose-derived stromal cells by 3D mechanical stimulation can substitute the use of growth factors in vascular tissue engineering

    NARCIS (Netherlands)

    Parvizi, Mojtaba; Bolhuis-Versteeg, Lydia A. M.; Poot, Andre A.; Harmsen, Martin C.

    Occluding artery disease causes a high demand for bioartificial replacement vessels. We investigated the combined use of biodegradable and creep-free poly (1,3-trimethylene carbonate) (PTMC) with smooth muscle cells (SMC) derived by biochemical or mechanical stimulation of adipose tissue-derived

  16. Efficient generation of smooth muscle cells from adipose-derived stromal cells by 3D mechanical stimulation can substitute the use of growth factors in vascular tissue engineering

    NARCIS (Netherlands)

    Parvizi, M.; Bolhuis-Versteeg, Lydia A.M.; Poot, Andreas A.; Harmsen, M.C.

    2016-01-01

    Occluding artery disease causes a high demand for bioartificial replacement vessels. We investigated the combined use of biodegradable and creep-free poly (1,3-trimethylene carbonate) (PTMC) with smooth muscle cells (SMC) derived by biochemical or mechanical stimulation of adipose tissue-derived

  17. The human metapneumovirus matrix protein stimulates the inflammatory immune response in vitro.

    Directory of Open Access Journals (Sweden)

    Audrey Bagnaud-Baule

    Full Text Available Each year, during winter months, human Metapneumovirus (hMPV is associated with epidemics of bronchiolitis resulting in the hospitalization of many infants. Bronchiolitis is an acute illness of the lower respiratory tract with a consequent inflammation of the bronchioles. The rapid onset of inflammation suggests the innate immune response may have a role to play in the pathogenesis of this hMPV infection. Since, the matrix protein is one of the most abundant proteins in the Paramyxoviridae family virion, we hypothesized that the inflammatory modulation observed in hMPV infected patients may be partly associated with the matrix protein (M-hMPV response. By western blot analysis, we detected a soluble form of M-hMPV released from hMPV infected cell as well as from M-hMPV transfected HEK 293T cells suggesting that M-hMPV may be directly in contact with antigen presenting cells (APCs during the course of infection. Moreover, flow cytometry and confocal microscopy allowed determining that M-hMPV was taken up by dendritic cells (moDCs and macrophages inducing their activation. Furthermore, these moDCs enter into a maturation process inducing the secretion of a broad range of inflammatory cytokines when exposed to M-hMPV. Additionally, M-hMPV activated DCs were shown to stimulate IL-2 and IFN-γ production by allogeneic T lymphocytes. This M-hMPV-mediated activation and antigen presentation of APCs may in part explain the marked inflammatory immune response observed in pathology induced by hMPV in patients.

  18. Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation.

    Science.gov (United States)

    Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J

    2016-08-01

    The therapeutic actions of deep brain stimulation are not fully understood. The early inflammatory response of electrode implantation is associated with symptom relief without electrical stimulation, but is negated by anti-inflammatory drugs. Early excitotoxic necrosis and subsequent glial scarring modulate the conductivity of the tissue-electrode interface, which can provide some detail into the inflammatory response of individual patients. The feasibility of this was demonstrated by measuring resistance values across a bipolar electrode which was unilaterally implanted into the nucleus accumbens of a rat while receiving continuous deep brain stimulation with a portable back-mounted device using clinical parameters (130Hz, 200μA, 90μs) for 3 days. Daily resistance values rose significantly (pstimulation.

  19. A Model of Electrically Stimulated Auditory Nerve Fiber Responses with Peripheral and Central Sites of Spike Generation

    DEFF Research Database (Denmark)

    Joshi, Suyash Narendra; Dau, Torsten; Epp, Bastian

    2017-01-01

    A computational model of cat auditory nerve fiber (ANF) responses to electrical stimulation is presented. The model assumes that (1) there exist at least two sites of spike generation along the ANF and (2) both an anodic (positive) and a cathodic (negative) charge in isolation can evoke a spike...... of facilitation, accommodation, refractoriness, and spike-rate adaptation in ANF. Although the model is parameterized using data for either single or paired pulse stimulation with monophasic rectangular pulses, it correctly predicts effects of various stimulus pulse shapes, stimulation pulse rates, and level...... on the neural response statistics. The model may serve as a framework to explore the effects of different stimulus parameters on psychophysical performance measured in cochlear implant listeners....

  20. Blood Pressure Responses to Endovascular Stimulation: A Potential Therapy for Autonomic Disorders With Vasodilatation.

    Science.gov (United States)

    Naksuk, Niyada; Killu, Ammar M; Yogeswaran, Vidhushei; Desimone, Christopher V; Suddendorf, Scott H; Ladewig, Dorothy J; Powers, Joanne M; Weber, Sarah; Madhavan, Malini; Cha, Yong-Mei; Kapa, Suraj; Asirvatham, Samuel J

    2016-09-01

    We have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure. The pre-study protocol for endovascular stimulations included 2 minutes of stimulation (1-150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation. In 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15-150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings. Stimulation of intra-abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research. © 2016 Wiley Periodicals, Inc.

  1. Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/¿-hydroxylase/20-HETE pathways

    DEFF Research Database (Denmark)

    Inoue, Ryuji; Jensen, Lars Jørn; Jian, Zhong

    2009-01-01

    ). Single TRPC6 channel activity evoked by carbachol was also enhanced by a negative pressure added in the patch pipette. Mechanical potentiation of carbachol- or OAG-induced I(TRPC6) was abolished by small interfering RNA knockdown of cytosolic phospholipase A(2) or pharmacological inhibition of omega......-hydroxylation of arachidonic acid into 20-HETE (20-hydroxyeicosatetraenoic acid). Conversely, direct application of 20-HETE enhanced both OAG-induced macroscopic and single channel TRPC6 currents. Essentially the same results were obtained for TRPC6-like cation channel in A7r5 myocytes, where its activation by noradrenaline...... of receptor and mechanical stimulations may synergistically amplify transmembrane Ca(2+) mobilization through TRPC6 activation, thereby enhancing the vascular tone via phospholipase C/diacylglycerol and phospholipase A(2)/omega-hydroxylase/20-HETE pathways....

  2. Porcine neonatal blood dendritic cells, but not monocytes, are more responsive to TLRs stimulation than their adult counterparts.

    Directory of Open Access Journals (Sweden)

    Gael Auray

    Full Text Available The neonatal immune system is often considered as immature or impaired compared to the adult immune system. This higher susceptibility to infections is partly due to the skewing of the neonatal immune response towards a Th2 response. Activation and maturation of dendritic cells (DCs play an important role in shaping the immune response, therefore, DCs are a target of choice for the development of efficient and protective vaccine formulations able to redirect the neonatal immune response to a protective Th1 response. As pigs are becoming more important for vaccine development studies due to their similarity to the human immune system, we decided to compare the activation and maturation of a subpopulation of porcine DCs in adult and neonatal pigs following stimulation with different TLR ligands, which are promising candidates for adjuvants in vaccine formulations. Porcine blood derived DCs (BDCs were directly isolated from blood and consisted of a mix of conventional and plasmacytoid DCs. Following CpG ODN (TLR9 ligand and imiquimod (TLR7 ligand stimulation, neonatal BDCs showed higher levels of expression of costimulatory molecules and similar (CpG ODN or higher (imiquimod levels of IL-12 compared to adult BDCs. Another interesting feature was that only neonatal BDCs produced IFN-α after TLR7 or TLR9 ligand stimulation. Stimulation with CpG ODN and imiquimod also induced enhanced expression of several chemokines. Moreover, in a mixed leukocyte reaction assay, neonatal BDCs displayed a greater ability to induce lymphoproliferation. These findings suggest that when stimulated via TLR7 or TLR9 porcine DCs display similar if not better response than adult porcine DCs.

  3. EMMPRIN-Mediated Induction of Uterine and Vascular Matrix Metalloproteinases during Pregnancy and in Response to Estrogen and Progesterone

    OpenAIRE

    Dang, Yiping; Li, Wei; Tran, Victoria; Khalil, Raouf A.

    2013-01-01

    Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during p...

  4. Cortical Inhibition in Attention Deficit Hyperactivity Disorder: New Insights from the Electroencephalographic Response to Transcranial Magnetic Stimulation

    Science.gov (United States)

    Bruckmann, Sarah; Hauk, Daniela; Roessner, Veit; Resch, Franz; Freitag, Christine M.; Kammer, Thomas; Ziemann, Ulf; Rothenberger, Aribert; Weisbrod, Matthias; Bender, Stephan

    2012-01-01

    Attention deficit hyperactivity disorder is one of the most frequent neuropsychiatric disorders in childhood. Transcranial magnetic stimulation studies based on muscle responses (motor-evoked potentials) suggested that reduced motor inhibition contributes to hyperactivity, a core symptom of the disease. Here we employed the N100 component of the…

  5. Ultrasound guidance for brachial plexus block decreases the incidence of complete hemi-diaphragmatic paresis or vascular punctures and improves success rate of brachial plexus nerve block compared with peripheral nerve stimulator in adults.

    Science.gov (United States)

    Yuan, Jia-Min; Yang, Xiao-Hu; Fu, Shu-Kun; Yuan, Chao-Qun; Chen, Kai; Li, Jia-Yi; Li, Quan

    2012-05-01

    The use of traditional techniques (such as landmark techniques, paresthesia and peripheral nerve stimulator) for upper-limb anesthesia has often been restricted to the expert or enthusiast, which was blind. Recently, ultrasound (US) has been applied to differ blood vessel, pleura and nerve, thus may reduce the risk of complications while have a high rate of success. The aim of this study was to determine if the use of ultrasound guidance (vs. peripheral nerve stimulator, (PNS)) decreases risk of vascular puncture, risk of hemi-diaphragmatic paresis and risk of Horner syndrome and improves the success rate of nerve block. A search strategy was developed to identify randomized control trials (RCTs) reporting on complications of US and PNS guidance for upper-extremity peripheral nerve blocks (brachial plexus) in adults available through PubMed databases, the Cochrane Central Register of Controlled Trials, Embase databases, SinoMed databases and Wanfang data (date up to 2011-12-20). Two independent reviewers appraised eligible studies and extracted data. Risk ratios (OR) were calculated for each outcome and presented with 95% confidence intervals (CI) with the software of Review Manager 5.1.0 System (Cochrane Library). Sixteen trials involving 1321 adults met our criteria were included for analysis. Blocks performed using US guidance were more likely to be successful (risk ratio (RR) for block success 0.36, 95%CI 0.23 - 0.56, P block performance (RR 0.13, 95%CI 0.06 - 0.27, P complete hemi-diaphragmatic paresis (RR 0.09, 95%CI 0.03 - 0.52, P = 0.0001). US decreases risks of complete hemi-diaphragmatic paresis or vascular puncture and improves success rate of brachial plexus nerve block compared with techniques that utilize PNS for nerve localization. Larger studies are needed to determine whether or not the use of US can decrease risk of neurologic complications.

  6. Transcranial magnetic stimulation (TMS): compared sensitivity of different motor response parameters in ALS.

    Science.gov (United States)

    Pouget, J; Trefouret, S; Attarian, S

    2000-06-01

    Owing to the low sensitivity of clinical signs in assessing upper motor neuron (UMN) involvement in ALS, there is a need for investigative tools capable of detecting abnormal function of the pyramidal tract. Transcranial magnetic stimulation (TMS) may contribute to the diagnosis by reflecting a UMN dysfunction that is not clinically detectable. Several parameters for the motor responses to TMS can be evaluated with different levels of significance in healthy subjects compared with ALS patients. The central motor conduction time, however, is not sensitive in detecting subclinical UMN defects in individual ALS patients. The amplitude of the motor evoked potential (MEP), expressed as the percentage of the maximum wave, also has a low sensitivity. In some cases, the corticomotor threshold is decreased early in the disease course as a result of corticomotor neuron hyperexcitability induced by glutamate. Later, the threshold increases, indicating a loss of UMN. In our experience, a decreased silent period duration appears to be the most sensitive parameter when using motor TMS in ALS. TMS is also a sensitive technique for investigating the corticobulbar tract, which is difficult to study by other methods. TMS is a widely available, painless and safe technique with a good sensitivity that can visualize both corticospinal and corticobulbar tract abnormalities. The sensitivity can be improved further by taking into account the several MEP parameters, including latency and cortical silent period decreased duration.

  7. Challenges to deep brain stimulation: a pragmatic response to ethical, fiscal, and regulatory concerns.

    Science.gov (United States)

    Fins, Joseph J; Dorfman, Gary S; Pancrazio, Joseph J

    2012-08-01

    In response to the early success of deep brain stimulation, we offer some common-sense strategies to sustain the work, addressing the need to do so in a fiscally workable, ethically transparent, and scientifically informed manner. After delineating major threats, we will suggest reforms in both the legislative and regulatory spheres that might remediate these challenges. We will recommend (1) revisions to the Bayh-Dole Act of 1980, which governs intellectual property exchange resulting from federally funded research; (2) revisions to the Association of American Medical Colleges recommendations concerning the management of conflicts of interest when scientists with an intellectual property interest participate in clinical research in tandem; (3) revisions to the Food and Drug Administration's pre-market approval process for new devices, including a proposal for a mini-investigational device exemption; and (4) the establishment of a public-private partnership to build ethical and sustainable synergies between the scientific community, industry, and government that would foster discovery and innovation. © 2012 New York Academy of Sciences.

  8. Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine.

    Science.gov (United States)

    Calipari, Erin S; Godino, Arthur; Peck, Emily G; Salery, Marine; Mervosh, Nicholas L; Landry, Joseph A; Russo, Scott J; Hurd, Yasmin L; Nestler, Eric J; Kiraly, Drew D

    2018-01-16

    Cocaine addiction is characterized by dysfunction in reward-related brain circuits, leading to maladaptive motivation to seek and take the drug. There are currently no clinically available pharmacotherapies to treat cocaine addiction. Through a broad screen of innate immune mediators, we identify granulocyte-colony stimulating factor (G-CSF) as a potent mediator of cocaine-induced adaptations. Here we report that G-CSF potentiates cocaine-induced increases in neural activity in the nucleus accumbens (NAc) and prefrontal cortex. In addition, G-CSF injections potentiate cocaine place preference and enhance motivation to self-administer cocaine, while not affecting responses to natural rewards. Infusion of G-CSF neutralizing antibody into NAc blocks the ability of G-CSF to modulate cocaine's behavioral effects, providing a direct link between central G-CSF action in NAc and cocaine reward. These results demonstrate that manipulating G-CSF is sufficient to alter the motivation for cocaine, but not natural rewards, providing a pharmacotherapeutic avenue to manipulate addictive behaviors without abuse potential.

  9. Association Between Psychological Stress and Stimulation of Inflammatory Responses in Periodontal Disease

    Directory of Open Access Journals (Sweden)

    Mahvash MousaviJazi

    2013-01-01

    Full Text Available Objective: Based on the evidence regarding the relationship between inflammatory processes and stress responses, the present study investigated the association between psychological stress and elevation of inflammatory mediators related to periodontal disease in adult patients.Materials and Methods: The study consisted of 50 patients including 25 patients with chronic periodontitis and 25 cases with aggressive periodontitis. Twenty-five healthy subjects without any evidence of periodontal disorder were also randomly selected as the control group. The clinical parameters including plaque index (PI, bleeding on probing (BOP, probing depth (PPD and clinical attachment loss (CAL were recorded and GCF samples were collected for analysis of GCF contents of IL-6 and IL-1β levels. The Kettle stress questionnaire was also used to determine stress severity.Results: IL-1β was significantly higher, but IL-6 was only slightly higher(marginal p-value=0.058The median score of stress was higher in aggressive periodontitis than the chronic disorder and also in the two periodontal disease groups than the healthy subjects. Among studied clinical parameters, CAL and PPD were positively correlated with the GCF IL-1β level. No significant correlations were found between clinical parameters and GCF IL-6 level. There were strong positive relationships between stress severity and in both aggressive and chronic periodontitis; however stress did not influence GCF contents of IL-6.Conclusion: Psychological stress has a pivotal role in the stimulation of inflammatory processes via IL-1β increase in aggressive and chronic periodontitis.

  10. Multimodal Imaging in a Patient with Hemidystonia Responsive to GPi Deep Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Christos Sidiropoulos

    2017-01-01

    Full Text Available Background. Dystonia is a syndrome with varied phenomenology but our understanding of its mechanisms is deficient. With neuroimaging techniques, such as fiber tractography (FT and magnetoencephalography (MEG, pathway connectivity can be studied to that end. We present a hemidystonia patient treated with deep brain stimulation (DBS. Methods. After 10 years of left axial hemidystonia, a 45-year-old male underwent unilateral right globus pallidus internus (GPi DBS. Whole brain MEG before and after anticholinergic medication was performed prior to surgery. 26-direction diffusion tensor imaging (DTI was obtained in a 3 T MRI machine along with FT. The patient was assessed before and one year after surgery by using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS. Results. In the eyes-closed MEG study there was an increase in brain coherence in the gamma band after medication in the middle and inferior frontal region. FT demonstrated over 50% more intense ipsilateral connectivity in the right hemisphere compared to the left. After DBS, BFMDRS motor and disability scores both dropped by 71%. Conclusion. Multimodal neuroimaging techniques can offer insights into the pathophysiology of dystonia and can direct choices for developing therapeutics. Unilateral pallidal DBS can provide significant symptom control in axial hemidystonia poorly responsive to medication.

  11. Probiotic Lactobacillus Strains Stimulate the Inflammatory Response and Activate Human Macrophages

    Directory of Open Access Journals (Sweden)

    L. M. Rocha-Ramírez

    2017-01-01

    Full Text Available Lactobacilli have been shown to promote health functions. In this study, we analyzed the mechanism by which four different strains of probiotics affected innate immunity, such as regulation of ROS, cytokines, phagocytosis, bactericidal activity, signaling by NF-κB pp65, and TLR2 activation. The production of ROS was dependent on the concentration and species of Lactobacillus. The results obtained from the tested strains (Lactobacillus rhamnosus GG, L. rhamnosus KLSD, L. helveticus IMAU70129, and L. casei IMAU60214 showed that strains induced early proinflammatory cytokines such as IL-8,TNF-α, IL-12p70, and IL-6. However, IL-1β expression was induced only by L. helveticus and L. casei strains (after 24 h stimulation. Phagocytosis and bactericidal activity of macrophages against various pathogens, such as S. aureus, S. typhimurium, and E. coli, were increased by pretreatment with Lactobacillus. The nuclear translocation NF-κB pp65 and TLR2-dependent signaling were also increased by treatment with the probiotics. Taken together, the experiments demonstrate that probiotic strains of Lactobacillus exert early immunostimulatory effects that may be directly linked to the initial inflammation of the response of human macrophages.

  12. Redox Stimulation of Human THP-1 Monocytes in Response to Cold Physical Plasma

    Directory of Open Access Journals (Sweden)

    Sander Bekeschus

    2016-01-01

    Full Text Available In plasma medicine, cold physical plasma delivers a delicate mixture of reactive components to cells and tissues. Recent studies suggested a beneficial role of cold plasma in wound healing. Yet, the biological processes related to the redox modulation via plasma are not fully understood. We here used the monocytic cell line THP-1 as a model to test their response to cold plasma in vitro. Intriguingly, short term plasma treatment stimulated cell growth. Longer exposure only modestly compromised cell viability but apparently supported the growth of cells that were enlarged in size and that showed enhanced metabolic activity. A significantly increased mitochondrial content in plasma treated cells supported this notion. On THP-1 cell proteome level, we identified an increase of protein translation with key regulatory proteins being involved in redox regulation (hypoxia inducible factor 2α, differentiation (retinoic acid signaling and interferon inducible factors, and cell growth (Yin Yang 1. Regulation of inflammation is a key element in many chronic diseases, and we found a significantly increased expression of the anti-inflammatory heme oxygenase 1 (HMOX1 and of the neutrophil attractant chemokine interleukin-8 (IL-8. Together, these results foster the view that cold physical plasma modulates the redox balance and inflammatory processes in wound related cells.

  13. Immunization with recombinant enterovirus 71 viral capsid protein 1 fragment stimulated antibody responses in hamsters

    Directory of Open Access Journals (Sweden)

    Ch’ng Wei-Choong

    2012-08-01

    Full Text Available Abstract Enterovirus 71 (EV71 causes severe neurological diseases resulting in high mortality in young children worldwide. Development of an effective vaccine against EV71 infection is hampered by the lack of appropriate animal models for efficacy testing of candidate vaccines. Previously, we have successfully tested the immunogenicity and protectiveness of a candidate EV71 vaccine, containing recombinant Newcastle disease virus capsids that display an EV71 VP1 fragment (NPt-VP11-100 protein, in a mouse model of EV71 infection. A drawback of this system is its limited window of EV71 susceptibility period, 2 weeks after birth, leading to restricted options in the evaluation of optimal dosing regimens. To address this issue, we have assessed the NPt-VP11-100 candidate vaccine in a hamster system, which offers a 4-week susceptibility period to EV71 infection. Results obtained showed that the NPt-VP11-100 candidate vaccine stimulated excellent humoral immune response in the hamsters. Despite the high level of antibody production, they failed to neutralize EV71 viruses or protect vaccinated hamsters in viral challenge studies. Nevertheless, these findings have contributed towards a better understanding of the NPt-VP11-100 recombinant protein as a candidate vaccine in an alternative animal model system.

  14. Sensory trigeminal ULF-TENS stimulation reduces HRV response to experimentally induced arithmetic stress: A randomized clinical trial.

    Science.gov (United States)

    Monaco, Annalisa; Cattaneo, Ruggero; Ortu, Eleonora; Constantinescu, Marian Vladimir; Pietropaoli, Davide

    2017-05-01

    Ultra Low Frequency Transcutaneous Electric Nervous Stimulation (ULF-TENS) is extensively used for pain relief and for the diagnosis and treatment of temporomandibular disorders (TMD). In addition to its local effects, ULF-TENS acts on the autonomic nervous system (ANS), with particular reference to the periaqueductal gray (PAG), promoting the release of endogenous opioids and modulating descending pain systems. It has been suggested that the PAG participates in the coupling between the emotional stimulus and the appropriate behavioral autonomic response. This function is successfully investigated by HRV. Therefore, our goal is to investigate the effects of trigeminal ULF-TENS stimulation on autonomic behavior in terms of HRV and respiratory parameters during an experimentally-induced arithmetic stress test in healthy subjects. Thirty healthy women between 25 and 35years of age were enrolled and randomly assigned to either the control (TENS stimulation off) or test group (TENS stimulation on). Heart (HR, LF, HF, LF/HF ratio, DET, RMSSD, PNN50, RR) and respiratory (BR) rate were evaluated under basal, T1 (TENS off/on), and stress (mathematical task) conditions. Results showed that HRV parameters and BR significantly changed during the arithmetic stress paradigm (psensory ULF-TENS reduces the autonomic response in terms of HRV and BR during acute mental stress in healthy subjects. Future directions of our work aim at applying the HRV and BR analysis, with and without TENS stimulation, to individuals with dysfunctional ANS among those with TMD. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Time-dependent Increase in the Network Response to the Stimulation of Neuronal Cell Cultures on Micro-electrode Arrays.

    Science.gov (United States)

    Gertz, Monica L; Baker, Zachary; Jose, Sharon; Peixoto, Nathalia

    2017-05-29

    Micro-electrode arrays (MEAs) can be used to investigate drug toxicity, design paradigms for next-generation personalized medicine, and study network dynamics in neuronal cultures. In contrast with more traditional methods, such as patch-clamping, which can only record activity from a single cell, MEAs can record simultaneously from multiple sites in a network, without requiring the arduous task of placing each electrode individually. Moreover, numerous control and stimulation configurations can be easily applied within the same experimental setup, allowing for a broad range of dynamics to be explored. One of the key dynamics of interest in these in vitro studies has been the extent to which cultured networks display properties indicative of learning. Mouse neuronal cells cultured on MEAs display an increase in response following training induced by electrical stimulation. This protocol demonstrates how to culture neuronal cells on MEAs; successfully record from over 95% of the plated dishes; establish a protocol to train the networks to respond to patterns of stimulation; and sort, plot, and interpret the results from such experiments. The use of a proprietary system for stimulating and recording neuronal cultures is demonstrated. Software packages are also used to sort neuronal units. A custom-designed graphical user interface is used to visualize post-stimulus time histograms, inter-burst intervals, and burst duration, as well as to compare the cellular response to stimulation before and after a training protocol. Finally, representative results and future directions of this research effort are discussed.

  16. Effects of transcutaneous electric acupoint stimulation on drug use and responses to cue-induced craving: a pilot study

    Directory of Open Access Journals (Sweden)

    Penetar David M

    2012-06-01

    Full Text Available Abstract Background Transcutaneous electric acupoint stimulation (TEAS avoids the use of needles, and instead delivers a mild electric current at traditional acupoints. This technique has been used for treating heroin addiction, but has not been systematically tested for other drugs of abuse. This study aims to investigate the effects of TEAS on drug addiction. Methods Volunteers who were either cocaine-dependent (n = 9 or cannabis-dependent (n = 11 but were not seeking treatment for their dependence participated in a within-subject, single-blind study. Treatment consisted of twice daily 30-minute sessions of TEAS or sham stimulation for 3.5 days. The active TEAS levels were individually adjusted to produce a distinct twitching response in the fingers, while the sham stimulation involved 2 minutes of stimulation at threshold levels followed by 28 minutes of stimulation below the detection levels. The participants recorded their drug use and drug cravings daily. At 1 hour after the last morning session of TEAS or sham stimulation, a cue-induced craving EEG evaluation was conducted. Event-related P300 potentials (ERPs were recorded, sorted, and analyzed for specific image types (neutral objects, non-drug-related arousing images, or drug-related images. Results TEAS treatment did not significantly reduce the drug use or drug cravings, or significantly alter the ERP peak voltage or latency to peak response. However, the TEAS treatment did significantly modulate several self-reported measures of mood and anxiety. Conclusion The results of this pilot study with a limited sample size suggest that the acupoint stimulation techniques and protocol used in this trial alone do not significantly reduce cravings for or use of cocaine or cannabis. The findings that TEAS modulates mood and anxiety suggest that TEAS could be used as an adjunct in a multimodal therapy program to treat cocaine and cannabis dependence if confirmed in a full randomized

  17. Tachykinin receptors mediating responses to sensory nerve stimulation and exogenous tachykinins and analogues in the rabbit isolated iris sphincter.

    Science.gov (United States)

    Hall, J. M.; Mitchell, D.; Morton, I. K.

    1993-01-01

    1. We have used selective tachykinin receptor agonists and antagonists to investigate the nature of the receptors mediating responses to endogenous and exogenous tachykinins in the rabbit iris sphincter preparation in vitro. 2. The NK1-selective agonist, substance P methyl ester, induced contraction with a pD2 of 9.16 indicating the presence of NK1 receptors. In confirmation, the NK1-selective antagonist, GR82334, competitively antagonized responses to substance P methyl ester with high affinity (pKB 7.46). 3. NK3 receptors also mediate contraction since NK3-selective agonists exhibited high potency, e.g. the pD2 of [Me-Phe7]-neurokinin B was 9.67, and their responses were not inhibited by GR82334 (10 microM). 4. NK2 receptor activation does not seem to contribute to contraction since the NK2-selective agonist [beta-Ala8]-neurokinin A(4-10) had relatively low potency (pD2 6.43), and the NK2-selective antagonists MEN10207 (1 microM) and L-659,877 (10 microM) were inactive or had low affinity, respectively. 5. GR82334 (1 microM) significantly inhibited responses to electrical field-stimulation of non-adrenergic non-cholinergic sensory nerves (3, 10 and 30 Hz), and caused a rightward shift of the log concentration-response curve to bradykinin (lateral shift ca. 1000 fold). Higher concentrations of GR82334 (10 microM) significantly attenuated responses to capsaicin (1-60 microM) whilst completely abolishing responses to field-stimulation (3, 10 and 30 Hz) and bradykinin (1 nM- 3 microM). 6. In conclusion, NK1 and NK3 receptor activation results in contraction of the rabbit iris sphincter. The contractile response following sensory nerve stimulation by bradykinin, capsaicin and electrical field stimulation results from NK1 receptor activation. PMID:8401912

  18. Imaging the Spatio-Temporal Dynamics of Supragranular Activity in the Rat Somatosensory Cortex in Response to Stimulation of the Paws

    Science.gov (United States)

    Morales-Botello, M. L.; Aguilar, J.; Foffani, G.

    2012-01-01

    We employed voltage-sensitive dye (VSD) imaging to investigate the spatio-temporal dynamics of the responses of the supragranular somatosensory cortex to stimulation of the four paws in urethane-anesthetized rats. We obtained the following main results. (1) Stimulation of the contralateral forepaw evoked VSD responses with greater amplitude and smaller latency than stimulation of the contralateral hindpaw, and ipsilateral VSD responses had a lower amplitude and greater latency than contralateral responses. (2) While the contralateral stimulation initially activated only one focus, the ipsilateral stimulation initially activated two foci: one focus was typically medial to the focus activated by contralateral stimulation and was stereotaxically localized in the motor cortex; the other focus was typically posterior to the focus activated by contralateral stimulation and was stereotaxically localized in the somatosensory cortex. (3) Forepaw and hindpaw somatosensory stimuli activated large areas of the sensorimotor cortex, well beyond the forepaw and hindpaw somatosensory areas of classical somatotopic maps, and forepaw stimuli activated larger cortical areas with greater activation velocity than hindpaw stimuli. (4) Stimulation of the forepaw and hindpaw evoked different cortical activation dynamics: forepaw responses displayed a clear medial directionality, whereas hindpaw responses were much more uniform in all directions. In conclusion, this work offers a complete spatio-temporal map of the supragranular VSD cortical activation in response to stimulation of the paws, showing important somatotopic differences between contralateral and ipsilateral maps as well as differences in the spatio-temporal activation dynamics in response to forepaw and hindpaw stimuli. PMID:22829873

  19. The effect of music and multimodal stimulation on responses of premature infants in neonatal intensive care.

    Science.gov (United States)

    Standley, J M

    1998-01-01

    To assess the benefits of lullaby singing and multimodal stimulation on premature infants in neonatal intensive care, 40 infants in a Level III Newborn Intermediate Care Unit were divided into control (n = 20) and experimental (n = 20) groups by pair matching on the basis of gender, birthweight, gestational age at birth and severity of medical complications. Participants met these project criteria: (a) corrected gestational age > 32 weeks; (b) age since birth > 10 days; and (c) weight > 1700 g. All participants had been referred for developmental stimulation by the medical staff. Experimental infants received reciprocal, multimodal (ATVV) stimulation paired with line singing of Brahms' Lullaby. Stimulation was provided for 15-30 minutes, one or two times per week from referral to discharge. Dependent variables were (a) days to discharge, (b) weight gain/day, and (c) experimental infants' tolerance for stimulation. Results showed that music and multimodal stimulation significantly benefited females' days to discharge and increased weight gain/day for both males and females. Both male and female infants' tolerance for stimulation showed marked and steady increase across the stimulation intervals with females' tolerance increasing more rapidly than males.

  20. Stimulation of gluconeogenesis by intravenous lipids in preterm infants: response depends on fatty acid profile

    NARCIS (Netherlands)

    van Kempen, Anne A. M. W.; van der Crabben, Saskia N.; Ackermans, Mariëtte T.; Endert, Erik; Kok, Joke H.; Sauerwein, Hans P.

    2006-01-01

    In preterm infants, both hypo- and hyperglycemia are a frequent problem. Intravenous lipids can affect glucose metabolism by stimulation of gluconeogenesis by providing glycerol, which is a gluconeogenic precursor, and/or free fatty acids (FFA), which are stimulants of the rate of gluconeogenesis.

  1. The beta-cell response to glucagon and mixed meal stimulation in non-insulin dependent diabetes

    DEFF Research Database (Denmark)

    Gjessing, H J; Damsgaard, E M; Matzen, L E

    1988-01-01

    The aim of this study was to evaluate the correlations of the C-peptide and insulin responses after stimulation with glucagon intravenously as well as the 24-h urinary excretion of C-peptide to the C-peptide response to a standard mixed meal in 30 patients with non-insulin dependent diabetes...... mellitus (NIDDM). Fasting plasma C-peptide as well as the C-peptide and insulin responses to glucagon, showed similar but only modest correlations with the C-peptide response to the meal. Urinary C-peptide showed no correlation with the C-peptide response to the meal, but correlated modestly with fasting...... plasma C-peptide (r = 0.55, p less than 0.01). The C-peptide and insulin responses after meal stimulation correlated modestly inversely with HbA1. In conclusion, measurement of C-peptide in fasting state, as well as measurements of C-peptide and insulin after glucagon stimulation, only modestly predict...

  2. Simulated auditory nerve axon demyelination alters sensitivity and response timing to extracellular stimulation.

    Science.gov (United States)

    Resnick, Jesse M; O'Brien, Gabrielle E; Rubinstein, Jay T

    2018-04-01

    Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor in cochlear implant (CI) outcomes. This expected relationship has, however, been difficult to confirm in implant recipients. Suggestively, animal studies have demonstrated both acute and progressive SGN ultrastructural changes (notably axon demyelination), even in the absence of soma death, and corresponding altered physiology following sensorineural deafening. Whether such demyelination occurs in humans and how such changes might impact CI function remains unknown. To approach this problem, we incorporated SGN demyelination into a biophysical model of extracellular stimulation of SGN fibers. Our approach enabled exploration of the entire parameter space corresponding to simulated myelin diameter and extent of fiber affected. All simulated fibers were stimulated distally with anodic monophasic, cathodic monophasic, anode-phase-first (AF) biphasic, and cathode-phase-first (CF) biphasic pulses from an extracellular disc electrode and monitored for spikes centrally. Not surprisingly, axon sensitivity generally decreased with demyelination, resulting in elevated thresholds, however, this effect was strongly non-uniform. Fibers with severe demyelination affecting only the most peripheral nodes responded nearly identically to normally myelinated fibers. Additionally, partial demyelination (<50%) yielded only minimal increases in threshold even when the entire fiber was impacted. The temporal effects of demyelination were more unexpected. Both latency and jitter of responses demonstrated resilience to modest changes but exhibited strongly non-monotonic and stimulus-dependent relationships to more profound demyelination. Normal, and modestly demyelinated fibers, were more sensitive to cathodic than anodic monophasic pulses and to CF than AF biphasic pulses, however, when demyelination was more severe these

  3. Effect of Acetazolamide and Gingko Biloba on the Human Pulmonary Vascular Response to an Acute Altitude Ascent

    Science.gov (United States)

    Ke, Tao; Wang, Jiye; Swenson, Erik R.; Zhang, Xiangnan; Hu, Yunlong; Chen, Yaoming; Liu, Mingchao; Zhang, Wenbin; Zhao, Feng; Shen, Xuefeng; Yang, Qun

    2013-01-01

    Abstract Ke, Tao, Jiye Wang, Erik R. Swenson, Xiangnan Zhang, Yunlong Hu, Yaoming Chen, Mingchao Liu, Wenbin Zhang, Feng Zhao, Xuefeng Shen, Qun Yang, Jingyuan Chen, and Wenjing Luo. Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent. High Alt Med Biol 14:162–167, 2013.—Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (pbiloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6–16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, pgingko biloba, mitigates the early increase of PASP in a quick ascent profile. PMID:23795737

  4. An investigation of the vascular organisation of the canine submandibular gland.

    OpenAIRE

    Lung, M A

    1993-01-01

    It is known that parasympathetic nerve stimulation elevates venous pressure in the dog submandibular gland, and that the venous pressure wave is transformed to that of the arterial pulse. The vascular arrangements and histological characteristics of the dog submandibular gland were therefore examined to establish which anatomical structures are responsible for the change in venous pressure during salivation induced by parasympathetic stimulation. The acinar and ductal circulations were found ...

  5. Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression.

    Science.gov (United States)

    Wagner, Henrik; Fischer, Helene; Degerblad, Marie; Alvarsson, Michael; Gustafsson, Thomas

    2016-09-01

    Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2. Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression. A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations. The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies. © The Author(s) 2016.

  6. Characterizing Rat PNS Electrophysiological Response to Electrical Stimulation Using in vitro Chip-Based Human Investigational Platform (iCHIP)

    Energy Technology Data Exchange (ETDEWEB)

    Khani, Joshua [Georgetown Univ., Washington, DC (United States); Prescod, Lindsay [Georgetown Univ., Washington, DC (United States); Enright, Heather [Georgetown Univ., Washington, DC (United States); Felix, Sarah [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Osburn, Joanne [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Wheeler, Elizabeth [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Kulp, Kris [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-08-18

    Ex vivo systems and organ-on-a-chip technology offer an unprecedented approach to modeling the inner workings of the human body. The ultimate goal of LLNL’s in vitro Chip-based Human Investigational Platform (iCHIP) is to integrate multiple organ tissue cultures using microfluidic channels, multi-electrode arrays (MEA), and other biosensors in order to effectively simulate and study the responses and interactions of the major organs to chemical and physical stimulation. In this study, we focused on the peripheral nervous system (PNS) component of the iCHIP system. Specifically we sought to expound on prior research investigating the electrophysiological response of rat dorsal root ganglion cells (rDRGs) to chemical exposures, such as capsaicin. Our aim was to establish a protocol for electrical stimulation using the iCHIP device that would reliably elicit a characteristic response in rDRGs. By varying the parameters for both the stimulation properties – amplitude, phase width, phase shape, and stimulation/ return configuration – and the culture conditions – day in vitro and neural cell types - we were able to make several key observations and uncover a potential convention with a minimal number of devices tested. Future work will seek to establish a standard protocol for human DRGs in the iCHIP which will afford a portable, rapid method for determining the effects of toxins and novel therapeutics on the PNS.

  7. Responses of bacterial and archaeal communities to nitrate stimulation after oil pollution in mangrove sediment revealed by Illumina sequencing.

    Science.gov (United States)

    Wang, Lei; Huang, Xu; Zheng, Tian-Ling

    2016-08-15

    This study aimed to investigate microbial responses to nitrate stimulation in oiled mangrove mesocosm. Both supplementary oil and nitrate changed the water and sediment chemical properties contributing to the shift of microbial communities. Denitrifying genes nirS and nirK were increased several times by the interaction of oil spiking and nitrate addition. Bacterial chao1 was reduced by oil spiking and further by nitrate stimulation, whereas archaeal chao1 was only inhibited by oil pollution on early time. Sampling depth explained most of variation and significantly impacted bacterial and archaeal communities, while oil pollution only significantly impacted bacterial communities (pcommunities during nitrate stimulation. Our study suggests introducing genera Desulfotignum and Marinobacter into oiled mangrove for bioaugmentation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Multichannel time domain fNIRS mapping of cortical activation and superficial systemic responses during neuromuscular electrical stimulation

    Science.gov (United States)

    Re, R.; Muthalib, M.; Zucchelli, L.; Perrey, S.; Contini, D.; Caffini, M.; Spinelli, L.; Kerr, G.; Torricelli, A.

    2013-06-01

    We recorded maps of cortical and systemic hemodynamic responses (oxy-hemoglobin, O2Hb and deoxy-hemoglobin, HHb) during incremental neuromuscular electrical stimulation (NMES) of the right forearm in nine subjects by a 32- channel time domain fNIRS (TD-fNIRS) instrument. Statistical parametric maps (SPM) relative to the different current stimulations (under and over the maximal tolerated intensity-MTI) versus the 10%MTI were generated. Exploiting the temporal information contained in the TD-fNIRS signal it was possible to create different maps referring to the deeper (cortical activations) and the more superficial (systemic changes) head layers. The increasing of the stimulation current on the right forearm muscle produced a significantly larger bilateral sensorimotor and prefrontal cortical activations (i.e. increase in the O2Hb and decrease in HHb) than the systemic changes. Physiological parameters (heart rate, breathing rate and skin conductance) were also monitored.

  9. Functional response of white rats isolated heart to the stimulation of adrenergic receptors after gamma-irradiation in low doses

    International Nuclear Information System (INIS)

    Antonenko, A.N.; Lobanok, L.M.

    1999-01-01

    It was investigated the effects of acute gamma-irradiation on bio mechanical activity of rats heart isolated by Langendorf's method in early and delayed terms after exposure to gamma-rays. Intra ventricle pressure and the rate of its growth, volumetric rate of coronal flow, frequency of heart contraction were registered. Stimulation of alpha-adrenergic receptors was conducted by means of specific agonist mesatone and stimulation of beta-adrenergic receptors was made by means of isoprenaline. The study has shown that acute irradiation of rats caused the decrease of both contractile ability and relaxation of myocardium in a 10 days after exposure. In delayed period bio mechanical activity of isolated heart was restored. Functional response of heart to the stimulation of alpha- and beta-adrenergic receptors was decreased in all terms of investigation

  10. RESPUESTAS CARDIOVASCULARES AL ENTRENAMIENTO DE FUERZA BAJO OCLUSIÓN VASCULAR [Cardiovascular responses to strength training under occlusive training

    Directory of Open Access Journals (Sweden)

    Sergio Benito Hernández

    2013-11-01

    Full Text Available El entrenamiento de la fuerza bajo oclusión vascular se muestra como una alternativa al entrenamiento de alta intensidad. El presente estudio muestra las respuestas cardiovasculares a este tipo de entrenamiento. 10 sujetos fueron sometidos a dos protocolos de entrenamiento oclusivo diferenciados por el peso levantado, (30% del peso máximo, post30, y 70% del peso máximo, post70. Se registraron los valores de tensión arterial sistólica (TAS, diastólica (TAD y frecuencia cardiaca (FC. Los resultados evidencian disminución significativa en TAS y TAD en el grupo post30 en 7 y 13 mm Hg respectivamente en referencia a los valores basales (p<0.05, resultando un descenso muy significativo en el grupo post70, 14 y 20 mm Hg respectivamente (p<0.005. Los valores de la FC no se vieron alterados por ninguno de los protocolos experimentales (p>0.05. Los efectos de tamaño para todos los grupos resultaron triviales (d<0.25. En conclusión los resultados del presente estudios presentan una tendencia a la reducción de la tensión arterial significativa en TAS y TAD en los protocolos de entrenamiento oclusivo, resultando más notable cuando se aplica la mayor intensidad de entrenamiento. Resultan necesarios más estudios que examinen el comportamiento de los parámetros cardiovasculares tras el entrenamiento de fuerza bajo oclusión vascular.AbstractOcclusive strength training is shown like an alternative to intensive training. Present study shown cardiovascular responses to this training. 10 subjects were subjected to two occlusion training protocols, differentiated by the weight lifted (30 % of maximum weight lifted, post30, and 70 % of maximum weight lifted, post70. The values of arterial systolic tension (TAS, diastolic (TAD and heart rate (FC were recorded. The results showing a significant decline in TAS and TAD after post30 of 7 and 13 mm Hg respectively from basis values (p<0.05, resulting a very significant decline in post70 group, 14 and 20 mm Hg

  11. Enrichment of Geobacter species in response to stimulation of Fe(III) reduction in sandy aquifer sediments

    Science.gov (United States)

    Snoeyenbos-West, O.L.; Nevin, K.P.; Anderson, R.T.; Lovely, D.R.

    2000-01-01

    Engineered stimulation of Fe(III) has been proposed as a strategy to enhance the immobilization of radioactive and toxic metals in metal-contaminated subsurface environments. Therefore, laboratory and field studies were conducted to determine which microbial populations would respond to stimulation of Fe(III) reduction in the sediments of sandy aquifers. In laboratory studies, the addition of either various organic electron donors or electron shuttle compounds stimulated Fe(III) reduction and resulted in Geobacter sequences becoming important constituents of the Bacterial 16S rDNA sequences that could be detected with PCR amplification and denaturing gradient gel electrophoresis (DGGE). Quantification of Geobacteraceae sequences with a PCR most-probable-number technique indicated that the extent to which numbers of Geobacter increased was related to the degree of stimulation of Fe(III) reduction. Geothrix species were also enriched in some instances, but were orders of magnitude less numerous than Geobacter species. Shewanella species were not detected, even when organic compounds known to be electron donors for Shewanella species were used to stimulate Fe(III) reduction in the sediments. Geobacter species were also enriched in two field experiments in which Fe(III) reduction was stimulated with the addition of benzoate or aromatic hydrocarbons. The apparent growth of Geobacter species concurrent with increased Fe(III) reduction suggests that Geobacter species were responsible for much of the Fe(III) reduction in all of the stimulation approaches evaluated in three geographically distinct aquifers. Therefore, strategies for subsurface remediation that involve enhancing the activity of indigenous Fe(III)-reducing populations in aquifers should consider the physiological properties of Geobacter species in their treatment design.

  12. Four-pulse transcranial magnetic stimulation using multiple conditioning inputs. Normative MEP responses.

    Science.gov (United States)

    Calancie, Blair; Wang, Dongliang; Young, Eufrosina; Alexeeva, Natalia

    2018-04-01

    A four-pulse pattern of transcranial magnetic stimulation (TMS) was compared to traditional dual-pulse TMS for its ability to modulate motor cortical excitability. This novel pattern consisted of a three-pulse train of subthreshold conditioning pulses followed by a suprathreshold test pulse (i.e., SC-T). The intervals between these superconditioning (SC) pulses (1, 3, or 6 ms) and the follow-on test pulse (1, 3, 10, or 25 ms) were varied, and the resultant MEPs were compared to those elicited by: (1) single-pulse TMS; and (2) dual-pulse conditioning-test (C-T) TMS with either short (3 ms) or long (10 ms) intervals to elicit short-interval intracortical inhibition (SICI) or intracortical facilitation (ICF), respectively. Testing included abductor pollicis brevis (APB) and tibialis anterior (TA) in 15 neurologically normal adults. For superconditioning inputs, 10 ms test intervals caused especially strong facilitation of the test MEP, while 1 ms test intervals were particularly effective at causing inhibition of the test response. For both muscles and across all subjects, the most effective of the 12 SC-T inputs tested for causing either facilitation or inhibition was-with rare exception-superior to the dual-pulse TMS input for causing facilitation (i.e., ICF) or inhibition (i.e., SICI), while the overall magnitude of effect was more pronounced in APB compared to TA. Nevertheless, after normalization, the impact of a superconditioning input train on the test MEP was similar in APB and TA muscles, suggesting similar mechanisms of action. Limited findings from a single subject with amyotrophic lateral sclerosis (ALS) are included to further illustrate the potential advantages of using a train of conditioning pulses preceding a TMS test pulse to selectively investigate abnormal motor cortical excitatory and inhibitory circuitry.

  13. Waddlia chondrophila infects and multiplies in ovine trophoblast cells stimulating an inflammatory immune response.

    Directory of Open Access Journals (Sweden)

    Nick Wheelhouse

    Full Text Available Waddlia chondrophila (W. chondrophila is an emerging abortifacient organism which has been identified in the placentae of humans and cattle. The organism is a member of the order Chlamydiales, and shares many similarities at the genome level and in growth studies with other well-characterised zoonotic chlamydial abortifacients, such as Chlamydia abortus (C. abortus. This study investigates the growth of the organism and its effects upon pro-inflammatory cytokine expression in a ruminant placental cell line which we have previously utilised in a model of C. abortus pathogenicity.Using qPCR, fluorescent immunocytochemistry and electron microscopy, we characterised the infection and growth of W. chondrophila within the ovine trophoblast AH-1 cell line. Inclusions were visible from 6 h post-infection (p.i. and exponential growth of the organism could be observed over a 60 h time-course, with significant levels of host cell lysis being observed only after 36 h p.i. Expression of CXCL8, TNF-α, IL-1α and IL-1β were determined 24 h p.i. A statistically significant response in the expression of CXCL8, TNF-α and IL-1β could be observed following active infection with W. chondrophila. However a significant increase in IL-1β expression was also observed following the exposure of cells to UV-killed organisms, indicating the stimulation of multiple innate recognition pathways.W. chondrophila infects and grows in the ruminant trophoblast AH-1 cell line exhibiting a complete chlamydial replicative cycle. Infection of the trophoblasts resulted in the expression of pro-inflammatory cytokines in a dose-dependent manner similar to that observed with C. abortus in previous studies, suggesting similarities in the pathogenesis of infection between the two organisms.

  14. Waddlia chondrophila infects and multiplies in ovine trophoblast cells stimulating an inflammatory immune response.

    Science.gov (United States)

    Wheelhouse, Nick; Coyle, Christopher; Barlow, Peter G; Mitchell, Stephen; Greub, Gilbert; Baszler, Tim; Rae, Mick T; Longbottom, David

    2014-01-01

    Waddlia chondrophila (W. chondrophila) is an emerging abortifacient organism which has been identified in the placentae of humans and cattle. The organism is a member of the order Chlamydiales, and shares many similarities at the genome level and in growth studies with other well-characterised zoonotic chlamydial abortifacients, such as Chlamydia abortus (C. abortus). This study investigates the growth of the organism and its effects upon pro-inflammatory cytokine expression in a ruminant placental cell line which we have previously utilised in a model of C. abortus pathogenicity. Using qPCR, fluorescent immunocytochemistry and electron microscopy, we characterised the infection and growth of W. chondrophila within the ovine trophoblast AH-1 cell line. Inclusions were visible from 6 h post-infection (p.i.) and exponential growth of the organism could be observed over a 60 h time-course, with significant levels of host cell lysis being observed only after 36 h p.i. Expression of CXCL8, TNF-α, IL-1α and IL-1β were determined 24 h p.i. A statistically significant response in the expression of CXCL8, TNF-α and IL-1β could be observed following active infection with W. chondrophila. However a significant increase in IL-1β expression was also observed following the exposure of cells to UV-killed organisms, indicating the stimulation of multiple innate recognition pathways. W. chondrophila infects and grows in the ruminant trophoblast AH-1 cell line exhibiting a complete chlamydial replicative cycle. Infection of the trophoblasts resulted in the expression of pro-inflammatory cytokines in a dose-dependent manner similar to that observed with C. abortus in previous studies, suggesting similarities in the pathogenesis of infection between the two organisms.

  15. Effect of Stimulation of Neurotransmitter Systems on Heart Rate Variability and β-Adrenergic Responsiveness of Erythrocytes in Outbred Rats.

    Science.gov (United States)

    Kur'yanova, E V; Tryasuchev, A V; Stupin, V O; Teplyi, D L

    2017-05-01

    We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated

  16. High-density PhyloChip profiling of stimulated aquifer microbial communities reveals a complex response to acetate amendment.

    Science.gov (United States)

    Handley, Kim M; Wrighton, Kelly C; Piceno, Yvette M; Andersen, Gary L; DeSantis, Todd Z; Williams, Kenneth H; Wilkins, Michael J; N'Guessan, A Lucie; Peacock, Aaron; Bargar, John; Long, Philip E; Banfield, Jillian F

    2012-07-01

    There is increasing interest in harnessing the functional capacities of indigenous microbial communities to transform and remediate a wide range of environmental contaminants. Information about which community members respond to stimulation can guide the interpretation and development of remediation approaches. To comprehensively determine community membership and abundance patterns among a suite of samples associated with uranium bioremediation experiments, we employed a high-density microarray (PhyloChip). Samples were unstimulated, naturally reducing, or collected during Fe(III) (early) and sulfate reduction (late biostimulation) from an acetate re-amended/amended aquifer in Rifle, Colorado, and from laboratory experiments using field-collected materials. Deep community sampling with PhyloChip identified hundreds-to-thousands of operational taxonomic units (OTUs) present during amendment, and revealed close similarity among highly enriched taxa from drill core and groundwater well-deployed column sediment. Overall, phylogenetic data suggested that stimulated community membership was most affected by a carryover effect between annual stimulation events. Nevertheless, OTUs within the Fe(III)- and sulfate-reducing lineages, Desulfuromonadales and Desulfobacterales, were repeatedly stimulated. Less consistent, co-enriched taxa represented additional lineages associated with Fe(III) and sulfate reduction (e.g. Desulfovibrionales; Syntrophobacterales; Peptococcaceae) and autotrophic sulfur oxidation (Sulfurovum; Campylobacterales). Data implies complex membership among highly stimulated taxa and, by inference, biogeochemical responses to acetate, a nonfermentable substrate. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  17. Responses of neurons of lizard's, Lacerta viridis, vestibular nuclei to electrical stimulation of the ipsi- and contralateral VIIIth nerves.

    Science.gov (United States)

    Richter, A; Precht, W; Ozawa, S

    1975-03-22

    Field and intracellular potentials were recorded in the vestibular nuclei of the lizard following stimulation of the ipsi- and contralateral vestibular nerves. The field potentials induced by ipsilateral VIIIth nerve stimulation consisted of an early negative or positive-negative wave (presynaptic component) followed by a slow negativity (transsynaptic component). The spatial distribution of the field potential complex closely paralleled the extension of the vestibular nuclei. Mono- and polysynaptic EPSPs were recorded from vestibular neurons after ipsilateral VIIIth nerve stimulation. In some neurons early depolarizations preceded the EPSPs. These potentials may be elicited by electrical transmission. Often spikelike partial responses were superimposed on the EPSPs. It is assumed that these potentials represent dendritic spikes. Contralateral VIIIth nerve stimulation generated disynaptic and polysynaptic IPSPs in some neurons and EPSPs in others. The possible role of commissural inhibition in phylogeny is discussed. In a group of vestibular neurons stimulation of the ipsilateral VIIIth nerve evoked full action potentials with latencies ranging from 0.25-1.1msec. These potentials are caused by antidromic activation of neurons which send their axons to the labyrinth.

  18. Bilateral responses of prefrontal and motor cortices to repetitive transcranial magnetic stimulation as measured by functional near infrared spectroscopy

    Science.gov (United States)

    Tian, Fenghua; Kozel, Frank Andrew; Dhamne, Sameer; McClintock, Shawn M.; Croarkin, Paul; Mapes, Kimberly; Husain, Mustafa M.; Liu, Hanli

    2009-02-01

    Simultaneously acquiring cortical functional Near Infrared Spectroscopy (fNIRS) during repeated Transcranial Magnetic Stimulation (rTMS) offers the possibility of directly investigating the effects of rTMS on brain regions without quantifiable behavioral changes. In this study, the left motor cortex and subsequently the left prefrontal cortex were stimulated at 1 Hz while fNIRS data was simultaneously acquired. Changes in hemodynamic signals were measured on both ipsilateral and contralateral sides. In each cortex, a significantly larger decrease in the concentration of oxygenated hemoglobin and a smaller increase in the concentration of deoxygenated hemoglobin during the stimulation periods were observed in both the motor and prefrontal cortices. The ipsilateral and contralateral changes showed high temporal consistency. Same experiment was repeated for each subject 2 or 3 days later. The hemodynamic responses associated with the stimulation showed good reproducibility in two sessions. To our knowledge, this is the first report of simultaneous fNIRS measurement of ipsilateral and contralateral changes of either the motor or prefrontal cortex during rTMS stimulation.

  19. Prolonged presence of VEGF promotes vascularization in 3D bioprinted scaffolds with defined architecture

    NARCIS (Netherlands)

    Poldervaart, Michelle T; Gremmels, Hendrik; van Deventer, Kelly; Fledderus, Joost O; Oner, F Cumhur; Verhaar, Marianne C; Dhert, Wouter J A; Alblas, Jacqueline

    2014-01-01

    Timely vascularization is essential for optimal performance of bone regenerative constructs. Vascularization is efficiently stimulated by vascular endothelial growth factor (VEGF), a substance with a short half-life time. This study investigates the controlled release of VEGF from gelatin

  20. Gender-related asymmetric brain vasomotor response to color stimulation: a functional transcranial Doppler spectroscopy study

    OpenAIRE

    Njemanze Philip C

    2010-01-01

    Abstract Background and Purpose The present study was designed to examine the effects of color stimulation on cerebral blood mean flow velocity (MFV) in men and women. Methods The study included 16 (8 men and 8 women) right-handed healthy subjects. The MFV was recorded simultaneously in both right and left middle cerebral arteries in Dark and white Light conditions, and during color (Blue, Yellow and Red) stimulations, and was analyzed using functional transcranial Doppler spectroscopy (fTCDS...

  1. Online Transcranial Magnetic Stimulation Protocol for Measuring Cortical Physiology Associated with Response Inhibition.

    Science.gov (United States)

    Guthrie, Michael D; Gilbert, Donald L; Huddleston, David A; Pedapati, Ernest V; Horn, Paul S; Mostofsky, Stewart H; Wu, Steve W

    2018-02-08

    We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) characterization of primary motor cortex (M1) excitability and inhibition. Motor response inhibition prevents unwanted actions and is abnormal in several neuropsychiatric conditions. TMS is a non-invasive technology that can quantify M1 excitability and inhibition using single- and paired-pulse protocols and can be precisely timed to study cortical physiology with high temporal resolution. We modified the original Slater-Hammel (S-H) stop signal task to create a "racecar" version with TMS pulses time-locked to intra-trial events. This task is self-paced, with each trial initiating after a button push to move the racecar towards the 800 ms target. GO trials require a finger-lift to stop the racecar just before this target. Interspersed randomly are STOP trials (25%) during which the dynamically adjusted stop signal prompts subjects to prevent finger-lift. For GO trials, TMS pulses were delivered at 650 ms after trial onset; whereas, for STOP trials, the TMS pulses occurred 150 ms after the stop signal. The timings of the TMS pulses were decided based on electroencephalography (EEG) studies showing event-related changes in these time ranges during stop signal tasks. This task was studied in 3 blocks at two study sites (n=38) and we recorded behavioral performance and event-related motor-evoked potentials (MEP). Regression modelling was used to analyze MEP amplitudes using age as a covariate with multiple independent variables (sex, study site, block, TMS pulse condition [single- vs. paired-pulse], trial condition [GO, successful STOP, failed STOP]). The analysis showed that TMS pulse condition (p<0.0001) and its interaction with trial condition (p=0.009) were significant. Future applications for this online S-H/TMS paradigm include the addition of simultaneous EEG acquisition to measure TMS-evoked EEG potentials. A