WorldWideScience

Sample records for blood-retinal barrier disruption

  1. Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles.

    Directory of Open Access Journals (Sweden)

    Juyoung Park

    Full Text Available The blood-retinal barrier (BRB prevents most systemically-administered drugs from reaching the retina. This study investigated whether burst ultrasound applied with a circulating microbubble agent can disrupt the BRB, providing a noninvasive method for the targeted delivery of systemically administered drugs to the retina. To demonstrate the efficacy and reversibility of such a procedure, five overlapping targets around the optic nerve head were sonicated through the cornea and lens in 20 healthy male Sprague-Dawley rats using a 690 kHz focused ultrasound transducer. For BRB disruption, 10 ms bursts were applied at 1 Hz for 60 s with different peak rarefactional pressure amplitudes (0.81, 0.88 and 1.1 MPa. Each sonication was combined with an IV injection of a microbubble ultrasound contrast agent (Definity. To evaluate BRB disruption, an MRI contrast agent (Magnevist was injected IV immediately after the last sonication, and serial T1-weighted MR images were acquired up to 30 minutes. MRI contrast enhancement into the vitreous humor near targeted area was observed for all tested pressure amplitudes, with more signal enhancement evident at the highest pressure amplitude. At 0.81 MPa, BRB disruption was not detected 3 h post sonication, after an additional MRI contrast injection. A day after sonication, the eyes were processed for histology of the retina. At the two lower exposure levels (0.81 and 0.88 MPa, most of the sonicated regions were indistinguishable from the control eyes, although a few tiny clusters of extravasated erythrocytes (petechaie were observed. More severe retinal damage was observed at 1.1 MPa. These results demonstrate that focused ultrasound and microbubbles can offer a noninvasive and targeted means to transiently disrupt the BRB for ocular drug delivery.

  2. Lycium barbarum polysaccharides reduce neuronal damage, blood-retinal barrier disruption and oxidative stress in retinal ischemia/reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Suk-Yee Li

    Full Text Available Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R injuries. Lycium barbarum polysaccharides (LBP, extracts from the wolfberries, are good for "eye health" according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS or LBP (1 mg/kg once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP, aquaporin-4 (AQP4, poly(ADP-ribose (PAR and nitrotyrosine (NT were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL and the inner nuclear layer (INL of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.

  3. The blood-retinal barrier permeability in diabetic patients

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J

    1981-01-01

    By the of aid an extended corpus vitreum fluorophotometric technique, the blood-retinal barrier permeability for fluorescein was studied in diabetologically well characterized patients with insulin dependent diabetes mellitus. The method, which involves simultaneous determination of the fluoresce...... found in normal volunteers. Simplex retinopathy without macular oedema showed values of 2.5 . 10(-7) cm . sec-1 while simplex retinopathy with macular oedema showed P-values of 10 . 10(-7) cm . sec-1....... concentration in corpus vitreum and plasma, is described and discussed. A clear correlation was found between the degree of retinopathy and permeability (P). Patients with normal visus, ophthalmoscophy, fundus photo and fluorescence angiography exhibited P-values of 1.10(-7) cm . sec-1. This was similar to P-values...

  4. Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.

    Science.gov (United States)

    Kaya, Abdullah; Kar, Taner; Aksoy, Yakup; Özalper, Veysel; Başbuğ, Barbaros

    2013-12-01

    Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal

  5. Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction

    Science.gov (United States)

    Coburn, Phillip S.; Wiskur, Brandt J.; Miller, Frederick C.; LaGrow, Austin L.; Astley, Roger A.; Elliott, Michael H.; Callegan, Michelle C.

    2016-01-01

    The blood-retinal barrier (BRB) functions to maintain the immune privilege of the eye, which is necessary for normal vision. The outer BRB is formed by tightly-associated retinal pigment epithelial (RPE) cells which limit transport within the retinal environment, maintaining retinal function and viability. Retinal microvascular complications and RPE dysfunction resulting from diabetes and diabetic retinopathy cause permeability changes in the BRB that compromise barrier function. Diabetes is the major predisposing condition underlying endogenous bacterial endophthalmitis (EBE), a blinding intraocular infection resulting from bacterial invasion of the eye from the bloodstream. However, significant numbers of EBE cases occur in non-diabetics. In this work, we hypothesized that dysfunction of the outer BRB may be associated with EBE development. To disrupt the RPE component of the outer BRB in vivo, sodium iodate (NaIO3) was administered to C57BL/6J mice. NaIO3-treated and untreated mice were intravenously injected with 108 colony forming units (cfu) of Staphylococcus aureus or Klebsiella pneumoniae. At 4 and 6 days postinfection, EBE was observed in NaIO3-treated mice after infection with K. pneumoniae and S. aureus, although the incidence was higher following S. aureus infection. Invasion of the eye was observed in control mice following S. aureus infection, but not in control mice following K. pneumoniae infection. Immunohistochemistry and FITC-dextran conjugate transmigration assays of human RPE barriers after infection with an exoprotein-deficient agr/sar mutant of S. aureus suggested that S. aureus exoproteins may be required for the loss of the tight junction protein, ZO-1, and for permeability of this in vitro barrier. Our results support the clinical findings that for both pathogens, complications which result in BRB permeability increase the likelihood of bacterial transmigration from the bloodstream into the eye. For S. aureus, however, BRB permeability is

  6. Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction.

    Science.gov (United States)

    Coburn, Phillip S; Wiskur, Brandt J; Miller, Frederick C; LaGrow, Austin L; Astley, Roger A; Elliott, Michael H; Callegan, Michelle C

    2016-01-01

    The blood-retinal barrier (BRB) functions to maintain the immune privilege of the eye, which is necessary for normal vision. The outer BRB is formed by tightly-associated retinal pigment epithelial (RPE) cells which limit transport within the retinal environment, maintaining retinal function and viability. Retinal microvascular complications and RPE dysfunction resulting from diabetes and diabetic retinopathy cause permeability changes in the BRB that compromise barrier function. Diabetes is the major predisposing condition underlying endogenous bacterial endophthalmitis (EBE), a blinding intraocular infection resulting from bacterial invasion of the eye from the bloodstream. However, significant numbers of EBE cases occur in non-diabetics. In this work, we hypothesized that dysfunction of the outer BRB may be associated with EBE development. To disrupt the RPE component of the outer BRB in vivo, sodium iodate (NaIO3) was administered to C57BL/6J mice. NaIO3-treated and untreated mice were intravenously injected with 108 colony forming units (cfu) of Staphylococcus aureus or Klebsiella pneumoniae. At 4 and 6 days postinfection, EBE was observed in NaIO3-treated mice after infection with K. pneumoniae and S. aureus, although the incidence was higher following S. aureus infection. Invasion of the eye was observed in control mice following S. aureus infection, but not in control mice following K. pneumoniae infection. Immunohistochemistry and FITC-dextran conjugate transmigration assays of human RPE barriers after infection with an exoprotein-deficient agr/sar mutant of S. aureus suggested that S. aureus exoproteins may be required for the loss of the tight junction protein, ZO-1, and for permeability of this in vitro barrier. Our results support the clinical findings that for both pathogens, complications which result in BRB permeability increase the likelihood of bacterial transmigration from the bloodstream into the eye. For S. aureus, however, BRB permeability is

  7. Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction.

    Directory of Open Access Journals (Sweden)

    Phillip S Coburn

    Full Text Available The blood-retinal barrier (BRB functions to maintain the immune privilege of the eye, which is necessary for normal vision. The outer BRB is formed by tightly-associated retinal pigment epithelial (RPE cells which limit transport within the retinal environment, maintaining retinal function and viability. Retinal microvascular complications and RPE dysfunction resulting from diabetes and diabetic retinopathy cause permeability changes in the BRB that compromise barrier function. Diabetes is the major predisposing condition underlying endogenous bacterial endophthalmitis (EBE, a blinding intraocular infection resulting from bacterial invasion of the eye from the bloodstream. However, significant numbers of EBE cases occur in non-diabetics. In this work, we hypothesized that dysfunction of the outer BRB may be associated with EBE development. To disrupt the RPE component of the outer BRB in vivo, sodium iodate (NaIO3 was administered to C57BL/6J mice. NaIO3-treated and untreated mice were intravenously injected with 108 colony forming units (cfu of Staphylococcus aureus or Klebsiella pneumoniae. At 4 and 6 days postinfection, EBE was observed in NaIO3-treated mice after infection with K. pneumoniae and S. aureus, although the incidence was higher following S. aureus infection. Invasion of the eye was observed in control mice following S. aureus infection, but not in control mice following K. pneumoniae infection. Immunohistochemistry and FITC-dextran conjugate transmigration assays of human RPE barriers after infection with an exoprotein-deficient agr/sar mutant of S. aureus suggested that S. aureus exoproteins may be required for the loss of the tight junction protein, ZO-1, and for permeability of this in vitro barrier. Our results support the clinical findings that for both pathogens, complications which result in BRB permeability increase the likelihood of bacterial transmigration from the bloodstream into the eye. For S. aureus, however, BRB

  8. The development of blood-retinal barrier during the interaction of astrocytes with vascular wall cells

    Institute of Scientific and Technical Information of China (English)

    Huanling Yao; Tianshi Wang; Jiexin Deng; Ding Liu; Xiaofei Li; Jinbo Deng

    2014-01-01

    Astrocytes are intimately involved in the formation and development of retinal vessels. Astrocyte dysfunction is a major cause of blood-retinal barrier injury and other retinal vascular diseases. In this study, the development of the retinal vascular system and the formation of the blood-ret-inal barrier in mice were investigated using immunolfuorescence staining, gelatin-ink perfusion, and transmission electron microscopy. The results showed that the retinal vascular system of mice develops from the optic disc after birth, and radiates out gradually to cover the entire retina, taking the papilla optica as the center. First, the superifcial vasculature is formed on the inner retinal layer;then, the vasculature extends into the inner and outer edges of the retinal inner nuclear layer, forming the deep vasculature that is parallel to the superifcial vasculature. The blood-retinal barrier is mainly composed of endothelium, basal lamina and the end-feet of astrocytes, which become mature during mouse development. Initially, the naive endothelial cells were immature with few organelles and many microvilli. The basal lamina was uniform in thickness, and the glial end-feet surrounded the outer basal lamina incompletely. In the end, the blood-retinal barrier matures with smooth endothelia connected through tight junctions, rela-tively thin and even basal lamina, and relatively thin glial cell end-feet. These ifndings indicate that the development of the vasculature in the retina follows the rules of“center to periphery”and“superifcial layer to deep layers”. Its development and maturation are spatially and tempo-rally consistent with the functional performance of retinal neurons and photosensitivity. The blood-retinal barrier gradually becomes mature via the process of interactions between astro-cytes and blood vessel cells.

  9. Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J;

    1987-01-01

    The blood-retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured...... the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood-retinal barrier correlated well with changes in retinal morphology as seen...... in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5-10 times the normal value. Onset of diabetes in the decade before and after puberty did not change...

  10. A novel transgenic zebrafish model for blood-brain and blood-retinal barrier development

    Directory of Open Access Journals (Sweden)

    Sugimoto Masahiko

    2010-07-01

    Full Text Available Abstract Background Development and maintenance of the blood-brain and blood-retinal barrier is critical for the homeostasis of brain and retinal tissue. Despite decades of research our knowledge of the formation and maintenance of the blood-brain (BBB and blood-retinal (BRB barrier is very limited. We have established an in vivo model to study the development and maintenance of these barriers by generating a transgenic zebrafish line that expresses a vitamin D-binding protein fused with enhanced green fluorescent protein (DBP-EGFP in blood plasma, as an endogenous tracer. Results The temporal establishment of the BBB and BRB was examined using this transgenic line and the results were compared with that obtained by injection of fluorescent dyes into the sinus venosus of embryos at various stages of development. We also examined the expression of claudin-5, a component of tight junctions during the first 4 days of development. We observed that the BBB of zebrafish starts to develop by 3 dpf, with expression of claudin-5 in the central arteries preceding it at 2 dpf. The hyaloid vasculature in the zebrafish retina develops a barrier function at 3 dpf, which endows the zebrafish with unique advantages for studying the BRB. Conclusion Zebrafish embryos develop BBB and BRB function simultaneously by 3 dpf, which is regulated by tight junction proteins. The Tg(l-fabp:DBP-EGFP zebrafish will have great advantages in studying development and maintenance of the blood-neural barrier, which is a new application for the widely used vertebrate model.

  11. Plasmalemma Vesicle-Associated Protein Has a Key Role in Blood-Retinal Barrier Loss.

    Science.gov (United States)

    Wisniewska-Kruk, Joanna; van der Wijk, Anne-Eva; van Veen, Henk A; Gorgels, Theo G M F; Vogels, Ilse M C; Versteeg, Danielle; Van Noorden, Cornelis J F; Schlingemann, Reinier O; Klaassen, Ingeborg

    2016-04-01

    Loss of blood-retinal barrier (BRB) properties induced by vascular endothelial growth factor (VEGF) and other factors is an important cause of diabetic macular edema. Previously, we found that the presence of plasmalemma vesicle-associated protein (PLVAP) in retinal capillaries associates with loss of BRB properties and correlates with increased vascular permeability in diabetic macular edema. In this study, we investigated whether absence of PLVAP protects the BRB from VEGF-induced permeability. We used lentiviral-delivered shRNA or siRNA to inhibit PLVAP expression. The barrier properties of in vitro BRB models were assessed by measuring transendothelial electrical resistance, permeability of differently sized tracers, and the presence of endothelial junction complexes. The effect of VEGF on caveolae formation was studied in human retinal explants. BRB loss in vivo was studied in the mouse oxygen-induced retinopathy model. The inhibition of PLVAP expression resulted in decreased VEGF-induced BRB permeability of fluorescent tracers, both in vivo and in vitro. PLVAP inhibition attenuated transendothelial electrical resistance reduction induced by VEGF in BRB models in vitro and significantly increased transendothelial electrical resistance of the nonbarrier human umbilical vein endothelial cells. Furthermore, PLVAP knockdown prevented VEGF-induced caveolae formation in retinal explants but did not rescue VEGF-induced alterations in endothelial junction complexes. In conclusion, PLVAP is an essential cofactor in VEGF-induced BRB permeability and may become an interesting novel target for diabetic macular edema therapy.

  12. Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration.

    Science.gov (United States)

    Gu, Xiaowu; Fliesler, Steven J; Zhao, You-Yang; Stallcup, William B; Cohen, Alex W; Elliott, Michael H

    2014-02-01

    Blood-retinal barrier (BRB) breakdown and related vascular changes are implicated in several ocular diseases. The molecules and mechanisms regulating BRB integrity and pathophysiology are not fully elucidated. Caveolin-1 (Cav-1) ablation results in loss of caveolae and microvascular pathologies, but the role of Cav-1 in the retina is largely unknown. We examined BRB integrity and vasculature in Cav-1 knockout mice and found a significant increase in BRB permeability, compared with wild-type controls, with branch veins being frequent sites of breakdown. Vascular hyperpermeability occurred without apparent alteration in junctional proteins. Such hyperpermeability was not rescued by inhibiting eNOS activity. Veins of Cav-1 knockout retinas exhibited additional pathological features, including i) eNOS-independent enlargement, ii) altered expression of mural cell markers (eg, down-regulation of NG2 and up-regulation of αSMA), and iii) dramatic alterations in mural cell phenotype near the optic nerve head. We observed a significant NO-dependent increase in retinal artery diameter in Cav-1 knockout mice, suggesting that Cav-1 plays a role in autoregulation of resistance vessels in the retina. These findings implicate Cav-1 in maintaining BRB integrity in retinal vasculature and suggest a previously undefined role in the retinal venous system and associated mural cells. Our results are relevant to clinically significant retinal disorders with vascular pathologies, including diabetic retinopathy, uveoretinitis, and primary open-angle glaucoma.

  13. The blood-retinal barrier permeability to fluorescein in normal subjects and in juvenile diabetics without retinopathy

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J;

    1986-01-01

    The blood-retinal barrier permeability to fluorescein was determined in 20 eyes from 17 normal volunteers (mean age 31 years) and in 20 eyes from 19 juvenile diabetics without apparent retinopathy (mean age 35 years - mean duration of diabetes 6 years). The permeability was in normal subjects (1...... coefficient in the vitreous body was determined and juvenile diabetics without apparent retinopathy showed a diffusion coefficient of (0.80 +/- 0.25) X 10(-5) cm2/sec (mean +/- 2 X SD), which was the same as in normals where the diffusion coefficient was (0.69 +/- 0.46) X 10(-5) cm2/sec (mean +/- 2 X SD)....

  14. Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood-Retinal Barrier and in the Liver.

    Science.gov (United States)

    Kubo, Yoshiyuki; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi

    2016-01-01

    Cumulative studies showed that taurine (2-aminoethanesulfonic acid) contributes to a variety of physiological events. Transport study suggested the cellular taurine transport in an Na(+)- and Cl(-)-dependent manner, and the several members of SLC6A family have been shown as taurine transporter. At the inner blood-retinal barrier (BRB), taurine transporter (TauT/SLC6A) is involved in the transport of taurine to the retina from the circulating blood. The involvement of TauT is also suggested in γ-aminobutyric acid (GABA) transport at the inner BRB, and its role is assumed in the elimination of GABA from the retinal interstitial fluid. In the retina, taurine is thought to be a major organic osmolyte, and its influx and efflux through TauT and volume-sensitive organic osmolyte and anion channel (VSOAC) in Müller cells regulate the osmolarity in the retinal microenvironment to maintain a healthy retina. In the liver, hepatocytes take up taurine via GABA transporter 2 (GAT2/SLC6A13, the orthologue of mouse GAT3) expressed at the sinusoidal membrane of periportal hepatocytes, contributing to the metabolism of bile acid. Site-directed mutagenesis study suggests amino acid residues that are crucial in the recognition of substrates by GATs and TauT. The evidence suggests the physiological impact of taurine transporters in tissues.

  15. Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes

    Science.gov (United States)

    Singh, Pawan Kumar; Guest, John-Michael; Kanwar, Mamta; Gao, Nan; Juzych, Mark S.; Abrams, Gary W.; Yu, Fu-Shin

    2017-01-01

    Zika virus (ZIKV) is an important pathogen that causes not only neurologic, but also ocular, abnormalities. Thus, it is imperative that models to study ZIKV pathogenesis in the eye are developed to identify potential targets for interventions. Here, we studied ZIKV interactions with human retinal cells and evaluated ZIKV’s pathobiology in mouse eyes. We showed that cells lining the blood-retinal barrier (BRB), the retinal endothelium, and retinal pigment epithelium (RPE) were highly permissive and susceptible to ZIKV-induced cell death. Direct inoculation of ZIKV in eyes of adult C57BL/6 and IFN-stimulated gene 15 (ISG15) KO mice caused chorioretinal atrophy with RPE mottling, a common ocular manifestation of congenital ZIKV infection in humans. This response was associated with induced expression of multiple inflammatory and antiviral (IFNs) response genes in the infected mouse retina. Interestingly, ISG15 KO eyes exhibited severe chorioretinitis, which coincided with increased retinal cell death and higher ZIKV replication. Collectively, our study provides the first evidence to our knowledge that ZIKV causes retinal lesions and infects the cells lining the BRB and that ISG15 plays a role in retinal innate defense against ZIKV infection. Our mouse model can be used to study mechanisms underlying ZIKV-induced chorioretinitis and to gauge ocular antiviral therapies. PMID:28239662

  16. Effect of Chinese medicine Qidengmingmu capsule on the STZ induced hyperglycemia rat's blood-retinal barrier

    Directory of Open Access Journals (Sweden)

    Fu-Wen Zhang

    2013-06-01

    Full Text Available AIM: To observe retinal vessel leakage of streptozotocin(STZinduced diabetic rat, and the effect of traditional Chinese medicine on it. METHODS: We induced diabetic rat model by peritoneal injection of STZ, after the blood glucose raised, we used Evans blue to trace the leakage of blood-retina barrier(BRBevery month. After blood glucose rose three months later, we treated the Chinese medicine group diabetic rat with Qidengmingmu capsule. There were three groups of different dose, low dose group of 125mg/kg, middle dose group of 250mg/kg, high dose group of 500mg/kg. The control group was treated with calcium dobesilate(200mg/kg. After three months treated by medicine, the leakage of rat blood-retina barrier was evaluated. RESULTS: The damage of BRB and visual function occurred at two week after the blood glucose rose, and the damage aggravated with the continuing of high diabetic. But after the Chinese medicine treated three months, the rat's retina vessel leakage was reduced. CONCLUSION: BRB break down and visual acuity damage appears in early phase of STZ diabetic rat and get worse as the hyperglycemia keep on. The Chinese medicine Qidengmingmu capsule can prevent the vessel leakage by damage of BRB.

  17. Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress

    Directory of Open Access Journals (Sweden)

    David eArredondo Zamarripa

    2014-10-01

    Full Text Available Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK production contributes to the increased transport through the blood-retina barrier (BRB in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC, blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19 cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies.

  18. Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3.

    Directory of Open Access Journals (Sweden)

    Yagna P R Jarajapu

    Full Text Available Previously, we showed that insulin growth factor (IGF-1 binding protein-3 (IGFBP-3, independent of IGF-1, reduces pathological angiogenesis in a mouse model of the oxygen-induced retinopathy (OIR. The current study evaluates novel endothelium-dependent functions of IGFBP-3 including blood retinal barrier (BRB integrity and vasorelaxation. To evaluate vascular barrier function, either plasmid expressing IGFBP-3 under the regulation of an endothelial-specific promoter or a control plasmid was injected into the vitreous humor of mouse pups (P1 and compared to the non-injected eyes of the same pups undergoing standard OIR protocol. Prior to sacrifice, the mice were given an injection of horseradish peroxidase (HRP. IGFBP-3 plasmid-injected eyes displayed near-normal vessel morphology and enhanced vascular barrier function. Further, in vitro IGFBP-3 protects retinal endothelial cells from VEGF-induced loss of junctional integrity by antagonizing the dissociation of the junctional complexes. To assess the vasodilatory effects of IGFBP-3, rat posterior cerebral arteries were examined in vitro. Intraluminal IGFBP-3 decreased both pressure- and serotonin-induced constrictions by stimulating nitric oxide (NO release that were blocked by L-NAME or scavenger receptor-B1 neutralizing antibody (SRB1-Ab. Both wild-type and IGF-1-nonbinding mutant IGFBP-3 (IGFBP-3NB stimulated eNOS activity/NO release to a similar extent in human microvascular endothelial cells (HMVECs. NO release was neither associated with an increase in intracellular calcium nor decreased by Ca(2+/calmodulin-dependent protein kinase II (CamKII blockade; however, dephosphorylation of eNOS-Thr(495 was observed. Phosphatidylinositol 3-kinase (PI3K activity and Akt-Ser(473 phosphorylation were both increased by IGFBP-3 and selectively blocked by the SRB1-Ab or PI3K blocker LY294002. In conclusion, IGFBP-3 mediates protective effects on BRB integrity and mediates robust NO release to stimulate

  19. Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Nianting Tong

    Full Text Available BACKGROUND AND PURPOSE: Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. METHODS: Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB extravasation was determined to assess blood-retinal barrier (BRB disruption and the structure of tight junctions (TJ was examined by transmission electron microscopy. RESULTS: Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1 and occludin protein expression and decreased VEGF/PEDF ratio. CONCLUSIONS: Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.

  20. Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model

    Directory of Open Access Journals (Sweden)

    Rui-Jin Ran

    2016-11-01

    Full Text Available AIM: To examine the expression of high mobility group box-1 (HMGB-1 and intercellular adhesion molecule-1 (ICAM-1 in the retina and the hippocampal tissues; and further to evaluate the association of these two molecules with the alterations of blood-retinal barrier (BRB and blood-brain barrier (BBB in a rat model of type 2 diabetes. METHODS: The type-2 diabetes mellitus (DM model was established with a high-fat and high-glucose diet combined with streptozotocin (STZ. Sixteen weeks after DM induction, morphological changes of retina and hippocampus were observed with hematoxylin-eosin staining, and alternations of BRB and BBB permeability were measured using Evans blue method. Levels of HMGB-1 and ICAM-1 in retina and hippocampus were detected by Western blot. Serum HMGB-1 levels were determined by enzyme-linked immunosorbent assay (ELISA. RESULTS: A significantly higher serum fasting blood glucose level in DM rats was observed 2wk after STZ injection (P<0.01. The serum levels of fasting insulin, Insulin resistance homeostatic model assessment (IRHOMA, total cholesterol (TC, total triglycerides (TG and low density lipoprotein cholesterol (LDL-C in the DM rats significantly higher than those in the controls (all P<0.01. HMGB-1 (0.96±0.03, P<0.01 and ICAM-1 (0.76±0.12, P<0.05 levels in the retina in the DM rats were significantly higher than those in the controls. HMGB-1 (0.83±0.13, P<0.01 and ICAM-1 (1.15±0.08, P<0.01 levels in the hippocampal tissues in the DM rats were also significantly higher than those in the controls. Sixteen weeks after induction of DM, the BRB permeability to albumin-bound Evans blue dye in the DM rats was significantly higher than that in the controls (P<0.01. However, there was no difference of BBB permeability between the DM rats and controls. When compared to the controls, hematoxylin and eosin staining showed obvious irregularities in the DM rats. CONCLUSION: BRB permeability increases significantly

  1. Blood-retinal barrier glycerol permeability in diabetic macular edema and healthy eyes: estimations from macular volume changes after peroral glycerol

    DEFF Research Database (Denmark)

    Thornit, Dorte Nellemann; Vinten, Carl Martin; Sander, Birgit

    2010-01-01

    PURPOSE: To compare the changes in macular volume (MV) between healthy subjects and patients with diabetic macular edema (DME) after an osmotic load and to determine the glycerol permeability (P(gly)) of the blood-retinal barrier (BRB). METHODS: In this unmasked study, 13 patients with DME and 5...... model of glycerol and osmotic water movements across the BRB was constructed to estimate P(gly). RESULTS: Median MV decreased from 7.30 mm(3) (range, 6.68-7.35) to the maximum median DeltaMV of -0.30 mm(3) (25%-75% quartile: -0.34 to -0.25) in the healthy volunteers and from 7.97 mm(3) (range, 6...

  2. The biocompatibility of a polyelectrolyte vitreous body substitute on a high resistance in vitro model of the blood-retinal barrier.

    Science.gov (United States)

    Strotmann, Falko; Wolf, Isabel; Galla, Hans-Joachim

    2013-09-01

    The vitreous body can be regarded as a fascinating simple but important tissue, since it represents the main compartment of the eye and plays a crucial role for proper vision. Several diseases require its removal with following substitution using a liquid artificial vitreous body replacement. We explore the biocompatibility of a poly(AMPS-Na(+))-graft-poly(NIPAAm) polyelectrolyte following the innovative concept of thermo-responsive behaviour, exhibiting enhanced shear viscosity at physiological temperatures. As a powerful model for the blood-retinal barrier, we use the well-established in vitro cell culture model based on highly differentiated porcine brain capillary endothelial cells. Via the quantification of the transendothelial electrical resistance and immunocytochemical staining of tight junction proteins, we are able to show that a barrier integrity affecting impact of the polyelectrolyte was only transient and nearly reversible. Furthermore, the polyelectrolyte hydrogel is characterized by the absence of any acute cell morphology, cell vitality or proliferation affecting impacts. It does not trigger acute apoptotic processes, as can be substantiated via caspase-3 activity and DNA fragmentation assays. In view of the results of this study, it is shown that the polyelectrolyte does not affect the vitality parameters of our porcine brain capillary endothelial cells. It can be suggested that the tested thermo-responsive polyelectrolyte does not affect the sensitive retinal barrier integrity. Thus from the cellular tolerance it might serve as a potential liquid artificial vitreous body replacement to overcome the most prominent difficulties of common vitreal endotamponades.

  3. Down-regulation of pigment epithelium-derived factor in uveitic lesion associates with focal vascular endothelial growth factor expression and breakdown of the blood-retinal barrier.

    Science.gov (United States)

    Deeg, Cornelia A; Altmann, Frank; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius

    2007-05-01

    Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Identifying biological markers or pathways associated with this disease may allow the understanding of its pathogenesis at a molecular level. The vitreous is the body fluid closest to the disease-affected tissue and possibly also an effector of pathological processes relevant for ERU. Surgical removal of vitreous leads to cessation of relapses in spontaneous uveitis of both man and horse, therefore vitreous composites are likely to contribute to disease progression. Uveitic vitreous is likely to contain potential biomarkers in relatively undiluted quantities. With the goal to identify these markers, we systematically compared vitreous from healthy and disease-affected eyes by proteomic profiling. Nine differentially expressed proteins were identified, that are functionally related to immune response, inflammation, and maintenance of the blood-retinal barrier. One of these, pigment epithelium-derived factor, a protein involved in maintaining a proper blood-retina barrier as well as protecting from neoangiogenesis was additionally found to be down-regulated within uveitic retinal lesions whereas, conversely, vascular endothelial growth factor was found to be up-regulated at these sites. Together, these changes point to as of yet undiscovered biological pathways involved in the pathogenesis of this autoimmune disease.

  4. Consumption of Polyphenol-Rich Zingiber Zerumbet Rhizome Extracts Protects against the Breakdown of the Blood-Retinal Barrier and Retinal Inflammation Induced by Diabetes

    Directory of Open Access Journals (Sweden)

    Thing-Fong Tzeng

    2015-09-01

    Full Text Available The present study investigates the amelioration of diabetic retinopathy (DR by Zingiber zerumbet rhizome ethanol extracts (ZZRext in streptozotocin-induced diabetic rats (STZ-diabetic rats. ZZRext contains high phenolic and flavonoid contents. STZ-diabetic rats were treated orally with ZZRext (200, 300 mg/kg per day for three months. Blood-retinal barrier (BRB breakdown and increased vascular permeability were found in diabetic rats, with downregulation of occludin, and claudin-5. ZZRext treatment effectively preserved the expression of occludin, and claudin-5, leading to less BRB breakdown and less vascular permeability. Retinal histopathological observation showed that the disarrangement and reduction in thickness of retinal layers were reversed in ZZRext-treated diabetic rats. Retinal gene expression of tumor necrosis factor-α, interleukin (IL-1β, IL-6, vascular endothelial growth factor, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were all decreased in ZZRext-treated diabetic rats. Moreover, ZZRext treatment not only inhibited the nuclear factor κB (NF-κB activation, but also downregulated the protein expression of p38 mitogen-activated protein kinase (MAPK in diabetic retina. In conclusion, the results suggest that the retinal protective effects of ZZRext occur through improved retinal structural change and inhibiting retinal inflammation. The antiretinopathy property of ZZRext might be related to the downregulation of p38 MAPK and NF-κB signal transduction induced by diabetes.

  5. Intravenously administered gold nanoparticles pass through the blood-retinal barrier depending on the particle size, and induce no retinal toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jeong Hun; Kim, Jin Hyoung; Yu, Young Suk [Department of Ophthalmology, Seoul National University College of Medicine and Seoul Artificial Eye Center, Clinical Research Institute, Seoul National University Hospital, Seoul 151744 (Korea, Republic of); Kim, Kyu-Won [NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151742 (Korea, Republic of); Kim, Myung Hun, E-mail: hunin315@paran.com, E-mail: ysyu@snu.ac.kr [Department of Chemistry, Yonsei University, 134 Shinchon-dong, Seodaemun-ku, Seoul 120749 (Korea, Republic of)

    2009-12-16

    The retina maintains homeostasis through the blood-retinal barrier (BRB). Although it is ideal to deliver the drug to the retina via systemic administration, it is still challenging due to the BRB strictly regulating permeation from blood to the retina. Herein, we demonstrated that intravenously administered gold nanoparticles could pass through the BRB and are distributed in all retinal layers without cytotoxicity. After intravenous injection of gold nanoparticles into C57BL/6 mice, 100 nm nanoparticles were not detected in the retina whereas 20 nm nanoparticles passed through the BRB and were distributed in all retinal layers. 20 nm nanoparticles in the retina were observed in neurons (75 {+-} 5%), endothelial cells (17 {+-} 6%) and peri-endothelial glial cells (8 {+-} 3%), where nanoparticles were bound on the membrane. In the retina, cells containing nanoparticles did not show any structural abnormality and increase of cell death compared to cells without nanoparticles. Gold nanoparticles never affected the viability of retinal endothelial cells, astrocytes and retinoblastoma cells. Furthermore, gold nanoparticles never led to any change in expression of representative biological molecules including zonula occludens-1 and glut-1 in retinal endothelial cells, neurofilaments in differentiated retinoblastoma cells and glial fibrillary acidic protein in astrocytes. Therefore, our data suggests that small gold nanoparticles (20 nm) could be an alternative for drug delivery across the BRB, which could be safely applied in vivo.

  6. Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy.

    Directory of Open Access Journals (Sweden)

    Sampathkumar Rangasamy

    Full Text Available Inflammation in the diabetic retina is mediated by leukocyte adhesion to the retinal vasculature and alteration of the blood-retinal barrier (BRB. We investigated the role of chemokines in the alteration of the BRB in diabetes. Animals were made diabetic by streptozotocin injection and analyzed for gene expression and monocyte/macrophage infiltration. The expression of CCL2 (chemokine ligand 2 was significantly up-regulated in the retinas of rats with 4 and 8 weeks of diabetes and also in human retinal endothelial cells treated with high glucose and glucose flux. Additionally, diabetes or intraocular injection of recombinant CCL2 resulted in increased expression of the macrophage marker, F4/80. Cell culture impedance sensing studies showed that purified CCL2 was unable to alter the integrity of the human retinal endothelial cell barrier, whereas monocyte conditioned medium resulted in significant reduction in cell resistance, suggesting the relevance of CCL2 in early immune cell recruitment for subsequent barrier alterations. Further, using Cx3cr1-GFP mice, we found that intraocular injection of CCL2 increased retinal GFP+ monocyte/macrophage infiltration. When these mice were made diabetic, increased infiltration of monocytes/macrophages was also present in retinal tissues. Diabetes and CCL2 injection also induced activation of retinal microglia in these animals. Quantification by flow cytometry demonstrated a two-fold increase of CX3CR1+/CD11b+ (monocyte/macrophage and microglia cells in retinas of wildtype diabetic animals in comparison to control non-diabetic ones. Using CCL2 knockout (Ccl2-/- mice, we show a significant reduction in retinal vascular leakage and monocyte infiltration following induction of diabetes indicating the importance of this chemokine in alteration of the BRB. Thus, CCL2 may be an important therapeutic target for the treatment of diabetic macular edema.

  7. Hyperthermia of magnetic nanoparticles allows passage of sodium fluorescein and Evans blue dye across the blood-retinal barrier.

    Science.gov (United States)

    Tabatabaei, Seyed Nasrollah; Tabatabaei, Maryam Sadat; Girouard, Hélène; Martel, Sylvain

    2016-09-01

    The blood-retina barrier (BRB) is a biological barrier consisting of tightly interconnected endothelial cells inside the retinal vascular network that protects the neural tissue from harmful pathogens and neurotoxic molecules circulating in the bloodstream. Unfortunately, with regard to retinoblastoma, this barrier also prevents systemically administered therapeutics reaching the retinal tissue. In this study we introduce a novel technique to locally and transiently increase BRB permeability for drug delivery using hyperthermia of magnetic nanoparticles (MNPs). An alternating current (AC) magnetic field was used to induce hyperthermia of locally injected MNPs in the left ophthalmic artery of a rat model. To improve adherence on the surface of the endothelium, commercially available MNPs coated with human transferrin glycoproteins were used. After hyperthermia we assessed the extravasation of systemically injected sodium fluorescein (NaF) as well as Evans blue dye (EBD) into the retinal tissue. Spectrofluorometry and fluorescent microscopy image analysis show a significant increase of dye penetration in the retina where hyperthermia of MNPs was applied. Our proposed new technique can allow both small and large dye molecules to cross the BRB. While the results are preliminary and thorough evaluation of the retinal tissue following hyperthermia is necessary, this technique has the potential to be an effective mean for the treatment of various diseases such as retinoblastoma.

  8. Β-alanine and l-histidine transport across the inner blood-retinal barrier: potential involvement in L-carnosine supply.

    Science.gov (United States)

    Usui, Takuya; Kubo, Yoshiyuki; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi

    2013-08-01

    The supply of L-carnosine, a bioactive dipeptide of β-alanine and l-histidine, to the retina across the blood-retinal barrier (BRB) was studied. The in vivo and in vitro studies revealed low uptake activities for [(3)H]Gly-Sar, a representative dipeptide, suggesting that l-carnosine transport plays only a minor role at the BRB. The in vivo study using rats showed approximately 18- and 23-fold greater retinal uptake indexes (RUI) for [(3)H]β-alanine and [(3)H]l-histidine compared with that of a paracellular marker, respectively. The RUI of [(3)H]β-alanine was taurine- and γ-aminobutyric acid-sensitive, and the in vitro uptake by TR-iBRB2 cells showed time- concentration- and temperature-dependent [(3)H]β-alanine uptake, suggesting that a carrier-mediated process was involved in β-alanine transport across the inner BRB. [(3)H]β-Alanine uptake was inhibited by taurine and β-guanidinopropionic acid, suggesting that taurine transporter (TAUT/SLC6A6) is responsible for the influx transport of β-alanine across the inner BRB. Regarding l-histidine, the l-leucine-sensitive RUI of [(3)H]l-histidine was identified, and the in vitro [(3)H]l-histidine uptake by TR-iBRB2 cells suggested that a carrier-mediated process was involved in l-histidine transport across the inner BRB. The inhibition profile suggested that L-type amino acid transporter (LAT1/SLC7A5) is responsible for the influx transport of l-histidine across the inner BRB. These results show that the influx transports of β-alanine and l-histidine across the inner BRB is carried out by TAUT and LAT1, respectively, suggesting that the retinal l-carnosine is supplied by enzymatic synthesis from two kinds of amino acids transported across the inner BRB.

  9. Trityl dyes patent blue V and brilliant blue G - clinical relevance and in vitro analysis of the function of the outer blood-retinal barrier.

    Science.gov (United States)

    Mennel, Stefan; Meyer, Carsten H; Schmidt, Jörg C; Kaempf, Stefanie; Thumann, Gabriele

    2008-01-01

    The use of vital dyes during vitrectomy allows easier removal of less recognizable structures like epiretinal membranes or the internal limiting membrane (ILM). In recent years, numerous studies have investigated the use of indocyanine green (ICG), trypan blue (Membrane Blue), triamcinolone, autologous blood and presently trityl dyes such as patent blue V (PBV, Blueron), crystal violet and brilliant blue G (BBG, Brilliant Peel) in chromovitrectomy. Reports on potential risks of these dyes, especially ICG, such as reduced visual acuity, possible visual field defects or alterations of the retinal pigment epithelium (RPE) limited their application. A systematic review of the literature up to July 2007 was performed using Medline (http://www.ncbi.nlm.nih.gov/ PubMed/) where we specifically searched for relevant information regarding the laboratory as well as clinical use of PB and BBG. To evaluate the effect of PB and BBG on the RPE, PB and BBG have been added to an in vitro model of the outer blood-retinal barrier to assess dye-associated barrier properties. Two concentrations of PB (2.4 and 1.2 mg/ml) and BBG (0.25 and 2.4 mg/ml) were investigated. To simulate in vivo conditions of a fluid-filled eye and an air-filled eye the dyes were added either to the culture medium or directly to the RPE cells where they remained for 2.5 min. To determine barrier properties, transepithelial resistance (TER) was measured at 3 days of follow-up. Ultrastructural integrity of RPE cells was evaluated by transmission electron microscopy. Following application of PB, barrier properties in the fluid- as well as in the air-filled eye showed only mild, transient and no significant decrease in TER. BBG did not cause a breakdown of the outer bloodretinal barrier at the concentration of 0.25 mg/ml in the model of the fluid-filled eye. The concentration of 2.4 mg/ml in the model of the fluid-filled eye as well as both concentrations in the model of the air-filled eye showed a minor decrease

  10. "Targeted disruption of the epithelial-barrier by Helicobacter pylori"

    Directory of Open Access Journals (Sweden)

    Wroblewski Lydia E

    2011-11-01

    Full Text Available Abstract Helicobacter pylori colonizes the human gastric epithelium and induces chronic gastritis, which can lead to gastric cancer. Through cell-cell contacts the gastric epithelium forms a barrier to protect underlying tissue from pathogenic bacteria; however, H. pylori have evolved numerous strategies to perturb the integrity of the gastric barrier. In this review, we summarize recent research into the mechanisms through which H. pylori disrupts intercellular junctions and disrupts the gastric epithelial barrier.

  11. "Targeted disruption of the epithelial-barrier by Helicobacter pylori"

    OpenAIRE

    Wroblewski Lydia E; Peek Richard M

    2011-01-01

    Abstract Helicobacter pylori colonizes the human gastric epithelium and induces chronic gastritis, which can lead to gastric cancer. Through cell-cell contacts the gastric epithelium forms a barrier to protect underlying tissue from pathogenic bacteria; however, H. pylori have evolved numerous strategies to perturb the integrity of the gastric barrier. In this review, we summarize recent research into the mechanisms through which H. pylori disrupts intercellular junctions and disrupts the gas...

  12. Effect of Chinese medicine Qidengmingmu capsule on the STZ induced hyperglycemia rat's blood-retinal barrier%芪灯明目胶囊对高血糖大鼠血视网膜屏障影响的研究

    Institute of Scientific and Technical Information of China (English)

    张富文; 段俊国; 赵凌; 路雪婧; 李强

    2013-01-01

    目的:观察链脲佐菌素(STZ)诱发糖尿病大鼠在造模后血-视网膜屏障(blood-retina barrier,BRB)变化情况,并以阳性药为对照研究中药芪灯明目胶囊对STZ诱发糖尿病大鼠的视网膜血管渗漏影响.方法:采用STZ腹腔注射制作糖尿病大鼠模型,在造模后6mo内各时点(2wk;1,2,3,4,5,6mo)采用伊文思蓝灌注示踪显示血-视网膜的渗漏情况,在造模后3mo开始用中药芪灯明目胶囊(低中高剂量组分别给予125,250,500mg/kg体质量剂量的胶囊内容物灌胃),对照组用安多明胶囊(200mg/kg体质量剂量,相当于10倍成人剂量),灌胃3mo,观察药物对 BRB的影响.结果:STZ糖尿病大鼠在2wk即可出现BRB的损害,并随着高血糖状态的持续而不断加重.对造模3mo STZ糖尿病模型大鼠连续灌胃中药芪灯治疗3mo,结果提示:中药芪灯对STZ糖尿病BRB有保护作用,可明显减少视网膜血管的渗漏.结论:STZ糖尿病模型大鼠在早期即可出现BRB损害,并随着高血糖的持续而加重,中药芪灯明目胶囊可减少高血糖导致的BRB损害.%AIM: To observe retinal vessel leakage of streptozotocin (STZ) induced diabetic rat, and the effect of traditional Chinese medicine on it.METHODS: We induced diabetic rat model by peritoneal injection of STZ, after the blood glucose raised, we used Evans blue to trace the leakage of blood - retina barrier (BRB) every month. After blood glucose rose three months later, we treated the Chinese medicine group diabetic rat with Qidengmingmu capsule. There were three groups of different dose, low dose group of 125mg/kg, middle dose group of 250mg/kg, high dose group of 500mg/kg. The control group was treated with calcium dobesilate (200mg/kg). After three months treated by medicine, the leakage of rat blood - retina barrier was evaluated.RESULTS: The damage of BRB and visual function occurred at two week after the blood glucose rose, and the damage aggravated with the continuing of high diabetic

  13. Cytotoxity of HIV-1 gp120 protein on human blood-retinal barrier ceils%HIV-1 gp120蛋白对人血-视网膜屏障细胞的毒性作用

    Institute of Scientific and Technical Information of China (English)

    林浩添; 张振平; 余秋蓉; 晏丕松; 汪琪璘; 柏凌

    2009-01-01

    Objective To study the mechanism of human blood-retina barrier (BRB) destroyed by HIV- 1 gp120 protein. Methods Human blood-retina barrier cells (HBRBCs) including human retina capillary endothelial cells (HRCECs), human retina capillary perieytes (HRCPCs), human retinal pigment epithelium (HRPE) were primarily cultured. Culture media were regarded as eontrol. MTT method was used to observe the inhibition effect of HIV-1 gp120 protein on eell viability at 7 different concentrations (0.01 to 0.15 mg/L) for 24 h, and at a fixed concentration(0.08 mg/L) for different times (4-72 h). After 0.08, 0.1, 0.12 and 0.15 mg/L HIV- 1 gp120 protein were applied in those cells for 24 h, cell apoptotie rates and membrane potential of mitochondria (△ψm) were measured by flow eytometry. Activation of Cleaved caspase-9 was detected by Western blot. Change of cell mierostructure with 0.08mg/L HIV-1 gp120 protein before and after 24 h was detected by transmission electron microscopy (TEM). Results Concentration of HIV-1 gp120 protein less than 0.08 mg/L did not influence cell viability at 24 h. But at the concentration of more than 0.08 mg/L, HIV-1 gp120 protein could obviously inhibit HBRBCs proliferation with a concentration-dependent manner(HRCECs: r=-0.763, P<0.01 ; HRCPCs: r=-0.804, P<0.01 ; HRPE: r=-0.698, P<0.01). HIV-1 gp120 protein(0.08 mg/L) significantly inhibited cells proliferation at 12 h, and this inhibition effect was more stronger at 24,48,72 h with a time-dependent increase (HRCECs: r=-0.833, P<0.01 ; HRCPCs: r=-0.784, P<0.01 ; HRPE: r=-0.701, P<0.01). The relative growth rates were HRCECs: 84%, 70%, 41%, 22% ; HRCPCs: 80%, 69%, 38%, 18% ; HRPE: 86%, 73%, 45%, 26% respectively. Compared with control group, the ratio of apoptotic cells of HBRBCs and expression level of Cleaved caspase-9 protein increased but △ψm decreased at different concentrations with HIV-1 gp120 protein treatment for 24 h. The changes of these indexes were all concentration-dependent manner

  14. Skin barrier disruption by acetone: observations in a hairless mouse skin model

    NARCIS (Netherlands)

    Rissmann, R.; Oudshoorn, M.H.M.; Hennink, W.E.; Ponec, M.; Bouwstra, J.A.

    2009-01-01

    To disrupt the barrier function of the skin, different in vivo methods have been established, e.g., by acetone wiping or tape-stripping. In this study, the acetone-induced barrier disruption of hairless mice was investigated in order to establish a reliable model to study beneficial, long-term effec

  15. Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

    Directory of Open Access Journals (Sweden)

    Analiz Rodriguez

    2015-08-01

    Full Text Available The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB. We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE. These technologies can lead to transient BBB and blood–brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal.

  16. Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions.

    Science.gov (United States)

    Miclescu, Adriana; Sharma, Hari Shanker; Martijn, Cécile; Wiklund, Lars

    2010-11-01

    To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. Randomized, prospective, laboratory animal study. University-affiliated research laboratory. Forty-five piglets. Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. An increase of injured neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p blue treatment reduced cerebral tissue nitrite/nitrate content (p blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites.

  17. Disruption of barrier function in dermatophytosis and pityriasis versicolor.

    Science.gov (United States)

    Lee, Weon Ju; Kim, Jun Young; Song, Chang Hyun; Jung, Hong Dae; Lee, Su Hyun; Lee, Seok-Jong; Kim, Do Won

    2011-11-01

    Dermatophytes have the ability to form molecular attachments to keratin and use it as a source of nutrients, colonizing keratinized tissues, including the stratum corneum of the skin. Malassezia species also affect the stratum corneum of the skin. Therefore, dermatophytosis and pityriasis versicolor of the skin are thought to be important factors of profound changes in skin barrier structure and function. We aimed to describe the changes in transepidermal water loss (TEWL), stratum corneum hydration, and skin pH in the lesions of the dermatophytosis and pityriasis versicolor. Thirty-six patients with dermatophytosis (14 with tinea cruris, 13 with tinea corporis and nine with tinea pedis or tinea manus) and 11 patients with pityriasis versicolor were included in this study. TEWL, stratum corneum conductance and skin pH were determined by biophysical methods to examine whether our patients exhibited changes in barrier function. Dermatophytosis and pityriasis versicolor except tinea pedis and tinea manus showed highly significant increase in TEWL compared with adjacent infection-free skin. Hydration was significantly reduced in lesional skin compared with adjacent infection-free skin. From this study, infections with dermatophytes and Malassezia species on the body can alter biophysical properties of the skin, especially the function of stratum corneum as a barrier to water loss. On the contrary, infections with dermatophytes on the palms and soles little affect the barrier function of the skin. © 2011 Japanese Dermatological Association.

  18. Quantifying the evolution of vascular barrier disruption in advanced atherosclerosis with semipermeant nanoparticle contrast agents.

    Directory of Open Access Journals (Sweden)

    Huiying Zhang

    Full Text Available RATIONALE: Acute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment. OBJECTIVE: To develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques. METHODS AND RESULTS: Sustained hypercholesterolemia in New Zealand White (NZW rabbits for >7-14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo, but not younger plaques (<3 mo demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine ((19F magnetic resonance imaging and spectroscopy (MRI/MRS enabled absolute quantification (in nanoMolar of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP. CONCLUSIONS: The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the

  19. Loss of ceramide synthase 3 causes lethal skin barrier disruption.

    Science.gov (United States)

    Jennemann, Richard; Rabionet, Mariona; Gorgas, Karin; Epstein, Sharon; Dalpke, Alexander; Rothermel, Ulrike; Bayerle, Aline; van der Hoeven, Franciscus; Imgrund, Silke; Kirsch, Joachim; Nickel, Walter; Willecke, Klaus; Riezman, Howard; Gröne, Hermann-Josef; Sandhoff, Roger

    2012-02-01

    The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (≥C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.

  20. Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury.

    Science.gov (United States)

    Kumar, Hemant; Ropper, Alexander E; Lee, Soo-Hong; Han, Inbo

    2016-05-18

    The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.

  1. Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo.

    Science.gov (United States)

    Ashina, Kohei; Tsubosaka, Yoshiki; Nakamura, Tatsuro; Omori, Keisuke; Kobayashi, Koji; Hori, Masatoshi; Ozaki, Hiroshi; Murata, Takahisa

    2015-01-01

    Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

  2. Biomarkers Indicative of Blood-Brain Barrier Disruption in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Emmanuelle Waubant

    2006-01-01

    Full Text Available Blood-brain barrier (BBB disruption is one of the hallmarks of multiple sclerosis (MS. It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS. The presence of gadolinium enhancing (Gd+ lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1 improve the monitoring of disease activity; 2 improve the monitoring of response to MS therapies which target BBB disruption; and 3 advance our understanding of dynamic MS processes participating in BBB disruption.

  3. The effects of barrier disruption and moisturization on the dynamic drying mechanics of human stratum corneum.

    Science.gov (United States)

    Liu, X; German, G K

    2015-09-01

    We study the dynamic drying mechanics of human stratum corneum, the most superficial layer of skin and essential physical and chemical barrier to the external environment. Barrier disruption caused by a depletion of lipids ordinarily found in healthy stratum corneum can occur with ageing, aggressive cleansing or with dry skin disorders and diseases such as atopic dermatitis and psoriasis. We establish the effects of severe barrier disruption on the dynamic drying mechanics of human stratum corneum by measuring variations in thickness and spatially resolved in-plane displacements in healthy and lipid depleted tissue samples drying in controlled environmental conditions. In-plane displacements recorded at regular intervals during drying are azimuthally averaged and fitted with a profile based on a linear elastic model. The measured thickness of the tissue sample is accounted for in each model fit. Dynamic variations in the drying stress and elastic modulus of the tissue are then established from the model fits. We find that barrier disruption causes dramatic reductions in drying timescales, increases in the elastic modulus of the tissue and larger drying stresses. We expect these changes to increase the propensity for cracking and chapping in skin. The maximum elastic modulus and drying stress of barrier disrupted stratum corneum (ESC=85.4±6.8 MPa, PSC=10.9±0.9 MPa) is reduced to levels comparable with stratum corneum containing lipids (ESC=26.1±3.2 MPa, PSC=2.58±0.45 MPa) after treatment with a 5% aqueous solution of glycerol. Neither 2% nor 5% glycerol solutions slow the accelerated drying timescales in barrier disrupted stratum corneum.

  4. Fibronectin changes in eosinophilic meningitis with blood-CSF barrier disruption.

    Science.gov (United States)

    Shyu, Ling-Yuh; Hu, Ming-E; Chou, Chun-Hui; Chen, Ke-Min; Chiu, Ping-Sung; Lai, Shih-Chan

    2015-01-01

    Fibronectin, which is present at relatively low levels in healthy central nervous systems (CNS), shows increased levels in meningitis. In this study, fibronectin processing was correlated with the increased permeability of the blood-cerebrospinal fluid (CSF) barrier as well as with the formation of eosinophil infiltrates in angiostrongyliasis meningitis. The immunohistochemistry results show matrix metalloproteinase-9 (MMP-9) is localized in the choroid plexus epithelium. Coimmunoprecipitation demonstrated fibronectin strongly binds MMP-9. Furthermore, treatment with the MMP-9 inhibitor GM6001 significantly inhibited fibronectin processing, reduced the blood-CSF barrier permeability, and decreased the eosinophil counts. The decreased fibronectin processing in CSF implies decreased cellular invasion of the subarachnoid space across the blood-CSF barrier. Therefore, increased fibronectin processing may be associated with barrier disruption and participate in the extravasation and migration of eosinophils into the CNS during experimental parasitic infection.

  5. Connexin 43 reboots meiosis and reseals blood-testis barrier following toxicant-mediated aspermatogenesis and barrier disruption.

    Science.gov (United States)

    Li, Nan; Mruk, Dolores D; Mok, Ka-Wai; Li, Michelle W M; Wong, Chris K C; Lee, Will M; Han, Daishu; Silvestrini, Bruno; Cheng, C Yan

    2016-04-01

    Earlier studies have shown that rats treated with an acute dose of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (adjudin, a male contraceptive under development) causes permanent infertility due to irreversible blood-testis barrier (BTB) disruption even though the population of undifferentiated spermatogonia remains similar to normal rat testes, because spermatogonia fail to differentiate into spermatocytes to enter meiosis. Since other studies have illustrated the significance of connexin 43 (Cx43)-based gap junction in maintaining the homeostasis of BTB in the rat testis and the phenotypes of Sertoli cell-conditional Cx43 knockout mice share many of the similarities of the adjudin-treated rats, we sought to examine if overexpression of Cx43 in these adjudin-treated rats would reseal the disrupted BTB and reinitiate spermatogenesis. A full-length Cx43 cloned into mammalian expression vector pCI-neo was used to transfect testes of adjudin-treated ratsversusempty vector. It was found that overexpression of Cx43 indeed resealed the Sertoli cell tight junction-permeability barrier based on a functionalin vivoassay in tubules displaying signs of meiosis as noted by the presence of round spermatids. Thus, these findings suggest that overexpression of Cx43 reinitiated spermatogenesis at least through the steps of meiosis to generate round spermatids in testes of rats treated with an acute dose of adjudin that led to aspermatogenesis. It was also noted that the round spermatids underwent eventual degeneration with the formation of multinucleated cells following Cx43 overexpression due to the failure of spermiogenesis because no elongating/elongated spermatids were detected in any of the tubules examined. The mechanism by which overexpression of Cx43 reboots meiosis and rescues BTB function was also examined. In summary, overexpression of Cx43 in the testis with aspermatogenesis reboots meiosis and reseals toxicant-induced BTB disruption, even though it fails to

  6. Comparison of blood-brain barrier disruption by intracarotid iopamidol and methylglucamine iothalamate.

    Science.gov (United States)

    Sage, M R; Wilcox, J; Evill, C A; Benness, G T

    1983-01-01

    Using a canine model, the effect of intracarotid injections of the ionic contrast medium methylglucamine iothalamate was compared with that of the nonionic contrast medium iopamidol of similar iodine concentration (280 mg 1/ml). The degree and distribution of blood-brain barrier disruption was assessed using Evans blue stain as a visual marker and by contrast enhancement measured by a computed tomographic (CT) scanner. In all studies with methylglucamine iothalamate, Evans blue staining was demonstrated, and CT enhancement demonstrated a significant mean difference (p less than 0.01) between the control and injected hemispheres. The absence of blood-brain barrier disruption with iopamidol is probably related to its lower osmolality (570 mosmol/kg) compared with methylglucamine iothalamate (1,424 mosmol/kg) and the absence of any cation.

  7. Sensing of EGTA Mediated Barrier Tissue Disruption with an Organic Transistor

    Directory of Open Access Journals (Sweden)

    Scherrine Tria

    2013-01-01

    Full Text Available Barrier tissue protects the body against external factors by restricting the passage of molecules. The gastrointestinal epithelium is an example of barrier tissue with the primary purpose of allowing the passage of ions and nutrients, while restricting the passage of pathogens and toxins. It is well known that the loss of barrier function can be instigated by a decrease in extracellular calcium levels, leading to changes in protein conformation and an increase in paracellular transport. In this study, ethylene glycol-bis(beta-aminoethyl ether-N,N,N',N'-tetra acetic acid (EGTA, a calcium chelator, was used to disrupt the gastrointestinal epithelial barrier. The effect of EGTA on barrier tissue was monitored by a novel label-free method based on an organic electrochemical transistor (OECT integrated with living cells and validated against conventional methods for measuring barrier tissue integrity. We demonstrate that the OECT can detect breaches in barrier tissue upon exposure to EGTA with the same sensitivity as existing methods but with increased temporal resolution. Due to the potential of low cost processing techniques and the flexibility in design associated with organic electronics, the OECT has great potential for high-throughput, disposable sensing and diagnostics.

  8. Liposomal membrane disruption by means of miniaturized dielectric-barrier discharge in air: liposome characterization

    Science.gov (United States)

    Svarnas, P.; Asimakoulas, L.; Katsafadou, M.; Pachis, K.; Kostazos, N.; Antimisiaris, S. G.

    2017-08-01

    The increasing interest of the plasma community in the application of atmospheric-pressure cold plasmas to bio-specimen treatment has led to the creation of the emerging field of plasma biomedicine. Accordingly, plasma setups based on dielectric-barrier discharges have already been widely tested for the inactivation of various cells. Most of these systems refer to the plasma jet concept where noble gases penetrate atmospheric air and are subjected to the influence of high electric fields, thus forming guided streamers. Following the original works of our group where liposomal membranes were proposed as models for studying the interaction between plasma jets and cells, we present herein a study on liposomal membrane disruption by means of miniaturized dielectric-barrier discharge running in atmospheric air. Liposomal membranes of various lipid compositions, lamellarities, and sizes are treated at different times. It is shown that the dielectric-barrier discharge of low mean power leads to efficient liposomal membrane disruption. The latter is achieved in a controllable manner and depends on liposome properties. Additionally, it is clearly demonstrated that liposomal membrane disruption takes place even after plasma extinction, i.e. during post-treatment, resembling thus an ‘apoptosis’ effect, which is well known today mainly for cell membranes. Thus, the adoption of the present concept would be beneficial for tailoring studies on plasma-treated cell-mimics. Finally, the liposome treatment is discussed with respect to possible physicochemical mechanisms and potential discharge modification due to the various compositions of the liquid electrode.

  9. Non-Saccharomyces yeasts protect against epithelial cell barrier disruption induced by Salmonella enterica subsp. enterica serovar Typhimurium

    DEFF Research Database (Denmark)

    Smith, Ida Mosbech; Baker, A; Arneborg, Nils

    2015-01-01

    UNLABELLED: The human gastrointestinal epithelium makes up the largest barrier separating the body from the external environment. Whereas invasive pathogens cause epithelial barrier disruption, probiotic micro-organisms modulate tight junction regulation and improve epithelial barrier function....... In addition, probiotic strains may be able to reduce epithelial barrier disruption caused by pathogenic species. The aim of this study was to explore non-Saccharomyces yeast modulation of epithelial cell barrier function in vitro. Benchmarking against established probiotic strains, we evaluated the ability......). In addition, our data demonstrate significant yeast-mediated modulation of Salmonella-induced epithelial cell barrier disruption and identify K. marxianus and Metschnikowia gruessii as two non-Saccharomyces yeasts capable of protecting human epithelial cells from pathogen invasion. SIGNIFICANCE AND IMPACT...

  10. Lipopolysaccharide disrupts the milk-blood barrier by modulating claudins in mammary alveolar tight junctions.

    Directory of Open Access Journals (Sweden)

    Ken Kobayashi

    Full Text Available Mastitis, inflammation of the mammary gland, is the most costly common disease in the dairy industry, and is caused by mammary pathogenic bacteria, including Escherichia coli. The bacteria invade the mammary alveolar lumen and disrupt the blood-milk barrier. In normal mammary gland, alveolar epithelial tight junctions (TJs contribute the blood-milk barrier of alveolar epithelium by blocking the leakage of milk components from the luminal side into the blood serum. In this study, we focused on claudin subtypes that participate in the alveolar epithelial TJs, because the composition of claudins is an important factor that affects TJ permeability. In normal mouse lactating mammary glands, alveolar TJs consist of claudin-3 without claudin-1, -4, and -7. In lipopolysaccharide (LPS-induced mastitis, alveolar TJs showed 2-staged compositional changes in claudins. First, a qualitative change in claudin-3, presumably caused by phosphorylation and participation of claudin-7 in alveolar TJs, was recognized in parallel with the leakage of fluorescein isothiocyanate-conjugated albumin (FITC-albumin via the alveolar epithelium. Second, claudin-4 participated in alveolar TJs with claudin-3 and claudin-7 12 h after LPS injection. The partial localization of claudin-1 was also observed by immunostaining. Coinciding with the second change of alveolar TJs, the severe disruption of the blood-milk barrier was recognized by ectopic localization of β-casein and much leakage of FITC-albumin. Furthermore, the localization of toll-like receptor 4 (TLR4 on the luminal side and NFκB activation by LPS was observed in the alveolar epithelial cells. We suggest that the weakening and disruption of the blood-milk barrier are caused by compositional changes of claudins in alveolar epithelial TJs through LPS/TLR4 signaling.

  11. Assessment of skin barrier function and biochemical changes of ex vivo human skin in response to physical and chemical barrier disruption.

    Science.gov (United States)

    Döge, Nadine; Avetisyan, Araks; Hadam, Sabrina; Pfannes, Eva Katharina Barbosa; Rancan, Fiorenza; Blume-Peytavi, Ulrike; Vogt, Annika

    2016-12-21

    Topical dermatotherapy is intended to be used on diseased skin. Novel drug delivery systems even address differences between intact and diseased skin underlining the need for pre-clinical assessment of different states of barrier disruption. Herein, we studied how short-term incubation in culture media compared to incubation in humidified chambers affects human skin barrier function and viability. On both models we assessed different types and intensities of physical and chemical barrier disruption methods with regard to structural integrity, biophysical parameters and cytokine levels. Tissue degeneration and proliferative activity limited the use of tissue cultures to 48h. Viability is better preserved in cultured tissue. Tape-stripping (50×TS) and 4h sodium lauryl sulfate (SLS) pre-treatment were identified as highly reproducible and effective procedures for barrier disruption. Transepidermal water loss (TEWL) values reproducibly increased with the intensity of disruption while sebum content and skin surface pH were of limited value. Interleukin (IL)-6/8 and various chemokines and proteases were increased in tape-stripped skin which was more pronounced in SLS-treated skin tissue extracts. Thus, albeit limited to 48h, cultured full-thickness skin maintained several barrier characteristics and responded to different intensities of barrier disruption. Potentially, these models can be used to assess pre-clinically the efficacy and penetration of anti-inflammatory compounds.

  12. Protective effects of nonionic tri-block copolymers on bile acid-mediated epithelial barrier disruption.

    Energy Technology Data Exchange (ETDEWEB)

    Edelstein, A.; Fink, D.; Musch, M.; Valuckaite, V.; Zabornia, O.; Grubjesic, S.; Firestone, M. A.; Matthews, J. B.; Alverdy, J. C. (Materials Science Division); (Univ. of Chicago)

    2011-11-01

    Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.

  13. Disruption of the blood-brain barrier exacerbates spreading depression in the locust CNS.

    Science.gov (United States)

    Spong, Kristin E; Rochon-Terry, Geneviève; Money, Tomas G A; Robertson, R Meldrum

    2014-07-01

    In response to cellular stress in the nervous system of the locust (Locusta migratoria) neural function is interrupted in association with ionic disturbances propagating throughout nervous tissue (Spreading depression; SD). The insect blood-brain barrier (BBB) plays a critical role in the regulation of ion levels within the CNS. We investigated how a disruption in barrier function by transient exposure to 3M urea affects locusts' vulnerability to disturbances in ion levels. Repetitive SD was induced by bath application of ouabain and the extracellular potassium concentration ([K(+)]o) within the metathoracic ganglion (MTG) was monitored. Urea treatment increased the susceptibility to ouabain and caused a progressive impairment in the ability to maintain baseline [K(+)]o levels during episodes of repetitive SD. Additionally, using a within animal protocol we demonstrate that waves of SD, induced by high K(+), propagate throughout the MTG faster following disruption of the BBB. Lastly, we show that targeting the BBB of intact animals reduces their ability to sustain neural function during anoxic conditions. Our findings indicate that locust's ability to withstand stress is diminished following a reduction in barrier function likely due to an impairment of the ability of neural tissue to maintain ionic gradients.

  14. Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

    Science.gov (United States)

    Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

    2016-02-01

    The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue.

  15. Implications of MMP9 for Blood Brain Barrier Disruption And Hemorrhagic Transformation Following Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Renee Jade Turner

    2016-03-01

    Full Text Available Numerous studies have documented increases in matrix metalloproteinases (MMPs, specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB, increased risk of hemorrhagic complications and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke.

  16. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

    Science.gov (United States)

    Turner, Renée J.; Sharp, Frank R.

    2016-01-01

    Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke. PMID:26973468

  17. Myosin light chain kinase mediates intestinal barrier disruption following burn injury.

    Directory of Open Access Journals (Sweden)

    Chuanli Chen

    Full Text Available BACKGROUND: Severe burn injury results in the loss of intestinal barrier function, however, the underlying mechanism remains unclear. Myosin light chain (MLC phosphorylation mediated by MLC kinase (MLCK is critical to the pathophysiological regulation of intestinal barrier function. We hypothesized that the MLCK-dependent MLC phosphorylation mediates the regulation of intestinal barrier function following burn injury, and that MLCK inhibition attenuates the burn-induced intestinal barrier disfunction. METHODOLOGY/PRINCIPAL FINDINGS: Male balb/c mice were assigned randomly to either sham burn (control or 30% total body surface area (TBSA full thickness burn without or with intraperitoneal injection of ML-9 (2 mg/kg, an MLCK inhibitor. In vivo intestinal permeability to fluorescein isothiocyanate (FITC-dextran was measured. Intestinal mucosa injury was assessed histologically. Tight junction proteins ZO-1, occludin and claudin-1 was analyzed by immunofluorescent assay. Expression of MLCK and phosphorylated MLC in ileal mucosa was assessed by Western blot. Intestinal permeability was increased significantly after burn injury, which was accompanied by mucosa injury, tight junction protein alterations, and increase of both MLCK and MLC phosphorylation. Treatment with ML-9 attenuated the burn-caused increase of intestinal permeability, mucosa injury, tight junction protein alterations, and decreased MLC phosphorylation, but not MLCK expression. CONCLUSIONS/SIGNIFICANCE: The MLCK-dependent MLC phosphorylation mediates intestinal epithelial barrier dysfunction after severe burn injury. It is suggested that MLCK-dependent MLC phosphorylation may be a critical target for the therapeutic treatment of intestinal epithelial barrier disruption after severe burn injury.

  18. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

    Science.gov (United States)

    Hougaard, Anders; Amin, Faisal M; Christensen, Casper E; Younis, Samaira; Wolfram, Frauke; Cramer, Stig P; Larsson, Henrik B W; Ashina, Messoud

    2017-06-01

    See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier

  19. MRI study on reversible and irreversible electroporation induced blood brain barrier disruption.

    Directory of Open Access Journals (Sweden)

    Mohammad Hjouj

    Full Text Available Electroporation, is known to induce cell membrane permeabilization in the reversible (RE mode and cell death in the irreversible (IRE mode. Using an experimental system designed to produce a continuum of IRE followed by RE around a single electrode we used MRI to study the effects of electroporation on the brain. Fifty-four rats were injected with Gd-DOTA and treated with a G25 electrode implanted 5.5 mm deep into the striata. MRI was acquired immediately after treatment, 10 min, 20 min, 30 min, and up to three weeks following the treatment using: T1W, T2W, Gradient echo (GE, serial SPGR (DCE-MRI with flip angles ranging over 5-25°, and diffusion-weighted MRI (DWMRI. Blood brain barrier (BBB disruption was depicted as clear enhancement on T1W images. The average signal intensity in the regions of T1-enhancement, representing BBB disruption, increased from 1887±83 (arbitrary units immediately post treatment to 2246±94 20 min post treatment, then reached a plateau towards the 30 min scan where it reached 2289±87. DWMRI at 30 min showed no significant effects. Early treatment effects and late irreversible damage were clearly depicted on T2W. The enhancing volume on T2W has increased by an average of 2.27±0.27 in the first 24-48 hours post treatment, suggesting an inflammatory tissue response. The permanent tissue damage, depicted as an enhancing region on T2W, 3 weeks post treatment, decreased to an average of 50±10% of the T2W enhancing volumes on the day of the treatment which was 33±5% of the BBB disruption volume. Permanent tissue damage was significantly smaller than the volume of BBB disruption, suggesting, that BBB disruption is associated with RE while tissue damage with IRE. These results demonstrate the feasibility of applying reversible and irreversible electroporation for transient BBB disruption or permanent damage, respectively, and applying MRI for planning/monitoring disruption volume/shape by optimizing electrode positions

  20. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

    Science.gov (United States)

    Wang, Yue; Jin, Shijie; Sonobe, Yoshifumi; Cheng, Yi; Horiuchi, Hiroshi; Parajuli, Bijay; Kawanokuchi, Jun; Mizuno, Tetsuya; Takeuchi, Hideyuki; Suzumura, Akio

    2014-01-01

    The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.

  1. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

    Directory of Open Access Journals (Sweden)

    Yue Wang

    Full Text Available The blood-brain barrier (BBB is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β, a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.

  2. Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ghribi Othman

    2008-04-01

    Full Text Available Abstract High levels of serum cholesterol and disruptions of the blood brain barrier (BBB have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease.

  3. Bacterial induction of Snail1 contributes to blood-brain barrier disruption

    Science.gov (United States)

    Kim, Brandon J.; Hancock, Bryan M.; Bermudez, Andres; Cid, Natasha Del; Reyes, Efren; van Sorge, Nina M.; Lauth, Xavier; Smurthwaite, Cameron A.; Hilton, Brett J.; Stotland, Aleksandr; Banerjee, Anirban; Buchanan, John; Wolkowicz, Roland; Traver, David; Doran, Kelly S.

    2015-01-01

    Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein–encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens. PMID:25961453

  4. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  5. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  6. Selective disruption of the blood-brain barrier by photochemical internalization

    Science.gov (United States)

    Hirschberg, Henry; Zhang, Michelle J.; Gach, Michael H.; Uzal, Francisco A.; Chighvinadze, David; Madsen, Steen J.

    2009-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of photochemical internalization (PCI) to selectively disrupt the BBB in rats. This will permit access of anti-cancer drugs to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: PCI treatment, coupling a macromolecule therapy of Clostridium perfringens (Cl p) epsilon prototoxin with AlPcS2a-PDT, was performed on non-tumor bearing inbred Fisher rats. T1-weighted post-contrast magnetic resonance imaging (MRI) scans were used to evaluate the extent of BBB disruption which can be inferred from the volume contrast enhancement. Results: The synergistic effect of PCI to disrupt the BBB was observed at a fluence level of 1 J with an intraperitoneal injection of Cl p prototoxin. At the fluence level of 2.5J, the extent of BBB opening induced by PCI was similar to the result of PDT suggesting no synergistic effect evoked under these conditions. Conclusion: PCI was found to be highly effective and efficient for inducing selective and localized disruption of the BBB. The extent of BBB opening peaked on day 3 and the BBB was completed restored by day 18 post treatment.

  7. Disruption of the leptomeningeal blood barrier in neuromyelitis optica spectrum disorder

    Science.gov (United States)

    Flanagan, Eoin P.; Fujihara, Kazuo; Kim, Ho Jin; Skejoe, Hanne P.; Wuerfel, Jens; Kuroda, Hiroshi; Kim, Su Hyun; Maillart, Elisabeth; Marignier, Romain; Pittock, Sean J.; Paul, Friedemann; Weinshenker, Brian G.

    2017-01-01

    Objective: To describe leptomeningeal blood-barrier impairment reflected by MRI gadolinium-enhanced lesions in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)–positive neuromyelitis optica spectrum disorder (NMOSD). Methods: A retrospective case series of 11 AQP4-IgG–positive NMOSD patients with leptomeningeal enhancement (LME) were collected from 5 centers. External neuroradiologists, blinded to the clinical details, evaluated MRIs. Results: LME was demonstrated on postcontrast T1-weighted and fluid-attenuated inversion recovery images as a sign of leptomeningeal blood-barrier disruption and transient leakage of contrast agent into the subarachnoid space in 11 patients, 6 in the brain and 6 in the spinal cord. The patterns of LME were linear or extensive and were accompanied by periependymal enhancement in 5 cases and intraparenchymal enhancement in all cases. The location of LME in the spinal cord was adjacent to intraparenchymal contrast enhancement with involvement of a median number of 12 (range 5–17) vertebral segments. At the time of LME on MRI, all patients had a clinical attack such as encephalopathy (36%) and/or myelopathy (70%) with median interval between symptom onset and LME of 12 days (range 2–30). LME occurred in association with an initial area postrema attack (44%), signs of systemic infection (33%), or AQP4-IgG in CSF (22%) followed by clinical progression. LME was found at initial clinical presentation in 5 cases and at clinical relapses leading to a diagnosis of NMOSD in 6 cases. Conclusion: This study suggests that altered leptomeningeal blood barrier may be accompanied by intraparenchymal blood-brain barrier breakdown in patients with AQP4-IgG–positive NMOSD during relapses. PMID:28451627

  8. Disruption of the blood-brain barrier in Parkinson's disease: curse or route to a cure?

    Science.gov (United States)

    Lee, Heyne; Pienaar, Ilse S

    2014-01-01

    The vertebrate blood-brain barrier (BBB) is critical for ensuring the maintenance of brain homeostasis, whilst protecting the brain against toxic insults. Various pathological events disrupt BBB integrity, holding several important clinical implications. In instances where the normal mechanisms controlling passage of substances into the brain are compromised, these could sensitize or even worsen endogenous pathological conditions. Recognition has grown recently that patients diagnosed with Parkinson's disease (PD) present with concurrent medical problems, including cerebrovascular lesions. However, cerebrovascular disturbances may also result from PD-related disease processes; the pathological mechanisms which could entail interaction between environment-derived and genetic factors. The current review addresses the accumulation of studies aimed at better understanding the series of processes affecting the neurovascular unit in human Parkinsonism, due in part to the BBB presenting as a formidable opponent in the effective delivery of therapeutics that have shown promise as therapeutic strategies for treating aspects of PD when tested in vitro.

  9. Hantavirus-induced disruption of the endothelial barrier: Neutrophils are on the payroll

    Directory of Open Access Journals (Sweden)

    Günther eSchönrich

    2015-03-01

    Full Text Available Viral hemorrhagic fever caused by hantaviruses is an emerging infectious disease for which suita-ble treatments are not available. In order to improve this situation a better understanding of han-taviral pathogenesis is urgently required. Hantaviruses infect endothelial cell layers in vitro with-out causing any cytopathogenic effect and without increasing permeability. This implies that the mechanisms underlying vascular hyperpermeability in hantavirus-associated disease are more complex and that immune mechanisms play an important role. In this review we highlight the lat-est developments in hantavirus-induced immunopathogenesis. A possible contribution of neutro-phils has been neglected so far. For this reason, we place special emphasis on the pathogenic role of neutrophils in disrupting the endothelial barrier.

  10. MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage.

    Science.gov (United States)

    Klei, Linda R; Hu, Dong; Panek, Robert; Alfano, Danielle N; Bridwell, Rachel E; Bailey, Kelly M; Oravecz-Wilson, Katherine I; Concel, Vincent J; Hess, Emily M; Van Beek, Matthew; Delekta, Phillip C; Gu, Shufang; Watkins, Simon C; Ting, Adrian T; Gough, Peter J; Foley, Kevin P; Bertin, John; McAllister-Lucas, Linda M; Lucas, Peter C

    2016-09-27

    Microvascular endothelial cells maintain a tight barrier to prevent passage of plasma and circulating immune cells into the extravascular tissue compartment, yet endothelial cells respond rapidly to vasoactive substances, including thrombin, allowing transient paracellular permeability. This response is a cornerstone of acute inflammation, but the mechanisms responsible are still incompletely understood. Here, we demonstrate that thrombin triggers MALT1 to proteolytically cleave cylindromatosis (CYLD). Fragmentation of CYLD results in microtubule disruption and a cascade of events leading to endothelial cell retraction and an acute permeability response. This finding reveals an unexpected role for the MALT1 protease, which previously has been viewed mostly as a driver of pro-inflammatory NF-κB signaling in lymphocytes. Thus, MALT1 not only promotes immune cell activation but also acutely regulates endothelial cell biology, actions that together facilitate tissue inflammation. Pharmacologic inhibition of MALT1 may therefore have synergistic impact by targeting multiple disparate steps in the overall inflammatory response.

  11. MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage

    Directory of Open Access Journals (Sweden)

    Linda R. Klei

    2016-09-01

    Full Text Available Microvascular endothelial cells maintain a tight barrier to prevent passage of plasma and circulating immune cells into the extravascular tissue compartment, yet endothelial cells respond rapidly to vasoactive substances, including thrombin, allowing transient paracellular permeability. This response is a cornerstone of acute inflammation, but the mechanisms responsible are still incompletely understood. Here, we demonstrate that thrombin triggers MALT1 to proteolytically cleave cylindromatosis (CYLD. Fragmentation of CYLD results in microtubule disruption and a cascade of events leading to endothelial cell retraction and an acute permeability response. This finding reveals an unexpected role for the MALT1 protease, which previously has been viewed mostly as a driver of pro-inflammatory NF-κB signaling in lymphocytes. Thus, MALT1 not only promotes immune cell activation but also acutely regulates endothelial cell biology, actions that together facilitate tissue inflammation. Pharmacologic inhibition of MALT1 may therefore have synergistic impact by targeting multiple disparate steps in the overall inflammatory response.

  12. Effect of "rose essential oil" inhalation on stress-induced skin-barrier disruption in rats and humans.

    Science.gov (United States)

    Fukada, Mika; Kano, Eri; Miyoshi, Michio; Komaki, Ryoichi; Watanabe, Tatsuo

    2012-05-01

    In stressed animals, several brain regions (e.g., hypothalamic paraventricular nucleus [PVN]) exhibit neuronal activation, which increases plasma adrenocorticotropic hormone (ACTH) and glucocorticoids. We previously reported that so-called "green odor" inhibits stress-induced activation of the hypothalamo-pituitary-adrenocortical axis (HPA axis) and thereby prevents the chronic stress-induced disruption of the skin barrier. Here, we investigated whether rose essential oil, another sedative odorant, inhibits the stress-induced 1) increases in PVN neuronal activity in rats and plasma glucocorticoids (corticosterone [CORT] in rats and cortisol in humans) and 2) skin-barrier disruption in rats and humans. The results showed that in rats subjected to acute restraint stress, rose essential oil inhalation significantly inhibited the increase in plasma CORT and reduced the increases in the number of c-Fos-positive cells in PVN. Inhalation of rose essential oil significantly inhibited the following effects of chronic stress: 1) the elevation of transepidermal water loss (TEWL), an index of the disruption of skin-barrier function, in both rats and humans and 2) the increase in the salivary concentration of cortisol in humans. These results suggest that in rats and humans, chronic stress-induced disruption of the skin barrier can be limited or prevented by rose essential oil inhalation, possibly through its inhibitory effect on the HPA axis.

  13. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

    Directory of Open Access Journals (Sweden)

    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  14. Consequences of repeated blood-brain barrier disruption in football players.

    Directory of Open Access Journals (Sweden)

    Nicola Marchi

    Full Text Available The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT scans. Players from three college football teams were enrolled (total of 67 volunteers. None of the players experienced a concussion. Blood samples were collected before and after games (n = 57; the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games. A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10. Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes.

  15. Consequences of Repeated Blood-Brain Barrier Disruption in Football Players

    Science.gov (United States)

    Puvenna, Vikram; Janigro, Mattia; Ghosh, Chaitali; Zhong, Jianhui; Zhu, Tong; Blackman, Eric; Stewart, Desiree; Ellis, Jasmina; Butler, Robert; Janigro, Damir

    2013-01-01

    The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes. PMID:23483891

  16. Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review

    Directory of Open Access Journals (Sweden)

    Anna K. Heye

    2014-01-01

    Full Text Available There is increasing recognition of the importance of blood–brain barrier (BBB disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated KTrans values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimer's disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI.

  17. Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review

    Science.gov (United States)

    Heye, Anna K.; Culling, Ross D.; Valdés Hernández, Maria del C.; Thrippleton, Michael J.; Wardlaw, Joanna M.

    2014-01-01

    There is increasing recognition of the importance of blood–brain barrier (BBB) disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI) is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated KTrans values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimer's disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI. PMID:25379439

  18. Disruption of the blood brain barrier following ALA mediated photodynamic therapy

    Science.gov (United States)

    Hirschberg, Henry; Peng, Qian; Uzal, Francisco A.; Chighvinadze, David; Zhang, Michelle J.; Madsen, Steen J.

    2008-02-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to tumor cells as well as degradation of the blood brain barrier (BBB). We have evaluated the ability of ALA mediated PDT to open the BBB in rats. This will permit access of chemotherapeutic agents to brain tumor cells remaining in the resection cavity wall, but limit their penetration into normal brain remote from the site of illumination. Materials and Methods: ALA-PDT was performed on non tumor bearing inbred Fisher rats at increasing fluence levels. T2 weighted MRI scans were used to evaluate edema formation and post-contrast T I MRI scans were used to monitor the degree BBB disruption which could be inferred from the intensity and volume of the contrast agent visualized. Results. PDT at increasing fluence levels between 9J and 26J demonstrated an increasing contrast flow rate. No effect on the BBB was observed if 26J of light were given in the absence of ALA. A similar increased contrast volume was observed with increasing fluence rates. The BBB was found to be disrupted 2hrs. following PDT and 80-100% restored 72hrs later. Conclusion: PDT was highly effective in opening the BBB in a limited region of the brain. The degradation of the BBB was temporary in nature, opening rapidly following treatment and significantly restored during the next 72 hrs.

  19. Protection of human corneal epithelial cells from TNF-α-induced disruption of barrier function by rebamipide.

    Science.gov (United States)

    Kimura, Kazuhiro; Morita, Yukiko; Orita, Tomoko; Haruta, Junpei; Takeji, Yasuhiro; Sonoda, Koh-Hei

    2013-04-17

    TNF-α disrupts the barrier function of cultured human corneal epithelial (HCE) cells. We investigated the effects of the cytoprotective drug rebamipide on this barrier disruption by TNF-α as well as on corneal epithelial damage in a rat model of dry eye. The barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance. The distribution of tight-junction (ZO-1, occludin) and adherens-junction (E-cadherin, β-catenin) proteins, and the p65 subunit of nuclear factor-κB (NF-κB) was determined by immunofluorescence microscopy. Expression of junctional proteins as well as phosphorylation of the NF-κB inhibitor IκB-α and myosin light chain (MLC) were examined by immunoblot analysis. A rat model of dry eye was developed by surgical removal of exorbital lacrimal glands. Rebamipide inhibited the disruption of barrier function as well as the downregulation of ZO-1 expression, and the disappearance of ZO-1 from the interfaces of neighboring HCE cells induced by TNF-α. It also inhibited the phosphorylation and downregulation of IκB-α, the translocation of p65 to the nucleus, the formation of actin stress fibers, and the phosphorylation of MLC induced by TNF-α in HCE cells. Treatment with rebamipide eyedrops promoted the healing of corneal epithelial defects as well as attenuated the loss of ZO-1 from the surface of corneal epithelial cells in rats. Rebamipide protects corneal epithelial cells from the TNF-α-induced disruption of barrier function by maintaining the distribution and expression of ZO-1 as well as the organization of the actin cytoskeleton. Rebamipide is, thus, a potential drug for preventing or ameliorating the loss of corneal epithelial barrier function associated with ocular inflammation.

  20. Capsaicin pretreatment prevents disruption of the blood-aqueous barrier in the rabbit eye

    Energy Technology Data Exchange (ETDEWEB)

    Bynke, G.

    1983-06-01

    Capsaicin, the irritating agent of red pepper, produces ocular inflammation through a neurogenic mechanism. The present study is concerned with the long-term effects of capsaicin pretreatment on the capacity of the eye to respond to different inflammatory stimuli. Following retrobulbar injection of capsaicin to rabbits the aqueous flare response induced by subsequent infrared irradiation (IR) of the iris, subcutaneously administered alpha-melanocyte-stimulating hormone (alpha-MSH) and exogenously administered prostaglandin E2 (PGE2) was reduced greatly. In the case of IR and alpha-MSH the reduced responsiveness was manifest for several weeks after capsaicin pretreatment, involving first the capsaicin-treated eye, but later also the contralateral control eye. After 2-3 months the aqueous flare response was normal in both eyes. In the case of PGE2 the responsiveness was reduced for a shorter time; after 3 weeks the response was normal in both eyes. The results indicate that all three stimuli tested are at least partly dependent upon an intact sensory innervation to disrupt the blood-aqueous barrier, but that the mechanism of action of PGE2 is different from that of IR and alpha-MSH.

  1. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Shaheen E Lakhan

    2013-04-01

    Full Text Available Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue-type plasminogen activator (tPA remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs in blood-brain barrier (BBB disruption as a consequence of ischemic stroke. MMP-9 in particular appears to play an important role in tPAassociated hemorrhagic complications.Reactive oxygen species (ROS can enhance the effects of tPA on MMP activation through the loss of caveolin-1, a protein encoded in the cav-1 gene that serves as a critical determinant of BBB permeability. This review provides an overview of MMPs' role in BBB breakdown during acute ischemic stroke. The possible role of MMPs in combination treatment of acute ischemic stroke is also examined.

  2. Novel Peptide for Attenuation of Hyperoxia-induced Disruption of Lung Endothelial Barrier and Pulmonary Edema via Modulating Peroxynitrite Formation*

    Science.gov (United States)

    Kondrikov, Dmitry; Gross, Christine; Black, Stephen M.; Su, Yunchao

    2014-01-01

    Pulmonary damages of oxygen toxicity include vascular leakage and pulmonary edema. We have previously reported that hyperoxia increases the formation of NO and peroxynitrite in lung endothelial cells via increased interaction of endothelial nitric oxide (eNOS) with β-actin. A peptide (P326TAT) with amino acid sequence corresponding to the actin binding region of eNOS residues 326–333 has been shown to reduce the hyperoxia-induced formation of NO and peroxynitrite in lung endothelial cells. In the present study, we found that exposure of pulmonary artery endothelial cells to hyperoxia (95% oxygen and 5% CO2) for 48 h resulted in disruption of monolayer barrier integrity in two phases, and apoptosis occurred in the second phase. NOS inhibitor NG-nitro-l-arginine methyl ester attenuated the endothelial barrier disruption in both phases. Peroxynitrite scavenger uric acid did not affect the first phase but ameliorated the second phase of endothelial barrier disruption and apoptosis. P326TAT inhibited hyperoxia-induced disruption of monolayer barrier integrity in two phases and apoptosis in the second phase. More importantly, injection of P326TAT attenuated vascular leakage, pulmonary edema, and endothelial apoptosis in the lungs of mice exposed to hyperoxia. P326TAT also significantly reduced the increase in eNOS-β-actin association and protein tyrosine nitration. Together, these results indicate that peptide P326TAT ameliorates barrier dysfunction of hyperoxic lung endothelial monolayer and attenuates eNOS-β-actin association, peroxynitrite formation, endothelial apoptosis, and pulmonary edema in lungs of hyperoxic mice. P326TAT can be a novel therapeutic agent to treat or prevent acute lung injury in oxygen toxicity. PMID:25315770

  3. Obesity promotes oxidative stress and exacerbates blood-brain barrier disruption after high-intensity exercise

    Directory of Open Access Journals (Sweden)

    Hee-Tae Roh

    2017-06-01

    Conclusion: Our study suggests that episodic vigorous exercise can increase oxidative stress and blood neurotrophic factor levels and induce disruption of the BBB. Moreover, high levels of neurotrophic factor in the blood after exercise in the obese group may be due to BBB disruption, and it is assumed that oxidative stress was the main cause of this BBB disruption.

  4. MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

    Science.gov (United States)

    Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

    2011-09-01

    Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain

  5. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Hideaki Nishihara

    Full Text Available OBJECTIVE: Effect of fingolimod in multiple sclerosis (MS is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB. However, brain microvascular endothelial cells (BMECs represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera. METHODS: Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR MS, stable phase of RRMS and secondary progressive MS (SPMS, on the function of BBB in the presence of fingolimod-phosphate were assessed. RESULTS: Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera. CONCLUSIONS: Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.

  6. Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia.

    Directory of Open Access Journals (Sweden)

    Zheng Jiang

    Full Text Available The role of nitric oxide synthases (NOSs in early blood-brain barrier (BBB disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB and sodium fluorescein (Na-F extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS inhibitor significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS inhibitors significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG (an inducible NOS (iNOS inhibitor had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

  7. Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

    Science.gov (United States)

    Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

    2017-01-01

    Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison

  8. Vessel Wall Enhancement and Blood-Cerebrospinal Fluid Barrier Disruption After Mechanical Thrombectomy in Acute Ischemic Stroke.

    Science.gov (United States)

    Renú, Arturo; Laredo, Carlos; Lopez-Rueda, Antonio; Llull, Laura; Tudela, Raúl; San-Roman, Luis; Urra, Xabier; Blasco, Jordi; Macho, Juan; Oleaga, Laura; Chamorro, Angel; Amaro, Sergio

    2017-03-01

    Less than half of acute ischemic stroke patients treated with mechanical thrombectomy obtain permanent clinical benefits. Consequently, there is an urgent need to identify mechanisms implicated in the limited efficacy of early reperfusion. We evaluated the predictors and prognostic significance of vessel wall permeability impairment and its association with blood-cerebrospinal fluid barrier (BCSFB) disruption after acute stroke treated with thrombectomy. A prospective cohort of acute stroke patients treated with stent retrievers was analyzed. Vessel wall permeability impairment was identified as gadolinium vessel wall enhancement (GVE) in a 24- to 48-hour follow-up contrast-enhanced magnetic resonance imaging, and severe BCSFB disruption was defined as subarachnoid hemorrhage or gadolinium sulcal enhancement (present across >10 slices). Infarct volume was evaluated in follow-up magnetic resonance imaging, and clinical outcome was evaluated with the modified Rankin Scale at day 90. A total of 60 patients (median National Institutes of Health Stroke Scale score, 18) were analyzed, of whom 28 (47%) received intravenous alteplase before mechanical thrombectomy. Overall, 34 (57%) patients had GVE and 27 (45%) had severe BCSFB disruption. GVE was significantly associated with alteplase use before thrombectomy and with more stent retriever passes, along with the presence of severe BCSFB disruption. GVE was associated with poor clinical outcome, and both GVE and severe BCSFB disruption were associated with increased final infarct volume. These findings may support the clinical relevance of direct vessel damage and BCSFB disruption after acute stroke and reinforce the need for further improvements in reperfusion strategies. Further validation in larger cohorts of patients is warranted. © 2017 American Heart Association, Inc.

  9. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    Science.gov (United States)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-05-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.

  10. Disruption of the blood–brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment

    Science.gov (United States)

    Guerra-Giraldez, Cristina; Marzal, Miguel; Cangalaya, Carla; Balboa, Diana; Orrego, Miguel Ángel; Paredes, Adriana; Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; García, Hector H.; González, Armando E.; Mahanty, Siddhartha; Nash, Theodore E.

    2014-01-01

    Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected into 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120 h before the EB infusion, indicating a greater compromise of the blood brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis. PMID:23684909

  11. Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption.

    Science.gov (United States)

    Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi; McDannold, Nathan J

    2016-09-28

    HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007mm(3)/day, compared to a growth constant 0.043±0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in

  12. Pharmacokinetics of BPA in gliomas with ultrasound induced blood-brain barrier disruption as measured by microdialysis.

    Directory of Open Access Journals (Sweden)

    Feng-Yi Yang

    Full Text Available The blood-brain barrier (BBB can be transiently disrupted by focused ultrasound (FUS in the presence of microbubbles for targeted drug delivery. Previous studies have illustrated the pharmacokinetics of drug delivery across the BBB after sonication using indirect visualization techniques. In this study, we investigated the in vivo extracellular kinetics of boronophenylalanine-fructose (BPA-f in glioma-bearing rats with FUS-induced BBB disruption by microdialysis. After simultaneous intravenous administration of BPA and FUS exposure, the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. With FUS, the mean peak concentration of BPA-f in the glioma dialysate was 3.6 times greater than without FUS, and the area under the concentration-time curve was 2.1 times greater. This study demonstrates that intracerebral microdialysis can be used to assess local BBB transport profiles of drugs in a sonicated site. Applying microdialysis to the study of metabolism and pharmacokinetics is useful for obtaining selective information within a specific brain site after FUS-induced BBB disruption.

  13. Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity.

    Science.gov (United States)

    Manda, Vamshi K; Mittapalli, Rajendar K; Geldenhuys, Werner J; Lockman, Paul R

    2010-10-01

    Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia.

  14. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.

    Science.gov (United States)

    Yu, Jinyan; Ma, Zhongsen; Shetty, Sreerama; Ma, Mengshi; Fu, Jian

    2016-07-01

    Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction.

  15. Is viscosity important in the production of blood-brain barrier disruption by intracarotid contrast media

    Energy Technology Data Exchange (ETDEWEB)

    Wilcox, J.; Sage, M.R.

    1984-11-01

    A canine model was used to investigate the effects of intracarotid methylglucamine iothalamate (280 mgI/ml) at different viscosities on the normal blood-brain barrier. To alter viscosity, without changing physicochemical parameters, injections were made at either 23/sup 0/C or 37/sup 0/C. The degree of blood-brain barrier damage was assessed using Evans' Blue dye as a visual marker and by contrast enhancement measured by a computed tomographic (CT) scanner. It was found that methylglucamine iothalamate caused more blood-brain barrier damage at 23/sup 0/C than at 37/sup 0/C (p<0.1). Control studies at each temperature using intracarotid injections of physiological saline showed no temperature effect (p>0.1). The implications of these findings are discussed.

  16. 7.0-T magnetic resonance imaging characterization of acute blood-brain-barrier disruption achieved with intracranial irreversible electroporation.

    Directory of Open Access Journals (Sweden)

    Paulo A Garcia

    Full Text Available The blood-brain-barrier (BBB presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd uptake as a surrogate marker for BBB disruption. The study was performed in a Good Laboratory Practices (GLP compliant facility and had Institutional Animal Care and Use Committee (IACUC approval. IRE ablations were performed in vivo in normal rat brain (n = 21 with 1-mm electrodes (0.45 mm diameter separated by an edge-to-edge distance of 4 mm. We used an ECM830 pulse generator to deliver ninety 50-μs pulse treatments (0, 200, 400, 600, 800, and 1000 V/cm at 1 Hz. The effects of applied electric fields and timing of Gd administration (-5, +5, +15, and +30 min was assessed by systematically characterizing IRE-induced regions of cell death and BBB disruption with 7.0-T magnetic resonance imaging (MRI and histopathologic evaluations. Statistical analysis on the effect of applied electric field and Gd timing was conducted via Fit of Least Squares with α = 0.05 and linear regression analysis. The focal nature of IRE treatment was confirmed with 3D MRI reconstructions with linear correlations between volume of ablation and electric field. Our results also demonstrated that IRE is an ablation technique that kills brain tissue in a focal manner depicted by MRI (n = 16 and transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner as seen with Evan's Blue (n = 5 and Gd administration.

  17. Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice.

    Directory of Open Access Journals (Sweden)

    Emil Zeynalov

    Full Text Available Stroke is a major cause of morbidity and mortality. Stroke is complicated by brain edema and blood-brain barrier (BBB disruption, and is often accompanied by increased release of arginine-vasopressin (AVP. AVP acts through V1a and V2 receptors to trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. The AVP receptor blockers conivaptan (V1a and V2 and tolvaptan (V2 are used to correct hyponatremia, but their effect on post-ischemic brain edema and BBB disruption remains to be elucidated. Therefore, we conducted this study to investigate if these drugs can prevent brain edema and BBB disruption in mice after stroke.Experimental mice underwent the filament model of middle cerebral artery occlusion (MCAO with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan or orally (tolvaptan for 48 hours. Physiological variables, neurological deficit scores (NDS, plasma and urine sodium and osmolality were recorded. Brain water content (BWC and Evans Blue (EB extravasation index were evaluated at the end point.Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66 ± 0.43% (vehicle to 78.28 ± 0.48% (conivaptan, 0.2 mg, p < 0.05 vs vehicle. Conivaptan also attenuated the EB extravasation from 1.22 ± 0.08 (vehicle to 1.01 ± 0.02 (conivaptan, 0.2 mg, p < 0.05.Continuous IV infusion with conivaptan for 48 hours after experimental stroke reduces brain edema, and BBB disruption. Conivaptan but not tolvaptan may potentially be used in patients to prevent brain edema after stroke.

  18. Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice.

    Science.gov (United States)

    Fujimoto, Masashi; Shiba, Masato; Kawakita, Fumihiro; Liu, Lei; Shimojo, Naoshi; Imanaka-Yoshida, Kyoko; Yoshida, Toshimichi; Suzuki, Hidenori

    2016-06-01

    OBJECT Tenascin-C (TNC), a matricellular protein, is induced in the brain following subarachnoid hemorrhage (SAH). The authors investigated if TNC causes brain edema and blood-brain barrier (BBB) disruption following experimental SAH. METHODS C57BL/6 wild-type (WT) or TNC knockout (TNKO) mice were subjected to SAH by endovascular puncture. Ninety-seven mice were randomly allocated to WT sham-operated (n = 16), TNKO sham-operated (n = 16), WT SAH (n = 34), and TNKO SAH (n = 31) groups. Mice were examined by means of neuroscore and brain water content 24-48 hours post-SAH; and Evans blue dye extravasation and Western blotting of TNC, matrix metalloproteinase (MMP)-9, and zona occludens (ZO)-1 at 24 hours post-SAH. As a separate study, 16 mice were randomized to WT sham-operated, TNKO sham-operated, WT SAH, and TNKO SAH groups (n = 4 in each group), and activation of mitogen-activated protein kinases (MAPKs) was immunohistochemically evaluated at 24 hours post-SAH. Moreover, 40 TNKO mice randomly received an intracerebroventricular injection of TNC or phosphate-buffered saline, and effects of exogenous TNC on brain edema and BBB disruption following SAH were studied. RESULTS Deficiency of endogenous TNC prevented neurological impairments, brain edema formation, and BBB disruption following SAH; it was also associated with the inhibition of both MMP-9 induction and ZO-1 degradation. Endogenous TNC deficiency also inhibited post-SAH MAPK activation in brain capillary endothelial cells. Exogenous TNC treatment abolished the neuroprotective effects shown in TNKO mice with SAH. CONCLUSIONS Tenascin-C may be an important mediator in the development of brain edema and BBB disruption following SAH, mechanisms for which may involve MAPK-mediated MMP-9 induction and ZO-1 degradation. TNC could be a molecular target against which to develop new therapies for SAH-induced brain injuries.

  19. Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury.

    Science.gov (United States)

    Lee, Jee Y; Choi, Hae Y; Yune, Tae Y

    2016-10-01

    Recently we reported that fluoxetine (10 mg/kg) improves functional recovery by attenuating blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI). Here we investigated whether a low-dose of fluoxetine (1 mg/kg) and vitamin C (100 mg/kg), separately not possessing any protective effect, prevents BSCB disruption and improves functional recovery when combined. After a moderate contusion injury at T9 in rat, a low-dose of fluoxetine and vitamin C, or the combination of both was administered intraperitoneally immediately after SCI and further treated once a day for 14 d. Co-treatment with fluoxetine and vitamin C significantly attenuated BSCB permeability at 1 d after SCI. When only fluoxetine or vitamin C was treated after injury, however, there was no effect on BSCB disruption. Co-treatment with fluoxetine and vitamin C also significantly inhibited the expression and activation of MMP-9 at 8 h and 1 d after injury, respectively, and the infiltration of neutrophils (at 1 d) and macrophages (at 5 d) and the expression of inflammatory mediators (at 2 h, 6 h, 8 h or 24 h after injury) were significantly inhibited by co-treatment with fluoxetine and vitamin C. Furthermore, the combination of fluoxetine and vitamin C attenuated apoptotic cell death at 1 d and 5 d and improved locomotor function at 5 weeks after SCI. These results demonstrate the synergistic effect combination of low-dose fluoxetine and vitamin C on BSCB disruption after SCI and furthermore support the effectiveness of the combination treatment regimen for the management of acute SCI.

  20. Dietary Milk Sphingomyelin Prevents Disruption of Skin Barrier Function in Hairless Mice after UV-B Irradiation.

    Directory of Open Access Journals (Sweden)

    Chisato Oba

    Full Text Available Exposure to ultraviolet-B (UV-B irradiation causes skin barrier defects. Based on earlier findings that milk phospholipids containing high amounts of sphingomyelin (SM improved the water content of the stratum corneum (SC in normal mice, here we investigated the effects of dietary milk SM on skin barrier defects induced by a single dose of UV-B irradiation in hairless mice. Nine week old hairless mice were orally administrated SM (146 mg/kg BW/day for a total of ten days. After seven days of SM administration, the dorsal skin was exposed to a single dose of UV-B (20 mJ/cm2. Administration of SM significantly suppressed an increase in transepidermal water loss and a decrease in SC water content induced by UV-B irradiation. SM supplementation significantly maintained covalently-bound ω-hydroxy ceramide levels and down-regulated mRNA levels of acute inflammation-associated genes, including thymic stromal lymphopoietin, interleukin-1 beta, and interleukin-6. Furthermore, significantly higher levels of loricrin and transglutaminase-3 mRNA were observed in the SM group. Our study shows for the first time that dietary SM modulates epidermal structures, and can help prevent disruption of skin barrier function after UV-B irradiation.

  1. Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection.

    Science.gov (United States)

    Li, Fang; Wang, Yueyun; Yu, Lan; Cao, Shengbo; Wang, Ke; Yuan, Jiaolong; Wang, Chong; Wang, Kunlun; Cui, Min; Fu, Zhen F

    2015-05-01

    Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage. In vitro studies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB. Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate

  2. Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta

    Science.gov (United States)

    Xie, Lishi; Chiang, Eddie T.; Kelly, Gabriel T.; Kanteti, Prasad; Singleton, Patrick A.; Camp, Sara M.; Zhou, Tingting; Dudek, Steven M.; Natarajan, Viswanathan; Wang, Ting; Black, Steven M.; Garcia, Joe G. N.; Jacobson, Jeffrey R.

    2016-01-01

    Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue–specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin), dominant negative PKCδ construct and PKCδ silencing (siRNA). In addition, we identified PKCδ as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKCδ activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKCμ) and CPI-17, two known PKCδ targets, were found to be activated by PKCδ in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKCδ in EC cytoskeleton regulation, and highlight PKCδ as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis. PMID:27442243

  3. Kiwifruit cysteine protease actinidin compromises the intestinal barrier by disrupting tight junctions

    NARCIS (Netherlands)

    Grozdanovic, Milica M; Čavić, Milena; Nešić, Andrijana; Andjelković, Uroš; Akbari, Peyman; Smit, Joost J; Gavrović-Jankulović, Marija

    2016-01-01

    BACKGROUND: The intestinal epithelium forms a barrier that food allergens must cross in order to induce sensitization. The aim of this study was to evaluate the impact of the plant-derived food cysteine protease--actinidin (Act d1) on the integrity of intestinal epithelium tight junctions (TJs). MET

  4. Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms.

    Science.gov (United States)

    Lechuga, Susana; Ivanov, Andrei I

    2017-03-16

    The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders.

  5. Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta.

    Directory of Open Access Journals (Sweden)

    Lishi Xie

    Full Text Available Protein Kinase C (PKC plays a significant role in thrombin-induced loss of endothelial cell (EC barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin, dominant negative PKCδ construct and PKCδ silencing (siRNA. In addition, we identified PKCδ as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKCδ activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKCμ and CPI-17, two known PKCδ targets, were found to be activated by PKCδ in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKCδ in EC cytoskeleton regulation, and highlight PKCδ as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis.

  6. Propionate Protects against Lipopolysaccharide-Induced Mastitis in Mice by Restoring Blood–Milk Barrier Disruption and Suppressing Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Jingjing Wang

    2017-09-01

    Full Text Available Mastitis, an inflammation of the mammary glands, is a major disease affecting dairy animal worldwide. Propionate is one of the main short-chain fatty acid that can exert multiple effects on the inflammatory process. The purpose of this study is to investigate the mechanisms underlying the protective effects of sodium propionate against lipopolysaccharide (LPS-induced mastitis model in mice. The data mainly confirm that inflammation and blood–milk barrier breakdown contribute to progression of the disease in this model. In mice with LPS, sodium propionate attenuates the LPS-induced histopathological changes, inflammatory cytokines tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, and interleukin-1β (IL-1β production, myeloperoxidase activity in mammary tissues. Given their importance in the blood–milk barrier, tight junction proteins occludin and claudin-3 are further investigated. Our results show that sodium propionate strikingly increases the expressions of occludin and claudin-3 and reduces the blood–milk barrier permeability in this model. Furthermore, in LPS-stimulated mouse mammary epithelial cells (mMECs, LPS increased the expressions of phosphorylated (p-p65, p-IκB proteins, which is attenuated by sodium propionate. Finally, we examine the possibility that propionate acts as a histone deacetylase (HDAC inhibitor, the results show that both sodium propionate and trichostatin A increase the level of histone H3 acetylation and inhibit the increased production of TNF-α, IL-6, and IL-1β in LPS-stimulated mMECs. These data suggest that sodium propionate protects against LPS-induced mastitis mainly by restoring blood–milk barrier disruption and suppressing inflammation via NF-κB signaling pathway and HDAC inhibition.

  7. Role of hydrogen sulfide in early blood-brain barrier disruption following transient focal cerebral ischemia.

    Directory of Open Access Journals (Sweden)

    Zheng Jiang

    Full Text Available We determined the role of endogenous hydrogen sulfide (H2S in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA for two hours. Regional vascular response and cerebral blood flow (CBF during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB and sodium fluorescein (Na-F extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST, but not O-(Carboxymethylhydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS, abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/- reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn't further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia.

  8. Enteric Pathogens and Their Toxin-Induced Disruption of the Intestinal Barrier through Alteration of Tight Junctions in Chickens

    Science.gov (United States)

    Awad, Wageha A.; Hess, Claudia; Hess, Michael

    2017-01-01

    can utilize tight junction proteins as receptors for attachment and subsequent internalization, while others modify or destroy the tight junction proteins by different pathways and thereby provide a gateway to the underlying tissue. This review aims to deliver an overview of the tight junction structures and function, and its role in enteric bacterial pathogenesis with a special focus on chickens. A main conclusion will be that the molecular mechanisms used by enteric pathogens to disrupt epithelial barrier function in chickens needs a much better understanding, explicitly highlighted for Campylobacter jejuni, Salmonella enterica and Clostridium perfringens. This is a requirement in order to assist in discovering new strategies to avoid damages of the intestinal barrier or to minimize consequences from infections. PMID:28208612

  9. Enteric Pathogens and Their Toxin-Induced Disruption of the Intestinal Barrier through Alteration of Tight Junctions in Chickens

    Directory of Open Access Journals (Sweden)

    Wageha A. Awad

    2017-02-01

    , because some pathogens can utilize tight junction proteins as receptors for attachment and subsequent internalization, while others modify or destroy the tight junction proteins by different pathways and thereby provide a gateway to the underlying tissue. This review aims to deliver an overview of the tight junction structures and function, and its role in enteric bacterial pathogenesis with a special focus on chickens. A main conclusion will be that the molecular mechanisms used by enteric pathogens to disrupt epithelial barrier function in chickens needs a much better understanding, explicitly highlighted for Campylobacter jejuni, Salmonella enterica and Clostridium perfringens. This is a requirement in order to assist in discovering new strategies to avoid damages of the intestinal barrier or to minimize consequences from infections.

  10. Host Epithelial Interactions with Helicobacter Pylori: A Role for Disrupted Gastric Barrier Function in the Clinical Outcome of Infection?

    Directory of Open Access Journals (Sweden)

    Andre G Buret

    2005-01-01

    Full Text Available Infection of the human stomach with Helicobacter pylori may develop into gastritis, ulceration, adenocarcinoma and mucosal lymphomas. The pathogenic mechanisms that determine the clinical outcome from this microbial-epithelial interaction remain poorly understood. An increasing number of reports suggests that disruptions of epithelial barrier function may contribute to pathology and postinfectious complications in a variety of gastrointestinal infections. The aim of this review is to critically discuss the implications of H pylori persistence on gastric disease, with emphasis on the role of myosin light chain kinase, claudins and matrix metalloproteinases in gastric permeability defects, and their contribution to the development of cancer. These mechanisms and the associated signalling events may represent novel therapeutic targets to control disease processes induced by H pylori, a microbial pathogen that colonizes the stomach of over 50% of the human population.

  11. EMP-induced alterations of tight junction protein expression and disruption of the blood-brain barrier.

    Science.gov (United States)

    Ding, Gui-Rong; Qiu, Lian-Bo; Wang, Xiao-Wu; Li, Kang-Chu; Zhou, Yong-Chun; Zhou, Yan; Zhang, Jie; Zhou, Jia-Xing; Li, Yu-Rong; Guo, Guo-Zhen

    2010-07-15

    The blood-brain barrier (BBB) is critical to maintain cerebral homeostasis. In this study, we examined the effects of exposure to electromagnetic pulse (EMP) on the functional integrity of BBB and, on the localization and expression of tight junction (TJ) proteins (occludin and ZO-1) in rats. Animals were sham or whole-body exposed to EMP at 200 kV/m for 400 pulses. The permeability of BBB in rat cerebral cortex was examined by using Evans Blue (EB) and lanthanum nitrate as vascular tracers. The localization and expression of TJ proteins were assessed by western blot and immunofluorescence analysis, respectively. The data indicated that EMP exposure caused: (i) increased permeability of BBB, and (ii) altered localization as well as decreased levels of TJ protein ZO-1. These results suggested that the alteration of ZO-1 may play an important role in the disruption of tight junctions, which may lead to dysfunction of BBB after EMP exposure.

  12. Penetration of spherical and rod-like gold nanoparticles into intact and barrier-disrupted human skin

    Science.gov (United States)

    Graf, Christina; Nordmeyer, Daniel; Ahlberg, Sebastian; Raabe, Jörg; Vogt, Annika; Lademann, Jürgen; Rancan, Fiorenza; Rühl, Eckart

    2015-03-01

    The penetration of spherical and rod-like gold nanoparticles into human skin is reported. Several skin preparation techniques are applied, including cryo techniques, such as plunge freezing and freeze drying, and the use of wet cells. Their advantages and drawbacks for observing nanoparticle uptake are discussed. Independent of the particle shape no uptake into intact skin is observed by a combination of imaging approaches, including scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and scanning X-ray microscopy (STXM). These results are discussed along with suitable skin preparation approaches. Experiments on barrier-disrupted skin, i.e. mechanical lesions made by pricking, indicate, however, that gold particles can be identified deep in the dermis, as follows from STXM studies on wet skin samples.

  13. Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

    Directory of Open Access Journals (Sweden)

    Jay P. Patel

    2015-01-01

    Full Text Available The blood-brain barrier (BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD, here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

  14. Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke.

    Directory of Open Access Journals (Sweden)

    Ying Bai

    Full Text Available Disruption of the blood-brain barrier (BBB integrity occurring during the early onset of stroke is not only a consequence of, but also contributes to the further progression of stroke. Although it has been well documented that brain microvascular endothelial cells and astrocytes play a critical role in the maintenance of BBB integrity, pericytes, sandwiched between endothelial cells and astrocytes, remain poorly studied in the pathogenesis of stroke. Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus. Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody. The in vivo relevance of these findings was further corroborated in the stroke model of mice wherein the mice, demonstrated disruption of the BBB integrity and concomitant increase in the expression of VEGF in the brain tissue as well as in the isolated microvessel. These findings thus suggest the role of pericyte-derived VEGF in modulating increased permeability of BBB during stroke. Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.

  15. EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice

    Directory of Open Access Journals (Sweden)

    Bo Young Choi

    2014-10-01

    Full Text Available EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.

  16. Barrier disrupting effects of alternaria alternata extract on bronchial epithelium from asthmatic donors.

    Directory of Open Access Journals (Sweden)

    Marina S Leino

    Full Text Available Sensitization and exposure to the allergenic fungus Alternaria alternata has been associated with increased risk of asthma and asthma exacerbations. The first cells to encounter inhaled allergens are epithelial cells at the airway mucosal surface. Epithelial barrier function has previously been reported to be defective in asthma. This study investigated the contribution of proteases from Alternaria alternata on epithelial barrier function and inflammatory responses and compared responses of in vitro cultures of differentiated bronchial epithelial cells derived from severely asthmatic donors with those from non-asthmatic controls. Polarised 16HBE cells or air-liquid interface (ALI bronchial epithelial cultures from non-asthmatic or severe asthmatic donors were challenged apically with extracts of Alternaria and changes in inflammatory cytokine release and transepithelial electrical resistance (TER were measured. Protease activity in Alternaria extracts was characterised and the effect of selectively inhibiting protease activity on epithelial responses was examined using protease inhibitors and heat-treatment. In 16HBE cells, Alternaria extracts stimulated release of IL-8 and TNFα, with concomitant reduction in TER; these effects were prevented by heat-treatment of the extracts. Examination of the effects of protease inhibitors suggested that serine proteases were the predominant class of proteases mediating these effects. ALI cultures from asthmatic donors exhibited a reduced IL-8 response to Alternaria relative to those from healthy controls, while neither responded with increased thymic stromal lymphopoietin (TSLP release. Only cultures from asthmatic donors were susceptible to the barrier-weakening effects of Alternaria. Therefore, the bronchial epithelium of severely asthmatic individuals may be more susceptible to the deleterious effects of Alternaria.

  17. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

  18. Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

    OpenAIRE

    2001-01-01

    Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurol...

  19. Plasmalemmal Vesicle Associated Protein-1 (PV-1 is a marker of blood-brain barrier disruption in rodent models

    Directory of Open Access Journals (Sweden)

    Ali Zarina S

    2008-02-01

    Full Text Available Abstract Background Plasmalemmal vesicle associated protein-1 (PV-1 is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. Results We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. Conclusion Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

  20. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia

    Directory of Open Access Journals (Sweden)

    Ted Menghsiung Hsu

    2014-05-01

    Full Text Available Both obesity and Alzheimer’s disease are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of Western diets, diets high in saturated fatty acids and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier degradation, and subsequent hippocampal damage and dementia pathology.

  1. Blood-brain barrier disruption by continuous-wave radio frequency radiation.

    Science.gov (United States)

    Sirav, Bahriye; Seyhan, Nesrin

    2009-01-01

    The increasing use of cellular phones and the increasing number of associated base stations are becoming a widespread source of non ionizing electromagnetic radiation. Some biological effects are likely to occur even at low-level EM fields. This study was designed to investigate the effects of 900 and 1,800 MHz Continuous Wave Radio Frequency Radiation (CW RFR) on the permeability of Blood Brain Barrier (BBB) of rats. Results have shown that 20 min RFR exposure of 900 and 1,800 MHz induces an effect and increases the permeability of BBB of male rats. There was no change in female rats. The scientific evidence on RFR safety or harm remains inconclusive. More studies are needed to demonstrate the effects of RFR on the permeability of BBB and the mechanisms of that breakdown.

  2. Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.

    Science.gov (United States)

    Kamat, Pradip K; Kyles, Philip; Kalani, Anuradha; Tyagi, Neetu

    2016-05-01

    Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy

  3. P38丝裂素活化蛋白激酶信号通路阻断对糖尿病鼠早期血视网膜屏障和视网膜节细胞的保护作用%Protective effect of blocking the signal path of p38 mitogen-activated protein kinase on blood-retinal barrier and retinal ganglion cells in early diabetic rats

    Institute of Scientific and Technical Information of China (English)

    李永浩; 吕林; 陈凌燕; 黄新华; 张静琳; 李石毅; 王祥珪

    2010-01-01

    diabetes rats 8 weeks after intravitreal injection (2.9 times much more than that in the control group), the fluorescence expression of VEGF decreased in diabetes rats six weeks after intravitreal injection (1.8 times much more than that in the control group). The apoptisis RGC number in rats 6 weeks after intravitreal injection of SB203580 was much less than that in rats without intravitreal injection (t=5. 731, P<0. 01). Conclusions SB203580 can alleviate the disruption of BRB and apoptosis of RGC in early diabetes rats, which suggests that p38 MAPK pathways appear to be directly involved in the pathogenesis of early diabetic retinopathy.

  4. Computational and in vitro studies of blast-induced blood-brain barrier disruption

    CERN Document Server

    Del Razo, Mauricio J; Meabon, James S; Huber, B Russell; Peskind, Elaine R; Banks, William A; Mourad, Pierre D; Leveque, Randall J; Cook, David G

    2015-01-01

    There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an {\\em in vitro} model in which BBB endothelial cells are grown in transwell vessels and exposed in a shock tube, confirming that BBB integrity is directly related to shock wave intensity. It is difficult to directly measure the forces acting on these cells in the transwell container during the experiments, and so a computational tool has been developed and presented in this paper. Two-dimensional axisymmetric Euler equations with the Tammann equation of state were used to model the transwell materials, and a high-resolution finite volume method b...

  5. Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain.

    Science.gov (United States)

    Saeed, Ahmed A; Genové, Guillem; Li, Tian; Lütjohann, Dieter; Olin, Maria; Mast, Natalia; Pikuleva, Irina A; Crick, Peter; Wang, Yuqin; Griffiths, William; Betsholtz, Christer; Björkhem, Ingemar

    2014-08-22

    The presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism have not been studied previously. Here we used a pericyte-deficient mouse model, Pdgfb(ret/ret), shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brains of the Pdgfb(ret/ret) mice. By dietary treatment with 0.3% deuterium-labeled cholesterol, we could demonstrate a significant flux of cholesterol from the circulation into the brains of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a down-regulation of cholesterol synthesis. Instead, cholesterol synthesis was increased by about 60%. The levels of 24(S)-hydroxycholesterol (24S-OHC) were significantly reduced in the brains of the pericyte-deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet, the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis, and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge, this is the first demonstration that a defective BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed.

  6. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Fumitaka Shimizu

    Full Text Available BACKGROUND: Pathological destruction of blood-brain barrier (BBB has been thought to be the initial key event in the process of developing multiple sclerosis (MS. The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS and secondary progressive MS (SPMS patients. METHODS: We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R, stable phase of RRMS (RRMS-S and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1, and on the transendothelial electrical resistance (TEER in human brain microvascular endothelial cells (BMECs. RESULTS: Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. CONCLUSIONS: The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.

  7. Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier.

    Science.gov (United States)

    Caron, Tyler J; Scott, Kathleen E; Fox, James G; Hagen, Susan J

    2015-10-28

    Long-term chronic infection with Helicobacter pylori (H. pylori) is a risk factor for gastric cancer development. In the multi-step process that leads to gastric cancer, tight junction dysfunction is thought to occur and serve as a risk factor by permitting the permeation of luminal contents across an otherwise tight mucosa. Mechanisms that regulate tight junction function and structure in the normal stomach, or dysfunction in the infected stomach, however, are largely unknown. Although conventional tight junction components are expressed in gastric epithelial cells, claudins regulate paracellular permeability and are likely the target of inflammation or H. pylori itself. There are 27 different claudin molecules, each with unique properties that render the mucosa an intact barrier that is permselective in a way that is consistent with cell physiology. Understanding the architecture of tight junctions in the normal stomach and then changes that occur during infection is important but challenging, because most of the reports that catalog claudin expression in gastric cancer pathogenesis are contradictory. Furthermore, the role of H. pylori virulence factors, such as cytotoxin-associated gene A and vacoulating cytotoxin, in regulating tight junction dysfunction during infection is inconsistent in different gastric cell lines and in vivo, likely because non-gastric epithelial cell cultures were initially used to unravel the details of their effects on the stomach. Hampering further study, as well, is the relative lack of cultured cell models that have tight junction claudins that are consistent with native tissues. This summary will review the current state of knowledge about gastric tight junctions, normally and in H. pylori infection, and make predictions about the consequences of claudin reorganization during H. pylori infection.

  8. Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke.

    Directory of Open Access Journals (Sweden)

    Di Yang

    Full Text Available BACKGROUND AND PURPOSE: Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP, a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model. METHODS: C57BL/6N male mice were first fed with either vehicle (PBS or LBP (1 or 10 mg/kg daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB extravasation was determined to assess blood-brain barrier (BBB disruption after MCAO. RESULTS: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains. CONCLUSIONS: Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.

  9. Blood-Brain Barrier Disruption and Oxidative Stress in Guinea Pig after Systemic Exposure to Modified Cell-Free Hemoglobin

    Science.gov (United States)

    Butt, Omer I.; Buehler, Paul W.; D'Agnillo, Felice

    2011-01-01

    Systemic exposure to cell-free hemoglobin (Hb) or its breakdown products after hemolysis or with the use of Hb-based oxygen therapeutics may alter the function and integrity of the blood-brain barrier. Using a guinea pig exchange transfusion model, we investigated the effect of a polymerized cell-free Hb (HbG) on the expression of endothelial tight junction proteins (zonula occludens 1, claudin-5, and occludin), astrocyte activation, IgG extravasation, heme oxygenase (HO), iron deposition, oxidative end products (4-hydroxynonenal adducts and 8-hydroxydeoxyguanosine), and apoptosis (cleaved caspase 3). Reduced zonula occludens 1 expression was observed after HbG transfusion as evidenced by Western blot and confocal microscopy. Claudin-5 distribution was altered in small- to medium-sized vessels. However, total expression of claudin-5 and occludin remained unchanged except for a notable increase in occludin 72 hours after HbG transfusion. HbG-transfused animals also showed increased astrocytic glial fibrillary acidic protein expression and IgG extravasation after 72 hours. Increased HO activity and HO-1 expression with prominent enhancement of HO-1 immunoreactivity in CD163-expressing perivascular cells and infiltrating monocytes/macrophages were also observed. Consistent with oxidative stress, HbG increased iron deposition, 4-hydroxynonenal and 8-hydroxydeoxyguanosine immunoreactivity, and cleaved caspase-3 expression. Systemic exposure to an extracellular Hb triggers blood-brain barrier disruption and oxidative stress, which may have important implications for the use of Hb-based therapeutics and may provide indirect insight on the central nervous system vasculopathies associated with excessive hemolysis. PMID:21356382

  10. Methylophiopogonanone A Protects against Cerebral Ischemia/Reperfusion Injury and Attenuates Blood-Brain Barrier Disruption In Vitro.

    Directory of Open Access Journals (Sweden)

    Mingbao Lin

    Full Text Available Methylophiopogonanone A (MO-A, an active homoisoflavonoid of the Chinese herb Ophiopogon japonicus which has been shown to have protective effects on cerebral ischemia/reperfusion (I/R injury, has been demonstrated to have anti-inflammatory and anti-oxidative properties. However, little is known about its role in cerebral I/R injury. Therefore, in this study, by using a middle cerebral artery occlusion (MCAO and reperfusion rat model, the effect of MO-A on cerebral I/R injury was examined. The results showed that MO-A treatment reduced infarct volume and brain edema, improved neurological deficit scores, reversed animal body weight decreases, and increased animal survival time in the stroke groups. Western blotting showed that MO-A suppressed MMP-9, but restored the expression of claudin-3 and claudin-5. Furthermore, transmission electron microscopy were monitored to determine the blood-brain barrier (BBB alterations in vitro. The results showed that MO-A markedly attenuated BBB damage in vitro. Additionally, MO-A inhibited ROS production in ECs and MMP-9 release in differentiated THP-1 cells in vitro, and suppressed ICAM-1 and VCAM-1 expression in ECs and leukocyte/EC adhesion. In conclusion, our data indicate that MO-A has therapeutic potential against cerebral I/R injury through its ability to attenuate BBB disruption by regulating the expression of MMP-9 and tight junction proteins.

  11. Influence of radiation-crosslinking on flame retarded polymer materials-How crosslinking disrupts the barrier effect

    Science.gov (United States)

    Sonnier, Rodolphe; Caro-Bretelle, Anne-Sophie; Dumazert, Loïc; Longerey, Marc; Otazaghine, Belkacem

    2015-01-01

    Fire behavior of flame retardant-free and flame retarded PP/PA6 blends was studied using pyrolysis-combustion flow calorimeter, cone calorimeter and epiradiator equipped with infrared camera and pyrometer. Blends were previously γ-irradiated in presence of crosslinking agents at various doses (up to 100 kGy) in order to assess the influence of irradiation crosslinking on flame retardancy. Crosslinked specimens exhibit a solid-like behavior under high temperature gradient in cone calorimeter and then distort considerably. The influence of such a behavior depends on the material properties. When the flame retardancy is provided by heat shielding effect, heat distortion disrupts the top protective layer leading to a substantial increase of peak of heat release rate (pHRR). The barrier layer is no longer able to prevent the heat transfer to the underlying condensed phase. In other cases (flame retardant-free blends or flame retardancy provided by other effects than heat shielding), heat distortion has negligible influence on heat release rate curves in cone calorimeter tests.

  12. Dexmedetomidine Attenuates Blood-Spinal Cord Barrier Disruption Induced by Spinal Cord Ischemia Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Bo Fang

    2015-05-01

    Full Text Available Background/Aims: Dexmedetomidine has beneficial effects on ischemia reperfusion (I/R injury to the spinal cord, but the underlying mechanisms are not fully understood. This study investigated the effects and possible mechanisms of dexmedetomidine on blood-spinal cord barrier (BSCB disruption induced by spinal cord I/R injury. Methods: Rats were intrathecally pretreated with dexmedetomidine or PBS control 30 minutes before undergoing 14-minute occlusion of aortic arch. Hind-limb motor function was assessed using Tarlov criteria, and motor neurons in the ventral gray matter were counted by histological examination. The permeability of the BSCB was examined using Evans blue (EB as a vascular tracer. The spinal cord edema was evaluated using the wet-dry method. The expression and localization of matrix metalloproteinase-9 (MMP-9, Angiopoietin-1 (Ang1 and Tie2 were assessed by western blot, real-time polymerase chain reaction, and immunofluorescence. Results: Intrathecal preconditioning with dexmedetomidine minimized the neuromotor dysfunction and histopathological deficits, and attenuated EB extravasation after spinal cord I/R injury. In addition, dexmedetomidine preconditioning suppressed I/R-induced increase in MMP-9. Finally, Dexmedetomidine preconditioning enhanced the Ang1-Tie2 system activity after spinal cord I/R injury. Conclusions: Dexmedetomidine preconditioning stabilized the BSCB integrity against spinal cord I/R injury by inhibition of MMP-9, and enhancing the Ang1-Tie2 system.

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

    Science.gov (United States)

    Aryal, Muna

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

  14. Mitochondrial expression and activity of P-glycoprotein under oxidative stress in outer blood-retinal barrier.

    Science.gov (United States)

    Zhang, Yue-Hong; Li, Juan; Yang, Wei-Zhong; Xian, Zhuan-Hua; Feng, Qi-Ting; Ruan, Xiang-Cai

    2017-01-01

    To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein (P-gp) in mitochondria of D407 cells. D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123 (Rho-123) alone and in the presence of P-gp inhibitor (Tariquidar) using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine (NAC) for 30min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry. P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up-regulated P-gp in D407 cells, which could be reversed by NAC treatment. H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress-induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy.

  15. Mitochondrial expression and activity of P-glycoprotein under oxidative stress in outer blood-retinal barrier

    Directory of Open Access Journals (Sweden)

    Yue-Hong Zhang

    2017-07-01

    Full Text Available AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein (P-gp in mitochondria of D407 cells. METHODS: D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123 (Rho-123 alone and in the presence of P-gp inhibitor (Tariquidar using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine (NAC for 30min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry. RESULTS: P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up-regulated P-gp in D407 cells, which could be reversed by NAC treatment. CONCLUSION: H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress-induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy.

  16. The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.

    Science.gov (United States)

    Lee, Jae-Min; Park, Jong-Min; Song, Min Kyung; Oh, Yoo Joung; Kim, Chang-Ju; Kim, Youn-Jung

    2017-01-18

    Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.

  17. Large germinoma in basal ganglia treated by intraarterial chemotherapy with ACNU following osmotic blood-brain barrier disruption and radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Miyagami, Mitsusuke; Tsubokawa, Takashi; Kobayashi, Makio.

    1988-10-01

    A rare case of large germinoma in the basal ganglia is reported which was effectively treated by intracarotid chemotherapy with ACNU following osmotic blood-brain barrier disruption using 20 % mannitol and radiation therapy. A 19-year-old man displayed slowly progressive right hemiparesis, motor aphasia and predementia on admission. Plain CT demonstrated a tumor which had a slightly high density with intratumoral calcification and a small cyst, and slight to moderate enhancement was observed following intravenous injection of contrast medium, but there was no unilateral ventricular enlargement. Cerebral angiography revealed hypervascular tumor staining with early draining veins. After biopsy, and as a result of intracarotid chemotherapy with ACNU following osmotic blood-brain barrier disruption and radiation therapy, the tumor decreased rapidly to about 20 % of its original mass. After discharge, tumor progression was observed. However, the enlarged tumor mass almost disappeared (except for calcification) on CT with clinical improvement in response to intracarotid chemotherapy with ACNU following 20 % mannitol.

  18. Efficiency of drug delivery enhanced by acoustic pressure during blood–brain barrier disruption induced by focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-05-01

    Full Text Available Feng-Yi Yang, Pei-Yi LeeDepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, TaiwanPurpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood–brain barrier (BBB-D, induced by focused ultrasound (FUS using various acoustic parameters.Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to

  19. Disruption of colonic barrier function and induction of mediator release by strains of Campylobacter jejuni that invade epithelial cells

    Institute of Scientific and Technical Information of China (English)

    Johannes Beltinger; Jo del Buono; Maeve M Skelly; John Thornley; Robin C Spiller; William A Stack; Christopher J Hawkey

    2008-01-01

    AIM:To study the mechanisms by which Campylobacter jejuni (C.jejuni) causes inflammation and diarrhea.In particular,direct interactions with intestinal epithelial cells and effects on barrier function are poorly understood.METHODS:To model the initial pathogenic effects of C.jejuni on intestinal epithelium,polarized human colonic HCA-7 monolayerswere grown on permeabilized filters and infected apically with clinical isolates of C.jejuni.Integrity of the monolayer was monitored by changes in monolayer resistance,release of lactate dehydrogenase,mannitol fluxes and electron microscopy.Invasion of HCA-7 cells was assessed by a modified gentamicin protection assay,translocation by counting colony forming units in the basal chamber,stimulation of mediator release by immunoassays and secretory responses in monolayers stimulated by bradykinin in an Ussing chamber.RESULTS:All strains translocated across monolayers but only a minority invaded HCA-7 cells.Strains that invaded HCA-7 cells destroyed rnonolayer resistance over 6 h,accompanied by increased release of lactate dehydrogenase,a four-fold increase in permeability to [3H] mannitol,and ultrastructural disruption of tight junctions,with rounding and lifting of cells off the filter membrane.Synthesis of interleukin (IL)-8 and prostaglandin E2 was increased with strains that invaded the rnonolayer but not with those that did not.CONCLUSION:These data demonstrate two distinct effects of C.jejuni on colonic epithelial cells and provide an informative model for further investigation of initial host cell responses to C.jejuni.

  20. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-08-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

  1. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, HongSeok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-01-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs. PMID:27510760

  2. Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit.

    Science.gov (United States)

    Brown, Jacquelyn A; Codreanu, Simona G; Shi, Mingjian; Sherrod, Stacy D; Markov, Dmitry A; Neely, M Diana; Britt, Clayton M; Hoilett, Orlando S; Reiserer, Ronald S; Samson, Philip C; McCawley, Lisa J; Webb, Donna J; Bowman, Aaron B; McLean, John A; Wikswo, John P

    2016-12-12

    can use metabolite analysis to identify critical pathways in inflammatory response. Taken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure.

  3. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    Energy Technology Data Exchange (ETDEWEB)

    Eum, Sung Yong, E-mail: seum@miami.edu; Jaraki, Dima; András, Ibolya E.; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP

  4. Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

    Science.gov (United States)

    Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

    2012-02-01

    Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

  5. Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia.

    Science.gov (United States)

    Chi, Oak Z; Mellender, Scott J; Kiss, Geza K; Liu, Xia; Weiss, Harvey R

    2017-02-24

    One of the important factors altering the degree of blood-brain barrier (BBB) disruption in cerebral ischemia is the anesthetic used. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be involved in modulating BBB permeability and in isoflurane induced neuroprotection. This study was performed to compare the degree of BBB disruption in focal cerebral ischemia under isoflurane vs pentobarbital anesthesia and to determine whether inhibition of PI3K/Akt would affect the disruption in the early stage of focal cerebral ischemia. Permanent middle cerebral artery (MCA) occlusion was performed in rats under 1.4% isoflurane or pentobarbital (50mg/kg i.p.) anesthesia with controlled ventilation. In half of each group LY294002, which is a PI3K/Akt inhibitor, was applied on the ischemic cortex immediately after MCA occlusion. After one hour of MCA occlusion, the transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid ((14)C-AIB) was determined to quantify the degree of BBB disruption. MCA occlusion increased the Ki both in the isoflurane and pentobarbital anesthetized rats. However, the value of Ki was lower under isoflurane (11.5±6.0μL/g/min) than under pentobarbital (18.3±7.1μL/g/min) anesthesia. The Ki of the contralateral cortex of the pentobarbital group was higher (+74%) than that of the isoflurane group. Application of LY294002 on the ischemic cortex increased the Ki (+99%) only in the isoflurane group. The degree of BBB disruption by MCA occlusion was significantly lower under isoflurane than pentobarbital anesthesia in the early stage of cerebral ischemia. Our data demonstrated the importance of choice of anesthetics and suggest that PI3K/Akt signaling pathway plays a significant role in altering BBB disruption in cerebral ischemia during isoflurane but not during pentobarbital anesthesia.

  6. Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

    DEFF Research Database (Denmark)

    Schellenberg, Angela E; Buist, Richard; Del Bigio, Marc R

    2012-01-01

    ABSTRACT: BACKGROUND: The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, which i...... of disruption in endothelial tight junctions was observed. CONCLUSION: Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation....

  7. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2.

    Science.gov (United States)

    Eum, Sung Yong; Jaraki, Dima; András, Ibolya E; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.

  8. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    Science.gov (United States)

    Eum, Sung Yong; Jaraki, Dima; András, Ibolya E.; Toborek, Michal

    2015-01-01

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. PMID:26080028

  9. Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice.

    Science.gov (United States)

    Chaudhry, Kamaljit K; Shukla, Pradeep K; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E; Rao, RadhaKrishna

    2016-01-01

    Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of Gln in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed with Gln-free diet and absent in mice fed with Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury.

  10. S-100 protein as marker of the blood-brain barrier disruption in children with internal hydrocephalus and epilepsy--a preliminary study.

    Science.gov (United States)

    Sendrowski, K; Sobaniec, W; Sobaniec-Lotowska, M E; Lewczuk, P

    2004-01-01

    S-100 is a structural protein of the central nervous system. An elevated level of S-100 in CSF is generally considered to be a marker of nervous tissue damage. The presence of this protein in blood serum points to the functional and/or morphological disruption of the blood-brain barrier. We measured S-100 in the cerebrospinal fluid and blood of children with two of the most often observed pathological states in child neurology--internal hydrocephalus and epilepsy. High levels of S-100 in CSF were detectable in children with internal hydrocephalus. Increased blood levels of S-100 protein were detectable in both groups of paediatric patients. Our preliminary results indicate neuronal damage in internal hydrocephalus and morphological and/or functional disturbances of the blood-brain barrier (their increased permeability) in both above mentioned disabilities.

  11. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption

    Science.gov (United States)

    Kinoshita, Manabu; McDannold, Nathan; Jolesz, Ferenc A.; Hynynen, Kullervo

    2006-08-01

    Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system. brain tumor | microbubble

  12. Na+/K+-ATPase α1 identified as an abundant protein in the blood-labyrinth barrier that plays an essential role in the barrier integrity.

    Directory of Open Access Journals (Sweden)

    Yue Yang

    Full Text Available The endothelial-blood/tissue barrier is critical for maintaining tissue homeostasis. The ear harbors a unique endothelial-blood/tissue barrier which we term "blood-labyrinth-barrier". This barrier is critical for maintaining inner ear homeostasis. Disruption of the blood-labyrinth-barrier is closely associated with a number of hearing disorders. Many proteins of the blood-brain-barrier and blood-retinal-barrier have been identified, leading to significant advances in understanding their tissue specific functions. In contrast, capillaries in the ear are small in volume and anatomically complex. This presents a challenge for protein analysis studies, which has resulted in limited knowledge of the molecular and functional components of the blood-labyrinth-barrier. In this study, we developed a novel method for isolation of the stria vascularis capillary from CBA/CaJ mouse cochlea and provided the first database of protein components in the blood-labyrinth barrier as well as evidence that the interaction of Na(+/K(+-ATPase α1 (ATP1A1 with protein kinase C eta (PKCη and occludin is one of the mechanisms of loud sound-induced vascular permeability increase.Using a mass-spectrometry, shotgun-proteomics approach combined with a novel "sandwich-dissociation" method, more than 600 proteins from isolated stria vascularis capillaries were identified from adult CBA/CaJ mouse cochlea. The ion transporter ATP1A1 was the most abundant protein in the blood-labyrinth barrier. Pharmacological inhibition of ATP1A1 activity resulted in hyperphosphorylation of tight junction proteins such as occludin which increased the blood-labyrinth-barrier permeability. PKCη directly interacted with ATP1A1 and was an essential mediator of ATP1A1-initiated occludin phosphorylation. Moreover, this identified signaling pathway was involved in the breakdown of the blood-labyrinth-barrier resulting from loud sound trauma.The results presented here provide a novel method for

  13. Human intestinal cell monolayers are preferentially sensitive to disruption of barrier function from basolateral exposure to cholic acid: correlation with membrane transport and transepithelial secretion.

    Science.gov (United States)

    Lowes, S; Simmons, N L

    2001-11-01

    Unconjugated bile acids such as cholic acid cause diarrhoea, mucosal irritation and toxicity. We sought to define the mechanism of cholate permeation across intestinal mucosal cells to understand how cellular exposure and accumulation are deleterious to mucosal function. Human intestinal Caco-2 and T84 cell monolayers were prepared by high-density seeding and cultured for >14 days on permeable culture supports. Cholate transport and cellular accumulation were determined using [3H]cholic acid. Epithelial barrier function was assessed by measuring transepithelial electrical resistance (Rt) and [14C]mannitol fluxes. Exposure of Caco-2 epithelia to serosal cholate caused a dose- and time-dependent disruption of barrier function. Apical exposure was without disruptive effect. Similar responses were observed for T84 epithelia. Cholate was preferentially accumulated across the basolateral surfaces in both Caco-2 and T84 cells, but was subject to active transepithelial secretion in Caco-2 monolayers only. Net secretion was substantially reduced by ATP depletion, showed saturation kinetics, and was subject to competitive inhibition by other bile acids. Cholate secretion was also sensitive to inhibition by the leukotriene antagonist MK-571 but not by digoxin, suggesting that MRP2, not MDR1, was responsible. RT-PCR and Western blotting confirmed MRP2 expression in Caco-2 epithelia but indicated its apparent absence from T84 cells.

  14. Hypoxia-inducible factor-1α is involved in isoflurane-induced blood-brain barrier disruption in aged rats model of POCD.

    Science.gov (United States)

    Cao, Yiyun; Li, Zhengqian; Li, Hongping; Ni, Cheng; Li, Lunxu; Yang, Ning; Shi, Chengmei; Zhong, Yanfeng; Cui, Dehua; Guo, Xiangyang

    2017-09-05

    Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1α (HIF-1α) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1α and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1α activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1α, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1α/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD. Copyright © 2017. Published by Elsevier B.V.

  15. The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2.

    Directory of Open Access Journals (Sweden)

    Victor H Ferreira

    Full Text Available Inflammation is a known mechanism that facilitates HIV acquisition and the spread of infection. In this study, we evaluated whether curcumin, a potent and safe anti-inflammatory compound, could be used to abrogate inflammatory processes that facilitate HIV-1 acquisition in the female genital tract (FGT and contribute to HIV amplification. Primary, human genital epithelial cells (GECs were pretreated with curcumin and exposed to HIV-1 or HIV glycoprotein 120 (gp120, both of which have been shown to disrupt epithelial tight junction proteins, including ZO-1 and occludin. Pre-treatment with curcumin prevented disruption of the mucosal barrier by maintaining ZO-1 and occludin expression and maintained trans-epithelial electric resistance across the genital epithelium. Curcumin pre-treatment also abrogated the gp120-mediated upregulation of the proinflammatory cytokines tumor necrosis factor-α and interleukin (IL-6, which mediate barrier disruption, as well as the chemokines IL-8, RANTES and interferon gamma-induced protein-10 (IP-10, which are capable of recruiting HIV target cells to the FGT. GECs treated with curcumin and exposed to the sexually transmitted co-infecting microbes HSV-1, HSV-2 and Neisseria gonorrhoeae were unable to elicit innate inflammatory responses that indirectly induced activation of the HIV promoter and curcumin blocked Toll-like receptor (TLR-mediated induction of HIV replication in chronically infected T-cells. Finally, curcumin treatment resulted in significantly decreased HIV-1 and HSV-2 replication in chronically infected T-cells and primary GECs, respectively. All together, our results suggest that the use of anti-inflammatory compounds such as curcumin may offer a viable alternative for the prevention and/or control of HIV replication in the FGT.

  16. Annexin A1 restores Aβ1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway.

    Science.gov (United States)

    Park, Jong-Chan; Baik, Sung Hoon; Han, Sun-Ho; Cho, Hyun Jin; Choi, Hyunjung; Kim, Haeng Jun; Choi, Heesun; Lee, Wonik; Kim, Dong Kyu; Mook-Jung, Inhee

    2017-02-01

    The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.

  17. Cordycepin-enriched WIB-801C from Cordyceps militaris improves functional recovery by attenuating blood-spinal cord barrier disruption after spinal cord injury.

    Science.gov (United States)

    Lee, Jee Youn; Choi, Hye Young; Baik, Hyung Hwan; Ju, Bong G; Kim, Won-Ki; Yune, Tae Young

    2017-05-05

    Cordyceps militaris is an ingredient of traditional Chinese medicine and have been widely used for inflammatory diseases and cancer. Cordycepin is one of the major bioactive components of Cordyceps militaris, and has been known to have anti-inflammatory and anti-oxidant effects. In the present study, we examined whether WIB-801C, a standardized and cordycepin-enriched extract of caterpillar fungus (Cordyceps militaris), would attenuate blood-spinal cord barrier (BSCB) disruption by inhibiting matrix metalloprotease (MMP)-9 activity, leading to improvement of functional outcomes after spinal cord injury (SCI). Male Sprague-Dawley rats were subjected to contusive SCI using a New York University (NYU) impactor, and WIB-801C (50mg/kg) was administered at 2h and 8h after injury orally and further treated once a day for indicated time points. BSCB disruption, MMP-9 activity, blood infiltration, inflammation, neuronal apoptosis, axonal loss, demyelination, and neurological deficit were evaluated. We found that WIB-801C significantly attenuated BSCB disruption by inhibiting MMP-9 expression and activation after injury. The infiltration of neutrophils at 1 d and macrophage at 5 d after SCI was also ameliorated by WIB-801C as compared with vehicle control. In addition, the expression of inflammatory cytokines and mediators such as Tnf-α, IL-1β, IL-6, Cox-2, and inos as well as chemokines such as Gro-α and Mip-2α was significantly inhibited by WIB-801C. Furthermore, WIB-801C inhibits p38MAPK activation and proNGF production in microglia after injury. These events eventually led to the inhibition of apoptotic cell death of neurons and oligodendrocytes, improved functional recovery and attenuated demyelination and axon loss after SCI. Our results suggest that WIB-801C can be used as a therapeutic agent after SCI by attenuating BSCB disruption followed inflammation. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  18. Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP/TIMP in aged rats

    Directory of Open Access Journals (Sweden)

    Zhengqian eLi

    2016-04-01

    Full Text Available Reversible BBB disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD. Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2 and -9 (MMP-9, as well as three of their endogenous tissue inhibitors (TIMP-1, -2, -3, and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II and Ang II receptor type 1 (AT1 after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1, as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.

  19. Activation of the Epithelial-to-Mesenchymal Transition Factor Snail Mediated Acetaldehyde-Induced Intestinal Epithelial Barrier Disruption

    NARCIS (Netherlands)

    Elamin, E.; Masclee, A.; Troost, F.; Dekker, J.; Jonkers, D.

    2014-01-01

    Background : Acetaldehyde (AcH) is mutagenic and can reach high concentrations in colonic lumen after ethanol consumption and is associated with intestinal barrier dysfunction and an increased risk of progressive cancers, including colorectal carcinoma. Snail, the transcription factor of epithelial-

  20. Protective effects of Lactobacillus plantarum on epithelial barrier disruption caused by enterotoxigenic Escherichia coli in intestinal porcine epithelial cells.

    Science.gov (United States)

    Wu, Yunpeng; Zhu, Cui; Chen, Zhuang; Chen, Zhongjian; Zhang, Weina; Ma, Xianyong; Wang, Li; Yang, Xuefen; Jiang, Zongyong

    2016-04-01

    Tight junctions (TJs) play an important role in maintaining the mucosal barrier function and gastrointestinal health of animals. Lactobacillus plantarum (L. plantarum) was reported to protect the intestinal barrier function of early-weaned piglets against enterotoxigenic Escherichia coli (ETEC) K88 challenge; however, the underlying cellular mechanism of this protection was unclear. Here, an established intestinal porcine epithelia cell (IPEC-J2) model was used to investigate the protective effects and related mechanisms of L. plantarum on epithelial barrier damages induced by ETEC K88. Epithelial permeability, expression of inflammatory cytokines, and abundance of TJ proteins, were determined. Pre-treatment with L. plantarum for 6h prevented the reduction in transepithelial electrical resistance (TEER) (Pplantarum were higher (Pplantarum was shown to regulate proteins of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. These results indicated that L. plantarum may improve epithelial barrier function by maintenance of TEER, inhibiting the reduction of TJ proteins, and reducing the expression of proinflammatory cytokines induced by ETEC K88, possibly through modulation of TLRs, NF-κB and MAPK pathways.

  1. Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Su Zhang; Quan-Cheng Kan; Yuming Xu; Guang-Xian Zhang; Lin Zhu

    2013-01-01

    Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a th...

  2. A role for VEGFR2 activation in endothelial responses caused by barrier disruptive OxPAPC concentrations.

    Directory of Open Access Journals (Sweden)

    Anna A Birukova

    Full Text Available Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC differentially modulate endothelial cell (EC barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2 is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation.EC monolayer permeability in human pulmonary artery endothelial cells (HPAEC and human aortic endothelial cells (HAEC was monitored by changes in transendothelial electrical resistance (TER across EC monolayers. Actin cytoskeleton was examined by immunostaining with Texas Red labeled phalloidin. Phosphorylation of myosin light chains (MLC and VE-Cadherin was examined by Western blot and immunofluorescence techniques. The role of VEGFR2 in OxPAPC-induced permeability and cytoskeletal arrangement were determined using siRNA-induced VEGFR2 knockdown.Low OxPAPC concentrations (5-20 µg/ml induced a barrier protective response in both HPAEC and HAEC, while high OxPAPC concentrations (50-100 µg/ml caused a rapid increase in permeability; actin stress fiber formation and increased MLC phosphorylation were observed as early as 30 min after treatment. VEGFR2 knockdown dramatically decreased the amount of MLC phosphorylation and stress fiber formation caused by high OxPAPC concentrations with modest effects on the amount of VE-cadherin phosphorylation at Y(731. We present evidence that activation of Rho is involved in the OxPAPC/VEGFR2 mechanism of EC permeability induced by high OxPAPC concentrations. Knockdown of VEGFR2 did not rescue the early drop in TER but prevented further development of OxPAPC-induced barrier dysfunction.This study shows that VEGFR2 is involved in the delayed phase of EC barrier dysfunction caused by high Ox

  3. Transgenic over-expression of slit2 enhances disruption of blood-brain barrier and increases cell death after traumatic brain injury in mice.

    Science.gov (United States)

    Li, Shuai; Li, Hang; He, Xiao-Fei; Li, Ge; Zhang, Qun; Liang, Feng-Ying; Jia, Huan-Huan; Li, Jiang-Chao; Huang, Ren; Pei, Zhong; Wang, Li-Jing; Zhang, Yu

    2016-09-19

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among male adolescents and young adults; and mild traumatic brain injury is the most common type of traumatic brain injury. The disruption of blood-brain barrier (BBB) plays an important role in brain trauma. Previously, we have found that slit2, a member of slit protein family, increases permeability of BBB. In the present study, we examined the role of slit2 in the pathogenesis of mild TBI in a mouse model of micro TBI. Rhodamine BandPI (PropidiumIodide) staining were used to detect the permeability of BBB and cell death, respectively. The leakage of Rhodamine B and cell death were significantly increased in Slit2-Tg mice than in C57 control mice after micro TBI. The present results suggest that over expression of slit2 plays a detrimental role in the pathophysiology of mild TBI.

  4. Intra-subtype variation in enteroadhesion accounts for differences in epithelial barrier disruption and is associated with metronidazole resistance in Blastocystis subtype-7.

    Science.gov (United States)

    Wu, Zhaona; Mirza, Haris; Tan, Kevin Shyong Wei

    2014-05-01

    Blastocystis is an extracellular, enteric pathogen that induces intestinal disorders in a range of hosts including humans. Recent studies have identified potential parasite virulence factors in and host responses to this parasite; however, little is known about Blastocystis-host attachment, which is crucial for colonization and virulence of luminal stages. By utilizing 7 different strains of the parasite belonging to two clinically relevant subtypes ST-4 and ST-7, we investigated Blastocystis-enterocyte adhesion and its association with parasite-induced epithelial barrier disruption. We also suggest that drug resistance in ST-7 strains might result in fitness cost that manifested as impairment of parasite adhesion and, consequently, virulence. ST-7 parasites were generally highly adhesive to Caco-2 cells and preferred binding to intercellular junctions. These strains also induced disruption of ZO-1 and occludin tight junction proteins as well as increased dextran-FITC flux across epithelial monolayers. Interestingly, their adhesion was correlated with metronidazole (Mz) susceptibility. Mz resistant (Mzr) strains were found to be less pathogenic, owing to compromised adhesion. Moreover, tolerance of nitrosative stress was also reduced in the Mzr strains. In conclusion, the findings indicate that Blastocystis attaches to intestinal epithelium and leads to epithelial barrier dysfunction and that drug resistance might entail a fitness cost in parasite virulence by limiting entero-adhesiveness. This is the first study of the cellular basis for strain-to-strain variation in parasite pathogenicity. Intra- and inter-subtype variability in cytopathogenicity provides a possible explanation for the diverse clinical outcomes of Blastocystis infections.

  5. Interferon-Stimulated Gene 15 Upregulation Precedes the Development of Blood-Brain Barrier Disruption and Cerebral Edema after Traumatic Brain Injury in Young Mice.

    Science.gov (United States)

    Rossi, Janet L; Todd, Tracey; Daniels, Zachary; Bazan, Nicolas G; Belayev, Ludmila

    2015-07-15

    Recent studies show that myosin light chain kinase (MLCK) plays a pivotal role in development of cerebral edema, a known complication following traumatic brain injury (TBI) in children and a contributing factor to worsened neurologic recovery. Interferon-stimulated gene 15 (ISG15) is upregulated after cerebral ischemia and is neuroprotective. The significant role of ISG15 after TBI has not been studied. Postnatal Day (PND) 21 and PND24 mice were subjected to lateral closed-skull injury with impact depth of 2.0 or 2.25 mm. Behavior was examined at 7 d using two-object novel recognition and Wire Hang tests. Mice were sacrificed at 6 h, 12 h, 24 h, 48 h, 72 h, and 7 d. ISG15 and MLCK were analyzed by Western blot and immunohistochemistry, blood-brain barrier (BBB) disruption with Evans Blue (EB), and cerebral edema with wet/dry weights. EB extravasation and edema peaked at 72 h in both ages. PND21 mice had more severe neurological deficits, compared with PND24 mice. PND24 mice showed peak ISG15 expression at 6 h, and PND21 mice at 72 h. MLCK peaked in both age groups at 12 h and co-localized with ISG15 on immunohistochemistry and co-immunoprecipitation. These studies provide evidence, ISG15 is elevated following TBI in mice, preceding MLCK elevation, development of BBB disruption, and cerebral edema.

  6. Mild hypothermia alleviates brain oedema and blood-brain barrier disruption by attenuating tight junction and adherens junction breakdown in a swine model of cardiopulmonary resuscitation

    Science.gov (United States)

    Li, Jiebin; Li, Chunsheng; Yuan, Wei; Wu, Junyuan; Li, Jie; Li, Zhenhua; Zhao, Yongzhen

    2017-01-01

    Mild hypothermia improves survival and neurological recovery after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). However, the mechanism underlying this phenomenon is not fully elucidated. The aim of this study was to determine whether mild hypothermia alleviates early blood–brain barrier (BBB) disruption. We investigated the effects of mild hypothermia on neurologic outcome, survival rate, brain water content, BBB permeability and changes in tight junctions (TJs) and adherens junctions (AJs) after CA and CPR. Pigs were subjected to 8 min of untreated ventricular fibrillation followed by CPR. Mild hypothermia (33°C) was intravascularly induced and maintained at this temperature for 12 h, followed by active rewarming. Mild hypothermia significantly reduced cortical water content, decreased BBB permeability and attenuated TJ ultrastructural and basement membrane breakdown in brain cortical microvessels. Mild hypothermia also attenuated the CPR-induced decreases in TJ (occludin, claudin-5, ZO-1) and AJ (VE-cadherin) protein and mRNA expression. Furthermore, mild hypothermia decreased the CA- and CPR-induced increases in matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression and increased angiogenin-1 (Ang-1) expression. Our findings suggest that mild hypothermia attenuates the CA- and resuscitation-induced early brain oedema and BBB disruption, and this improvement might be at least partially associated with attenuation of the breakdown of TJ and AJ, suppression of MMP-9 and VEGF expression, and upregulation of Ang-1 expression. PMID:28355299

  7. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator

    Science.gov (United States)

    Jin, Rong; Yang, Guojun; Li, Guohong

    2010-01-01

    Blood-brain barrier (BBB) disruption, mediated through matrix metalloproteinases (MMPs) and other mechanisms, is a critical event during ischemic stroke. Tissue plasminogen activator (tPA) is the only FDA-approved thrombolytic therapy for acute ischemic stroke, but the efficacy and safety of its therapeutic application is limited by narrow treatment time windows and side effects. Thus, there is a pressing need to develop combinational therapy that could offset tPA side effects and improve efficacy in clinical practice. Recent experimental studies indicate that tPA has previously unidentified functions in the brain beyond its well established thrombolytic activity, which might contribute to tPA-related side effects through MMPs (mainly MMP-9) and several signaling pathways involved in LDL receptor-related protein (LRP), activated protein C (APC) and protease-activated receptor 1 (PAR-1), platelet-derived growth factor C (PDGF-C), and N-methyl-D-aspartate (NMDA) receptor. Therapeutic targeting of MMPs and/or tPA-related signaling pathways might offer promising new approaches to combination therapies for ischemic stroke. This review provides an overview of the relationship between structural components and function of the BBB/neurovascular unit with respect to ischemic stroke. We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy. PMID:20302940

  8. ATP Induces Disruption of Tight Junction Proteins via IL-1 Beta-Dependent MMP-9 Activation of Human Blood-Brain Barrier In Vitro

    Directory of Open Access Journals (Sweden)

    Fuxing Yang

    2016-01-01

    Full Text Available Disruption of blood-brain barrier (BBB follows brain trauma or central nervous system (CNS stress. However, the mechanisms leading to this process or the underlying neural plasticity are not clearly known. We hypothesized that ATP/P2X7R signaling regulates the integrity of BBB. Activation of P2X7 receptor (P2X7R by ATP induces the release of interleukin-1β (IL-1β, which in turn enhances the activity of matrix metalloproteinase-9 (MMP-9. Degradation of tight junction proteins (TJPs such as ZO-1 and occludin occurs, which finally contributes to disruption of BBB. A contact coculture system using human astrocytes and hCMEC/D3, an immortalized human brain endothelial cell line, was used to mimic BBB in vitro. Permeability was used to evaluate changes in the integrity of TJPs. ELISA, Western blot, and immunofluorescent staining procedures were used. Our data demonstrated that exposure to the photoreactive ATP analog, 3′-O-(4-benzoylbenzoyl adenosine 5′-triphosphate (BzATP, induced a significant decrease in ZO-1 and occludin expression. Meanwhile, the decrease of ZO-1 and occludin was significantly attenuated by P2X7R inhibitors, as well as IL-1R and MMP antagonists. Further, the induction of IL-1β and MMP-9 was closely linked to ATP/P2X7R-associated BBB leakage. In conclusion, our study explored the mechanism of ATP/P2X7R signaling in the disruption of BBB following brain trauma/stress injury, especially focusing on the relationship with IL-1β and MMP-9.

  9. Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

    Science.gov (United States)

    Doolittle, N D; Anderson, C P; Bleyer, W A; Cairncross, J G; Cloughesy, T; Eck, S L; Guastadisegni, P; Hall, W A; Muldoon, L L; Patel, S J; Peereboom, D; Siegal, T; Neuwelt, E A

    2001-01-01

    Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.

  10. Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases.

    Science.gov (United States)

    Chen, Xuesong; Ghribi, Othman; Geiger, Jonathan D

    2010-01-01

    Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage.

  11. Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment.

    Science.gov (United States)

    Da Silva, Stéphanie; Robbe-Masselot, Catherine; Ait-Belgnaoui, Afifa; Mancuso, Alessandro; Mercade-Loubière, Myriam; Salvador-Cartier, Christel; Gillet, Marion; Ferrier, Laurent; Loubière, Pascal; Dague, Etienne; Theodorou, Vassilia; Mercier-Bonin, Muriel

    2014-08-15

    Despite well-known intestinal epithelial barrier impairment and visceral hypersensitivity in irritable bowel syndrome (IBS) patients and IBS-like models, structural and physical changes in the mucus layer remain poorly understood. Using a water avoidance stress (WAS) model, we aimed at evaluating whether 1) WAS modified gut permeability, visceral sensitivity, mucin expression, biochemical structure of O-glycans, and related mucus physical properties, and 2) whether Lactobacillus farciminis treatment prevented these alterations. Wistar rats received orally L. farciminis or vehicle for 14 days; at day 10, they were submitted to either sham or 4-day WAS. Intestinal paracellular permeability and visceral sensitivity were measured in vivo. The number of goblet cells and Muc2 expression were evaluated by histology and immunohistochemistry, respectively. Mucosal adhesion of L. farciminis was determined ex situ. The mucin O-glycosylation profile was obtained by mass spectrometry. Surface imaging of intestinal mucus was performed at nanoscale by atomic force microscopy. WAS induced gut hyperpermeability and visceral hypersensitivity but did not modify either the number of intestinal goblet cells or Muc2 expression. In contrast, O-glycosylation of mucins was strongly affected, with the appearance of elongated polylactosaminic chain containing O-glycan structures, associated with flattening and loss of the mucus layer cohesive properties. L. farciminis bound to intestinal Muc2 and prevented WAS-induced functional alterations and changes in mucin O-glycosylation and mucus physical properties. WAS-induced functional changes were associated with mucus alterations resulting from a shift in O-glycosylation rather than from changes in mucin expression. L. farciminis treatment prevented these alterations, conferring epithelial and mucus barrier strengthening.

  12. Cigarette smoke-induced disruption of pulmonary barrier and bacterial translocation drive tumor-associated inflammation and growth.

    Science.gov (United States)

    Jungnickel, C; Wonnenberg, B; Karabiber, O; Wolf, A; Voss, M; Wolf, L; Honecker, A; Kamyschnikow, A; Herr, C; Bals, R; Beisswenger, C

    2015-09-15

    Microorganisms have an important role in tumorgenesis by the induction of inflammation and by a direct impact on tumor cells. Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and microbial colonization. We asked whether bacterial pathogens act as tumor promoters during CS-induced pulmonary inflammation. In a metastatic lung cancer (LC) model, Lewis lung carcinoma (LLC) cells were injected in mice to initiate the growth of tumors in the lung. Exposure to the combination of cigarette smoke (CS) and nontypeable Haemophilus influenzae (NTHi) synergistically increased metastatic growth. Lung levels of albumin and LDH, translocation of bacterial factors into tumor tissue, tumor inflammation, and tumor proliferation were significantly increased in mice exposed to CS in combination with NTHi. Bacterial pathogens increased the proliferation of cultured LLC cells and human cancer cell lines. Metastatic growth induced by the exposure to CS in combination with NTHi was reduced in mice deficient for IL-17. Our data provide evidence that CS-induced loss of pulmonary barrier integrity allows bacterial factors to translocate into tumor tissue and to regulate tumor-associated inflammation and tumor proliferation. Translocation of bacterial factors in tumor tissue links CS-induced inflammation with tumor proliferation.

  13. Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Su Zhang

    2013-01-01

    Full Text Available Dysfunction of the blood-brain barrier (BBB is a primary characteristic of experimental autoimmune encephalomyelitis (EAE, an experimental model of multiple sclerosis (MS. Matrine (MAT, a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ adaptor protein Zonula occludens-1 (ZO-1. Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2, while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2. Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

  14. Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

    Directory of Open Access Journals (Sweden)

    Ching-Hsiang Fan

    Full Text Available The use of focused ultrasound (FUS with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening. However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

  15. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke.

    Science.gov (United States)

    Alfieri, Alessio; Srivastava, Salil; Siow, Richard C M; Cash, Diana; Modo, Michel; Duchen, Michael R; Fraser, Paul A; Williams, Steven C R; Mann, Giovanni E

    2013-12-01

    Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  16. Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

    Directory of Open Access Journals (Sweden)

    Xu L

    2015-09-01

    Full Text Available Liming Xu,1,2,* Mo Dan,1,* Anliang Shao,1 Xiang Cheng,1,3 Cuiping Zhang,4 Robert A Yokel,5 Taro Takemura,6 Nobutaka Hanagata,6 Masami Niwa,7,8 Daisuke Watanabe7,81National Institutes for Food and Drug Control, No 2, Temple of Heaven, Beijing, 2School of Information and Engineering, Wenzhou Medical University, Wenzhou, 3School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 4Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 5College of Pharmacy, University of Kentucky, Lexington, KY, USA; 6Nanotechnology Innovation Station for Nanoscale Science and Technology, National Institute for Materials Science, Tsukuba, Ibaraki, 7Department of Pharmacology, Nagasaki University, 8BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, Japan*These authors contributed equally to this workBackground: Silver nanoparticles (Ag-NPs can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB and the underlying mechanism(s of action on the BBB and the brain are not well understood.Method: To investigate Ag-NP suspension (Ag-NPS-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM. Global gene expression of astrocytes was measured using a DNA microarray.Results: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the

  17. Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound.

    Directory of Open Access Journals (Sweden)

    Feng-Yi Yang

    Full Text Available The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D induced by focused ultrasound (FUS. An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM 8401 cells was developed in this study. (111In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111In-AP-1 Lipo-Dox or (111In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05. Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111In-AP-1 Lipo-Dox with sonication. The (111In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

  18. The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.

    Science.gov (United States)

    Jackson, Sadhana; Anders, Nicole M; Mangraviti, Antonella; Wanjiku, Teresia M; Sankey, Eric W; Liu, Ann; Brem, Henry; Tyler, Betty; Rudek, Michelle A; Grossman, Stuart A

    2016-02-01

    The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

  19. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Vida Naderi

    2015-02-01

    Full Text Available Objective(s:Estrogen (E2 has neuroprotective effects on blood-brain-barrier (BBB after traumatic brain injury (TBI. In order to investigate the roles of estrogen receptors (ERs in these effects, ER-α antagonist (MPP and, ER-β antagonist (PHTPP, or non-selective estrogen receptors antagonist (ICI 182780 were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg or oil were administered 30 min after TBI. 1 dose (150 µg/Kg of each of MPP, PHTPP, and (4 mg/kg ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content and brain edema (brain water content evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P

  20. Dual function of novel pollen coat (surface proteins: IgE-binding capacity and proteolytic activity disrupting the airway epithelial barrier.

    Directory of Open Access Journals (Sweden)

    Mohamed Elfatih H Bashir

    Full Text Available BACKGROUND: The pollen coat is the first structure of the pollen to encounter the mucosal immune system upon inhalation. Prior characterizations of pollen allergens have focused on water-soluble, cytoplasmic proteins, but have overlooked much of the extracellular pollen coat. Due to washing with organic solvents when prepared, these pollen coat proteins are typically absent from commercial standardized allergenic extracts (i.e., "de-fatted", and, as a result, their involvement in allergy has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: Using a unique approach to search for pollen allergenic proteins residing in the pollen coat, we employed transmission electron microscopy (TEM to assess the impact of organic solvents on the structural integrity of the pollen coat. TEM results indicated that de-fatting of Cynodon dactylon (Bermuda grass pollen (BGP by use of organic solvents altered the structural integrity of the pollen coat. The novel IgE-binding proteins of the BGP coat include a cysteine protease (CP and endoxylanase (EXY. The full-length cDNA that encodes the novel IgE-reactive CP was cloned from floral RNA. The EXY and CP were purified to homogeneity and tested for IgE reactivity. The CP from the BGP coat increased the permeability of human airway epithelial cells, caused a clear concentration-dependent detachment of cells, and damaged their barrier integrity. CONCLUSIONS/SIGNIFICANCE: Using an immunoproteomics approach, novel allergenic proteins of the BGP coat were identified. These proteins represent a class of novel dual-function proteins residing on the coat of the pollen grain that have IgE-binding capacity and proteolytic activity, which disrupts the integrity of the airway epithelial barrier. The identification of pollen coat allergens might explain the IgE-negative response to available skin-prick-testing proteins in patients who have positive symptoms. Further study of the role of these pollen coat proteins in allergic

  1. Vasodilatation and disruption of the blood brain barrier determine hyperfixation with {sup 99m}Tc-HMPAO brain SPECT in subacute stroke

    Energy Technology Data Exchange (ETDEWEB)

    Cho, I. H.; Won, K. J.; Lee, H. W. [College of Medicine, Yungnam Univ., Kyungsan (Korea, Republic of); Norihico, Kume; Koheai, Hayasida [National Cardiovascular Center, Osacar (Japan)

    1998-07-01

    Hyperfixation characterized by excess tracer activity compared with cerebral blood flow (CBF) using {sup 99m}Tc-d, l-hexamethylpropyleneamine oxime (HMPAO) brain single photon emission tomography (SPECT), has not been measured in terms of cerebral metabolic rate of oxygen consumption (CMRO{sub 2}) oxygen extraction fraction (OEF) and cerebral blood volume (CBV). We studied four patients with subacute stroke who showed hot uptake in infarct areas with {sup 99C}Tc-HMPAO brain SPECT. We performed positron emission tomography (PET) and magnetic resonance (MR) imaging. Regions of interest (ROIs) were drawn in the same hot uptake areas in SPECT and PET images. The average counts per pixel of {sup 99m}Tc-HMPAO and the absolute values of CBF, CMRO{sub 2} OEF and DBV with PET were then obtained. The hyperfixation rate with {sup 99m}Tc-HMPAO is expressed as the surplus rate compared with PET-CBF. PET parameters in the hot uptake area were compared with those of 5 normal controls. OEF and CMRO{sub 2} at the hot uptake areas in the 4 patients were significantly lower than those of normal controls (P<0.01), but CBF and CBV were not significantly different between patients and normal controls (ns). The hyperfixation rate of 4 patients was 0.30{+-}0.15, which correlated well with CBV (r=0.97, y=11.75 + 0.42 ; P<0.05). The hyperfixation rate by {sup 99m}Tc-HMPAO brain SPECT correlated with CBV in the PET study and reflected Gd-DTPA enhancement by MR imaging. Therefore, {sup 99m}Tc-HMPAO hyperfixation in the infarct area might be caused by vascular dilatation and disruption of the blood brain barrier in terms of an increased capillary permeability-surface product.

  2. Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival

    Science.gov (United States)

    Burkhardt, Jan-Karl; Riina, Howard; Shin, Benjamin J.; Christos, Paul; Kesavabhotla, Kartik; Hofstetter, Christoph P.; Tsiouris, Apostolos John; Boockvar, John A.

    2013-01-01

    BACKGROUND This prospective, single-center study assesses progression-free survival (PFS) and overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) treated with a single dose of superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) after blood-brain barrier disruption (BBBD). Patients were initially enrolled in our phase I study, for which the primary end point was to determine the safety and maximum tolerated dose of SIACI BV. METHODS Fourteen patients with recurrent GBM were recruited between August 2009 and November 2010 after failing the standard treatment with radiation therapy and temozolomide. None of these patients were previously treated with BV. After receiving a single dose of IA BV (2 to 15 mg/kg), standard IV BV chemotherapy was continued in 12 of 14 patients (86%). The recently updated Response Assessment in Neuro-Oncology Working Group (RANO) criteria were used to evaluate PFS, and the Kaplan-Meier estimator was used to evaluate PFS and OS. RESULTS Using RANO criteria, the median PFS in these patients was 10 months. The median OS estimation for this cohort was 8.8 months. The OS was less than the PFS because 4 patients died without progressing. Toxicity attributed to the IA BV treatment was present in 2 patients (wound dehiscence and rash). Another patient suffered from seizures 1 week after the SIACI procedure; however, this patient had epilepsy before and seizure type/frequency were similar before and after therapy. CONCLUSIONS Our study shows that for patients naïve to BV, a single dose of SIACI BV after BBBD followed by IV BV offers an encouraging outcome in terms of PFS when compared with previous trials using IV BV with and without concomitant irinotecan (CPT-11). Larger phase II trials are warranted to determine whether repeated IA BV alone is superior to IV BV for recurrent GBM. PMID:22405392

  3. The effect of regadenoson-induced transient disruption of the blood–brain barrier on temozolomide delivery to normal rat brain

    Science.gov (United States)

    Jackson, Sadhana; Anders, Nicole M.; Mangraviti, Antonella; Wanjiku, Teresia M.; Sankey, Eric W.; Liu, Ann; Brem, Henry; Tyler, Betty; Rudek, Michelle A.

    2016-01-01

    The blood–brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60–90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 μg/g, P <0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60 % higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders. PMID:26626489

  4. The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury.

    Science.gov (United States)

    Sorby-Adams, Annabel J; Marcoionni, Amanda M; Dempsey, Eden R; Woenig, Joshua A; Turner, Renée J

    2017-08-17

    Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury.

  5. The effect of a combination of 0.1% octenidine dihydrochloride and 2% 2-phenoxyethanol (octenisept) on wound healing in pigs in vivo and its in vitro percutaneous permeation through intact and barrier disrupted porcine skin.

    Science.gov (United States)

    Stahl, Jessica; Braun, Michael; Siebert, Joerg; Kietzmann, Manfred

    2010-02-01

    A combination of 0.1% octenidine dihydrochloride and 2% 2-phenoxyethanol (octenisept) is a commonly used disinfectant in human medicine. As porcine skin represents an adequate model for human skin, the effect of octenidine dihydrochloride and phenoxyethanol on wound healing is studied in pigs. Furthermore, the in vitro percutaneous permeation of the test substances is studied. The impact of the test formulations on wound healing is examined (A) under non occlusive conditions and (B) in comparison to another disinfectant based on povidone-iodine under occlusive conditions, while wounds are treated daily with the test substances. The percutaneous permeation of octenidine dihydrochloride and phenoxyethanol is studied in Franz-type diffusion cells with intact skin as well as barrier disrupted after tape stripping. Compared with povidone-iodine or vehicle treatment as well as untreated control wounds the treatment of wounds with the test formulation has no influence on the healing rate in pigs and does not induce retardation of wound healing. The in vitro diffusion experiment reveals that octenidine dihydrochloride is only detectable in the acceptor chamber of three-barrier disrupted skin samples. Phenoxyethanol permeates through intact porcine skin in amounts of 11.3% and through barrier disrupted skin in amounts of 43.9%

  6. Imidazole-4-acetic acid, a new lead structure for interaction with the taurine transporter in outer blood-retinal barrier cells

    DEFF Research Database (Denmark)

    Valembois, Sophie; Krall, Jacob; Frølund, Bente

    2017-01-01

    therapeutic approach. The taurine transporter (TAUT) plays a key role in the retinal transport of GABA and has been previously suggested to display a higher functional activity in the retina compared to the brain. TAUT would therefore stand as a suitable target for the selective delivery of ρ GABAARs ligands...... by testing their ability to inhibit the TAUT-mediated influx of taurine in ARPE-19 cells. Results showed that taurine influx was seven-fold higher when the ARPE-19 cells were cultured under hyperosmotic conditions and was demonstrated to display saturable kinetics (Km=27.7±2.2μM and Jmax=24.2±0.6pmol/cm(2......)·min). Furthermore, the taurine influx was significantly inhibited in a concentration-dependent manner by GABA and imidazole-4-acetic acid (IAA), which is a naturally occurring metabolite of histamine. These compounds display similar Ki values of 644.2μM and 658.6μM, respectively. Moreover, IAA...

  7. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development...... invested in the issue of sustainable business development, in particular the leaders and employees of SMEs, but also to design education seeking new ways to consciously handle and teach the complexity inherent in sustainable transformation. Findings indicate that the SD design thinking approach contributes....... The tools have been applied in practice in collaboration with 11 small and medium sized companies (SMEs). The study investigates these approaches to further understand how design thinking can contribute to sustainable transition in a business context. The study and the findings are relevant to organizations...

  8. Rap1 GTPase activation and barrier enhancement in rpe inhibits choroidal neovascularization in vivo.

    Directory of Open Access Journals (Sweden)

    Erika S Wittchen

    Full Text Available Loss of barrier integrity precedes the development of pathologies such as metastasis, inflammatory disorders, and blood-retinal barrier breakdown present in neovascular age-related macular degeneration. Rap1 GTPase is involved in regulating both endothelial and epithelial cell junctions; the specific role of Rap1A vs. Rap1B isoforms is less clear. Compromise of retinal pigment epithelium barrier function is a contributing factor to the development of AMD. We utilized shRNA of Rap1 isoforms in cultured human retinal pigment epithelial cells, along with knockout mouse models to test the role of Rap1 on promoting RPE barrier properties, with emphasis on the dynamic junctional regulation that is triggered when the adhesion between cells is challenged. In vitro, Rap1A shRNA reduced steady-state barrier integrity, whereas Rap1B shRNA affected dynamic junctional responses. In a laser-induced choroidal neovascularization (CNV model of macular degeneration, Rap1b(-/- mice exhibited larger CNV volumes compared to wild-type or Rap1a(-/- . In vivo, intravitreal injection of a cAMP analog (8CPT-2'-O-Me-cAMP that is a known Rap1 activator significantly reduced laser-induced CNV volume, which correlated with the inhibition of CEC transmigration across 8CPT-2'O-Me-cAMP-treated RPE monolayers in vitro. Rap1 activation by 8CPT-2'-O-Me-cAMP treatment increased recruitment of junctional proteins and F-actin to cell-cell contacts, increasing both the linearity of junctions in vitro and in cells surrounding laser-induced lesions in vivo. We conclude that in vitro, Rap1A may be important for steady state barrier integrity, while Rap1B is involved more in dynamic junctional responses such as resistance to junctional disassembly induced by EGTA and reassembly of cell junctions following disruption. Furthermore, activation of Rap1 in vivo inhibited development of choroidal neovascular lesions in a laser-injury model. Our data suggest that targeting Rap1 isoforms in vivo

  9. Obesity in Aging Exacerbates Blood–Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimer’s Disease

    Science.gov (United States)

    Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Szalai, Gabor; Sonntag, William E.; Csiszar, Anna

    2014-01-01

    There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet–fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood–brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood–brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein–dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood–brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals. PMID:24269929

  10. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease.

    Science.gov (United States)

    Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Szalai, Gabor; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

    2014-10-01

    There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.

  11. Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis- and Alzheimer's disease-related animal models despite reported blood-brain barrier disruption.

    Science.gov (United States)

    Cheng, Ziqiang; Zhang, Jinqiang; Liu, Houfu; Li, Yi; Zhao, Yonggang; Yang, Eric

    2010-08-01

    Therapy for central nervous system (CNS) diseases requires drugs that can cross the blood-brain barrier (BBB). BBB disruption has been reported in patients with multiple sclerosis (MS) and Alzheimer's disease (AD) and the related animal models as evidenced by increased infiltration of inflammatory cells or increased staining of Igs in the central nervous system. Although CNS penetration of therapeutic agents under pathological conditions has rarely been investigated, it is commonly assumed that BBB disruption may lead to enhanced CNS penetration and also provide a "window of opportunity" through which drugs that do not normally cross BBB are able to do so. In this article, we have compared brain penetration of eight small molecules in naive animals and experimental autoimmune encephalomyelitis (EAE) mice, streptozotocin-induced mice, and TASTPM transgenic mice. The tool compounds are lipophilic transcellular drugs [GlaxoSmithKline (GSK)-A, GSK-B, GSK-C, and naproxen], lipophilic P-glycoprotein (P-gp) substrates (amprenavir and loperamide), and hydrophilic paracellular compounds (sodium fluorescein and atenolol). Our data showed that rate and extent of CNS penetration for lipophilic transcellular drugs and P-gp substrates are similar in naive and all tested animal models. The brain penetration for paracellular drugs in EAE mice is transiently increased but similar to that in naive mice at steady state. Our data suggest that, despite reported BBB disruption, CNS penetration for small molecule therapeutic agents does not increase in MS- and AD-related animal models.

  12. Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia

    Science.gov (United States)

    Ren, Changhong; Li, Ning; Wang, Brian; Yang, Yong; Gao, Jinhuan; Li, Sijie; Ding, Yuchuan; Jin, Kunlin; Ji, Xunming

    2015-01-01

    Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke. PMID:26618042

  13. Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity.

    Science.gov (United States)

    Lippmann, Kristina; Kamintsky, Lyn; Kim, Soo Young; Lublinsky, Svetlana; Prager, Ofer; Nichtweiss, Julia Friederike; Salar, Seda; Kaufer, Daniela; Heinemann, Uwe; Friedman, Alon

    2017-05-01

    Peri-infarct opening of the blood-brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood-brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood-brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input-output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.

  14. Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways.

    Directory of Open Access Journals (Sweden)

    Soonmi Won

    Full Text Available Maintaining blood-brain barrier integrity and minimizing neuronal injury are critical components of any therapeutic intervention following ischemic stroke. However, a low level of vitamin D hormone is a risk factor for many vascular diseases including stroke. The neuroprotective effects of 1,25(OH2D3 (vitamin D after ischemic stroke have been studied, but it is not known whether it prevents ischemic injury to brain endothelial cells, a key component of the neurovascular unit. We analyzed the effect of 1,25(OH2D3 on brain endothelial cell barrier integrity and tight junction proteins after hypoxia/reoxygenation in a mouse brain endothelial cell culture model that closely mimics many of the features of the blood-brain barrier in vitro. Following hypoxic injury in bEnd.3 cells, 1,25(OH2D3 treatment prevented the decrease in barrier function as measured by transendothelial electrical resistance and permeability of FITC-dextran (40 kDa, the decrease in the expression of the tight junction proteins zonula occludin-1, claudin-5, and occludin, the activation of NF-kB, and the increase in matrix metalloproteinase-9 expression. These responses were blocked when the interaction of 1,25(OH 2D3 with the vitamin D receptor (VDR was inhibited by pyridoxal 5'-phosphate treatment. Our findings show a direct, VDR-mediated, protective effect of 1,25(OH 2D3 against ischemic injury-induced blood-brain barrier dysfunction in cerebral endothelial cells.

  15. Strain-Dependent Induction of Human Enterocyte Apoptosis by Blastocystis Disrupts Epithelial Barrier and ZO-1 Organization in a Caspase 3- and 9-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Zhaona Wu

    2014-01-01

    Full Text Available Blastocystis is an emerging protistan parasite colonizing the human intestine. It is frequently reported to cause general intestinal symptoms of vomiting, diarrhea, and abdominal pain. We recently demonstrated that Blastocystis rearranged cytoskeletal proteins and induced intestinal epithelial barrier compromise. The effect of Blastocystis on enterocyte apoptosis is unknown, and a possible link between microbially induced enterocyte apoptosis and increased epithelial permeability has yet to be determined. The aim of this study is to assess if Blastocystis induces human enterocyte apoptosis and whether this effect influences human intestinal epithelial barrier function. Monolayers of polarized human colonic epithelial cell-line Caco-2 were incubated with Blastocystis subtype 7 and subtype 4. Assays for both early and late markers of apoptosis, phosphatidylserine externalization, and nuclear fragmentation, respectively, showed that Blastocystis ST-7, but not ST-4, significantly increased apoptosis in enterocytes, suggesting that Blastocystis exhibits host specificity and strain-to-strain variation in pathogenicity. ST-7 also activated Caco-2 caspases 3 and 9 but not 8. ST-7 induced changes in epithelial resistance, permeability, and tight junction (ZO-1 localization. Pretreatment of Caco-2 monolayers with a pan-caspase inhibitor z-VAD-fmk significantly inhibited these changes. This suggests a role for enterocyte apoptosis in Blastocystis-mediated epithelial barrier compromise in the human intestine.

  16. Strain-dependent induction of human enterocyte apoptosis by blastocystis disrupts epithelial barrier and ZO-1 organization in a caspase 3- and 9-dependent manner.

    Science.gov (United States)

    Wu, Zhaona; Mirza, Haris; Teo, Joshua D W; Tan, Kevin S W

    2014-01-01

    Blastocystis is an emerging protistan parasite colonizing the human intestine. It is frequently reported to cause general intestinal symptoms of vomiting, diarrhea, and abdominal pain. We recently demonstrated that Blastocystis rearranged cytoskeletal proteins and induced intestinal epithelial barrier compromise. The effect of Blastocystis on enterocyte apoptosis is unknown, and a possible link between microbially induced enterocyte apoptosis and increased epithelial permeability has yet to be determined. The aim of this study is to assess if Blastocystis induces human enterocyte apoptosis and whether this effect influences human intestinal epithelial barrier function. Monolayers of polarized human colonic epithelial cell-line Caco-2 were incubated with Blastocystis subtype 7 and subtype 4. Assays for both early and late markers of apoptosis, phosphatidylserine externalization, and nuclear fragmentation, respectively, showed that Blastocystis ST-7, but not ST-4, significantly increased apoptosis in enterocytes, suggesting that Blastocystis exhibits host specificity and strain-to-strain variation in pathogenicity. ST-7 also activated Caco-2 caspases 3 and 9 but not 8. ST-7 induced changes in epithelial resistance, permeability, and tight junction (ZO-1) localization. Pretreatment of Caco-2 monolayers with a pan-caspase inhibitor z-VAD-fmk significantly inhibited these changes. This suggests a role for enterocyte apoptosis in Blastocystis-mediated epithelial barrier compromise in the human intestine.

  17. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Solt, Anna C; Henríquez-Roldán, Carlos; Torres-Jardón, Ricardo; Nuse, Bryan; Herritt, Lou; Villarreal-Calderón, Rafael; Osnaya, Norma; Stone, Ida; García, Raquel; Brooks, Diane M; González-Maciel, Angelica; Reynoso-Robles, Rafael; Delgado-Chávez, Ricardo; Reed, William

    2008-02-01

    Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.

  18. Diet-induced obesity in male C57BL/6 mice decreases fertility as a consequence of disrupted blood-testis barrier.

    Directory of Open Access Journals (Sweden)

    Yong Fan

    Full Text Available Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB integrity may be one of the crucial underlying factors accounting for this change.

  19. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  20. Topiramate reduces blood-brain barrier disruption and inhibits seizure activity in hyperthermia-induced seizures in rats with cortical dysplasia.

    Science.gov (United States)

    Gürses, Candan; Orhan, Nurcan; Ahishali, Bulent; Yilmaz, Canan Ugur; Kemikler, Gonul; Elmas, Imdat; Cevik, Aydin; Kucuk, Mutlu; Arican, Nadir; Kaya, Mehmet

    2013-02-04

    We investigated the effects of topiramate (TPM), a novel broad spectrum anticonvulsant, on seizure severity, survival rate and blood-brain barrier (BBB) integrity during hyperthermic seizures in rats with cortical dysplasia (CD). Offsprings of irradiated mothers were used in this study. To show the functional and morphological alterations in BBB integrity, quantitative analysis of Evans blue (EB) extravasation, immunohistochemistry and electron microscopic assessment of horseradish peroxidase (HRP) permeability were performed. Rats with CD exposed to hyperthermia exhibited seizures with mean Racine's scores of 3.92 ± 1.2. Among the rats with CD pretreated with TPM, 21 of 24 rats showed no sign of seizure activity upon exposure to hyperthermia (pseizures increased BBB permeability to EB in animals with CD, but TPM pretreatment decreased the penetration of the tracer into the brain in these animals (pseizures, and TPM pretreatment prevented the development of HRP reaction products in these animals. The results of this study suggest that TPM inhibits seizure activity and maintains BBB integrity in the course of febrile seizures in the setting of CD. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration.

    Science.gov (United States)

    Dental, Clélia; Proust, Alizé; Ouellet, Michel; Barat, Corinne; Tremblay, Michel J

    2017-02-01

    A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4(+) and CD8(+) T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB. Copyright © 2017 by The American Association of Immunologists, Inc.

  2. Early Activation of MAPK p44/42 Is Partially Involved in DON-Induced Disruption of the Intestinal Barrier Function and Tight Junction Network

    Science.gov (United States)

    Springler, Alexandra; Hessenberger, Sabine; Schatzmayr, Gerd; Mayer, Elisabeth

    2016-01-01

    Deoxynivalenol (DON), produced by the plant pathogens Fusarium graminearum and Fusarium culmorum, is one of the most common mycotoxins, contaminating cereal and cereal-derived products. Although worldwide contamination of food and feed poses health threats to humans and animals, pigs are particularly susceptible to this mycotoxin. DON derivatives, such as deepoxy-deoxynivalenol (DOM-1), are produced by bacterial transformation of certain intestinal bacteria, which are naturally occurring or applied as feed additives. Intestinal epithelial cells are the initial barrier against these food- and feed-borne toxins. The present study confirms DON-induced activation of MAPK p44/42 and inhibition of p44/42 by MAPK-inhibitor U0126 monoethanolate. Influence of DON and DOM-1 on transepithelial electrical resistance (TEER), viability and expression of seven tight junction proteins (TJ), as well as the potential of U0126 to counteract DON-induced effects, was assessed. While DOM-1 showed no effect, DON significantly reduced TEER of differentiated IPEC-J2 and decreased expression of claudin-1 and -3, while leaving claudin-4; ZO-1, -2, and -3 and occludin unaffected. Inhibition of p44/42 counteracted DON-induced TEER decrease and restored claudin-3, but not claudin-1 expression. Therefore, effects of DON on TEER and claudin-3 are at least partially p44/42 mediated, while effects on viability and claudin-1 are likely mediated via alternative pathways. PMID:27618100

  3. Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage.

    Science.gov (United States)

    Glushakova, Olena Y; Johnson, Danny; Hayes, Ronald L

    2014-07-01

    Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased

  4. Moderate hypoxia followed by reoxygenation results in blood-brain barrier breakdown via oxidative stress-dependent tight-junction protein disruption.

    Directory of Open Access Journals (Sweden)

    Christoph M Zehendner

    Full Text Available Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR on the evolution of reactive oxygen species (ROS and blood-brain barrier (BBB integrity in brain endothelial cells (BEC. BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC or towards occlusion of the arteria cerebri media (MCAO with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF, MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1 and claudin 5 (Cl5, decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role

  5. The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine.

    Directory of Open Access Journals (Sweden)

    Hannah E Gavin

    2017-01-01

    Full Text Available Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin's central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity. We previously reported that the native MARTX toxin effector domain repertoire is dispensable for epithelial cellular necrosis in vitro, but essential for cell rounding and apoptosis prior to necrotic cell death. Here we use an intragastric mouse model to demonstrate that the effector domain region is required for bacterial virulence during intragastric infection. The MARTX effector domain region is essential for bacterial dissemination from the intestine, but dissemination occurs in the absence of overt intestinal tissue pathology. We employ an in vitro model of V. vulnificus interaction with polarized colonic epithelial cells to show that the MARTX effector domain region induces rapid intestinal barrier dysfunction and increased paracellular permeability prior to onset of cell lysis. Together, these results negate the inherent assumption that observations of necrosis in vitro directly predict bacterial virulence, and indicate a paradigm shift in our conceptual understanding of MARTX toxin function during intestinal infection. Results implicate the MARTX effector domain region in mediating early bacterial dissemination from the intestine to distal organs-a key step in V. vulnificus foodborne pathogenesis-even before onset of overt intestinal pathology.

  6. The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

    Science.gov (United States)

    Gavin, Hannah E.; Beubier, Nike T.

    2017-01-01

    Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin’s central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD) in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity. We previously reported that the native MARTX toxin effector domain repertoire is dispensable for epithelial cellular necrosis in vitro, but essential for cell rounding and apoptosis prior to necrotic cell death. Here we use an intragastric mouse model to demonstrate that the effector domain region is required for bacterial virulence during intragastric infection. The MARTX effector domain region is essential for bacterial dissemination from the intestine, but dissemination occurs in the absence of overt intestinal tissue pathology. We employ an in vitro model of V. vulnificus interaction with polarized colonic epithelial cells to show that the MARTX effector domain region induces rapid intestinal barrier dysfunction and increased paracellular permeability prior to onset of cell lysis. Together, these results negate the inherent assumption that observations of necrosis in vitro directly predict bacterial virulence, and indicate a paradigm shift in our conceptual understanding of MARTX toxin function during intestinal infection. Results implicate the MARTX effector domain region in mediating early bacterial dissemination from the intestine to distal organs–a key step in V. vulnificus foodborne pathogenesis–even before onset of overt intestinal pathology. PMID:28060924

  7. 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors.

    Science.gov (United States)

    Rubio-Araiz, Ana; Perez-Hernandez, Mercedes; Urrutia, Andrés; Porcu, Francesca; Borcel, Erika; Gutierrez-Lopez, Maria Dolores; O'Shea, Esther; Colado, Maria Isabel

    2014-08-01

    The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1β levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA-induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix.

  8. Moderate hypoxia followed by reoxygenation results in blood-brain barrier breakdown via oxidative stress-dependent tight-junction protein disruption.

    Science.gov (United States)

    Zehendner, Christoph M; Librizzi, Laura; Hedrich, Jana; Bauer, Nina M; Angamo, Eskedar A; de Curtis, Marco; Luhmann, Heiko J

    2013-01-01

    Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR) on the evolution of reactive oxygen species (ROS) and blood-brain barrier (BBB) integrity in brain endothelial cells (BEC). BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC) or towards occlusion of the arteria cerebri media (MCAO) with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER) and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF), MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ) integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI) was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1) and claudin 5 (Cl5), decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role in this

  9. Family Disruptions

    Science.gov (United States)

    ... stay angry, or avoid fights altogether? Your children model themselves on you. Departures and Returns Do you or your spouse frequently travel on business? These can be disruptive times for your child and for the family ...

  10. JNK signaling is the shared pathway linking neuroinflammation, blood–brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain

    Directory of Open Access Journals (Sweden)

    Wang Lan-Wan

    2012-07-01

    Full Text Available Abstract Background White matter injury is the major form of brain damage in very preterm infants. Selective white matter injury in the immature brain can be induced by lipopolysaccharide (LPS-sensitized hypoxic-ischemia (HI in the postpartum (P day 2 rat pups whose brain maturation status is equivalent to that in preterm infants less than 30 weeks of gestation. Neuroinflammation, blood–brain barrier (BBB damage and oligodendrocyte progenitor apoptosis may affect the susceptibility of LPS-sensitized HI in white matter injury. c-Jun N-terminal kinases (JNK are important stress-responsive kinases in various forms of insults. We hypothesized that LPS-sensitized HI causes white matter injury through JNK activation-mediated neuroinflammation, BBB leakage and oligodendroglial apoptosis in the white matter of P2 rat pups. Methods P2 pups received LPS (0.05 mg/kg or normal saline injection followed by 90-min HI. Immunohistochemistry and immunoblotting were used to determine microglia activation, TNF-α, BBB damage, cleaved caspase-3, JNK and phospho-JNK (p-JNK, myelin basic protein (MBP, and glial fibrillary acidic protein (GFAP expression. Immunofluorescence was performed to determine the cellular distribution of p-JNK. Pharmacological and genetic approaches were used to inhibit JNK activity. Results P2 pups had selective white matter injury associated with upregulation of activated microglia, TNF-α, IgG extravasation and oligodendroglial progenitor apoptosis after LPS-sensitized HI. Immunohistochemical analyses showed early and sustained JNK activation in the white matter at 6 and 24 h post-insult. Immunofluorescence demonstrated upregulation of p-JNK in activated microglia, vascular endothelial cells and oligodendrocyte progenitors, and also showed perivascular aggregation of p-JNK-positive cells around the vessels 24 h post-insult. JNK inhibition by AS601245 or by antisense oligodeoxynucleotides (ODN significantly reduced microglial

  11. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  12. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  13. Politisk disruption

    DEFF Research Database (Denmark)

    Tække, Jesper

    2017-01-01

    Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på.......Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på....

  14. EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model.

    Directory of Open Access Journals (Sweden)

    Wen-bin Wan

    Full Text Available Alzheimer's disease (AD is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aβ accumulation and deposition in brain parenchyma and cerebral capillaries, and leads to blood-brain barrier (BBB disruption. Despite great progress in understanding the etiology of AD, the underlying pathogenic mechanism of BBB damage is still unclear, and no effective treatment has been devised. The standard Ginkgo biloba extract EGb761 has been widely used as a potential cognitive enhancer for the treatment of AD. However, the cellular mechanism underlying the effect remain to be clarified. In this study, we employed an immortalized endothelial cell line (bEnd.3 and incubation of Aβ(1-42 oligomer, to mimic a monolayer BBB model under conditions found in the AD brain. We investigated the effect of EGb761 on BBB and found that Aβ1-42 oligomer-induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS, were attenuated by treatment with EGb761. Moreover, treatment of the cells with EGb761 decreased BBB permeability and increased tight junction scaffold protein levels including ZO-1, Claudin-5 and Occludin. We also found that the Aβ(1-42 oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE, which mediates Aβ cytotoxicity and plays an essential role in AD progression, was significantly decreased by treatment with EGb761. To our knowledge, we provide the first direct in vitro evidence of an effect of EGb761 on the brain endothelium exposed to Aβ(1-42 oligomer, and on the expression of tight junction (TJ scaffold proteins and RAGE. Our results provide a new insight into a possible mechanism of action of EGb761. This study provides a rational basis for the therapeutic application of EGb761 in the treatment of AD.

  15. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; Werthner, H.; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  16. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; H. Werthner; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  17. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    While projects of governance by transparency have become widespread over the past decades, theyare usually investigated and theorized in isolation from the wider field of visibility and surveillancein which they are embedded. Building on theories of governance, visibility and surveillance...... appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...... of surveillance produce new forms of governing, potentiallywidening the space of manoeuvring for corporations....

  18. Can probiotics modulate human disease by impacting intestinal barrier function?

    NARCIS (Netherlands)

    Bron, Peter A.; Kleerebezem, Michiel; Brummer, Robert Jan; Cani, Patrice D.; Mercenier, Annick; MacDonald, Thomas T.; Garcia-Ródenas, Clara L.; Wells, Jerry M.

    2017-01-01

    Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is

  19. Blood-neural barrier: intercellular communication at glio-vascular interface.

    Science.gov (United States)

    Kim, Jung Hun; Kim, Jin Hyoung; Park, Joeng Ae; Lee, Sae-Won; Kim, Woo Jean; Yu, Young Suk; Kim, Kyu-Won

    2006-07-31

    The blood-neural barrier (BNB), including blood-brain barrier (BBB) and blood-retinal barrier (BRB), is an endothelial barrier constructed by an extensive network of endothelial cells, astrocytes and neurons to form functional "neurovascular units", which has an important role in maintaining a precisely regulated microenvironment for reliable neuronal activity. Although failure of the BNB may be a precipitating event or a consequence, the breakdown of BNB is closely related with the development and progression of CNS diseases. Therefore, BNB is most essential in the regulation of microenvironment of the CNS. The BNB is a selective diffusion barrier characterized by tight junctions between endothelial cells, lack of fenestrations, and specific BNB transporters. The BNB have been shown to be astrocyte dependent, for it is formed by the CNS capillary endothelial cells, surrounded by astrocytic end-foot processes. Given the anatomical associations with endothelial cells, it could be supposed that astrocytes play a role in the development, maintenance, and breakdown of the BNB. Therefore, astrocytes-endothelial cells interaction influences the BNB in both physiological and pathological conditions. If we better understand mutual interactions between astrocytes and endothelial cells, in the near future, we could provide a critical solution to the BNB problems and create new opportunities for future success of treating CNS diseases. Here, we focused astrocyte-endothelial cell interaction in the formation and function of the BNB.

  20. Study on the disruption of blood brain barrier and variation of cerebrospinal fluid protein index in patients with tuberculous meningitis or viral encephalitis%结核性脑膜炎和病毒性脑炎患者的血脑屏障破坏与脑脊液蛋白质指数变化

    Institute of Scientific and Technical Information of China (English)

    张利娟; 刘信东; 赵丽君; 杨乐; 段海宇

    2015-01-01

    目的:分析结核性脑膜炎和病毒性脑炎患者血脑屏障破坏与脑脊液白蛋白指数变化的关系及中枢神经系统免疫状况,为临床治疗提供指导。方法结核组31例,27例病毒性脑炎患者为病毒组,同时选取性别、年龄无显著性差异、排除中枢神经系统感染的患者22例为对照组,采用免疫比浊法检测3组患者血清和脑脊液白蛋白及Ig A、Ig M、Ig G等免疫球蛋白水平,观察3组指标的变化情况。结果结核组脑脊液白蛋白水平及脑脊液白蛋白指数高于对照组(P<0.05)。结核组和病毒组血脑屏障损伤程度均高于对照组(P<0.05),结核组IgA、IgG、IgM指数均高于对照组(P<0.05)。结论结核性脑膜炎患者血脑屏障损害较病毒性脑炎患者严重,且中枢免疫反应强于病毒性脑炎患者。%Objective To investigate the relationship between the disruption of blood brain barrier and variation of cerebro‐spinal fluid protein index and the immune status of central nervous system in patients with tuberculous meningitis or viral en‐cephalitis. Methods 31 patients with tuberculous meningitis were selected as the tuberculosis group ,27 patients with viral en‐cephalitis were selected as virus group ,and while another 22 patients without any central nervous system infection were selected as the control group ,with no significant differences among the three groups in both sex and age. Immune turbidimetric method was used to detect the content of albumin ,IgA ,IgM and IgG in the serum and cerebrospinal fluid of three groups. The varia‐tion of indexes of albumin ,IgA ,IgM and IgG in the cerebrospinal fluid were calculated and analyzed.Results The level of al‐bumin in the cerebrospinal fluid and cerebrospinal fluid albumin index in the tuberculosis group were higher than those in the control group (P<0.05). The disruption of blood brain barrier and the indexes of IgA ,IgG and IgM in both the

  1. 伽玛刀照射正常大鼠后急性期血脑屏障通透性的改变%Early blood-brain barrier disruption after gamma irradiation in rats

    Institute of Scientific and Technical Information of China (English)

    钟强; 于新; 刘宗惠; 亓树彬

    2003-01-01

    目的:观察伽玛刀照射正常大鼠后急性期血脑屏障(blood-brain barrier,BBB)通透性的改变.方法:选择正常大鼠右侧尾状核头部为照射靶点,动物按伽玛刀最大照射剂量分为20、50、75、160 Gy 4组,准直器直径为4 mm.于伽玛刀照射后12 h至14 d内应用兔多抗清蛋白抗体行免疫组化染色半定量分析;并以硝酸镧作为示踪剂,应用透射电镜观察BBB的超微结构改变.结果: 免疫组化法显示160 Gy和75 Gy剂量组于照射后12 h,50 Gy和20 Gy剂量组于照射后1 d靶区内出现血浆蛋白外渗;硝酸镧示踪电镜显示160 Gy、75 Gy和50 Gy组于照射后1 2 h、20 Gy组于照射后1 d BBB内皮细胞间的紧密连接开放.75 Gy、50 Gy、20 Gy组变化高峰期出现在照射后3 d,而 7 d后开始消散,160 Gy组靶区阳性反应持续至照射后14 d.结论:大鼠在伽玛刀照射后急性期存在BBB通透性改变,这种改变在20~75 Gy范围内具有自限性.

  2. 陷窝蛋白在脑缺血后血脑屏障破坏中的作用%Role of caveolins in the blood-brain barrier disruption after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    王昭君; 王刘敏; 林颖; 刘亚红

    2016-01-01

    陷窝蛋白是陷窝的主要组成蛋白,也是实现其生理功能的重要蛋白。陷窝蛋白表达于平滑肌细胞、内皮细胞和脂肪细胞。陷窝既参与了细胞的脂肪摄取、胞吞和胞饮等基本生理过程,也对细胞的信号转导以及大分子物质的转运和通透起着非常重要的作用。随着对陷窝蛋白的分子构成和生物化学功能研究的深入,越来越多的研究表明陷窝及其主要成分陷窝蛋白在脑血管病的病理生理学过程起着重要作用。文章就陷窝蛋白在脑缺血后血脑屏障破坏中的作用进行了综述。%Caveolins are the major component proteins of the caveolae, and they are also the essential proteins to carry out the physiological functions of caveolae. Caveolins are expressed in smooth muscle cels, endothelial cels, and adipocytes. Caveolae are not only involved in the basic physiological processes, such as celular fat intake, endocytosis, and pinocytosis, but also play a very important role in cel signal transduction and transport and permeability of macromolecular substance. With the in-depth research on the molecular structure and biochemical function of caveolins, increasing studies have shown that caveolae and their main component caveolins play an important role in the pathophysiological process of cerebrovascular diseases. This article reviews the roles of caveolins in the blood-brain barrier destruction after cerebral ischemia.

  3. Stratum corneum barrier integrity controls skin homeostasis.

    Science.gov (United States)

    Smith, W

    1999-04-01

    The stratum corneum water barrier controls structural and functional properties of both the epidermis and the dermis. Treatments which chronically disrupt the stratum corneum water barrier can induce changes similar to those seen with 'anti-aging' treatments such as (-Hydroxy acids (AHAs) and Retin Atrade mark. Barrier disruption via daily tape stripping increases epidermal and dermal thickness, superficial and integral skin firmness, and improves skin surface texture. Modest or transitory disruption did not produce such effects. Similar results were observed with topical application of AHAs, retinoids or mild irritants after about 4-6 weeks provided such treatments resulted in prolonged elevation in TEWL (trans-epidermal water loss). Treatments that did not chronically elevate TEWL could also produce positive cosmetic effects, but such effects were in general restricted to the skin surface or epidermis. Irritation, which was observed with some treatments, was not solely responsible for the positive effects observed.

  4. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  5. Confronting the disruptive physician.

    Science.gov (United States)

    Linney, B J

    1997-01-01

    Ignoring disruptive behavior is no longer an option in today's changing health care environment. Competition and managed care have caused more organizations to deal with the disruptive physician, rather than look the other way as many did in years past. But it's not an easy task, possibly the toughest of your management career. How should you confront a disruptive physician? By having clearly stated expectations for physician behavior and policies in place for dealing with problem physicians, organizations have a context from which to address the situation.

  6. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts....... The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improves search in complementary technologies, while demoting it when strategic interests are misaligned in disruptive technologies....... However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives rise...

  7. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts....... The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improves search in complementary technologies, while demoting it when strategic interests are misaligned in disruptive technologies....... However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives rise...

  8. The biological significance of brain barrier mechanisms

    DEFF Research Database (Denmark)

    Saunders, Norman R; Habgood, Mark D; Møllgård, Kjeld;

    2016-01-01

    that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound...

  9. Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair.

    NARCIS (Netherlands)

    Koning, H.D. de; Bogaard, E.H.J. van den; Bergboer, J.G.M.; Kamsteeg, M.; Vlijmen-Willems, I.M.J.J. van; Hitomi, K.; Henry, J.; Simon, M.; Takashita, N.; Ishida-Yamamoto, A.; Schalkwijk, J.; Zeeuwen, P.L.J.M.

    2012-01-01

    BACKGROUND: Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope

  10. Drug Transport by the Blood-Aqueous Humor Barrier of the Eye.

    Science.gov (United States)

    Lee, Jonghwa; Pelis, Ryan M

    2016-10-01

    The ocular barriers (cornea, blood-retinal barrier, and blood-aqueous humor barrier) make treating eye diseases with therapeutic drugs challenging. The tight capillary endothelium of the iris and the ciliary body epithelium form the blood-aqueous humor barrier. The iris and ciliary body (iris-ciliary body) express a variety of drug transporters in the ATP-binding cassette and solute carrier (SLC) families. ATP-binding cassette family drug transporters that are present in the iris-ciliary body include P-glycoprotein, breast cancer resistance protein, and several multidrug resistance-associated proteins. SLC family drug transporters that are present in the iris-ciliary body include organic anion transporters, organic anion transporting polypeptides, bile acid transporters (apical sodium-dependent bile salt transporter and sodium taurocholate cotransporter), organic cation transporters (novel organic cation transporter and multidrug and toxin extrusion transporter) and peptide transporters. Freshly dissected iris-ciliary body preparations actively accumulate a variety of substrates of SLC drug transporters that are expressed in the tissue. The ciliary body in vitro supports active transport in the aqueous humor-to-blood direction of several substrates of organic anion transporters and multidrug resistance-associated proteins, consistent with the subcellular localization of these transporters in the ciliary body epithelium. In vivo data suggest that drug transporters in the iris-ciliary body reduce the permeation of drugs in the direction of blood-to-aqueous humor, thereby reducing ocular drug bioavailability, and are also involved in active drug elimination from the aqueous humor. An understanding of the influence on pharmacokinetics of drug transporters in the blood-aqueous humor barrier should help improve drug delivery and efficacy in the eye. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Mandrup, Karen

    BACKGROUND: Endocrine disrupting chemicals (EDCs) may contribute to reproductive changes in boys in the Western world, however, less is known about influence of EDCs in women. The incidence of precocious breast development is increasing in USA and Europe and mammary gland development has been...... suggested as particularly sensitive to endocrine disruption. Mammary gland examination in toxicological studies may be useful for improving knowledge on possible influences of EDCs on human mammary glands and also be useful for detection of endocrine disrupting effects of chemicals as part of safety testing...... and genistein, a mixture of phytoestrogens, and a mixture of environmentally relevant estrogenic EDCs of various origins. Moreover, mixtures of antiandrogenic chemicals were investigated. These include a mixture of pesticides and a mixture of environmentally relevant anti-androgenic EDCs of various origins...

  12. The disruption management model.

    Science.gov (United States)

    McAlister, James

    2011-10-01

    Within all organisations, business continuity disruptions present a set of dilemmas that managers may not have dealt with before in their normal daily duties. The disruption management model provides a simple but effective management tool to enable crisis management teams to stay focused on recovery in the midst of a business continuity incident. The model has four chronological primary headlines, which steer the team through a quick-time crisis decision-making process. The procedure facilitates timely, systematic, rationalised and justified decisions, which can withstand post-event scrutiny. The disruption management model has been thoroughly tested within an emergency services environment and is proven to significantly support clear and concise decision making in a business continuity context.

  13. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    Extant research on external knowledge search and open innovation assumes that collaborators are aligned in their strategic interests towards solving innovation problems. However, disruptive innovation is known to threaten the competitive advantage of incumbent firms, thereby creating a potential...... conflict of interest between these firms and their collaborators. This paper explores the extent to which strategic interests influence joint problem solving in both complementary and disruptive technologies by analyzing the effects of incumbent collaboration. The analysis disentangles inability...... and strategic intent to find that non-incumbents experience suppression of problem solving likelihood within disruptive technologies when incumbent collaborators are not strategically committed. The paper contributes to extant theory by showing the influence of firms’ underlying strategic interests...

  14. Emerging and Disruptive Technologies

    Science.gov (United States)

    2016-01-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages. PMID:27683538

  15. Changing circumstances, disrupting habits.

    Science.gov (United States)

    Wood, Wendy; Witt, Melissa Guerrero; Tam, Leona

    2005-06-01

    The present research investigated the mechanisms guiding habitual behavior, specifically, the stimulus cues that trigger habit performance. When usual contexts for performance change, habits cannot be cued by recurring stimuli, and performance should be disrupted. Thus, the exercising, newspaper reading, and TV watching habits of students transferring to a new university were found to survive the transfer only when aspects of the performance context did not change (e.g., participants continued to read the paper with others). In some cases, the disruption in habits also placed behavior under intentional control so that participants acted on their current intentions. Changes in circumstances also affected the favorability of intentions, but changes in intentions alone could not explain the disruption of habits. Furthermore, regardless of whether contexts changed, nonhabitual behavior was guided by intentions.

  16. Emerging and Disruptive Technologies.

    Science.gov (United States)

    Kricka, Larry J

    2016-08-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages.

  17. Interruptions disrupt reading comprehension.

    Science.gov (United States)

    Foroughi, Cyrus K; Werner, Nicole E; Barragán, Daniela; Boehm-Davis, Deborah A

    2015-06-01

    Previous research suggests that being interrupted while reading a text does not disrupt the later recognition or recall of information from that text. This research is used as support for Ericsson and Kintsch's (1995) long-term working memory (LT-WM) theory, which posits that disruptions while reading (e.g., interruptions) do not impair subsequent text comprehension. However, to fully comprehend a text, individuals may need to do more than recognize or recall information that has been presented in the text at a later time. Reading comprehension often requires individuals to connect and synthesize information across a text (e.g., successfully identifying complex topics such as themes and tones) and not just make a familiarity-based decision (i.e., recognition). The goal for this study was to determine whether interruptions while reading disrupt reading comprehension when the questions assessing comprehension require participants to connect and synthesize information across the passage. In Experiment 1, interruptions disrupted reading comprehension. In Experiment 2, interruptions disrupted reading comprehension but not recognition of information from the text. In Experiment 3, the addition of a 15-s time-out prior to the interruption successfully removed these negative effects. These data suggest that the time it takes to process the information needed to successfully comprehend text when reading is greater than that required for recognition. Any interference (e.g., an interruption) that occurs during the comprehension process may disrupt reading comprehension. This evidence supports the need for transient activation of information in working memory for successful text comprehension and does not support LT-WM theory. (c) 2015 APA, all rights reserved).

  18. Microbiome dynamics of human epidermis following skin barrier disruption

    NARCIS (Netherlands)

    Zeeuwen, P.L.; Boekhorst, te J.; Bogaard, van den E.H.; Koning, de H.D.; Kerkhof, van de P.M.; Saulnier, D.M.; Swam, van I.I.; Hijum, van S.A.F.T.; Kleerebezem, M.; Schalkwijk, J.; Timmerman, H.M.

    2012-01-01

    Background - Recent advances in sequencing technologies have enabled metagenomic analyses of many human body sites. Several studies have catalogued the composition of bacterial communities of the surface of human skin, mostly under static conditions in healthy volunteers. Skin injury will disturb th

  19. Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier

    DEFF Research Database (Denmark)

    Asgari, Nasrin; Berg, Carsten Tue; Mørch, Marlene Thorsen;

    2015-01-01

    To clarify the significance of immunoglobulin G autoantibody specific for the astrocyte water channel aquaporin-4 in cerebrospinal fluid, aquaporin-4-immunoglobulin G from a neuromyelitis optica patient was administered intrathecally to naïve mice, and the distribution and pathogenic impact...

  20. Microbiome dynamics of human epidermis following skin barrier disruption

    NARCIS (Netherlands)

    Zeeuwen, P.L.; Boekhorst, te J.; Bogaard, van den E.H.; Koning, de H.D.; Kerkhof, van de P.M.; Saulnier, D.M.; Swam, van I.I.; Hijum, van S.A.F.T.; Kleerebezem, M.; Schalkwijk, J.; Timmerman, H.M.

    2012-01-01

    Background - Recent advances in sequencing technologies have enabled metagenomic analyses of many human body sites. Several studies have catalogued the composition of bacterial communities of the surface of human skin, mostly under static conditions in healthy volunteers. Skin injury will disturb

  1. Therapeutic benefits of enhancing permeability barrier for atopic eczema

    Directory of Open Access Journals (Sweden)

    George Man

    2015-06-01

    Full Text Available The regulatory role of epidermal permeability barrier function in cutaneous inflammation has been well appreciated. While barrier disruption induces cutaneous inflammation, improvement of permeability barrier function alleviates inflammation. Studies have demonstrated that improvement of epidermal permeability barrier function not only prevents the development of atopic eczema, but also delays the relapse of these diseases. Moreover, enhancing the epidermal permeability barrier also alleviates atopic eczema. Furthermore, co-applications of barrier enhancing products with glucocorticoids can increase the therapeutic efficacy and reduce the adverse effects of glucocorticoids in the treatment of atopic eczema. Therefore, utilization of permeability barrier enhancing products alone or in combination with glucocorticoids could be a valuable approach in the treatment of atopic eczema. In this review, we discuss the benefits of improving the epidermal permeability barrier in the management of atopic eczema.

  2. Search and Disrupt

    OpenAIRE

    Ørding Olsen, Anders

    2015-01-01

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts. The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improv...

  3. The impact of disruptive innovations in orthopaedics.

    Science.gov (United States)

    Hansen, Erik; Bozic, Kevin J

    2009-10-01

    The US healthcare system is currently facing daunting demographic and economic challenges. Because musculoskeletal disorders and disease represent a substantial and growing portion of this healthcare burden, novel approaches will be needed to continue to provide high-quality, affordable, and accessible orthopaedic care to our population. The concept of "disruptive innovations," which has been studied and popularized by Harvard Business School Professor Clayton Christensen, may offer a potential framework for developing strategies to improve quality and control costs associated with musculoskeletal care. The introduction of mobile fluoroscopic imaging systems, the development of the Surgical Implant Generation Network intramedullary nail for treatment of long bone fractures in the developing world, the expanding role and contributions of physician assistants and nurse practitioners to the orthopaedic team, and the rise of ambulatory surgery centers are all examples of disruptive innovations in the field of orthopaedics. Although numerous cultural and regulatory barriers have limited the widespread adoption of these "disruptive innovations," we believe they represent an opportunity for clinicians to regain leadership in health care while at the same time improving quality and access to care for patients with musculoskeletal disease.

  4. Disruptive Space Technology

    OpenAIRE

    Benson, Jim

    2004-01-01

    In 1997 "The Innovator’s Dilemma" by Clayton M. Christensen became a popular book in the small satellite and launch vehicle communities. But like the weather, every one talks about “Disruptive Technology” but few do anything about it. In the ‘70s and ‘80s, people were looking for “Paradigm Shifts,” and since the resurrection of Donald Rumsfeld, a recent watchword has been “Transformational Technology.” But today’s buzzword is now “Responsive Space Systems.”

  5. Disruption - Access cards service

    CERN Multimedia

    2014-01-01

    We would like to inform you that between 10 November and 15 December 2014, the access cards service in Building 55 will be disrupted, as the GS Department has decided to improve the facilities for users of this building. During the work, you will find the registration, biometric registration and dosimeter exchange services on the second floor of Building 55 and the vehicle sticker service on the ground floor along with the access cards service. We thank you for your understanding and apologise for any inconvenience caused.

  6. Celibacy and Family Disruption

    Directory of Open Access Journals (Sweden)

    Emaletdinov B. M.

    2013-01-01

    Full Text Available Causes for celibacy, divorces and successful marriage are discussed in the article. Absence of true love and inability to build and keep it are the main reasons for family disruption. Amorousness, immature love and various forms of false or flawed love substitute the true feeling. It is caused by increased women’s independence, loss of mutual understanding and trust (due to infidelity or jealousy, incompatibility of characters or values. Celibacy is often conditioned by physical disability, revaluation of freedom and independence, huge requirements to partners, consumer attitude to life, infertility, alcohol and drug abuse, abnormalities in personality and sexuality.

  7. Manuel's asteroid disruption technique.

    Science.gov (United States)

    John, Manuel; Ipe, Abraham; Jacob, Ivan

    2015-06-01

    A seventy-year-old male presented with dense asteroid hyalosis in both eyes. He had undergone cataract extraction in one eye 3 years ago, and the other eye had immature cataract. Both the autorefractor and dilated streak retinoscopy did not give readings and subjective visual improvement could not be achieved. Immediately following YAG posterior capsulotomy and anterior vitreous asteroid disruption, the vision improved to 20/20 with recordable auto refractor and streak retinoscopy values. Our initial experience indicates that the treatment is simple, safe and effective but needs controlled and prospective studies to confirm its long-term safety.

  8. Cell disruption for microalgae biorefineries.

    Science.gov (United States)

    Günerken, E; D'Hondt, E; Eppink, M H M; Garcia-Gonzalez, L; Elst, K; Wijffels, R H

    2015-01-01

    Microalgae are a potential source for various valuable chemicals for commercial applications ranging from nutraceuticals to fuels. Objective in a biorefinery is to utilize biomass ingredients efficiently similarly to petroleum refineries in which oil is fractionated in fuels and a variety of products with higher value. Downstream processes in microalgae biorefineries consist of different steps whereof cell disruption is the most crucial part. To maintain the functionality of algae biochemicals during cell disruption while obtaining high disruption yields is an important challenge. Despite this need, studies on mild disruption of microalgae cells are limited. This review article focuses on the evaluation of conventional and emerging cell disruption technologies, and a comparison thereof with respect to their potential for the future microalgae biorefineries. The discussed techniques are bead milling, high pressure homogenization, high speed homogenization, ultrasonication, microwave treatment, pulsed electric field treatment, non-mechanical cell disruption and some emerging technologies.

  9. Sustainable Disruption Management

    DEFF Research Database (Denmark)

    Vaaben, Bo Valdemar

    an increasingly expensive resource, and it is being consumed in vast amounts by the transportation industry. The single largest expense for both airlines and shipping companies is fuel, which exceeds both labour costs and capital expenditure. This thesis addresses how fuel considerations can be taken into account...... management fits in to the larger scope of optimization related processes in an airline and provides a brief survey of these. The thesis goes into more detail with disruption management and does as its main contribution describe how this can be combined with flight planning. Flight planning is the calculation...... of the horizontal and vertical flight path, which an aircraft should follow in order to get from airport A to airport B. The objective of this calculation is typically to minimize fuel consumption, while satisfying airspace regulations. To the knowledge of the author the work in this thesis represents the first...

  10. Endocrine disrupters as obesogens.

    Science.gov (United States)

    Grün, Felix; Blumberg, Bruce

    2009-05-25

    The recent dramatic rise in obesity rates is an alarming global health trend that consumes an ever increasing portion of health care budgets in Western countries. The root cause of obesity is thought to be a prolonged positive energy balance. Hence, the major focus of preventative programs for obesity has been to target overeating and inadequate physical exercise. Recent research implicates environmental risk factors, including nutrient quality, stress, fetal environment and pharmaceutical or chemical exposure as relevant contributing influences. Evidence points to endocrine disrupting chemicals that interfere with the body's adipose tissue biology, endocrine hormone systems or central hypothalamic-pituitary-adrenal axis as suspects in derailing the homeostatic mechanisms important to weight control. This review highlights recent advances in our understanding of the molecular targets and mechanisms of action for these compounds and areas of future research needed to evaluate the significance of their contribution to obesity.

  11. The characteristics of railway service disruption: implications for disruption management.

    Science.gov (United States)

    Golightly, D; Dadashi, N

    2017-03-01

    Rail disruption management is central to operational continuity and customer satisfaction. Disruption is not a unitary phenomenon - it varies by time, cause, location and complexity of coordination. Effective, user-centred technology for rail disruption must reflect this variety. A repertory grid study was conducted to elicit disruption characteristics. Construct elicitation with a group of experts (n = 7) captured 26 characteristics relevant to rail disruption. A larger group of operational staff (n = 28) rated 10 types of rail incident against the 26 characteristics. The results revealed distinctions such as business impact and public perception, and the importance of management of the disruption over initial detection. There were clear differences between those events that stop the traffic, as opposed to those that only slow the traffic. The results also demonstrate the utility of repertory grid for capturing the characteristics of complex work domains. Practitioner Summary: The aim of the paper is to understand how variety in rail disruption influences socio-technical design. It uses repertory grid to identify and prioritise 26 constructs, and group 10 disruption types, identifying critical factors such as whether an incident stops or merely slows the service, and business reputation.

  12. HIV and mucosal barrier interactions: consequences for transmission and pathogenesis.

    Science.gov (United States)

    Burgener, Adam; McGowan, Ian; Klatt, Nichole R

    2015-10-01

    The mucosal barrier plays an integral function in human health as it is the primary defense against pathogens, and provides a critical transition between the external environment and the human internal body. In the context of HIV infection, the most relevant mucosal surfaces include those of the gastrointestinal (GI) and genital tract compartments. Several components help maintain the effectiveness of this mucosal surface, including the physical anatomy of the barrier, cellular immunity, soluble factors, and interactions between the epithelial barrier and the local microenvironment, including mucus and host microbiota. Any defects in barrier integrity or function can rapidly lead to an increase in acquisition risk, or with established infection may result in increased pathogenesis, morbidities, or mortality. Indeed, a key feature to all aspects of HIV infection from transmission to pathogenesis is disruption and/or dysfunction of mucosal barriers. Herein, we will detail the host-pathogen relationship of HIV and mucosal barriers in both of these scenarios.

  13. Probiotics the Good Neighbor: Guarding the Gut Mucosal Barrier

    Directory of Open Access Journals (Sweden)

    R. K. Rao

    2009-01-01

    Full Text Available Problem statement: The disruption of gut barrier function plays a crucial role in the pathogenesis of not only gastrointestinal diseases, but also the diseases of liver and other organs. Mucosal protective factors that preserve the gut barrier integrity are beneficial in the prevention and treatment of such diseases. Probiotics is a group of helpful bacteria that protect the gastrointestinal mucosa from a variety of insults. Therefore, understanding the mechanism of probiotic-mediated protection of gut barrier function is an important area of investigation. Approach: Several studies had addressed the role of probiotics in the protection of gut barrier integrity. In a recent study, we investigated the role of Lactobacillus rhamnosus GG and two soluble proteins, p40 and p75, in the protection of gut barrier function in Caco-2 cell monolayer, a model of the intestinal epithelium. Results: Studies demonstrated that live or dead Lactobacillus rhamnosus GG prevents oxidative stress-induced disruption of tight junctions and barrier function in Caco-2 cell monolayers. The isolated soluble proteins of this probiotic, p40 and p75, also prevent hydrogen peroxide-induced tight junction disruption. This protective effect of probiotic proteins was mediated by the activation of ERK1/2 and protein kinase C isoforms, PKCβI and PKCε. Conclusion: Lactobacillus rhamnosus GG prevent oxidative stress-induced disruption of intestinal epithelial tight junctions and barrier function, suggesting that preservation of epithelial barrier function is one of the mechanisms involved in the mucosal protective role of probiotics in the gut.

  14. Disrupting Ethnography through Rhizoanalysis

    Directory of Open Access Journals (Sweden)

    Diana Masny

    2014-10-01

    Full Text Available This article interrogates principles of ethnography in education proposed by Mills and Morton: raw tellings, analytic pattern, vignette and empathy. This article adopts a position that is uncomfortable, unconventional and interesting. It involves a deterritorialization/ rupture of ethnography in education in order to reterritorialize a different concept: rhizoanalysis, a way to position theory and data that is multilayered, complex and messy. Rhizoanalysis, the main focus of this article is not a method. It is an approach to research conditioned by a reality in which Deleuze and Guattari disrupt representation, interpretation and subjectivity. In this article, Multiple Literacies Theory, a theoretical and practical framework, becomes a lens to examine a rhizomatic study of a Korean family recently arrived to Australia and attending English as a second language classes. Observations and interviews recorded the daily lives of the family. The vignettes were selected by reading data intensively and immanently through a process of palpation, an innovative approach to educational research. Rhizoanalysis proposes to abandon the given and invent different ways of thinking about and doing research and what might happen when reading data differently, intensively and immanently, through Multiple Literacies Theory. Rhizoanalysis, a game-changer in the way research can be conducted, affords a different lens to tackle issues in education through research.

  15. Smart parking barrier

    KAUST Repository

    Alharbi, Abdulrazaq M.

    2016-05-06

    Various methods and systems are provided for smart parking barriers. In one example, among others, a smart parking barrier system includes a movable parking barrier located at one end of a parking space, a barrier drive configured to control positioning of the movable parking barrier, and a parking controller configured to initiate movement of the parking barrier, via the barrier drive. The movable parking barrier can be positioned between a first position that restricts access to the parking space and a second position that allows access to the parking space. The parking controller can initiate movement of the movable parking barrier in response to a positive identification of an individual allowed to use the parking space. The parking controller can identify the individual through, e.g., a RFID tag, a mobile device (e.g., a remote control, smartphone, tablet, etc.), an access card, biometric information, or other appropriate identifier.

  16. Tidal disruption event demographics

    Science.gov (United States)

    Kochanek, C. S.

    2016-09-01

    We survey the properties of stars destroyed in tidal disruption events (TDEs) as a function of black hole (BH) mass, stellar mass and evolutionary state, star formation history and redshift. For M_{BH} ≲ 10^7 M_{⊙}, the typical TDE is due to a M* ˜ 0.3 M⊙ M-dwarf, although the mass function is relatively flat for M_{ast } ≲ M_{⊙}. The contribution from older main-sequence stars and sub-giants is small but not negligible. From MBH ≃ 107.5-108.5 M⊙, the balance rapidly shifts to higher mass stars and a larger contribution from evolved stars, and is ultimately dominated by evolved stars at higher BH masses. The star formation history has little effect until the rates are dominated by evolved stars. TDE rates should decline very rapidly towards higher redshifts. The volumetric rate of TDEs is very high because the BH mass function diverges for low masses. However, any emission mechanism which is largely Eddington-limited for low BH masses suppresses this divergence in any observed sample and leads to TDE samples dominated by MBH ≃ 106.0-107.5 M⊙ BHs with roughly Eddington peak accretion rates. The typical fall-back time is relatively long, with 16 per cent having tfb plausible if tfb has any relation to the transient rise time. For almost any BH mass function, systematic searches for fainter, faster time-scale TDEs in smaller galaxies, and longer time-scale TDEs in more massive galaxies are likely to be rewarded.

  17. Interception and disruption

    Energy Technology Data Exchange (ETDEWEB)

    Solem, J.C.

    1995-07-01

    Given sufficient warning we might try to avert a collision with a comet or asteroid by using beamed energy or by using the kinetic energy of an interceptor rocket. If motivated by the opportunity to convert the object into a space asset, perhaps a microgravity mine for construction materials or spacecraft fuels, we might try a rendezvous to implant a propulsion system of some sort. But the most cost-effective means of disruption is a nuclear explosive. In this paper, I discuss optimal tactics for terminal intercept, which can be extended to remote-interdiction scenarios as well. I show that the optimal mass ratio of an interceptor rock carrying a nuclear explosive depends mainly on the ratio of the exhaust velocity to the assailant-object closing velocity. I compare the effectiveness of stand-off detonation, surface burst, and penetration, for both deflection and pulverization, concluding that a penetrator has no clear advantage over a surface-burst device for deflection, but is a distinctly more capable pulverizer. The advantage of a stand-off device is to distribute the impulse more evenly over the surface of the object and to prevent fracture, an event which would greatly complicate the intercept problem. Finally, I present some results of a model for gravitationally bound objects and obtain the maximum non-fracturing deflection speed for a variety of object sizes and structures. For a single engagement, I conclude that the non-fracturing deflection speed obtainable with a stand-off device is about four times the speed obtainable with a surface-burst device. Furthermore, the non-fracturing deflection speed is somewhat dependent on the number of competent components of the object, the speed for a 13 component object being about twice that for a 135 component object.

  18. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown

    NARCIS (Netherlands)

    Yamazaki, Y.; Baker, D.J.; Tachibana, M.; Liu, C.C.; Deursen, J.M.A. van; Brott, T.G.; Bu, G.; Kanekiyo, T.

    2016-01-01

    BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to

  19. Tidal disruption of inviscid protoplanets

    Science.gov (United States)

    Boss, Alan P.; Cameron, A. G. W.; Benz, W.

    1991-01-01

    Roche showed that equilibrium is impossible for a small fluid body synchronously orbiting a primary within a critical radius now termed the Roche limit. Tidal disruption of orbitally unbound bodies is a potentially important process for planetary formation through collisional accumulation, because the area of the Roche limit is considerably larger then the physical cross section of a protoplanet. Several previous studies were made of dynamical tidal disruption and different models of disruption were proposed. Because of the limitation of these analytical models, we have used a smoothed particle hydrodynamics (SPH) code to model the tidal disruption process. The code is basically the same as the one used to model giant impacts; we simply choose impact parameters large enough to avoid collisions. The primary and secondary both have iron cores and silicate mantles, and are initially isothermal at a molten temperature. The conclusions based on the analytical and numerical models are summarized.

  20. Vortex disruption by magnetohydrodynamic feedback

    CERN Document Server

    Mak, Julian; Hughes, D W

    2016-01-01

    In an electrically conducting fluid, vortices stretch out a weak, large-scale magnetic field to form strong current sheets on their edges. Associated with these current sheets are magnetic stresses, which are subsequently released through reconnection, leading to vortex disruption, and possibly even destruction. This disruption phenomenon is investigated here in the context of two-dimensional, homogeneous, incompressible magnetohydrodynamics. We derive a simple order of magnitude estimate for the magnetic stresses --- and thus the degree of disruption --- that depends on the strength of the background magnetic field (measured by the parameter $M$, a ratio between the Alfv\\'en speed and a typical flow speed) and on the magnetic diffusivity (measured by the magnetic Reynolds number $\\mbox{Rm}$). The resulting estimate suggests that significant disruption occurs when $M^{2}\\mbox{Rm} = O(1)$. To test our prediction, we analyse direct numerical simulations of vortices generated by the breakup of unstable shear flo...

  1. Ultrasonic disruption of algae cells

    Science.gov (United States)

    King, P. M.; Nowotarski, K.; Joyce, E. M.; Mason, T. J.

    2012-05-01

    During last decade there has been increasing interest in the production of sustainable fuels from microalgae (R.H. Wijffels and M.J. Barbosa, 2010; Singh et al 2011; D.H. Lee 2011). The aim of this project was to determine if algal cells can be ultrasonically disrupted to release lipids for biofuel production. Ultrasonic disruption of two unicellular algal species: Dunnaliella salina and Nannochloropsis oculata was investigated using a 20 kHz probe. Haemocytometer, optical density, UV-Vis, fluoro-spectrophotometer and confocal microscopy results demonstrated complete cell destruction of Dunaliella salina within 16 minutes of sonication. Results obtained for Nannochloropsis oculata differed in that ultrasound dispersed clumped cells with little or no cell disruption, as observed by haemocytometer and confocal microscopy analysis. However, UV-Visible and fluoro-spectrophotometer analysis indicated chlorophyll release following sonication, suggesting some cell disruption had occurred.

  2. Neurotoxicity of Thyroid Disrupting Contaminants

    Science.gov (United States)

    Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

  3. Persistent forecasting of disruptive technologies

    National Research Council Canada - National Science Library

    Committee on Forecasting Future Disruptive Technologies; National Research Council

    ...) and the Defense Intelligence Agency (DIA) tasked the Committee for Forecasting Future Disruptive Technologies with providing guidance and insight on how to build a persistent forecasting system to predict, analyze, and reduce the impact...

  4. Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers.

    Science.gov (United States)

    Samak, Geetha; Gangwar, Ruchika; Meena, Avtar S; Rao, Roshan G; Shukla, Pradeep K; Manda, Bhargavi; Narayanan, Damodaran; Jaggar, Jonathan H; Rao, RadhaKrishna

    2016-12-13

    Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca(2+)-free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or CaV1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L-cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK.

  5. Disruptive innovation: the demand side.

    Science.gov (United States)

    Havighurst, Clark C

    2008-01-01

    The notion of disruptive innovation provides a welcome framework for considering the prospects for low-cost alternatives in American medicine. Such innovations as have been seen, however, are largely the result of demand by patients paying their own bills because they have high-deductible coverage or are uninsured. Many other cost-saving innovations are discouraged by financing systems that are themselves largely immune to competition from disruptive innovators.

  6. A permeability barrier surrounds taste buds in lingual epithelia.

    Science.gov (United States)

    Dando, Robin; Pereira, Elizabeth; Kurian, Mani; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

    2015-01-01

    Epithelial tissues are characterized by specialized cell-cell junctions, typically localized to the apical regions of cells. These junctions are formed by interacting membrane proteins and by cytoskeletal and extracellular matrix components. Within the lingual epithelium, tight junctions join the apical tips of the gustatory sensory cells in taste buds. These junctions constitute a selective barrier that limits penetration of chemosensory stimuli into taste buds (Michlig et al. J Comp Neurol 502: 1003-1011, 2007). We tested the ability of chemical compounds to permeate into sensory end organs in the lingual epithelium. Our findings reveal a robust barrier that surrounds the entire body of taste buds, not limited to the apical tight junctions. This barrier prevents penetration of many, but not all, compounds, whether they are applied topically, injected into the parenchyma of the tongue, or circulating in the blood supply, into taste buds. Enzymatic treatments indicate that this barrier likely includes glycosaminoglycans, as it was disrupted by chondroitinase but, less effectively, by proteases. The barrier surrounding taste buds could also be disrupted by brief treatment of lingual tissue samples with DMSO. Brief exposure of lingual slices to DMSO did not affect the ability of taste buds within the slice to respond to chemical stimulation. The existence of a highly impermeable barrier surrounding taste buds and methods to break through this barrier may be relevant to basic research and to clinical treatments of taste.

  7. Safety-barrier diagrams

    DEFF Research Database (Denmark)

    Duijm, Nijs Jan

    2007-01-01

    are discussed. A simple method for quantification of safety-barrier diagrams is proposed, including situations where safety barriers depend on shared common elements. It is concluded that safety-barrier diagrams provide a useful framework for an electronic data structure that integrates information from risk......Safety-barrier diagrams and the related so-called "bow-tie" diagrams have become popular methods in risk analysis. This paper describes the syntax and principles for constructing consistent and valid safety-barrier diagrams. The relation with other methods such as fault trees and Bayesian networks...... analysis with operational safety management....

  8. Extremal surface barriers

    Energy Technology Data Exchange (ETDEWEB)

    Engelhardt, Netta; Wall, Aron C. [Department of Physics, University of California,Santa Barbara, CA 93106 (United States)

    2014-03-13

    We present a generic condition for Lorentzian manifolds to have a barrier that limits the reach of boundary-anchored extremal surfaces of arbitrary dimension. We show that any surface with nonpositive extrinsic curvature is a barrier, in the sense that extremal surfaces cannot be continuously deformed past it. Furthermore, the outermost barrier surface has nonnegative extrinsic curvature. Under certain conditions, we show that the existence of trapped surfaces implies a barrier, and conversely. In the context of AdS/CFT, these barriers imply that it is impossible to reconstruct the entire bulk using extremal surfaces. We comment on the implications for the firewall controversy.

  9. Online Education Cast as "Disruptive Innovation"

    Science.gov (United States)

    Totter, Andrew

    2008-01-01

    Technology-based forces of "disruptive innovation" are gathering around public education and will overhaul the way K-12 students learn--with potentially dramatic consequences for established public schools, according to an upcoming book that draws parallels to disruptions in other industries. In his "Disrupting Class: How Disruptive Innovation…

  10. Wall force produced during disruptions

    Science.gov (United States)

    Strauss, H.; Paccagnella, R.; Breslau, J.

    2009-11-01

    The study of disruptions is of great importance for ITER. Previous work on disruptions [1] is extended to compute toroidally asymmetric wall force in ITER, using the M3D code. The disruptions are produced by n = 1 resistive wall modes or external kink modes. A thin wall resistive boundary model is used to calculate the wall forces. The symmetric wall force, produced by a VDE, and the asymmetric wall force, produced by n = 1 modes, are comparable in magnitude. It is found that the asymmetric and axisymmetric forces scale with the growth rate of the instability multiplied by the square of the current divided by magnetic field. A similar scaling was reported for VDEs in JET [2]. Numerically, the study of disruptions is very challenging. In the M3D extended MHD code, dealiasing was applied in the toroidal direction. Advection terms were treated with a numerical upwind method. These techniques provided sufficient numerical stability to simulate entire disruption events. [4pt] [1] R. Paccagnella, H. R. Strauss, and J. Breslau, Nucl. Fusion (2009) 49 035003. [2] V. Riccardo, T. C. Hender, P. J. Lomas, et al., Plasma Phys. Control. Fusion (2004)

  11. Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress.

    Science.gov (United States)

    Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K; Nagaraja, Archana S; Dorniak, Piotr L; Pallikuth, Sandeep; Waters, Christopher M; Sood, Anil; Rao, RadhaKrishna

    2017-02-20

    The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction (TJ) disruption was investigated in Caco-2 cell monolayers in vitro and restraint stress-induced barrier dysfunction in mouse colon in vivo Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca(2+) by 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Knockdown of CaV1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated TJ disruption and barrier dysfunction. N-Acetyl l-cysteine (NAC) and l-N(G)-Nitroarginine methyl ester (l-NAME) blocked stress-induced TJ disruption and barrier dysfunction. NAC and l-NAME also blocked stress-induced activation of c-Jun N-terminal kinase (JNK) and c-Src. ROS was colocalized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, TJ disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and TJ disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca(2+), activation of JNK and c-Src, and disruption of TJ in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, TJ disruption and protein thiol oxidation in colonic mucosa. The present study demonstrates that oxidative stress is a common signal in the mechanism of TJ disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo.

  12. Tidal disruption of inviscid planetesimals

    Science.gov (United States)

    Boss, A. P.; Cameron, A. G. W.; Benz, W.

    1991-01-01

    In view of previous efforts' demonstration that strongly dissipative planetesimals are immune to tidal disruption, an examination is presently conducted of the complementary case of inviscid planetesimals arising from collisions that are sufficiently energetic to entirely melt the resulting planetesimal and debris. The tidal disruption is numerically simulated by means of the smoothed particle hydrodynamics (SPH) code of Cameron and Benz (1991), concentrating on the tidal disruption of 0.01 earth-mass planetesimals passing by the earth with variations in the impact parameter at perigee and velocity at infinity. The SPH models show that tidal forces during a close encounter can efficiently convert orbital angular momentum into spin angular momentum, thereby initiating equatorial mass-shedding to inviscid planetesimals that have been spun up beyond the limit of rotational stability.

  13. DISRUPTIVE BEHAVIOUR AMONGST DOCTORS, MYTH OR REALITY?

    OpenAIRE

    Avtar Singh

    2014-01-01

    BACKGROUND : Disruptive behavior in a medical setting is defined as objectionable or offensive interpersonal behavior that leads to disruption of professional activities in the workplace. 1 It has been observed that majority of doctors do not show disruptive behavior in their day today conduct and only few doctors are identified for their disruptive behavior . Special commi ttee on professional conduct and ethics defines disruptive behavio...

  14. Market Susceptibility Toward Disruptive Business Model Innovation

    OpenAIRE

    Dover, Oliver; Nord, Erik

    2015-01-01

    This paper discusses the conditional factors indicating market susceptibility toward disruptive innovation. There is a need to separate the different forms of disruptive innovation into segments targeting; technology, product or business model disruption. The concepts are fundamentally different and the literature to date is very one sided toward disruptive technology/product innovation. A shortage of studies on disruptive business model innovation has been discovered. This study therefore pr...

  15. Barriers to screening mammography.

    Science.gov (United States)

    Sarma, Elizabeth A

    2015-01-01

    Breast cancer (BRCA) is the second most commonly diagnosed cancer among women in the USA, and mammography is an effective means for the early detection of BRCA. Identifying the barriers to screening mammography can inform research, policy and practice aiming to increase mammography adherence. A literature review was conducted to determine common barriers to screening mammography adherence. PsycINFO and PubMed databases were searched to identify studies published between 2000 and 2012 that examined barriers associated with reduced mammography adherence. Three thematic groups of barriers, based on social ecology, were identified from the literature: healthcare system-level, social and individual-level barriers. Researchers must consider screening behaviour in context and, therefore, should simultaneously consider each level of barriers when attempting to understand screening behaviour and create interventions to increase mammography adherence.

  16. Renewable energy costs, potentials, barriers: Conceptual issues

    Energy Technology Data Exchange (ETDEWEB)

    Verbruggen, Aviel, E-mail: aviel.verbruggen@ua.ac.b [University of Antwerp (Belgium); Fischedick, Manfred [Wuppertal Institute for Climate, Environment, Energy (Germany); Moomaw, William [Tufts University, Center for International Environment and Resource Policy (United States); Weir, Tony [University of the South Pacific, Fiji Islands (Fiji); Nadai, Alain [Centre International de Recherche sur nvironnement et le Developpement CIRED (France); Nilsson, Lars J. [University of Lund (Sweden); Nyboer, John [Simon Fraser University, School of Resource and Environmental Management (Canada); Sathaye, Jayant [Lawrence Berkeley Laboratory (United States)

    2010-02-15

    Renewable energy can become the major energy supply option in low-carbon energy economies. Disruptive transformations in all energy systems are necessary for tapping widely available renewable energy resources. Organizing the energy transition from non-sustainable to renewable energy is often described as the major challenge of the first half of the 21st century. Technological innovation, the economy (costs and prices) and policies have to be aligned to achieve full renewable energy potentials, and barriers impeding that growth need to be removed. These issues are also covered by IPCC's special report on renewable energy and climate change to be completed in 2010. This article focuses on the interrelations among the drivers. It clarifies definitions of costs and prices, and of barriers. After reviewing how the third and fourth assessment reports of IPCC cover mitigation potentials and commenting on definitions of renewable energy potentials in the literature, we propose a consistent set of potentials of renewable energy supplies.

  17. Jogging Can Modify Disruptive Behaviors.

    Science.gov (United States)

    Allen, Jill I.

    1980-01-01

    Jogging was used to modify disruptive behavior as part of the classroom routine for 12 learning disabled elementary-grade boys. The number of incidents of each of five negative behaviors were reduced by half following the 10-minute jogging routine. (SBH)

  18. Strategic network disruption and defence

    NARCIS (Netherlands)

    Hoyer, Britta; De Jaegher, K.J.M.

    2016-01-01

    We study a game between a network designer, who uses costly links to connect nodes in a network, and a network disruptor who tries to disrupt the resulting network as much as possible by deleting either nodes or links. For low linking costs networks with all nodes in symmetric positions are a best r

  19. Disruptive Technologies in Higher Education

    Science.gov (United States)

    Flavin, Michael

    2012-01-01

    This paper analyses the role of "disruptive" innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs) have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs) being more or less universal, but these technologies have not been universally…

  20. Cleansing Formulations That Respect Skin Barrier Integrity

    Directory of Open Access Journals (Sweden)

    Russel M. Walters

    2012-01-01

    Full Text Available Surfactants in skin cleansers interact with the skin in several manners. In addition to the desired benefit of providing skin hygiene, surfactants also extract skin components during cleansing and remain in the stratum corneum (SC after rinsing. These side effects disrupt SC structure and degrade its barrier properties. Recent applications of vibrational spectroscopy and two-photon microscopy in skin research have provided molecular-level information to facilitate our understanding of the interaction between skin and surfactant. In the arena of commercial skin cleansers, technologies have been developed to produce cleansers that both cleanse and respect skin barrier. The main approach is to minimize surfactant interaction with skin through altering its solution properties. Recently, hydrophobically modified polymers (HMPs have been introduced to create skin compatible cleansing systems. At the presence of HMP, surfactants assemble into larger, more stable structures. These structures are less likely to penetrate the skin, thereby resulting in less aggressive cleansers and the integrity of the skin barrier is maintained. In this paper, we reviewed our recent findings on surfactant and SC interactions at molecular level and provided an overview of the HM technology for developing cleansers that respect skin barrier.

  1. Fisheries-induced disruptive selection.

    Science.gov (United States)

    Landi, Pietro; Hui, Cang; Dieckmann, Ulf

    2015-01-21

    Commercial harvesting is recognized to induce adaptive responses of life-history traits in fish populations, in particular by shifting the age and size at maturation through directional selection. In addition to such evolution of a target stock, the corresponding fishery itself may adapt, in terms of fishing policy, technological progress, fleet dynamics, and adaptive harvest. The aim of this study is to assess how the interplay between natural and artificial selection, in the simplest setting in which a fishery and a target stock coevolve, can lead to disruptive selection, which in turn may cause trait diversification. To this end, we build an eco-evolutionary model for a size-structured population, in which both the stock׳s maturation schedule and the fishery׳s harvest rate are adaptive, while fishing may be subject to a selective policy based on fish size and/or maturity stage. Using numerical bifurcation analysis, we study how the potential for disruptive selection changes with fishing policy, fishing mortality, harvest specialization, life-history tradeoffs associated with early maturation, and other demographic and environmental parameters. We report the following findings. First, fisheries-induced disruptive selection is readily caused by commonly used fishing policies, and occurs even for policies that are not specific for fish size or maturity, provided that the harvest is sufficiently adaptive and large individuals are targeted intensively. Second, disruptive selection is more likely in stocks in which the selective pressure for early maturation is naturally strong, provided life-history tradeoffs are sufficiently consequential. Third, when a fish stock is overexploited, fisheries targeting only large individuals might slightly increase sustainable yield by causing trait diversification (even though the resultant yield always remains lower than the maximum sustainable yield that could be obtained under low fishing mortality, without causing disruptive

  2. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature.

    Directory of Open Access Journals (Sweden)

    Tony E Walshe

    Full Text Available Pericyte-endothelial cell (EC interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-beta signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-beta signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-beta signaling was inhibited by systemic expression of soluble endoglin (sEng and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-beta signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG. Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-beta signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-beta signaling. These results implicate constitutive TGF-beta signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-beta signaling in vasoproliferative and vascular degenerative retinal diseases.

  3. Converse Barrier Certificate Theorems

    DEFF Research Database (Denmark)

    Wisniewski, Rafael; Sloth, Christoffer

    2016-01-01

    This paper shows that a barrier certificate exists for any safe dynamical system. Specifically, we prove converse barrier certificate theorems for a class of structurally stable dynamical systems. Other authors have developed a related result by assuming that the dynamical system has neither sing...

  4. Skin barrier function

    DEFF Research Database (Denmark)

    2016-01-01

    Renowned experts present the latest knowledge Although a very fragile structure, the skin barrier is probably one of the most important organs of the body. Inward/out it is responsible for body integrity and outward/in for keeping microbes, chemicals, and allergens from penetrating the skin. Since...... the role of barrier integrity in atopic dermatitis and the relationship to filaggrin mutations was discovered a decade ago, research focus has been on the skin barrier, and numerous new publications have become available. This book is an interdisciplinary update offering a wide range of information...... on the subject. It covers new basic research on skin markers, including results on filaggrin and on methods for the assessment of the barrier function. Biological variation and aspects of skin barrier function restoration are discussed as well. Further sections are dedicated to clinical implications of skin...

  5. Optimizing Barrier Removal to Restore Connectivity in Utah's Weber Basin

    Science.gov (United States)

    Kraft, M.; Null, S. E.

    2016-12-01

    Instream barriers, such as dams, culverts and diversions are economically important for water supply, but negatively affect river ecosystems and disrupt hydrologic processes. Removal of uneconomical and aging in-stream barriers to improve habitat connectivity is increasingly used to restore river connectivity. Most past barrier removal projects focused on individual barriers using a score-and-rank technique, ignoring cumulative change from multiple, spatially-connected barrier removals. Similarly, most water supply models optimize either human water use or aquatic connectivity, failing to holistically represent human and environmental benefits. In this study, a dual objective optimization model identified in-stream barriers that impede aquatic habitat connectivity for trout, using streamflow, temperature, and channel gradient as indicators of aquatic habitat suitability. Water scarcity costs are minimized using agricultural and urban economic penalty functions to incorporate water supply benefits and a budget monetizes costs of removing small barriers like culverts and road crossings. The optimization model developed is applied to a case study in Utah's Weber basin to prioritize removal of the most environmentally harmful barriers, while maintaining human water uses. The dual objective solution basis was developed to quantify and graphically visualize tradeoffs between connected quality-weighted habitat for Bonneville cutthroat trout and economic water uses. Modeled results include a spectrum of barrier removal alternatives based on budget and quality-weighted reconnected habitat that can be communicated with local stakeholders. This research will help prioritize barrier removals and future restoration decisions. The modeling approach expands current barrier removal optimization methods by explicitly including economic and environmental water uses.

  6. Blood-neural barrier: its diversity and coordinated cell-to-cell communication.

    Science.gov (United States)

    Choi, Yoon Kyung; Kim, Kyu-Won

    2008-05-31

    The cerebral microvessels possess barrier characteristics which are tightly sealed excluding many toxic substances and protecting neural tissues. The specialized blood-neural barriers as well as the cerebral microvascular barrier are recognized in the retina, inner ear, spinal cord, and cerebrospinal fluid. Microvascular endothelial cells in the brain closely interact with other components such as astrocytes, pericytes, perivascular microglia and neurons to form functional 'neurovascular unit'. Communication between endothelial cells and other surrounding cells enhances the barrier functions, consequently resulting in maintenance and elaboration of proper brain homeostasis. Furthermore, the disruption of the neurovascular unit is closely involved in cerebrovascular disorders. In this review, we focus on the location and function of these various blood-neural barriers, and the importance of the cell-to-cell communication for development and maintenance of the barrier integrity at the neurovascular unit. We also demonstrate the close relation between the alteration of the blood-neural barriers and cerebrovascular disorders.

  7. Bodily illusions disrupt tactile sensations.

    Science.gov (United States)

    D'Amour, Sarah; Pritchett, Lisa M; Harris, Laurence R

    2015-02-01

    To accurately interpret tactile information, the brain needs to have an accurate representation of the body to which to refer the sensations. Despite this, body representation has only recently been incorporated into the study of tactile perception. Here, we investigate whether distortions of body representation affect tactile sensations. We perceptually altered the length of the arm and the width of the waist using a tendon vibration illusion and measured spatial acuity and sensitivity. Surprisingly, we found reduction in both tactile acuity and sensitivity thresholds when the arm or waist was perceptually altered, which indicates a general disruption of low-level tactile processing. We postulate that the disruptive changes correspond to the preliminary stage as the body representation starts to change and may give new insights into sensory processing in people with long-term or sudden abnormal body representation such as are found in eating disorders or following amputation.

  8. Optimal Disruption of Complex Networks

    CERN Document Server

    Zhao, Jin-Hua

    2016-01-01

    The collection of all the strongly connected components in a directed graph, among each cluster of which any node has a path to another node, is a typical example of the intertwining structure and dynamics in complex networks, as its relative size indicates network cohesion and it also composes of all the feedback cycles in the network. Here we consider finding an optimal strategy with minimal effort in removal arcs (for example, deactivation of directed interactions) to fragment all the strongly connected components into tree structure with no effect from feedback mechanism. We map the optimal network disruption problem to the minimal feedback arc set problem, a non-deterministically polynomial hard combinatorial optimization problem in graph theory. We solve the problem with statistical physical methods from spin glass theory, resulting in a simple numerical method to extract sub-optimal disruption arc sets with significantly better results than a local heuristic method and a simulated annealing method both...

  9. Disrupting the habit of interviewing

    Directory of Open Access Journals (Sweden)

    Eileen Honan

    2014-06-01

    Full Text Available This paper contributes to the growing domain of ‘post-qualitative’ research and experiments with a new (representational form to move away from traditional and clichéd descriptions of research methods. In this paper, I want to interrogate the category of interview, and the habit of interviewing, to disrupt the clichés, so as to allow thinking of different ways of writing/speaking/representing the interactions between researcher and researched that will breathe new life into qualitative inquiries. I will attempt to flatten and shred, destabilise and disrupt our common-sense ideas about interview, including those held most sacred to the qualitative community, that of anonymity and confidentiality, as well as the privilege of the ‘transcript’ in re-presenting interview data.

  10. Disrupted Nighttime Sleep in Narcolepsy

    Science.gov (United States)

    Roth, Thomas; Dauvilliers, Yves; Mignot, Emmanuel; Montplaisir, Jacques; Paul, Josh; Swick, Todd; Zee, Phyllis

    2013-01-01

    Study Objectives: Characterize disrupted nighttime sleep (DNS) in narcolepsy, an important symptom of narcolepsy. Methods: A panel of international narcolepsy experts was convened in 2011 to build a consensus characterization of DNS in patients with narcolepsy. A literature search of the Medline (1965 to date), Medline In-Process (latest weeks), Embase (1974 to date), Embase Alert (latest 8 weeks), and Biosis (1965 to date) databases was conducted using the following search terms: narcolepsy and disrupted nighttime sleep, disturbed nighttime sleep, fragmented sleep, consolidated sleep, sleep disruption, and narcolepsy questionnaire. The purpose of the literature search was to identify publications characterizing the nighttime sleep of patients with narcolepsy. The panel reviewed the literature. Nocturnal sleep can also be disturbed by REM sleep abnormalities such as vivid dreaming and REM sleep behavior disorder; however, these were not reviewed in the current paper, as we were evaluating for idiopathic sleep disturbances. Results: The literature reviewed provide a consistent characterization of nighttime sleep in patients with narcolepsy as fragmented, with reports of frequent, brief nightly awakenings with difficulties returning to sleep and associated reports of poor sleep quality. Polysomnographic studies consistently report frequent awakenings/arousals after sleep onset, more stage 1 (S1) sleep, and more frequent shifts to S1 sleep or wake from deeper stages of sleep. The consensus of the International Experts' Panel on Narcolepsy was that DNS can be distressing for patients with narcolepsy and that treatment of DNS warrants consideration. Conclusions: Clinicians involved in the management of patients with narcolepsy should investigate patients' quality of nighttime sleep, give weight and consideration to patient reports of nighttime sleep experience, and consider DNS a target for treatment. Citation: Roth T; Dauvilliers Y; Mignot E; Montplaisir J; Paul J

  11. Disruptive technologies in higher education

    Directory of Open Access Journals (Sweden)

    Michael Flavin

    2012-08-01

    Full Text Available This paper analyses the role of “disruptive” innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs being more or less universal, but these technologies have not been universally adopted and used by students and staff. Instead, other technologies not owned or controlled by HEIs are widely used to support learning and teaching. According to Christensen's theory of Disruptive Innovation, these disruptive technologies are not designed explicitly to support learning and teaching in higher education, but have educational potential. This study uses Activity Theory and Expansive Learning to analyse data regarding the impact of disruptive technologies. The data were obtained through a questionnaire survey about awareness and use of technologies, and through observation and interviews, exploring participants’ actual practice. The survey answers tended to endorse Disruptive Innovation theory, with participants establishing meanings for technologies through their use of them, rather than in keeping with a designer's intentions. Observation revealed that learners use a narrow range of technologies to support learning, but with a tendency to use resources other than those supplied by their HEIs. Interviews showed that participants use simple and convenient technologies to support their learning and teaching. This study identifies a contradiction between learning technologies made available by HEIs, and technologies used in practice. There is no evidence to suggest that a wide range of technologies is being used to support learning and teaching. Instead, a small range of technologies is being used for a wide range of tasks. Students and lecturers are not dependent on their HEIs to support learning and teaching. Instead, they self-select technologies, with use weighted towards established brands. The

  12. HOW TO IDENTIFY DISRUPTIVE NEW BUSINESSES

    OpenAIRE

    Elizabeth Robles

    2015-01-01

    In almost any industry, the most dramatic stories of growth and success were launched from a platform of disruptive innovation (Christensen et al., 2002). The probability of creating a successful, new growth business is 10 times greater if the innovators pursue a disruptive strategy rather than a sustaining one. Genuinely disruptive innovations are the ones that result in the creation of entirely new markets and business models. Few companies have introduced these innovations. Disruptive inno...

  13. Converse Barrier Certificate Theorem

    DEFF Research Database (Denmark)

    Wisniewski, Rafael; Sloth, Christoffer

    2013-01-01

    This paper presents a converse barrier certificate theorem for a generic dynamical system.We show that a barrier certificate exists for any safe dynamical system defined on a compact manifold. Other authors have developed a related result, by assuming that the dynamical system has no singular...... points in the considered subset of the state space. In this paper, we redefine the standard notion of safety to comply with generic dynamical systems with multiple singularities. Afterwards, we prove the converse barrier certificate theorem and illustrate the differences between ours and previous work...

  14. Recycler barrier RF buckets

    Energy Technology Data Exchange (ETDEWEB)

    Bhat, C.M.; /Fermilab

    2011-03-01

    The Recycler Ring at Fermilab uses a barrier rf systems for all of its rf manipulations. In this paper, I will give an overview of historical perspective on barrier rf system, the longitudinal beam dynamics issues, aspects of rf linearization to produce long flat bunches and methods used for emittance measurements of the beam in the RR barrier rf buckets. Current rf manipulation schemes used for antiproton beam stacking and longitudinal momentum mining of the RR beam for the Tevatron collider operation are explained along with their importance in spectacular success of the Tevatron luminosity performance.

  15. Engineering analysis of TFTR disruption

    Energy Technology Data Exchange (ETDEWEB)

    Murray, J.G.; Rothe, K.E.; Bronner, G.

    1984-09-01

    This report covers an engineering approach quantifying the currents, forces, and times, as well as plasma position, for the worst-case disruption based on engineerign circuit assumptions for the plasma. As the plasma moves toward the wall during the current-decay phase of disruption, the wall currents affect the rate of movement and, hence, the decay time. The calculated structure-induced currents differ considerably from those calculated using a presently available criterion, which specifies that the plasma remains stationary in the center of the torus while decaying in 10 ms. This report outlines the method and basis for the engineering calculation used to determine the current and forces as a function of the circuit characteristics. It provides specific calculations for the Tokamak Fusion Test Reactor (TFTR) with variations in parameters such as the thermal decay time, the torus resistance, and plasma temperature during the current decay. The study reviews possible ways to reduce the disruption damage of TFTR by reducing the magnitude of the plasma external field energy that is absorbed by the plasma during the current decay.

  16. LYSOSOMAL DISRUPTION BY BACTERIAL TOXINS

    Science.gov (United States)

    Bernheimer, Alan W.; Schwartz, Lois L.

    1964-01-01

    Bernheimer, Alan W. (New York University School of Medicine, New York), and Lois L. Schwartz. Lysosomal disruption by bacterial toxins. J. Bacteriol. 87:1100–1104. 1964.—Seventeen bacterial toxins were examined for capacity (i) to disrupt rabbit leukocyte lysosomes as indicated by decrease in turbidity of lysosomal suspensions, and (ii) to alter rabbit liver lysosomes as measured by release of β-glucuronidase and acid phosphatase. Staphylococcal α-toxin, Clostridium perfringens α-toxin, and streptolysins O and S affected lysosomes in both systems. Staphylococcal β-toxin, leucocidin and enterotoxin, Shiga neurotoxin, Serratia endotoxin, diphtheria toxin, tetanus neurotoxin, C. botulinum type A toxin, and C. perfringens ε-toxin were not active in either system. Staphylococcal δ-toxin, C. histolyticum collagenase, crude C. perfringens β-toxin, and crude anthrax toxin caused lysosomal damage in only one of the test systems. There is a substantial correlation between the hemolytic property of a toxin and its capacity to disrupt lysosomes, lending support to the concept that erythrocytes and lysosomes are bounded by similar membranes. PMID:5874534

  17. The Blood-Brain Barrier: An Engineering Perspective

    OpenAIRE

    Andrew eWong; Mao eYe; Amanda eLevy; Jeffrey eRothstein; Dwight eBergles; Peter Charles Searson

    2013-01-01

    It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier...

  18. Disruptive innovation as an entrepreneurial process

    NARCIS (Netherlands)

    Chandra, Y.; Yang, S.-J.S.; Singh, P.; Prajogo, D.; O'Neill, P.; Rahman, S.

    2008-01-01

    Research on conditions and causal mechanisms that influence disruptive innovation has been relatively unexplored in the extant research in disruptive innovation. By re-conceptualizing disruptive innovation as an entrepreneurial process at product, firm and industry levels, this paper draws on emergi

  19. Disruption and Distinctiveness in Higher Education

    Science.gov (United States)

    Purcell, Wendy

    2014-01-01

    "Disruption"--while an evocative word triggering feelings of anxiety and perhaps even fear--also signals renewal and growth. The Higher Education (HE) sector in England has experienced some profound disruption over the years, and yet has emerged stronger and renewed in many ways. The impact of recent disruptive forces, from fees to the…

  20. Dealing with Disruptive Behavior of Adult Learners

    Science.gov (United States)

    Dobmeier, Robert; Moran, Joseph

    2008-01-01

    The adult education literature on disruptive behavior of adult learners was reviewed and a survey on disruptive behavior of adult learners was conducted with adult educators. The findings are synthesized in a conceptual framework for understanding the types and causes of disruptive behavior, which fall into the categories of inattention,…

  1. Disruptive innovation as an entrepreneurial process

    NARCIS (Netherlands)

    Chandra, Y.; Yang, S.-J.S.; Singh, P.; Prajogo, D.; O'Neill, P.; Rahman, S.

    2008-01-01

    Research on conditions and causal mechanisms that influence disruptive innovation has been relatively unexplored in the extant research in disruptive innovation. By re-conceptualizing disruptive innovation as an entrepreneurial process at product, firm and industry levels, this paper draws on

  2. [Vascular endothelial Barrier Function].

    Science.gov (United States)

    Ivanov, A N; Puchinyan, D M; Norkin, I A

    2015-01-01

    Endothelium is an important regulator of selective permeability of the vascular wall for different molecules and cells. This review summarizes current data on endothelial barrier function. Endothelial glycocalyx structure, its function and role in the molecular transport and leukocytes migration across the endothelial barrier are discussed. The mechanisms of transcellular transport of macromolecules and cell migration through endothelial cells are reviewed. Special section of this article addresses the structure and function of tight and adherens endothelial junction, as well as their importance for the regulation of paracellular transport across the endothelial barrier. Particular attention is paid to the signaling mechanism of endothelial barrier function regulation and the factors that influence on the vascular permeability.

  3. Barriers to Effective Listening.

    Science.gov (United States)

    Hulbert, Jack E.

    1989-01-01

    Discusses the following barriers which interfere with listening efficiency: content, speaker, medium, distractions, mindset, language, listening speed, and feedback. Suggests ways to combat these obstacles to accurate comprehension. (MM)

  4. Barriers to SCM implementing

    OpenAIRE

    M.E. Rosli; B. Md Dero; A. R. Ismail; M. N. Ab Rahman

    2008-01-01

    Purpose: This paper explores the barriers faced by Malaysian manufacturing companies in successfullyimplementing the Supply Chain Management (SCM). The study has highlighted some pertinent factorsperforming the barriers that are most frequently reported by the studied companies. Sixteen companies, fromservice and manufacturing companies were studied over a period of two years to assess their SCM practicesthrough survey and interview processes.Design/methodology/approach: This part discusses t...

  5. Changing perspectives in medical practice: disruptive innovation.

    Science.gov (United States)

    Paterick, Zachary R; Pradhan, Sala R; Paterick, Timothy E; Waterhouse, Blake E

    2009-01-01

    Disruptive innovation represents a business model that identifies a market location and increases consumer options. Retail clinics may represent a disruptive healthcare innovation that identifies strategies to reduce the cost of healthcare at the primary care level. The future of healthcare demands disruptive innovation that will allow for the 50 million uninsured members of our society to receive medical care. Disruptive innovative solutions need to ensure access, quality, and reasonable cost. Retail clinics represent the tip of the iceberg in disruptive innovative thinking. The obstacles that retail clinics must solve will be lessons learned for those that identify future innovative techniques.

  6. From Digital Disruption to Business Model Scalability

    DEFF Research Database (Denmark)

    Nielsen, Christian; Lund, Morten; Thomsen, Peter Poulsen

    2017-01-01

    This article discusses the terms disruption, digital disruption, business models and business model scalability. It illustrates how managers should be using these terms for the benefit of their business by developing business models capable of achieving exponentially increasing returns to scale...... will seldom lead to business model scalability capable of competing with digital disruption(s)....... as a response to digital disruption. A series of case studies illustrate that besides frequent existing messages in the business literature relating to the importance of creating agile businesses, both in growing and declining economies, as well as hard to copy value propositions or value propositions that take...

  7. The blood-brain barrier: an engineering perspective

    OpenAIRE

    Wong, Andrew D.; Ye, Mao; Levy, Amanda F.; Rothstein, Jeffrey D.; Bergles, Dwight E.; Searson, Peter C.

    2013-01-01

    It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of...

  8. Beyond substance abuse: stress, burnout, and depression as causes of physician impairment and disruptive behavior.

    Science.gov (United States)

    Brown, Stephen D; Goske, Marilyn J; Johnson, Craig M

    2009-07-01

    Disruptive physician behavior may diminish productivity, lead to medical errors, and compromise patient safety. The purpose of this paper is to review how common psychological conditions such as depression, stress, and burnout may drive disruptive behavior in the workplace and result in impaired patterns of professional conduct similar to what is seen with substance abuse. Problems related to these psychological morbidities may be more effectively managed with improved understanding of the conditions and behaviors, their associated risk factors, and the barriers that exist to reporting them. Further research and educational programs are warranted to address how these conditions might affect radiology.

  9. Professional Disruption in Health Regulation

    DEFF Research Database (Denmark)

    Hasselbalch, Jacob

    2016-01-01

    How do professions respond to fast-moving technological changes? Disruptive innovations overturn expectations about how markets function and develop, and they often raise moral, legal and scientific concerns among professionals. Sudden technological changes can result in a state of professional...... recent revision to the Tobacco Products Directive. Medical and public health professionals that control tobacco issues were challenged by a coalition of e-cigarette industry representatives, e-cigarette users, and liberal politicians. The challengers drew on the contending norm of harm reduction...

  10. Disruptive Innovation in Numerical Hydrodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Waltz, Jacob I. [Los Alamos National Laboratory

    2012-09-06

    We propose the research and development of a high-fidelity hydrodynamic algorithm for tetrahedral meshes that will lead to a disruptive innovation in the numerical modeling of Laboratory problems. Our proposed innovation has the potential to reduce turnaround time by orders of magnitude relative to Advanced Simulation and Computing (ASC) codes; reduce simulation setup costs by millions of dollars per year; and effectively leverage Graphics Processing Unit (GPU) and future Exascale computing hardware. If successful, this work will lead to a dramatic leap forward in the Laboratory's quest for a predictive simulation capability.

  11. Incumbent response to disruptive innovation

    DEFF Research Database (Denmark)

    Kaulio, Matti; Thorén, Kent; Rohrbeck, René

    changes, however successful in minor business model adaptions. An implication hereof is that the business model concept as such has low predictive power in explaining success and failure and is in the need of an operationalization. In addition, the article discusses the relationship between technological...... in relation to disruptive change. In relation to technical change the case company has successfully in transferred its technology from one generation to the next during more than 20 years. In relation to business model change the case company has been proactive but not successful in major business model...... innovation and business innovation....

  12. Hedging Double Barriers with Singles

    NARCIS (Netherlands)

    Sbuelz, A.

    2000-01-01

    Double barrier options provide risk managers with good-deal flexibility in tailoring portfolio returns.Their hedges offer full protection only if unwound along the barriers.This work provides non-dynamic hedges that project the risk of double barriers on to single barriers.Non-dynamic hedges overcom

  13. Vacuum barrier for excimer lasers

    Energy Technology Data Exchange (ETDEWEB)

    Shurter, Roger P. (Jemez Springs, NM)

    1992-01-01

    A barrier for separating the vacuum area of a diode from the pressurized gas area of an excimer laser. The barrier is a composite material comprising layers of a metal such as copper, along with layers of polyimide, and a matrix of graphite fiber yarns impregnated with epoxy. The barrier is stronger than conventional foil barriers, and allows greater electron throughput.

  14. Vacuum barrier for excimer lasers

    Energy Technology Data Exchange (ETDEWEB)

    Shurter, R.P.

    1992-09-15

    A barrier for separating the vacuum area of a diode from the pressurized gas area of an excimer laser. The barrier is a composite material comprising layers of a metal such as copper, along with layers of polyimide, and a matrix of graphite fiber yarns impregnated with epoxy. The barrier is stronger than conventional foil barriers, and allows greater electron throughput. 3 figs.

  15. Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.

    Science.gov (United States)

    Lampi, Marsha C; Faber, Courtney J; Huynh, John; Bordeleau, Francois; Zanotelli, Matthew R; Reinhart-King, Cynthia A

    2016-01-01

    Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.

  16. Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.

    Directory of Open Access Journals (Sweden)

    Marsha C Lampi

    Full Text Available Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.

  17. Influence of puerarin, paeoniflorin, and menthol on structure and barrier function of tight junctions in MDCK and MDCK-MDR1 Cells

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    2015-04-01

    Conclusion: Menthol but not puerarin and paeoniflorin may enhance paracellular transport and improve drug penetration of the BBB by disrupting the structure and, thereby, weakening the barrier function of TJs.

  18. Disruptive innovation for social change.

    Science.gov (United States)

    Christensen, Clayton M; Baumann, Heiner; Ruggles, Rudy; Sadtler, Thomas M

    2006-12-01

    Countries, organizations, and individuals around the globe spend aggressively to solve social problems, but these efforts often fail to deliver. Misdirected investment is the primary reason for that failure. Most of the money earmarked for social initiatives goes to organizations that are structured to support specific groups of recipients, often with sophisticated solutions. Such organizations rarely reach the broader populations that could be served by simpler alternatives. There is, however, an effective way to get to those underserved populations. The authors call it "catalytic innovation." Based on Clayton Christensen's disruptive-innovation model, catalytic innovations challenge organizational incumbents by offering simpler, good-enough solutions aimed at underserved groups. Unlike disruptive innovations, though, catalytic innovations are focused on creating social change. Catalytic innovators are defined by five distinct qualities. First, they create social change through scaling and replication. Second, they meet a need that is either overserved (that is, the existing solution is more complex than necessary for many people) or not served at all. Third, the products and services they offer are simpler and cheaper than alternatives, but recipients view them as good enough. Fourth, they bring in resources in ways that initially seem unattractive to incumbents. And fifth, they are often ignored, put down, or even encouraged by existing organizations, which don't see the catalytic innovators' solutions as viable. As the authors show through examples in health care, education, and economic development, both nonprofit and for-profit groups are finding ways to create catalytic innovation that drives social change.

  19. Gut barrier in health and disease: focus on childhood.

    Science.gov (United States)

    Viggiano, D; Ianiro, G; Vanella, G; Bibbò, S; Bruno, G; Simeone, G; Mele, G

    2015-01-01

    The gut barrier is a functional unit, organized as a multi-layer system, made up of two main components: a physical barrier surface, which prevents bacterial adhesion and regulates paracellular diffusion to the host tissues, and a deep functional barrier, that is able to discriminate between pathogens and commensal microorganisms, organizing the immune tolerance and the immune response to pathogens. Other mechanisms, such as gastric juice and pancreatic enzymes (which both have antibacterial properties) participate in the luminal integrity of the gut barrier. From the outer layer to the inner layer, the physical barrier is composed of gut microbiota (that competes with pathogens to gain space and energy resources, processes the molecules necessary to mucosal integrity and modulates the immunological activity of deep barrier), mucus (which separates the intraluminal content from more internal layers and contains antimicrobial products and secretory IgA), epithelial cells (which form a physical and immunological barrier) and the innate and adaptive immune cells forming the gut-associated lymphoid tissue (which is responsible for antigen sampling and immune responses). Disruption of the gut barrier has been associated with many gastrointestinal diseases, but also with extra-intestinal pathological condition, such as type 1 diabetes mellitus, allergic diseases or autism spectrum disorders. The maintenance of a healthy intestinal barrier is therefore of paramount importance in children, for both health and economic reasons. Many drugs or compounds used in the treatment of gastrointestinal disorders act through the restoration of a normal intestinal permeability. Several studies have highlighted the role of probiotics in the modulation and reduction of intestinal permeability, considering the strong influence of gut microbiota in the modulation of the function and structure of gut barrier, but also on the immune response of the host. To date, available weapons for the

  20. Free Radicals and Matrix Metalloproteinases in Blood-Brain Barrier Disruption after Cerebral Ischemia%自由基和基质金属蛋白酶介导脑缺血血脑屏障损伤的研究进展

    Institute of Scientific and Technical Information of China (English)

    戚智锋; 罗玉敏; 刘克建

    2012-01-01

    血脑屏障的破坏是引起脑缺血损伤及继发水肿、出血、炎症的微观原因.缺血缺氧和再灌注过程产生的自由基,以及后续基质金属蛋白酶的激活,是破坏血脑屏障结构和功能的重要分子机制.因而,在脑缺血早期及时抑制自由基产生并清除自由基,抑制基质金属蛋白酶的活性,是降低脑缺血血脑屏障损伤及其并发症的关键环节.本文将从血脑屏障损伤的角度,概述自由基与基质金属蛋白酶在脑缺血损伤过程中的作用.%Cerebral ischemia results in the compromise of blood-brain barrier (BBB) integrity, leading to neurovascular complications, including cerebral hemorrhage, edema, and inflammation. Free radicals and matrix metalloproteinases (MMPs) are critically involved in the mechanism of BBB breakdown following cerebral ischemia and reperfusion. Scavenging free radicals and inhibiting activation of MMPs are potential strategies to protect BBB integrity and reduce ischemia complications. In this review, we will focus on the the role of free radicals and MMPs activation in BBB damages in cerebral ischemia.

  1. Barriers to cancer screening.

    Science.gov (United States)

    Womeodu, R J; Bailey, J E

    1996-01-01

    Many barriers to cancer screening have been summarized and discussed. Barriers have been documented in all patient populations, but some groups such as ethnic minorities and the elderly face unique barriers. The barriers to cancer screening, are multifactorial, but much of the responsibility for change must lie with health care providers and the health care delivery industry. This is not to free the patient of all responsibility, but some significant barriers are beyond their direct control. Take, for example, socioeconomic status, disease knowledge, and culturally related perceptions and myths about cancer detection and treatment. The health care industry must do a better job identifying and overcoming these barriers. The significant effects of provider counseling and advice must not be underestimated. Patients must first be advised, and then further actions must be taken if they reject the screening advice. Did they refuse adherence to recommendations because they do not view themselves as susceptible, because of overwhelming personal barriers, or because of a fatalistic attitude toward cancer detection and treatment? If that is the case, physicians and health care institutions must attempt to change perceptions, educate, and personalize the message so that patients accept their disease susceptibility [table: see text]. Multiple patient and provider risk factors have been identified that can be used to target patients particularly at high risk for inadequate cancer screening and providers at high risk for performing inadequate screening. Research has clearly demonstrated the effectiveness of interventions to improve tracking of patient and physician compliance with screening recommendations. Further research is needed to show the impact of managed-care penetration and payer status on screening efforts, and incentive schemes need to be tested that reward institutions and third-party payers who develop uniform standards and procedures for cancer screening. The

  2. Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases.

    Science.gov (United States)

    Schleimer, Robert P; Berdnikovs, Sergejs

    2017-06-01

    Epithelial barriers of the skin, gastrointestinal tract, and airway serve common critical functions, such as maintaining a physical barrier against environmental insults and allergens and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward loss of differentiation, reduced junctional integrity, and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, and circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism, and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction using both systems biology tools and causality-driven laboratory experimentation will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergic patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Current concepts in neuroendocrine disruption.

    Science.gov (United States)

    León-Olea, Martha; Martyniuk, Christopher J; Orlando, Edward F; Ottinger, Mary Ann; Rosenfeld, Cheryl S; Wolstenholme, Jennifer T; Trudeau, Vance L

    2014-07-01

    In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and

  4. The Blood-Brain Barrier: An Engineering Perspective

    Directory of Open Access Journals (Sweden)

    Andrew eWong

    2013-08-01

    Full Text Available It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore advances in our understanding of the structure and function of the blood-brain barrier are key to advances in treatment of a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

  5. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce;

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption...... not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity....

  6. Catastrophic Disruption of Comet ISON

    Science.gov (United States)

    Keane, Jacqueline V.; Milam, Stefanie N.; Coulson, Iain M.; Kleyna, Jan T.; Sekanina, Zdenek; Kracht, Rainer; Riesen, Timm-Emmanuel; Meech, Karen J.; Charnley, Steven B.

    2016-01-01

    We report submillimeter 450 and 850 microns dust continuum observations for comet C/2012 S1 (ISON) obtained at heliocentric distances 0.31-0.08 au prior to perihelion on 2013 November 28 (rh?=?0.0125 au). These observations reveal a rapidly varying dust environment in which the dust emission was initially point-like. As ISON approached perihelion, the continuum emission became an elongated dust column spread out over as much as 60? (greater than 10(exp 5) km in the anti-solar direction. Deconvolution of the November 28.04 850 microns image reveals numerous distinct clumps consistent with the catastrophic disruption of comet ISON, producing approximately 5.2?×?10(exp 10) kg of submillimeter-sized dust. Orbital computations suggest that the SCUBA-2 emission peak coincides with the comet's residual nucleus.

  7. Disrupting Entanglement of Black Holes

    CERN Document Server

    Leichenauer, Stefan

    2014-01-01

    We study entanglement in thermofield double states of strongly coupled CFTs by analyzing two-sided Reissner-Nordstrom solutions in AdS. The central object of study is the mutual information between a pair of regions, one on each asymptotic boundary of the black hole. For large regions the mutual information is positive and for small ones it vanishes; we compute the critical length scale, which goes to infinity for extremal black holes, of the transition. We also generalize the butterfly effect of Shenker and Stanford to a wide class of charged black holes, showing that mutual information is disrupted upon perturbing the system and waiting for a time of order $\\log E/\\delta E$ in units of the temperature. We conjecture that the parametric form of this timescale is universal.

  8. Addressing disruptive behaviors in the organizational setting: the win-win approach.

    Science.gov (United States)

    Rosenstein, Alan H

    2013-01-01

    Disruptive behaviors can have a significant impact on organizational dynamics and work relationships and a profound negative effect on staff and patient satisfaction, performance efficiency, and patient outcomes. Despite the growing call for action, many organizations still have difficulty in addressing these issues in a consistent, effective manner. Presented below is a model that focuses on causes and barriers and offers solutions designed to promote a "What's in it for me?" win-win approach for improving morale, job satisfaction, and patient care.

  9. Resistance to disruption in a classroom setting.

    Science.gov (United States)

    Parry-Cruwys, Diana E; Neal, Carrie M; Ahearn, William H; Wheeler, Emily E; Premchander, Raseeka; Loeb, Melissa B; Dube, William V

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable-interval (VI) 7-s VI 30-s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within-session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants.

  10. Tumor vascular disruption using various radiation types

    Directory of Open Access Journals (Sweden)

    JJ Bevelacqua

    2014-04-01

    Full Text Available The feasibility of disrupting a tumor’s vascular structure with various radiation types and radionuclides is investigated. Calculated absorbed dose profiles for photons and 4He ions suggest that low-energy beta-gamma and alpha emitting radionuclides can deposit sufficient absorbed dose to disrupt a tumor’s vascular structure while minimizing the dose outside the blood vessel. Candidate radionuclides uniformly distributed in microspheres are theoretically investigated with respect to their vascular disruption potential and to offer an alternative to 90Y microsphere therapy. Requisite activities of candidate low-energy beta-gamma and alpha emitting radionuclides to facilitate vascular disruption are calculated.

  11. Automatic location of disruption times in JET.

    Science.gov (United States)

    Moreno, R; Vega, J; Murari, A

    2014-11-01

    The loss of stability and confinement in tokamak plasmas can induce critical events known as disruptions. Disruptions produce strong electromagnetic forces and thermal loads which can damage fundamental components of the devices. Determining the disruption time is extremely important for various disruption studies: theoretical models, physics-driven models, or disruption predictors. In JET, during the experimental campaigns with the JET-C (Carbon Fiber Composite) wall, a common criterion to determine the disruption time consisted of locating the time of the thermal quench. However, with the metallic ITER-like wall (JET-ILW), this criterion is usually not valid. Several thermal quenches may occur previous to the current quench but the temperature recovers. Therefore, a new criterion has to be defined. A possibility is to use the start of the current quench as disruption time. This work describes the implementation of an automatic data processing method to estimate the disruption time according to this new definition. This automatic determination allows both reducing human efforts to locate the disruption times and standardizing the estimates (with the benefit of being less vulnerable to human errors).

  12. Dipolarization front and current disruption

    Science.gov (United States)

    Lui, A. T. Y.

    2016-10-01

    The modification of current density on the dawn-dusk cross section of the magnetotail with the earthward approach of a dipolarization front (DF) is examined through the recently published results of a three-dimensional (3-D) particle-in-cell (PIC) simulation. It is found that the current density intensifies by 37% abruptly within 1.5 ion gyrotime as the DF approaches and shows localized regions with north-south extrusions. After reaching its peak value, it undergoes a drastic current reduction (DCR) by 65% within 2 ion gyrotime. Breakdown of the frozen-in condition occurs in the neutral sheet region in association with DCR, demonstrating the non-MHD behavior of the phenomenon. The evolution of current density from this 3-D PIC simulation bears several similarities to those observed for the current disruption (CD) phenomenon, such as explosive growth and disruption of the current density leading to a breakdown of the frozen-in condition. The evolution is also similar to those from a previous two-dimensional (2-D) PIC simulation specially designed to investigate the nonlinear evolution of the cross-field current instability for CD. One interpretation of these findings is that CD and substorm triggering can be associated with earthward intrusion of a DF into the near-Earth plasma sheet as indicated by previous Cluster and Time History of Events and Macroscale Interactions during Substorms observations. An alternative interpretation is that both DF and CD are consequences of a global evolution from an ion-tearing-like instability of the magnetotail.

  13. Support or Barrier?

    DEFF Research Database (Denmark)

    Sanden, Guro Refsum; Lønsmann, Dorte

    This study offers a critical look at how corporate-level language management influences front-line language practices among employees in three multinational corporations (MNCs) headquartered in Scandinavia. Based on interview and document data, we examine, firstly, what front-line practices emplo...... to a discussion of how a company’s language policy may be seen as both support and a barrier....

  14. Overcoming Language Barriers

    Science.gov (United States)

    De Buda, Yvonne

    1976-01-01

    Many family physicians in Canada experience language and cultural barriers between themselves and their patients. Several aspects of the ensuing problems are described and some practical suggestions for solutions are made. The importance of health education for new Canadians in the family physician's office as well as through the media and community projects is stressed. Imagesp68-ap68-bp70-a PMID:21308059

  15. Barriers to obesity treatment.

    Science.gov (United States)

    Mauro, Marina; Taylor, Valerie; Wharton, Sean; Sharma, Arya M

    2008-05-01

    Obesity, one of the most prevalent health problems in the Western world, is a chronic and progressive condition. Therefore, as with other chronic diseases, patients with obesity require lifelong treatment. Long-term efficacy and effectiveness of obesity treatments is notoriously poor. This may in part be attributable to the substantial barriers that undermine long-term obesity management strategies. These can include lack of recognition of obesity as a chronic condition, low socioeconomic status, time constraints, intimate saboteurs, and a wide range of comorbidities including mental health, sleep, chronic pain, musculoskeletal, cardiovascular, respiratory, digestive and endocrine disorders. Furthermore, medications used to treat some of these disorders may further undermine weight-loss efforts. Lack of specific obesity training of health professionals, attitudes and beliefs as well as coverage and availability of obesity treatments can likewise pose important barriers. Health professionals need to take care to identify, acknowledge and address these barriers where possible to increase patient success as well as compliance and adherence with treatments. Failure to do so may further undermine the sense of failure, low self esteem and self efficacy already common among obese individuals. Addressing treatment barriers can save resources and increase the prospect of long-term success.

  16. Barriers of the Human Capital Shaping

    Directory of Open Access Journals (Sweden)

    Joanna Krochmal

    2011-07-01

    Full Text Available Nowadays, in the age of the economy focused on knowledge and science, the process of formation and development of the employees is considered as a very important investment, inspiration and a tool to efficiency creating, success and first of all, the strategic potential of the company. Indeed, it is people who are the key and the path to success and on them, the strength, the power and the success of any business should be built. The aim of this elaboration is to highlight and emphasize the importance of investment in human capital and show fluctuations, as one of the barriers that can disrupt this development, what in general also may be caused by lack of adequate systems of employees motivation.

  17. Barrier mechanisms in the Drosophila blood-brain barrier

    OpenAIRE

    Samantha Jane Hindle; Roland Jerome Bainton

    2014-01-01

    The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated funct...

  18. Atmospheric-pressure guided streamers for liposomal membrane disruption

    Science.gov (United States)

    Svarnas, P.; Matrali, S. H.; Gazeli, K.; Aleiferis, Sp.; Clément, F.; Antimisiaris, S. G.

    2012-12-01

    The potential to use liposomes (LIPs) as a cellular model in order to study interactions of cold atmospheric-pressure plasma with cells is herein investigated. Cold atmospheric-pressure plasma is formed by a dielectric-barrier discharge reactor. Large multilamellar vesicle liposomes, consisted of phosphatidylcholine and cholesterol, are prepared by the thin film hydration technique, to encapsulate a small hydrophilic dye, i.e., calcein. The plasma-induced release of calcein from liposomes is then used as a measure of liposome membrane integrity and, consequently, interaction between the cold atmospheric plasma and lipid bilayers. Physical mechanisms leading to membrane disruption are suggested, based on the plasma characterization including gas temperature calculation.

  19. Atmospheric-pressure guided streamers for liposomal membrane disruption

    Energy Technology Data Exchange (ETDEWEB)

    Svarnas, P.; Aleiferis, Sp. [High Voltage Laboratory, Department of Electrical and Computer Engineering, University of Patras, Rion 26504 (Greece); Matrali, S. H. [Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion 26504 (Greece); Gazeli, K. [High Voltage Laboratory, Department of Electrical and Computer Engineering, University of Patras, Rion 26504 (Greece); IPREM-LCABIE, Plasmas et Applications, UPPA, 64000 Pau (France); Clement, F. [IPREM-LCABIE, Plasmas et Applications, UPPA, 64000 Pau (France); Antimisiaris, S. G. [Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion 26504 (Greece); Institute of Chemical Engineering Sciences (ICES)-FORTH, Rion 26504 (Greece)

    2012-12-24

    The potential to use liposomes (LIPs) as a cellular model in order to study interactions of cold atmospheric-pressure plasma with cells is herein investigated. Cold atmospheric-pressure plasma is formed by a dielectric-barrier discharge reactor. Large multilamellar vesicle liposomes, consisted of phosphatidylcholine and cholesterol, are prepared by the thin film hydration technique, to encapsulate a small hydrophilic dye, i.e., calcein. The plasma-induced release of calcein from liposomes is then used as a measure of liposome membrane integrity and, consequently, interaction between the cold atmospheric plasma and lipid bilayers. Physical mechanisms leading to membrane disruption are suggested, based on the plasma characterization including gas temperature calculation.

  20. Geophysical characterization of subsurface barriers

    Energy Technology Data Exchange (ETDEWEB)

    Borns, D.J.

    1995-08-01

    An option for controlling contaminant migration from plumes and buried waste sites is to construct a subsurface barrier of a low-permeability material. The successful application of subsurface barriers requires processes to verify the emplacement and effectiveness of barrier and to monitor the performance of a barrier after emplacement. Non destructive and remote sensing techniques, such as geophysical methods, are possible technologies to address these needs. The changes in mechanical, hydrologic and chemical properties associated with the emplacement of an engineered barrier will affect geophysical properties such a seismic velocity, electrical conductivity, and dielectric constant. Also, the barrier, once emplaced and interacting with the in situ geologic system, may affect the paths along which electrical current flows in the subsurface. These changes in properties and processes facilitate the detection and monitoring of the barrier. The approaches to characterizing and monitoring engineered barriers can be divided between (1) methods that directly image the barrier using the contrasts in physical properties between the barrier and the host soil or rock and (2) methods that reflect flow processes around or through the barrier. For example, seismic methods that delineate the changes in density and stiffness associated with the barrier represents a direct imaging method. Electrical self potential methods and flow probes based on heat flow methods represent techniques that can delineate the flow path or flow processes around and through a barrier.

  1. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is b...

  2. Network Formation under the Threat of Disruption

    NARCIS (Netherlands)

    Hoyer, B.

    2013-01-01

    The studies in this thesis are focused on the impact the presence of a network disruptor has on network formation models. In particular, we build two theoretical models to study the effect of network disruption on network formation and test the effect network disruption has on equilibrium selection

  3. Thyroid effects of endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Boas, Malene; Feldt-Rasmussen, Ulla; Main, Katharina M

    2012-01-01

    In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert ...

  4. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Groth, Julie Jespersen; Potthoff, Daniel; Clausen, Jens

    2009-01-01

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...

  5. Resistance to Disruption in a Classroom Setting

    Science.gov (United States)

    Parry-Cruwys, Diana E.; Neal, Carrie M.; Ahearn, William H.; Wheeler, Emily E.; Premchander, Raseeka; Loeb, Melissa B.; Dube, William V.

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple…

  6. Network Formation under the Threat of Disruption

    NARCIS (Netherlands)

    Hoyer, B.

    2013-01-01

    The studies in this thesis are focused on the impact the presence of a network disruptor has on network formation models. In particular, we build two theoretical models to study the effect of network disruption on network formation and test the effect network disruption has on equilibrium selection

  7. Vacuum barrier for excimer lasers

    Energy Technology Data Exchange (ETDEWEB)

    Shurter, R.P.

    1990-10-10

    This invention is comprised of a barrier for separating the vacuum area of a diode from the pressurized gas area of an excimer laser. The barrier is a composite material comprising layers of a metal such as copper, along with layers of polyimide, and a matrix of graphite fiber yearns impregnated with epoxy. The barrier is stronger than conventional foil barriers, and allows greater electron throughput.

  8. [The cultural barrier in care].

    Science.gov (United States)

    Djadaoudjee, Lisa

    2013-11-01

    French cultural diversity is evident within French hospitals, where nurses are confronted with communication problems resulting from the language barrier. While communication is indeed essential, there is another important aspect of caring for a patient for behind the language barrier lies a cultural barrier which must be taken into account in order to provide high-quality care.

  9. Thermal barrier coating materials

    Directory of Open Access Journals (Sweden)

    David R. Clarke

    2005-06-01

    Full Text Available Improved thermal barrier coatings (TBCs will enable future gas turbines to operate at higher gas temperatures. Considerable effort is being invested, therefore, in identifying new materials with even better performance than the current industry standard, yttria-stabilized zirconia (YSZ. We review recent progress and suggest that an integrated strategy of experiment, intuitive arguments based on crystallography, and simulation may lead most rapidly to the development of new TBC materials.

  10. Barrier-protective effects of activated protein C in human alveolar epithelial cells.

    Directory of Open Access Journals (Sweden)

    Ferranda Puig

    Full Text Available Acute lung injury (ALI is a clinical manifestation of respiratory failure, caused by lung inflammation and the disruption of the alveolar-capillary barrier. Preservation of the physical integrity of the alveolar epithelial monolayer is of critical importance to prevent alveolar edema. Barrier integrity depends largely on the balance between physical forces on cell-cell and cell-matrix contacts, and this balance might be affected by alterations in the coagulation cascade in patients with ALI. We aimed to study the effects of activated protein C (APC on mechanical tension and barrier integrity in human alveolar epithelial cells (A549 exposed to thrombin. Cells were pretreated for 3 h with APC (50 µg/ml or vehicle (control. Subsequently, thrombin (50 nM or medium was added to the cell culture. APC significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction, measured by electrical impedance, optical magnetic twisting cytometry, and traction microscopy, respectively, suggesting a barrier-protective response. The dynamics of the barrier integrity was also assessed by western blotting and immunofluorescence analysis of the tight junction ZO-1. Thrombin resulted in more elongated ZO-1 aggregates at cell-cell interface areas and induced an increase in ZO-1 membrane protein content. APC attenuated the length of these ZO-1 aggregates and reduced the ZO-1 membrane protein levels induced by thrombin. In conclusion, pretreatment with APC reduced the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection.

  11. Renewable energy costs, potentials, barriers. Conceptual issues

    Energy Technology Data Exchange (ETDEWEB)

    Verbruggen, Aviel [University of Antwerp (Belgium); Fischedick, Manfred [Wuppertal Institute for Climate, Environment, Energy (Germany); Moomaw, William [Tufts University, Center for International Environment and Resource Policy (United States); Weir, Tony [University of the South Pacific, Fiji Islands (Fiji); Nadai, Alain [Centre International de Recherche sur Environnement et le Developpement CIRED (France); Nilsson, Lars J. [University of Lund (Sweden); Nyboer, John [Simon Fraser University, School of Resource and Environmental Management (Canada); Sathaye, Jayant [Lawrence Berkeley Laboratory (United States)

    2010-02-15

    Renewable energy can become the major energy supply option in low-carbon energy economies. Disruptive transformations in all energy systems are necessary for tapping widely available renewable energy resources. Organizing the energy transition from non-sustainable to renewable energy is often described as the major challenge of the first half of the 21st century. Technological innovation, the economy (costs and prices) and policies have to be aligned to achieve full renewable energy potentials, and barriers impeding that growth need to be removed. These issues are also covered by IPCC's special report on renewable energy and climate change to be completed in 2010. This article focuses on the interrelations among the drivers. It clarifies definitions of costs and prices, and of barriers. After reviewing how the third and fourth assessment reports of IPCC cover mitigation potentials and commenting on definitions of renewable energy potentials in the literature, we propose a consistent set of potentials of renewable energy supplies. (author)

  12. Contribution of microbiota to the intestinal physicochemical barrier.

    Science.gov (United States)

    Malago, J J

    2015-01-01

    The large number of intestinal microorganisms, which exceeds the total number of human cells by ten folds, alludes to a significant contribution to human health. This is vivid in enteric and some systemic diseases emanating from disruption of the microbiota. As life style keeps shifting towards disruption of the microbiota in most societies worldwide, interest in the contribution of the microbiota to gut health has grown enormously. Many studies have been conducted to elucidate the exact contribution of the microbiota to human health. The knowledge gained from these studies indicates that the microbiota interacts with the intestinal milieu to maintain gut health. In this review, the crosstalk of microbiota with the intestinal physicochemical barrier pivotal to the gut innate immunity is highlighted. In particular, the review focuses on the role of the microbiota on competitive exclusion of pathogens, intestinal pH, epithelial mechanical barrier integrity, apical actin cytoskeleton, antimicrobial peptides, and the mucus layer. Understanding this microbe-host relationship will provide useful insight into overcoming some diseases related to the disruption of the host microbiota.

  13. [Components of plastic disrupt the function of the nervous system].

    Science.gov (United States)

    Szychowski, Konrad Andrzej; Wójtowicz, Anna Katarzyna

    2013-05-27

    Development of the chemical industry leads to the development of new chemical compounds, which naturally do not exist in the environment. These chemicals are used to reduce flammability, increase plasticity, or improve solubility of other substances. Many of these compounds, which are components of plastic, the new generation of cosmetics, medical devices, food packaging and other everyday products, are easily released into the environment. Many studies have shown that a major lipophilicity characterizes substances such as phthalates, BPA, TBBPA and PCBs. This feature allows them to easily penetrate into living cells, accumulate in the tissues and the organs, and affect human and animal health. Due to the chemical structures, these compounds are able to mimic some endogenous hormones such as estradiol and to disrupt the hormone homeostasis. They can also easily pass the placental barrier and the blood-brain barrier. As numerous studies have shown, these chemicals disturb the proper functions of the nervous system from the earliest moments of life. It has been proven that these compounds affect neurogenesis as well as the synaptic transmission process. As a consequence, they interfere with the formation of the sex of the brain, as well as with the learning processes, memory and behavior. Additionally, the cytotoxic and pro-apoptotic effect may cause neurodegenerative diseases. This article presents the current state of knowledge about the effects of phthalates, BPA, TBBPA, and PCBs on the nervous system.

  14. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life.

    Science.gov (United States)

    Takiishi, Tatiana; Fenero, Camila Ideli Morales; Câmara, Niels Olsen Saraiva

    2017-09-06

    The gastrointestinal (GI) tract is considered the largest immunological organ in the body having a central role in regulating immune homeostasis. Contrary to earlier belief, the intestinal epithelial barrier is not a static physical barrier but rather strongly interacts with the gut microbiome and cells of the immune system. This intense communication between epithelial cells, immune cells and microbiome will shape specific immune responses to antigens, balancing tolerance and effector immune functions. Recent studies indicate that composition of the gut microbiome affects immune system development and modulates immune mediators, which in turn affect the intestinal barrier. Moreover, dysbiosis may favor intestinal barrier disruption and could be related to increased susceptibility to certain diseases. This review will be focused on the development of the intestinal barrier and its function in host immune defense and how gut microbiome composition throughout life can affect this role.

  15. Microalgal cell disruption via ultrasonic nozzle spraying.

    Science.gov (United States)

    Wang, M; Yuan, W

    2015-01-01

    The objective of this study was to understand the effect of operating parameters, including ultrasound amplitude, spraying pressure, nozzle orifice diameter, and initial cell concentration on microalgal cell disruption and lipid extraction in an ultrasonic nozzle spraying system (UNSS). Two algal species including Scenedesmus dimorphus and Nannochloropsis oculata were evaluated. Experimental results demonstrated that the UNSS was effective in the disruption of microalgal cells indicated by significant changes in cell concentration and Nile red-stained lipid fluorescence density between all treatments and the control. It was found that increasing ultrasound amplitude generally enhanced cell disruption and lipid recovery although excessive input energy was not necessary for best results. The effect of spraying pressure and nozzle orifice diameter on cell disruption and lipid recovery was believed to be dependent on the competition between ultrasound-induced cavitation and spraying-generated shear forces. Optimal cell disruption was not always achieved at the highest spraying pressure or biggest nozzle orifice diameter; instead, they appeared at moderate levels depending on the algal strain and specific settings. Increasing initial algal cell concentration significantly reduced cell disruption efficiency. In all UNSS treatments, the effectiveness of cell disruption and lipid recovery was found to be dependent on the algal species treated.

  16. Plasma current asymmetries during disruptions in JET

    Science.gov (United States)

    Gerasimov, S. N.; Hender, T. C.; Morris, J.; Riccardo, V.; Zakharov, L. E.; EFDA Contributors, JET

    2014-07-01

    A key feature of disruptions during vertical displacement events, discovered in JET in 1996, is the toroidal variation in the measured plasma current Ip, i.e. the plasma current asymmetries, lasting for almost the entire current quench. The unique magnetic diagnostics at JET (full set of poloidal coils and saddle loops recorded either from two toroidally opposite or from four toroidally orthogonal locations) allow for a comprehensive analysis of asymmetrical disruptions with a large scale database. This paper presents an analysis of 4854 disruptions over an 18 year period that includes both the JET carbon (C) wall and the ITER-like (IL) wall (a mixed beryllium/tungsten first wall). In spite of the Ip quench time significantly increasing for the IL-wall compared to C-wall disruptions, the observed toroidal asymmetry time integral (˜ sideways force impulse), did not increase for IL-wall disruptions. The Ip asymmetry has a dominantly n = 1 structure. Its motion in the toroidal direction has a sporadic behaviour, in general. The distributions of the number of rotation periods are found to be very similar for both C- and IL-wall disruptions, and multi-turn rotation was sometimes observed. The Ip asymmetry amplitude has no degradation with rotation frequency for either the C- or IL-wall disruption. Therefore dynamic amplification remains a potentially serious issue for ITER due to possible mechanical resonance of the machine components with the rotating asymmetry.

  17. Disrupted Stars in Unusual Galaxies

    Science.gov (United States)

    Kohler, Susanna

    2016-03-01

    Tidal disruption events (TDEs) occur when a star passes a little too close to a supermassive black hole at the center of a galaxy. Tidal forces from the black hole cause the passing star to be torn apart, resulting in a brief flare of radiation as the stars material accretes onto the black hole. A recent study asks the following question: do TDEs occur most frequently in an unusual type of galaxy?A Trend in DisruptionsSo far, we have data from eight candidate TDEs that peaked in optical and ultraviolet wavelengths. The spectra from these observations have shown an intriguing trend: many of these TDEs host galaxies exhibit weak line emission (indicating little or no current star-formation activity), and yet they show strong Balmer absorption lines (indicating star formation activity occurred within the last Gyr). These quiescent, Balmer-strong galaxies likely underwent a period of intense star formation that recently ended.To determine if TDEs are overrepresented in such galaxies, a team of scientists led by Decker French (Steward Observatory, University of Arizona) has quantified the fraction of galaxies in the Sloan Digital Sky Survey (SDSS) that exhibit similar properties to those of TDE hosts.Quantifying OverrepresentationSpectral characteristics of SDSS galaxies (gray) and TDE candidate host galaxies (colored points): line emission vs. Balmer absorption. The lower right-hand box identifies thequiescent, Balmer-strong galaxies which contain most TDE events, yet are uncommon among the galaxy sample as a whole. Click for a better look! [French et al. 2016]French and collaborators compare the optical spectra of the TDE host galaxies to those of nearly 600,000 SDSS galaxies, using two different cutoffs for the Balmer absorption the indicator of past star formation. Their strictest cut, filtering for very high Balmer absorption, selected only 0.2% of the SDSS galaxies, yet 38% of the TDEs are hosted in such galaxies. Using a more relaxed cutoff selects 2.3% of

  18. Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease.

    Science.gov (United States)

    Cabezas, Ricardo; Avila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E

    2014-01-01

    The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

  19. Barrier mechanisms in the Drosophila blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Samantha Jane Hindle

    2014-12-01

    Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  20. DISRUPTIVE BEHAVIOUR AMONGST DOCTORS, MYTH OR REALITY?

    Directory of Open Access Journals (Sweden)

    Avtar Singh

    2014-01-01

    Full Text Available BACKGROUND : Disruptive behavior in a medical setting is defined as objectionable or offensive interpersonal behavior that leads to disruption of professional activities in the workplace. 1 It has been observed that majority of doctors do not show disruptive behavior in their day today conduct and only few doctors are identified for their disruptive behavior . Special commi ttee on professional conduct and ethics defines disruptive behavior in physicians as aberrant behavior manifested through personal interaction with physicians , hospital personnel , health care professionals , patients , family members or others which interferes with patient care or could reasonably be expected to interfere with the process of delivering quality care. 2 Common forms of disruptive behaviors generally seen amongst young doctors are use of abusive language , yelling or shouting at patients , colleagues and subordinate staff , showing in disciplined behavior and at times indulging in physical abuse. 3 - 4 STUDY DESIGN : Study was conducted at a tertiary care hospital where 614 health care professionals participated which included 108 doctors 432 nurs ing staff and 74 paramedical staff METHOD : Data collection was done by semi structured pretested questionnaire and was entered in Microsoft Excel and analyzed for frequency and percentages . RESULTS : 64 % doctor , 66% nursing staff and 50% of the paramedicals answered that they have seen doctors showing disruptive behavior at one time or the other . Not all the doctors show disruptive behavior but this type of aberrant behavior is seen mainly in2 - 3 percent of doctors only. While answering to the que stion as to the type of disruptive behavior , 57% health care professionals reported that commonest form of disruptive behavior noticed by them amongst doctors was yelling or shouting on junior staff , patients and colleagues . 47% answered that doctors with disruptive behavior do not follow laid down orders or

  1. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. Grøne; Krægpøth, Morten; Nielsen, Helena Skyt

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  2. School-based interventions for disruptive behavior.

    Science.gov (United States)

    Lee, Terry

    2012-01-01

    Youth disruptive behavior is a concern for youth, school personnel,families, and society. Early childhood disruptive behaviors negatively impact the classroom, and are associated with negative academic, social, behavioral, emotional, substance use, health, and justice system outcomes in adolescence and adulthood. Effective, comprehensive, multicomponent interventions targeting risk/protective factors and pathways associated with antisocial behavior reduce and/or mitigate these negative outcomes. Positive effects have been demonstrated for universal and indicated programs for participating youth and families in early childhood, and for high-risk youth in adolescence and young adulthood. These empirically supported programs inform the treatment of complex and difficult-to-treat disruptive behavior.

  3. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten; Nielsen, Helena Skyt

    2015-01-01

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  4. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten Visby; Skyt Nielsen, Helena

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving schoolcohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  5. Linguistic Barriers and Bridges

    DEFF Research Database (Denmark)

    Thuesen, Frederik

    2016-01-01

    The influence of language on social capital in low-skill and ethnically diverse workplaces has thus far received very limited attention within the sociology of work. As the ethnically diverse workplace is an important social space for the construction of social relations bridging different social...... and intercultural communication, this article analyses interviews with 31 employees from two highly ethnically diverse Danish workplaces. The article shows how linguistic barriers such as different levels of majority language competence and their consequent misunderstandings breed mistrust and hostility, whilst...

  6. [Barrier methods of contraception].

    Science.gov (United States)

    Goldsmith, A; Edelman, D A

    1982-01-01

    Vaginal methods of contraception were the earliest types used and some references to them date back to antiquity. Most of the vaginal contraceptive agents identified by the ancient Greeks, Indians, Japanese, and Chinese have been found in modern laboratory tests to have spermicidal properties, but it is doubtful that the methods were fully reliable or were used by many people. During the 19th century the condom, vaginal spermicides, and diaphragm became available. The development of nonoxynol-9 and other nonirritating but effective spermicidal agents improved vaginal contraceptives greatly by the 1950s, but starting in the 1960s newer methods began to replace the vaginal methods. Interest in barrier methods has been reawakened somewhat by concern about the health effects of hormonal methods. At present all barrier methods leave something to be desired. Failure rates of 3-30% for barrier methods in general have been estimated, but the higher rates are believed due to incorrect or inconsistent use. Theoretical failure rates of condoms and diaphragms have been estimated at 3/100 women-years, but in actual use failure rates may reach 15 for condoms and 13 for diaphragms used with spermicides. Use-effectiveness rates are greatly influenced by motivation. For a variety of reasons, the acceptability of barrier methods is low, especially in developing countries. New developments in spermicidal agents include sperm inhibitors, which impede the fertilizing capacity of sperm rather than attempting a spermicidal effect; a number of such agents have been studied and have proven more effective in animal tests than conventional spermicides. Neosampoon, a new spermicidal foam, has attracted an increasing number of users, especially in developing countries. A new condom, made of thin polymers and containing a standard dose of nonoxynol-9, has been designed to dissolve in the vaginal fluid. Further studies are needed of its acceptability, efficacy, and side effects before it becomes

  7. Technical barrier challenges

    Institute of Scientific and Technical Information of China (English)

    李思佳

    2014-01-01

    according to a famouse report,the foreign Technical Barriers to Trade(TBT)have some effects on the exports of the People’s Republic of China.Major findings are as follows:(1)TBT makes it more difficult for China to export;(2)TBT increases the costs of Chinese export commodities;(3)TBT causes friction and confilicts in the international trade;(4)SOME developed countries have moved their phase-outs to China and other developing countries,which have become victims of TBT.

  8. Support or Barrier?

    DEFF Research Database (Denmark)

    Sanden, Guro Refsum; Lønsmann, Dorte

    This study offers a critical look at how corporate-level language management influences front-line language practices among employees in three multinational corporations (MNCs) headquartered in Scandinavia. Based on interview and document data, we examine, firstly, what front-line practices...... employees use to cross language boundaries in their everyday work, and, secondly, how these practices relate to top-down language management in the case companies. Our findings show that employees are often dependent on ad hoc and informal solutions in cross- language situations, which leads us...... to a discussion of how a company’s language policy may be seen as both support and a barrier....

  9. Optimum Barrier Height for SiC Schottky Barrier Diode

    OpenAIRE

    Mohamed Abd El-Latif; Alaa El-Din Sayed Hafez

    2013-01-01

    The study of barrier height control and optimization for Schottky barrier diode (SBD) from its physical parameters have been introduced using particle swarm optimization (PSO) algorithm. SBD is the rectifying barrier for electrical conduction across the metal semiconductor (MS) junction and, therefore, is of vital importance to the successful operation of any semiconductor device. 4H-SiC is used as a semiconductor material for its good electrical characteristics with high-power semiconductor ...

  10. Shell Galaxies, Dynamical Friction, and Dwarf Disruption

    CERN Document Server

    Ebrova, Ivana; Canalizo, Gabriela; Bennert, Nicola; Jilkova, Lucie

    2009-01-01

    Using N-body simulations of shell galaxies created in nearly radial minor mergers, we investigate the error of collision dating, resulting from the neglect of dynamical friction and of gradual disruption of the cannibalized dwarf.

  11. Towards a Framework of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    2014-01-01

    Digital platforms are disruptive information technology (IT) artifacts that erode conventional business logic associated with traditional market structures. This paper presents a framework for examining the disruptive potential of digital platforms whereby we postulate that the strategic interplay...... of governance regimes and platform layers is deterministic of whether disruptive derivatives are permitted to flourish. This framework has been employed in a comparative case study between centralized (i.e., PayPal) and decentralized (i.e., Coinkite) digital payment platforms to illustrate its applicability...... and yield propositions on the nature and impact of digital platform disruptions. Preliminary findings indicate that centralized digital platforms attempt to create unique configurals to obtain monopolistic power by tightly coupling platform layers, which are difficult to replicate. Conversely, decentralized...

  12. The Logic of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    Digital platforms are disruptive IT artifacts, because they facilitate the quick release of innovative platform derivatives from third parties (e.g., apps). This study endeavours to unravel the disruptive potential, caused by distinct designs and configurations of digital platforms on market...... environments. We postulate that the disruptive potential of digital platforms is determined by the degree of alignment among the business, technology and platform profiles. Furthermore, we argue that the design and configuration of the aforementioned three elements dictates the extent to which open innovation...... is permitted. To shed light on the disruptive potential of digital platforms, we opted for payment platforms as our unit of analysis. Through interviews with experts and payment providers, we seek to gain an in-depth appreciation of how contemporary digital payment platforms are designed and configured...

  13. Report on Criteria for Endocrine Disrupters

    DEFF Research Database (Denmark)

    Holbech, Henrik

    2011-01-01

    This report has been prepared by the Danish Centre on Endocrine Disrupters as a project contracted by the Danish Environmental Protection Agency. The Danish Centre on Endocrine Disrupters is an interdisciplinary scientific network without walls. The main purpose of the Centre is to build and gather...... new knowledge on endocrine disrupters with the focus on providing information requested for the preventive work of the regulatory authorities. The Centre is financed by the Ministry of the Environment and the scientific work programme is followed by an international scientific advisory board....... The overall aim of this project is to provide a science based proposal for criteria for endocrine disrupters. The terms of reference for the project specify elements to be included and/or addressed when developing the criteria (Annex 1). Also, several international reports and papers dealing with assessment...

  14. Magnetic field evolution in tidal disruption events

    CERN Document Server

    Bonnerot, Clément; Lodato, Giuseppe; Rossi, Elena M

    2016-01-01

    When a star gets tidally disrupted by a supermassive black hole, its magnetic field is expected to be transmitted to the debris. In this paper, we study this process via smoothed particle magnetohydrodynamical simulations of the disruption and early debris evolution including the stellar magnetic field. As the gas stretches into a stream, we show that the magnetic field evolution is strongly dependent on its orientation with respect to the stretching direction. In particular, an alignment of the field lines with the direction of stretching induces an increase of the magnetic energy. For disruptions happening well within the tidal radius, the star compression causes the magnetic field strength to sharply increase by an order of magnitude at the time of pericentre passage. If the disruption is partial, we find evidence for a dynamo process occurring inside the surviving core due to the formation of vortices. This causes an amplification of the magnetic field strength by a factor of $\\sim 10$. However, this valu...

  15. Endocrine disruption in aquatic insects: a review.

    Science.gov (United States)

    Soin, Thomas; Smagghe, Guy

    2007-02-01

    There is mounting evidence that a wide variety of compounds can have endocrine disrupting effects on humans and wildlife. However, investigations so far have focused primarily on exposure to human and other vertebrates, with invertebrate findings largely restricted to marine mollusks or to the ecdysteroid and juvenile hormone agonists as purposely synthesized endocrine disrupters for the pest management of insects. This article provides a brief description of the insect hormone system, a short sum-up of the relevant insect groups with aquatic life stages, and an overview of the additional evidence for endocrine disruption in aquatic insects from laboratory and field studies since 1999. In addition, the suitability of insects as sentinels for endocrine disrupting chemicals in aquatic ecosystems is discussed. Conclusions are drawn and research needs are defined.

  16. Double tidal disruptions in galactic nuclei

    CERN Document Server

    Mandel, Ilya

    2015-01-01

    A star on a nearly radial trajectory approaching a massive black hole (MBH) gets tidally disrupted if it comes sufficiently close to the MBH. Here we explore what happens to binary stars whose centers of mass approach the MBH on nearly radial orbits. The interaction with the MBH often leads to both stars being disrupted in sequence. We argue that such events could produce light curves that are substantially different from those of the single disruptions, with possible features such as two local maxima. Tidal forces from the MBH can also lead the binary components to collide; these merger products can form highly magnetized stars, whose subsequent tidal disruption may enable prompt jet formation.

  17. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Jespersen-Groth, Julie; Potthoff, Daniel; Clausen, Jens

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...... the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an overview of the existing literature and we present some details of the specific situations at DSB S-tog and NS....... These are the railway operators in the suburban area of Copenhagen, Denmark, and on the main railway lines in the Netherlands, respectively. Since not much research has been carried out yet on Operations Research models for disruption management in the railway context, models and techniques that have been developed...

  18. Integrated Decision Support Tools for Disruption Management

    NARCIS (Netherlands)

    Besinovic, N.; Cacchiani, V.; Dollevoet, T.; Goverde, R.M.P.; Huisman, D.; Kidd, M.P.; Kroon, L.G.; Quaglietta, E.; Rodriguez, J.; Toth, P.; Veelenturf, L.; Wagenaar, J.

    2015-01-01

    During railway operations unexpected events can require railway operators and infrastructure managers to adjust their schedules. In this research we investigate the disruption management process. More specifically, we come up with an architecture and algorithmic framework which railway operators cou

  19. The Logic of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    Digital platforms are disruptive IT artifacts, because they facilitate the quick release of innovative platform derivatives from third parties (e.g., apps). This study endeavours to unravel the disruptive potential, caused by distinct designs and configurations of digital platforms on market...... environments. We postulate that the disruptive potential of digital platforms is determined by the degree of alignment among the business, technology and platform profiles. Furthermore, we argue that the design and configuration of the aforementioned three elements dictates the extent to which open innovation...... is permitted. To shed light on the disruptive potential of digital platforms, we opted for payment platforms as our unit of analysis. Through interviews with experts and payment providers, we seek to gain an in-depth appreciation of how contemporary digital payment platforms are designed and configured...

  20. Thyroid disrupting chemicals: Mechanisms and mixtures

    Science.gov (United States)

    Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

  1. DOUBLE TIDAL DISRUPTIONS IN GALACTIC NUCLEI

    Energy Technology Data Exchange (ETDEWEB)

    Mandel, Ilya [School of Physics and Astronomy, University of Birmingham, Birmingham, B15 2TT (United Kingdom); Levin, Yuri, E-mail: imandel@star.sr.bham.ac.uk, E-mail: yuri.levin@monash.edu [Monash Center for Astrophysics and School of Physics, Monash University, Clayton, VIC 3800 (Australia)

    2015-05-20

    A star on a nearly radial trajectory approaching a massive black hole (MBH) gets tidally disrupted if it comes sufficiently close to the MBH. Here we explore what happens to binary stars whose centers of mass approach the MBH on nearly radial orbits. The interaction with the MBH often leads to both stars being disrupted in sequence. We argue that such events could produce light curves that are substantially different from those of the single disruptions, with possible features such as two local maxima. Tidal forces from the MBH can also lead the binary components to collide; these merger products can form highly magnetized stars, whose subsequent tidal disruption may enable prompt jet formation.

  2. Structuring the Classroom to Prevent Disruptive Behaviors.

    Science.gov (United States)

    Stainback, William; And Others

    1987-01-01

    Specific suggestions to help teachers structure the classroom to prevent disruptive behaviors are offered in the areas of physical arrangement and "traffic rules" time management, assignments, grouping practices, classroom atmosphere, and professional demeanor. (DB)

  3. Disrupted functional brain networks in autistic toddlers

    NARCIS (Netherlands)

    Boersma, M.; Kemner, C.; Reus, M.A. de; Collin, G.; Snijders, T.M.; Hofman, D.; Buitelaar, J.K.; Stam, C.J.; Heuvel, M.P. van den

    2013-01-01

    Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions

  4. Nanomedicine Faces Barriers

    Directory of Open Access Journals (Sweden)

    Paul Debbage

    2010-10-01

    Full Text Available Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers and distribute not only into the lesion, but into almost all organs. Drug actions in the non-lesion organs are an inescapable part of the drug delivery principle, causing “side-effects” which limit the maximally tolerable doses and result in inadequate therapy of many lesions. Nanoparticles only cross barriers by design, so side-effects are not built into their mode of operation. Delivery rates of almost 90% have been reported. This review examines the significance of these statements and checks how far they need qualification. What type of targeting is required? Is a single targeting sufficient? What new types of clinical challenge, such as immunogenicity, might attend the use of targeted nanoparticles?

  5. Higgs vacua behind barriers

    CERN Document Server

    Tamarit, Carlos

    2014-01-01

    Scenarios in which the Higgs vacuum arises radiatively and separated from the origin by a potential barrier at zero temperature are known to be attainable in models with extra singlet scalars, which in the limit of zero barrier height give rise to Coleman-Weinberg realizations of electroweak symmetry breaking. However, this requires large values of Higgs-portal couplings or a large number N of singlets. This is quantified in detail by considering, for varying N, the full two-loop effective potential at zero temperature, as well as finite temperature effects including the dominant two-loop corrections due to the singlets. Despite the large couplings, two-loop effects near the electroweak scale are under control, and actually better behaved in models with larger couplings yet fewer singlets. Strong first-order phase transitions are guaranteed even in the Coleman-Weinberg scenarios. Cubic Higgs couplings and Higgs associated-production cross sections exhibit deviations from the Standard Model predictions which c...

  6. Endocrine Disrupting Chemicals and Disease Susceptibility

    OpenAIRE

    Schug, Thaddeus T; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J.

    2011-01-01

    Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are tho...

  7. Anastomotic disruption after large bowel resection

    Institute of Scientific and Technical Information of China (English)

    Mohammad U NasirKhan; Farshad Abir; Walter Longo; Robert Kozol

    2006-01-01

    Anastomotic disruption is a feared and serious complication of colon surgery. Decades of research have identified factors favoring successful healing of anastomoses as well as risk factors for anastomotic disruption. However, some factors, such as the role of mechanical bowel preparation, remain controversial.Despite proper caution and excellent surgical technique,some anastomotic leaks are inevitable. The rapid identification of anastomotic leaks and the timely treatment in these cases are paramount.

  8. ENDOCRINE DISRUPTING EFFECTS OF BUTYLPARABEN: A REVIEW

    OpenAIRE

    Pallabi Goswami; J.C Kalita

    2013-01-01

    In recent years, there has been an increasing concern in the field of endocrine disruption over the presence of various endocrine disrupting chemicals in Pharmaceuticals and Personal care products (PPCPs). This concern has also been as PPCPs are most widely used and had led to introduction of thousands of new and complex chemicals that enter the environment in large quantities. The effect of the chemicals has not only been restricted to human who are exposed directly to the chemicals or the a...

  9. BUSINESS MODEL PATTERNS FOR DISRUPTIVE TECHNOLOGIES

    OpenAIRE

    BENJAMIN AMSHOFF; CHRISTIAN DÜLME; JULIAN ECHTERFELD; JÜRGEN GAUSEMEIER

    2015-01-01

    Companies nowadays face a myriad of business opportunities as a direct consequence of manifold disruptive technology developments. As a basic characteristic, disruptive technologies lead to a severe shift in value-creation networks giving rise to new market segments. One of the key challenges is to anticipate the business logics within these nascent and formerly unknown markets. Business model patterns promise to tackle this challenge. They can be interpreted as proven business model elements...

  10. Magnetic field evolution in tidal disruption events

    Science.gov (United States)

    Bonnerot, Clément; Price, Daniel J.; Lodato, Giuseppe; Rossi, Elena M.

    2017-08-01

    When a star gets tidally disrupted by a supermassive black hole, its magnetic field is expected to pervade its debris. In this paper, we study this process via smoothed particle magnetohydrodynamical simulations of the disruption and early debris evolution including the stellar magnetic field. As the gas stretches into a stream, we show that the magnetic field evolution is strongly dependent on its orientation with respect to the stretching direction. In particular, an alignment of the field lines with the direction of stretching induces an increase of the magnetic energy. For disruptions happening well within the tidal radius, the star compression causes the magnetic field strength to sharply increase by an order of magnitude at the time of pericentre passage. If the disruption is partial, we find evidence for a dynamo process occurring inside the surviving core due to the formation of vortices. This causes an amplification of the magnetic field strength by a factor of ˜10. However, this value represents a lower limit since it increases with numerical resolution. For an initial field strength of 1 G, the magnetic field never becomes dynamically important. Instead, the disruption of a star with a strong 1 MG magnetic field produces a debris stream within which magnetic pressure becomes similar to gas pressure a few tens of hours after disruption. If the remnant of one or multiple partial disruptions is eventually fully disrupted, its magnetic field could be large enough to magnetically power the relativistic jet detected from Swift J1644+57. Magnetized streams could also be significantly thickened by magnetic pressure when it overcomes the confining effect of self-gravity.

  11. Stability of barrier buckets with zero RF-barrier separations

    Energy Technology Data Exchange (ETDEWEB)

    Ng, K.Y.; /Fermilab

    2005-03-01

    A barrier bucket with very small separation between the rf barriers (relative to the barrier widths) or even zero separation has its synchrotron tune decreasing rather slowly from a large value towards the boundary of the bucket. As a result, large area at the bucket edges can become unstable under the modulation of rf voltage and/or rf phase. In addition, chaotic regions may form near the bucket center and extend outward under increasing modulation. Application is made to those barrier buckets used in the process of momentum mining at the Fermilab Recycler Ring.

  12. An emulsion restores the skin barrier by decreasing the skin pH and inflammation in a canine experimental model.

    Science.gov (United States)

    Pin, D; Bekrich, M; Fantini, O; Noel, G; Vidémont, E

    2014-01-01

    The aim of this study was to investigate the effect of Douxo(®) Calm Mousse (Sogeval, Laval, France) on restoration of the skin barrier in a canine model of barrier disruption. Tape strips were performed, daily for 6 days, on the lateral thorax of five healthy beagle dogs. Douxo(®) Calm Mousse was applied daily for 5 days to one side of the thorax and the opposite side was left untreated. The effects of treatment were evaluated by measurement of transepidermal water loss (TEWL) and pH and by histological assessment of disrupted skin at various times during barrier repair. Although no effect on TEWL was observed, Douxo(®) Calm Mousse maintained an acidic pH after three applications and reduced skin inflammation, which was most pronounced after five applications. The results of the study suggest that Douxo(®) Calm Mousse exerts a beneficial effect on barrier restoration and on markers of inflammation.

  13. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper

    2004-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused by for ex......Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused...... by for example severe weather, technical problems and crew sickness. Thus, the field of Airline Disruption Management has emerged within the past few years. The increased focus on cutting cost at the major airlines has intensified the interest in the development of new and cost e cient methods to handle airline...... disruptions. The purpose of this paper is twofold. In the first part it o ers an introduction to airline disruption management, provides the readers with a description of the planning processes and delivers a detailed overview of the numerous aspects of airline disruption management. In the second part we...

  14. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper

    2007-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused by for ex......Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused...... by for example severe weather, technical problems and crew sickness. Thus, the field of Airline Disruption Management has emerged within the past few years. The increased focus on cutting cost at the major airlines has intensified the interest in the development of new and cost efficient methods to handle...... airline disruptions. The purpose of this paper is twofold. In the first part it offers an introduction to airline disruption management provides the readers with a description of the planning processes and delivers a detailed overview of the numerous aspects of airline disruption management. In the second...

  15. Neuro-inflammation, blood-brain barrier, seizures and autism

    Directory of Open Access Journals (Sweden)

    Theoharides Theoharis C

    2011-11-01

    Full Text Available Abstract Many children with Autism Spectrum Diseases (ASD present with seizure activity, but the pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures. Treating neuro-inflammation may be useful when anti-seizure medications are ineffective.

  16. Acyl-CoA binding protein and epidermal barrier function

    DEFF Research Database (Denmark)

    Bloksgaard, Maria; Neess, Ditte; Færgeman, Nils J

    2014-01-01

    enzymatic systems; however, the precise function remains unknown. ACBP is expressed at relatively high levels in the epidermis, particularly in the suprabasal layers, which are highly active in lipid synthesis. Targeted disruption of the ACBP gene in mice leads to a pronounced skin and fur phenotype, which...... levels of non-esterified very long chain fatty acids in the stratum corneum of ACBP(-/-) mice. Here we review the current knowledge of ACBP with special focus on the function of ACBP in the epidermal barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis...

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

    Science.gov (United States)

    2009-12-01

    acting drugs enhance photo- sensitizer activity. FASEB J. 2003;17:1121–3. 130. James DA, Swamy N, Paz N, Hanson RN, Ray R. Synthesis and estrogen...Shoemaker, Wai Lau, Rebecca L. Shattuck, Ann P. Kwiatkowski, Paul E. Matrisian, Luis Guerra -Santos, Emily Wilson, Thomas J. Lukas, Linda J. Van Eldik, and

  18. Membrane Vesicles of Group B Streptococcus Disrupt Feto-Maternal Barrier Leading to Preterm Birth.

    Science.gov (United States)

    Surve, Manalee Vishnu; Anil, Anjali; Kamath, Kshama Ganesh; Bhutda, Smita; Sthanam, Lakshmi Kavitha; Pradhan, Arpan; Srivastava, Rohit; Basu, Bhakti; Dutta, Suryendu; Sen, Shamik; Modi, Deepak; Banerjee, Anirban

    2016-09-01

    Infection of the genitourinary tract with Group B Streptococcus (GBS), an opportunistic gram positive pathogen, is associated with premature rupture of amniotic membrane and preterm birth. In this work, we demonstrate that GBS produces membrane vesicles (MVs) in a serotype independent manner. These MVs are loaded with virulence factors including extracellular matrix degrading proteases and pore forming toxins. Mice chorio-decidual membranes challenged with MVs ex vivo resulted in extensive collagen degradation leading to loss of stiffness and mechanical weakening. MVs when instilled vaginally are capable of anterograde transport in mouse reproductive tract. Intra-amniotic injections of GBS MVs in mice led to upregulation of pro-inflammatory cytokines and inflammation mimicking features of chorio-amnionitis; it also led to apoptosis in the chorio-decidual tissue. Instillation of MVs in the amniotic sac also resulted in intrauterine fetal death and preterm delivery. Our findings suggest that GBS MVs can independently orchestrate events at the feto-maternal interface causing chorio-amnionitis and membrane damage leading to preterm birth or fetal death.

  19. Delayed Hepatic Adaptation to Weaning in ACBP(-/-) Mice Is Caused by Disruption of the Epidermal Barrier

    DEFF Research Database (Denmark)

    Neess, Ditte; Bek, Signe; Bloksgaard, Maria

    2013-01-01

    We previously reported that mice deficient in acyl-CoA-binding protein (ACBP) display a delayed metabolic adaptation to weaning. This includes a delayed activation of the hepatic lipogenic gene program, which may result from hepatic accumulation of triacylglycerol and/or cholesteryl esters in the...

  20. Lipids and skin barrier function - a clinical perspective

    DEFF Research Database (Denmark)

    Jungersted, J.M.; Hellgren, Lars; Jemec, G.B.E.

    2008-01-01

    and in particular, the role of barrier function in the pathogenesis of skin disease and its subsequent treatment protocols. The 3 major lipids in the SC of importance are ceramides, free fatty acids, and cholesterol. Human studies comparing levels of the major SC lipids in patients with atopic dermatitis...... and healthy controls have suggested a possible role for ceramide 1 and to some extent ceramide 3 in the pathogenesis of the disease. Therapies used in diseases involving barrier disruption have been sparely investigated from a lipid perspective. It has been suggested that ultraviolet light as a treatment......The stratum corneum (SC) protects us from dehydration and external dangers. Much is known about the morphology of the SC and penetration of drugs through it, but the data are mainly derived from in vitro and animal experiments. In contrast, only a few studies have the human SC lipids as their focus...

  1. Silicon Carbide Schottky Barrier Diode

    Science.gov (United States)

    Zhao, Jian H.; Sheng, Kuang; Lebron-Velilla, Ramon C.

    2004-01-01

    This chapter reviews the status of SiC Schottky barrier diode development. The fundamental of Schottky barrier diodes is first provided, followed by the review of high-voltage SiC Schottky barrier diodes, junction-barrier Schottky diodes, and merged-pin-Schottky diodes. The development history is reviewed ad the key performance parameters are discussed. Applications of SiC SBDs in power electronic circuits as well as other areas such as gas sensors, microwave and UV detections are also presented, followed by discussion of remaining challenges.

  2. Translating barriers into potential improvements

    DEFF Research Database (Denmark)

    Altintzoglou, Themistoklis; Hansen, Karina Birch; Valsdottir, Thora

    2010-01-01

    Purpose: The aim of this study is to explore potential barriers to seafood consumption by The aim of this study is to explore potential barriers to seafood consumption by young adults and the parents of young children. Knowledge of these barriers will be used to assist the development of new...... to lead to practical input The present study combines qualitative methods to lead to practical input for NPD focusing on overcoming the barriers that keep consumers from choosing existing healthy seafood products. The importance of the consumers' confidence in their ability to successfully prepare...

  3. Countermeasures and barriers

    Energy Technology Data Exchange (ETDEWEB)

    Petersen, Johannes [Oersted - DTU, Automation, Kgs. Lyngby (Denmark)

    2005-10-01

    In 1973 Haddon proposed ten strategies for reducing and avoiding damages based on a model of potential harmful energy transfer (Haddon, 1973). The strategies apply to a large variety of unwanted phenomena. Haddon's pioneering work on countermeasures has had a major influence on later thinking about safety. Considering its impact it is remarkable that the literature offers almost no discussions related to the theoretical foundations of Haddon's countermeasure strategies. The present report addresses a number of theoretical issues related to Haddon's countermeasure strategies, which are: 1) A reformulation and formalization of Haddon's countermeasure strategies. 2) An identification and description of some of the problems associated with the term 'barrier'. 3) Suggestions for a more precise terminology based on the causal structure of countermeasures. 4) Extending the scope of countermeasures to include sign-based countermeasures. (au)

  4. Linguistic Barriers and Bridges

    DEFF Research Database (Denmark)

    Thuesen, Frederik

    2016-01-01

    and intercultural communication, this article analyses interviews with 31 employees from two highly ethnically diverse Danish workplaces. The article shows how linguistic barriers such as different levels of majority language competence and their consequent misunderstandings breed mistrust and hostility, whilst......The influence of language on social capital in low-skill and ethnically diverse workplaces has thus far received very limited attention within the sociology of work. As the ethnically diverse workplace is an important social space for the construction of social relations bridging different social...... groups, the sociology of work needs to develop a better understanding of the way in which linguistic diversity influences the formation of social capital, i.e. resources such as the trust and reciprocity inherent in social relations in such workplaces. Drawing on theories about intergroup contact...

  5. Disrupting incrementalism in health care innovation.

    Science.gov (United States)

    Soleimani, Farzad; Zenios, Stefanos

    2011-08-01

    To build enabling innovation frameworks for health care entrepreneurs to better identify, evaluate, and pursue entrepreneurial opportunities. Powerful frameworks have been developed to enable entrepreneurs and investors identify which opportunity areas are worth pursuing and which start-up ideas have the potential to succeed. These frameworks, however, have not been clearly defined and interpreted for innovations in health care. Having a better understanding of the process of innovation in health care allows physician entrepreneurs to innovate more successfully. A review of academic literature was conducted. Concepts and frameworks related to technology innovation were analyzed. A new set of health care specific frameworks was developed. These frameworks were then applied to innovations in various health care subsectors. Health care entrepreneurs would greatly benefit from distinguishing between incremental and disruptive innovations. The US regulatory and reimbursement systems favor incrementalism with a greater chance of success for established players. Small companies and individual groups, however, are more likely to thrive if they adopt a disruptive strategy. Disruption in health care occurs through various mechanisms as detailed in this article. While the main mechanism of disruption might vary across different health care subsectors, it is shown that disruptive innovations consistently require a component of contrarian interpretation to guarantee considerable payoff. If health care entrepreneurs choose to adopt an incrementalist approach, they need to build the risk of disruption into their models and also ascertain that they have a very strong intellectual property (IP) position to weather competition from established players. On the contrary, if they choose to pursue disruption in the market, albeit the competition will be less severe, they need to recognize that the regulatory and reimbursement hurdles are going to be very high. Thus, they would benefit

  6. Pathophysiology of the cochlear intrastrial fluid-blood barrier (review).

    Science.gov (United States)

    Shi, Xiaorui

    2016-08-01

    The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between blood and the intrastitial space in the cochlea. The barrier shields the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in the maintenance of cochlear homeostasis. Anatomically, the BLB is comprised of endothelial cells (ECs) in the strial microvasculature, elaborated tight and adherens junctions, pericytes (PCs), basement membrane (BM), and perivascular resident macrophage-like melanocytes (PVM/Ms), which together form a complex "cochlear-vascular unit" in the stria vascularis. Physical interactions between the ECs, PCs, and PVM/Ms, as well as signaling between the cells, is critical for controlling vascular permeability and providing a proper environment for hearing function. Breakdown of normal interactions between components of the BLB is seen in a wide range of pathological conditions, including genetic defects and conditions engendered by inflammation, loud sound trauma, and ageing. In this review, we will discuss prevailing views of the structure and function of the strial cochlear-vascular unit (also referred to as the "intrastrial fluid-blood barrier"). We will also discuss the disrupted homeostasis seen in a variety of hearing disorders. Therapeutic targeting of the strial barrier may offer opportunities for improvement of hearing health and amelioration of auditory disorders. This article is part of a Special Issue entitled .

  7. Simulation study of disruption characteristics in KSTAR

    Science.gov (United States)

    Lee, Jongkyu; Kim, J. Y.; Kessel, C. E.; Poli, F.

    2012-10-01

    A detailed simulation study of disruption in KSTAR had been performed using the Tokamak Simulation Code(TSC) [1] during the initial design phase of KSTAR [2]. Recently, however, a partial modification in the structure of passive plate was made in relation to reduce eddy current and increase the efficiency of control of vertical position. A substantial change can then occur in disruption characteristics and plasma behavior during disruption due to changes in passive plate structure. Because of this, growth rate of vertical instability is expected to be increased and eddy current and its associated electomagnetic force are expected to be reduced. To check this in more detail, a new simulation study is here given with modified passive plate structure of KSTAR. In particular, modeling of vertical disruption that is vertical displacement event (VDE) was carried out. We calculated vertical growth rate for a drift phase of plasma and electromagnetic force acting on PFC structures and compared the results between in a new model and an old model. [4pt] [1] S.C. Jardin, N. Pomphrey and J. Delucia, J. Comp. Phys. 66, 481 (1986).[0pt] [2] J.Y. Kim, S.Y. Cho and KSTAR Team, Disruption load analysis on KSTAR PFC structures, J. Accel. Plasma Res. 5, 149 (2000).

  8. Disruptive Intelligence : How to gather Information to deal with disruptive innovations

    NARCIS (Netherlands)

    Vriens, D.J.; Solberg Søilen, K.

    2014-01-01

    Disruptive innovations are innovations that have the capacity to transform a whole business into one with products that are more accessible and affordable (cf. Christensen et al. 2009). As Christensen et al. argue no business is immune to such disruptive innovations. If these authors are right, it

  9. Disruptive Intelligence : How to gather Information to deal with disruptive innovations

    NARCIS (Netherlands)

    Vriens, D.J.; Solberg Søilen, K.

    2014-01-01

    Disruptive innovations are innovations that have the capacity to transform a whole business into one with products that are more accessible and affordable (cf. Christensen et al. 2009). As Christensen et al. argue no business is immune to such disruptive innovations. If these authors are right, it m

  10. Preschool Children's Observed Disruptive Behavior: Variations across Sex, Interactional Context, and Disruptive Psychopathology

    Science.gov (United States)

    Gray, Sarah A. O.; Carter, Alice S.; Briggs-Gowan, Margaret J.; Hill, Carri; Danis, Barbara; Keenan, Kate; Wakschlag, Lauren S.

    2012-01-01

    Sex differences in disruptive behavior and sensitivity to social context are documented, but the intersection between them is rarely examined empirically. This report focuses on sex differences in observed disruptive behavior across interactional contexts and diagnostic status. Preschoolers (n = 327) were classified as nondisruptive (51%),…

  11. Informal export barriers and poverty

    OpenAIRE

    Porto, Guido G.

    2004-01-01

    The author investigates the poverty impacts of informal export barriers like transport costs, cumbersome customs practices, costly regulations, and bribes. He models these informal barriers as export taxes that distort the efficient allocation of resources. In low-income agricultural economies, this distortion lowers wages and household agricultural income, thereby leading to higher pover...

  12. Barriers to Women in Science

    Science.gov (United States)

    Butler, Rosemary

    2013-01-01

    The Presiding Officer of the National Assembly for Wales, Rosemary Butler AM, has put the issue of barriers to women in public life at the top of the political agenda in Wales. She has held sessions with women across Wales to find out what those barriers are and how they can be tackled. On International Women's Day in February, she invited…

  13. Barriers to Women in Science

    Science.gov (United States)

    Butler, Rosemary

    2013-01-01

    The Presiding Officer of the National Assembly for Wales, Rosemary Butler AM, has put the issue of barriers to women in public life at the top of the political agenda in Wales. She has held sessions with women across Wales to find out what those barriers are and how they can be tackled. On International Women's Day in February, she invited…

  14. BARRIERS OF STRATEGIC ALLIANCES ORGANIZATION

    Directory of Open Access Journals (Sweden)

    Vladislav M. Sannikov

    2014-01-01

    Full Text Available General barriers of organization of different types of strategic alliances have beenconsidered in the article. There are several recommendations for overcoming themin cases of international alliances, and in case of work in one state. The article also identified goals and tasks of single coordination center of alliance to overcome organization barriers.

  15. Spanning trees crossing few barriers

    NARCIS (Netherlands)

    Asano, T.; Berg, M. de; Cheong, O.; Guibas, L.J.; Snoeyink, J.; Tamaki, H.

    2002-01-01

    We consider the problem of finding low-cost spanning trees for sets of n points in the plane, where the cost of a spanning tree is defined as the total number of intersections of tree edges with a given set of m barriers. We obtain the following results: (i) if the barriers are possibly intersecting

  16. Epistemological barriers to radical behaviorism.

    Science.gov (United States)

    O'Donohue, W T; Callaghan, G M; Ruckstuhl, L E

    1998-01-01

    The historian and philosopher of science Gaston Bachelard proposed the concept of epistemological barriers to describe the intellectual challenges encountered by scientists in their work. In order to embrace novel ways of approaching a problem in science, scientists must overcome barriers or obstacles posed by their prior views. For example, Einsteinian physics presents scientists with claims that space is curved and that time and space are on the same continuum. We utilize Bachelard's concept of epistemological barriers to describe the differences between the intellectual journeys students pursuing advanced studies face when attempting to accept cognitive psychology or radical behaviorism. We contend that the folk psychological beliefs that students typically hold when entering these studies pose less challenge to cognitive psychology than to radical behaviorism. We also suggest that these barriers may also partly be involved in the problematic exegesis that has plagued radical behaviorism. In close, we offer some suggestions for dealing with these epistemological barriers.

  17. Epistemological barriers to radical behaviorism

    Science.gov (United States)

    O'Donohue, William T.; Callaghan, Glenn M.; Ruckstuhl, L. E.

    1998-01-01

    The historian and philosopher of science Gaston Bachelard proposed the concept of epistemological barriers to describe the intellectual challenges encountered by scientists in their work. In order to embrace novel ways of approaching a problem in science, scientists must overcome barriers or obstacles posed by their prior views. For example, Einsteinian physics presents scientists with claims that space is curved and that time and space are on the same continuum. We utilize Bachelard's concept of epistemological barriers to describe the differences between the intellectual journeys students pursuing advanced studies face when attempting to accept cognitive psychology or radical behaviorism. We contend that the folk psychological beliefs that students typically hold when entering these studies pose less challenge to cognitive psychology than to radical behaviorism. We also suggest that these barriers may also partly be involved in the problematic exegesis that has plagued radical behaviorism. In close, we offer some suggestions for dealing with these epistemological barriers. PMID:22478314

  18. Efficacy of vetiver oil and nootkatone as soil barriers against Formosan subterranean termite (Isoptera: Rhinotermitidae).

    Science.gov (United States)

    Maistrello, L; Henderson, G; Laine, R A

    2001-12-01

    Vetiver oil and its components nootkatone and cedrene were assessed as sand treatments for their efficacy to disrupt food recruitment by Coptotermes formosanus Shiraki. Termites were required to tunnel through sand treated with vetiver oil, nootkatone, cedrene, or untreated sand to reach a food source. Results showed that sand treated with vetiver oil or nootkatone disrupted termite tunneling behavior. As a consequence, after 21 d, wood consumption and termite survival were significantly lower compared with cedrene-treated or untreated sand treatments. Sand treated with vetiver oil or nootkatone at 100 microg/g substrate were effective barriers to termites.

  19. Bacillus cereus Certhrax ADP-ribosylates vinculin to disrupt focal adhesion complexes and cell adhesion.

    Science.gov (United States)

    Simon, Nathan C; Barbieri, Joseph T

    2014-04-11

    Bacillus cereus is often associated with mild to moderate gastroenteritis; however, some recent isolates cause inhalational anthrax-like diseases and death. These potential emerging human pathogens express multiple virulence factors. B. cereus strain G9241 expresses anthrax toxin, several polysaccharide capsules, and the novel ADP-ribosyltransferase, Certhrax. In this study, we show that Certhrax ADP-ribosylates Arg-433 of vinculin, a protein that coordinates actin cytoskeleton and extracellular matrix interactions. ADP-ribosylation of vinculin disrupted focal adhesion complexes and redistributed vinculin to the cytoplasm. Exogenous vinculin rescued these phenotypes. This provides a mechanism for strain G9241 to breach host barrier defenses and promote bacterial growth and spread. Certhrax is the first bacterial toxin to add a post-translational modification to vinculin to disrupt the actin cytoskeleton.

  20. Disruption, beamstrahlung, and beamstrahlung pair creation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, P.

    1988-12-01

    The two major effects from the interaction of e/sup /minus//e/sup +/ beams---beamstrahlung and disruption---are reviewed, with emphasis on flat beam collisions. For the disruption effects we discuss the luminosity enhancement factor, the maximum and rms disruption angles, and the ''kink instability''. All the results are obtained from computer simulations, and scaling laws based on these are deduced whenever possible. For the beamstrahlung effects, we concentrate only on the final electron energy spectrum and the deflection angle associated with low energy particles. In addition to the generic studies on the beam-beam effects, we also list the relevant beam-beam parameters obtained from simulations on two sample designs: the TLC and the ILC. As an addendum, the newly discovered phenomenon of coherent beamstrahlung pair creation, together with the incoherent process, are discussed. 18 refs., 15 figs., 1 tab.

  1. Isolated Sleep Paralysis: Fear, Prevention, and Disruption.

    Science.gov (United States)

    Sharpless, Brian Andrew; Grom, Jessica Lynn

    2016-01-01

    Relatively little is known about isolated sleep paralysis (ISP), and no empirically supported treatments are available. This study aims to determine: the clinical impact of ISP, the techniques used to prevent or disrupt ISP, and the effectiveness of these techniques. 156 undergraduates were assessed with lifetime ISP using a clinical interview. 75.64% experienced fear during ISP, and 15.38% experienced clinically significant distress/interference, while 19.23% attempted to prevent ISP, and 79.31% of these believed their methods were successful. Regarding disruption, 69.29% made attempts, but only 54.12% reported them effective. Disruption was more common than prevention, but several techniques were useful. Encouraging individuals to utilize these techniques and better monitor their symptoms may be an effective way to manage problematic ISP.

  2. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Groth, Julie Jespersen; Potthoff, Daniel; Clausen, Jens

    2009-01-01

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...... the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an overview of the existing literature and we present some details of the specific situations at DSB S-tog and NS....... These are the railway operators in the suburban area of Copenhagen, Denmark, and on the main railway lines in The Netherlands, respectively. Finally, we address the integration of the re-scheduling processes of the timetable, and the resources rolling stock and crew....

  3. Extensor mechanism disruption after total knee arthroplasty.

    Science.gov (United States)

    Bates, Michael D; Springer, Bryan D

    2015-02-01

    Extensor mechanism disruption is a rare and potentially devastating complication associated with total knee arthroplasty. Disruption can occur at the quadriceps or patellar tendons or, in the setting of a fracture, at the patella. Recognition of the risk factors for disruption and prevention via meticulous surgical technique are critical to avoid this complication. Various management techniques and the challenges associated with treatment have been described. Nonsurgical management consists of the use of walking aids and/or knee braces, which may not be acceptable for the active patient. Surgical options include primary repair and reconstructive techniques using allograft, autograft, synthetic material, and gastrocnemius rotational flaps. However, no single method has reliably demonstrated satisfactory outcomes. Although research on reconstructive procedures with synthetic materials has been promising, further study is need to assess the use of these materials.

  4. Disc formation from stellar tidal disruptions

    CERN Document Server

    Bonnerot, Clément; Lodato, Giuseppe; Price, Daniel J

    2015-01-01

    The potential of tidal disruption of stars to probe otherwise quiescent supermassive black holes cannot be exploited, if their dynamics is not fully understood. So far, the observational appearance of these events has been commonly derived from analytical extrapolations of the debris dynamical properties just after the stellar disruption. In this paper, we perform hydrodynamical simulations of stars in highly eccentric orbits, that follow the stellar debris after disruption and investigate their ultimate fate. We demonstrate that gas debris circularize on an orbital timescale because relativistic apsidal precession causes the stream to self-cross. The higher the eccentricity and/or the deeper the encounter, the faster is the circularization. If the internal energy deposited by shocks during stream self-interaction is readily radiated, the gas forms a narrow ring at the circularization radius. It will then proceed to accrete viscously at a super-Eddington rate, puffing up under radiation pressure. If instead c...

  5. Adherent-invasive Escherichia coli, strain LF82 disrupts apical junctional complexes in polarized epithelia

    Directory of Open Access Journals (Sweden)

    Ossa Juan C

    2009-08-01

    Full Text Available Abstract Background Although bacteria are implicated in the pathogenesis of chronic inflammatory bowel diseases (IBD, mechanisms of intestinal injury and immune activation remain unclear. Identification of adherent-invasive Escherichia coli (AIEC strains in IBD patients offers an opportunity to characterize the pathogenesis of microbial-induced intestinal inflammation in IBD. Previous studies have focused on the invasive phenotype of AIEC and the ability to replicate and survive in phagocytes. However, the precise mechanisms by which these newly identified microbes penetrate the epithelial lining remain to be clarified. Therefore, the aim of this study was to delineate the effects of AIEC, strain LF82 (serotype O83:H1 on model polarized epithelial monolayers as a contributor to intestinal injury in IBD. Results Infection of T84 and Madin-Darby Canine Kidney-I polarized epithelial cell monolayers with AIEC, strain LF82 led to a reduction in transepithelial electrical resistance and increased macromolecular (10 kilodalton dextran flux. Basolateral AIEC infection resulted in more severe disruption of the epithelial barrier. Increased permeability was accompanied by a redistribution of the tight junction adaptor protein, zonula occludens-1, demonstrated by confocal microscopy and formation of gaps between cells, as shown by transmission electron microscopy. After 4 h of infection of intestine 407 cells, bacteria replicated in the cell cytoplasm and were enclosed in membrane-bound vesicles positive for the late endosomal marker, LAMP1. Conclusion These findings indicate that AIEC, strain LF82 disrupts the integrity of the polarized epithelial cell barrier. This disruption enables bacteria to penetrate into the epithelium and replicate in the host cell cytoplasm. These findings provide important links between microbes related to IBD, the intestinal epithelial cell barrier and disease pathogenesis.

  6. Traditional facial tattoos disrupt face recognition processes.

    Science.gov (United States)

    Buttle, Heather; East, Julie

    2010-01-01

    Factors that are important to successful face recognition, such as features, configuration, and pigmentation/reflectance, are all subject to change when a face has been engraved with ink markings. Here we show that the application of facial tattoos, in the form of spiral patterns (typically associated with the Maori tradition of a Moko), disrupts face recognition to a similar extent as face inversion, with recognition accuracy little better than chance performance (2AFC). These results indicate that facial tattoos can severely disrupt our ability to recognise a face that previously did not have the pattern.

  7. 3D MHD Simulations of Tokamak Disruptions

    Science.gov (United States)

    Woodruff, Simon; Stuber, James

    2014-10-01

    Two disruption scenarios are modeled numerically by use of the CORSICA 2D equilibrium and NIMROD 3D MHD codes. The work follows the simulations of pressure-driven modes in DIII-D and VDEs in ITER. The aim of the work is to provide starting points for simulation of tokamak disruption mitigation techniques currently in the CDR phase for ITER. Pressure-driven instability growth rates previously observed in simulations of DIIID are verified; Halo and Hiro currents produced during vertical displacements are observed in simulations of ITER with implementation of resistive walls in NIMROD. We discuss plans to exercise new code capabilities and validation.

  8. Development of engineered barrier

    Energy Technology Data Exchange (ETDEWEB)

    Chun, Kwan Sik; Cho, Won Jin; Lee, Jae Owan; Kim, Seung Soo; Kang, Mu Ja

    1999-03-01

    Engineered barrier development was carried out into the three research fields : waste form, disposal container, and buffer. The waste form field dealt with long-term leaching tests with borosilicate waste glasses surrounded by compacted bentonite. The leach rate decreased with increasing time, and was higher for the waste specimen rich in U and Na. In the container field, preliminary concepts of disposal containers were recommended by conducting structural analysis, thermal analysis, and shielding analysis, and major properties of stainless steel, copper, and titanium as a container material were surveyed. The sensitization degrees of SUS 316 and316L were lower than those of SUS 304 and 304L, respectively. The crevice corrosion of sensitized stainless steel was sensitive to the content of salt. Researches into the buffer included establishment of its performance criteria followed by investigating major properties of buffer using potential material in Korea. Experiments were made for measuring hydraulic conductivities, swelling properties, mechanical properties, thermal conductivities, pore-water chemistry properties, and adsorption properties was also investigated. (author)

  9. Transcriptome analysis of the ependymal barrier during murine neurocysticercosis

    Directory of Open Access Journals (Sweden)

    Mishra Pramod

    2012-06-01

    Full Text Available Abstract Background Central nervous system (CNS barriers play a pivotal role in the protection and homeostasis of the CNS by enabling the exchange of metabolites while restricting the entry of xenobiotics, blood cells and blood-borne macromolecules. While the blood–brain barrier and blood-cerebrospinal fluid barrier (CSF control the interface between the blood and CNS, the ependyma acts as a barrier between the CSF and parenchyma, and regulates hydrocephalic pressure and metabolic toxicity. Neurocysticercosis (NCC is an infection of the CNS caused by the metacestode (larva of Taenia solium and a major cause of acquired epilepsy worldwide. The common clinical manifestations of NCC are seizures, hydrocephalus and symptoms due to increased intracranial pressure. The majority of the associated pathogenesis is attributed to the immune response against the parasite. The properties of the CNS barriers, including the ependyma, are affected during infection, resulting in disrupted homeostasis and infiltration of leukocytes, which correlates with the pathology and disease symptoms of NCC patients. Results In order to characterize the role of the ependymal barrier in the immunopathogenesis of NCC, we isolated ependymal cells using laser capture microdissection from mice infected or mock-infected with the closely related parasite Mesocestoides corti, and analyzed the genes that were differentially expressed using microarray analysis. The expression of 382 genes was altered. Immune response-related genes were verified by real-time RT-PCR. Ingenuity Pathway Analysis (IPA software was used to analyze the biological significance of the differentially expressed genes, and revealed that genes known to participate in innate immune responses, antigen presentation and leukocyte infiltration were affected along with the genes involved in carbohydrate, lipid and small molecule biochemistry. Further, MHC class II molecules and chemokines, including CCL12, were found

  10. Tritium/hydrogen barrier development

    Energy Technology Data Exchange (ETDEWEB)

    Hollenberg, G.W.; Simonen, E.P. [Pacific Northwest Lab., Richland, WA (United States); Kalinen, G. [Max-Planck-Institut fuer Plasmaphysik, Garching (Germany). International Thermonuclear Experimental Reactor (ITER) Team; Terlain, A. [CEA Centre d`Etudes de Fontenay-aux-Roses, 92 (France). Service de la Corrosion, d`Electrochimie et Chimie des Fluides

    1994-06-01

    A review of hydrogen permeation barriers that can be applied to structural metals used in fusion power plants is presented. Both implanted and chemically available hydrogen isotopes must be controlled in fusion plants. The need for permeation barriers appears strongest in Li17-Pb blanket designs, although barriers also appear necessary for other blanket and coolant systems. Barriers that provide greater than a 1000 fold reduction in the permeation of structural metals are desired. In laboratory experiments, aluminide and titanium ceramic coatings provide permeation reduction factors, PRFS, from 1000 to over 100,000 with a wide range of scatter. The rate-controlling mechanism for hydrogen permeation through these barriers may be related to the number and type of defects in the barriers. Although these barriers appear robust and resistant to liquid metal corrosion, irradiation tests which simulate blanket environments result in very low PRFs in comparison to laboratory experiments, i.e., <150. It is anticipated from fundamental research activities that the REID enhancement of hydrogen diffusion in oxides may contribute to the lower permeation reduction factors during in-reactor experiments.

  11. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.

    Science.gov (United States)

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua; Wu, Guangyu; Wang, Guansong

    2015-12-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation.

  12. A LOOK AT CULTURAL BARRIERS

    Directory of Open Access Journals (Sweden)

    Carmen A. VRÂNCEANU

    2015-06-01

    Full Text Available Nowadays the global market allows each individual to work in foreign countries. This fact is a great opportunity for business development, but also puts into light the problem of cultural barriers. Ineffective cross-cultural communication and collaboration can harm employees, customers, and other stakeholders. A company with employees from different cultures must acknowledge and understand these barriers in order to overcome them and to obtain the desired performance. The present study aims to expose the cultural barriers encountered by foreigners in a multinational company from Romania.

  13. Barriers in Concurrent Separation Logic

    Science.gov (United States)

    Hobor, Aquinas; Gherghina, Cristian

    We develop and prove sound a concurrent separation logic for Pthreads-style barriers. Although Pthreads barriers are widely used in systems, and separation logic is widely used for verification, there has not been any effort to combine the two. Unlike locks and critical sections, Pthreads barriers enable simultaneous resource redistribution between multiple threads and are inherently stateful, leading to significant complications in the design of the logic and its soundness proof. We show how our logic can be applied to a specific example program in a modular way. Our proofs are machine-checked in Coq.

  14. Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

    Directory of Open Access Journals (Sweden)

    Akihiro Watari

    2017-04-01

    Full Text Available Background/Aims: Although proinflammatory cytokine–induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. Methods: To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER and paracellular permeability were measured. Production levels and localization of tight junction (TJ proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC and MLC kinase (MLCK mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Results: Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Conclusion: Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation.

  15. Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production.

    Science.gov (United States)

    Watari, Akihiro; Sakamoto, Yuta; Hisaie, Kota; Iwamoto, Kazuki; Fueta, Miho; Yagi, Kiyohito; Kondoh, Masuo

    2017-01-01

    Although proinflammatory cytokine-induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation. © 2017 The Author(s)Published by S. Karger AG, Basel.

  16. Constraining Cluster Disruption in M83

    Science.gov (United States)

    Silva-Villa, E.; Adamo, A.; Bastian, N.; Fouesneau, M.

    2014-09-01

    Currently two contrasting models have been put forward to explain cluster disruption. These models are known as Mass Independent Disruption (MID) and Mass Dependent Disruption (MDD) models. Here we will shortly introduce the two models and present the latest observational results obtained in the field. We will focus on the results achieved us- ing the new and unprecedented Hubble Space Telescope-WFC3 dataset of the face-on, spiral galaxy M83. The dataset, composed of 7 different fields, covers the galaxy up to a radius of ˜8 kpc, and is used to construct one of the most complete and systematic star cluster catalogues for a galaxy in the local universe. The cluster properties were estimated comparing the photometry (NUV and optical) with Single Stellar Population (SSP) models. If the age distribution is approximated by a single power-law, we find indices between -0.6 and 0 for the seven fields (independently of the binning used), finding a systematic trend with the local environment. Additionally, our results are inconsistent with the expected slope of ˜1 from the MID model, showing to be flatter. The combination of our results with the M31 galaxy (The Panchromatic Hubble Andromeda Treasury program), and the LMC (Baumgardt et al. 2013), is starting to guide the global understanding on star cluster disruption, and how these systems are strongly correlated with the local environment where they were formed.

  17. Study of Endocrine Disrupting Chemicals in Environment

    Directory of Open Access Journals (Sweden)

    Zoltán Juvancz

    2008-06-01

    Full Text Available Endocrine disrupting chemicals (EDC cause more and more seriousenvironmental pollutions. The EDCs show only ng-μg/l concentration level in theenvironment, therefore their determinations require multistep sample preparationprocesses and highly sophisticated instrumentation. This paper discuss the EDC effects,and show examples for determination of such compounds.

  18. Heavy Metals Acting as Endocrine Disrupters

    Directory of Open Access Journals (Sweden)

    Bogdan Georgescu

    2011-10-01

    Full Text Available Last years researches focused on several natural and synthetic compounds that may interfere with the major functionsof the endocrine system and were termed endocrine disrupters. Endocrine disrupters are defined as chemicalsubstances with either agonist or antagonist endocrine effects in human and animals. These effects may be achievedby interferences with the biosynthesis or activity of several endogenous hormones. Recently, it was demonstratedthat heavy metals such as cadmium (Cd, arsen (As, mercury (Hg, nickel (Ni, lead (Pb and zinc (Zn may exhibitendocrine-disrupting activity in animal experiments. Emerging evidence of the intimate mechanisms of action ofthese heavy metals is accumulating. It was revealed, for example, that the Zn atom from the Zn fingers of theestrogen receptor can be replaced by several heavy metal molecules such as copper, cobalt, Ni and Cd. By replacingthe Zn atom with Ni or copper, binding of the estrogen receptor to the DNA hormone responsive elements in the cellnucleus is prevented. In both males and females, low-level exposure to Cd interferes with the biological effects ofsteroid hormones in reproductive organs. Arsen has the property to bind to the glucocorticoid receptor thusdisturbing glucocorticoids biological effects. With regard to Hg, this may induce alterations in male and femalefertility, may affect the function of the hypothalamo-pituitary-thyroid axis or the hypothalamo-pituitary-adrenal axis,and disrupt biosynthesis of steroid hormones.

  19. The Structure of Childhood Disruptive Behaviors

    Science.gov (United States)

    Martel, Michelle M.; Gremillion, Monica; Roberts, Bethan; von Eye, Alexander; Nigg, Joel T.

    2010-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a "g" factor in addition to…

  20. Analysis of recent fuel-disruption experiments

    Energy Technology Data Exchange (ETDEWEB)

    Kramer, J.M.; Kraft, T.E.; DiMelfi, R.J.; Fenske, G.R.; Gruber, E.E.

    1982-01-01

    Recent USDOE-sponsored DEH, FGR, and TREAT F series fuel-disruption experiments are analyzed with existing analytical models. The experiments are interpreted and the results used to evaluate the models. Calculations are presented using the FRAS3 fission-gas-behavior code and the DiMelfi-Deitrich fuel-response model.

  1. Family Disruption and Delinquency. Juvenile Justice Bulletin.

    Science.gov (United States)

    Thornberry, Terence P.; Smith, Carolyn A.; Rivera, Craig; Huizinga, David; Stouthamer-Loeber, Magda

    At study sites in Rochester (New York), Denver (Colorado) and Pittsburgh (Pennsylvania), three research teams studying the impact of family disruption on juvenile delinquency have interviewed approximately 4,000 participants at regular intervals for a decade, recording their lives in detail. Findings to date indicate that preventing delinquency…

  2. Endocrine disrupting chemicals and disease susceptibility.

    Science.gov (United States)

    Schug, Thaddeus T; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J

    2011-11-01

    Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products--including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.

  3. The Relative Ineffectiveness of Criminal Network Disruption

    Science.gov (United States)

    Duijn, Paul A. C.; Kashirin, Victor; Sloot, Peter M. A.

    2014-02-01

    Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in secrecy, data-driven knowledge concerning the effectiveness of different criminal network disruption strategies is very limited. By combining computational modeling and social network analysis with unique criminal network intelligence data from the Dutch Police, we discovered, in contrast to common belief, that criminal networks might even become `stronger', after targeted attacks. On the other hand increased efficiency within criminal networks decreases its internal security, thus offering opportunities for law enforcement agencies to target these networks more deliberately. Our results emphasize the importance of criminal network interventions at an early stage, before the network gets a chance to (re-)organize to maximum resilience. In the end disruption strategies force criminal networks to become more exposed, which causes successful network disruption to become a long-term effort.

  4. Traffic disruption route Einstein near building 170

    CERN Multimedia

    A Lopez - TS/CE

    2005-01-01

    The TS/CE Group informs you that, for the duration of the work at Building 170, there may be some disruption to traffic on route Einstein in the vicinity of Building 170. The work is due to take place from the 14th to 18th February. For more information, please contact 165029. A. Lopez TS/CE

  5. THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

    Science.gov (United States)

    A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

  6. Is Online Learning a Disruptive Innovation?

    Science.gov (United States)

    Meyer, Katrina A.

    2011-01-01

    In their desire to plan for the future, planners must assess the role of both internal and external influences on the institution. What then should people make of the idea that technology is disruptive? This perception fuels the views of Barone and Hagner (2001), who claimed that technology would "transform" higher education; Duderstadt (2000),…

  7. E-Learning: Between Augmentation and Disruption?

    Science.gov (United States)

    Heilesen, Simon B.; Josephsen, Jens

    2008-01-01

    Based on a framework for analysis combining diffusion theory, content layer analysis and sense making, this paper discusses the theme of "e-learning as augmentation or disruption" from the point of view of technological innovation. Two cases of on-campus blended learning at Roskilde University, Denmark, are introduced to illustrate the…

  8. The Structure of Childhood Disruptive Behaviors

    Science.gov (United States)

    Martel, Michelle M.; Gremillion, Monica; Roberts, Bethan; von Eye, Alexander; Nigg, Joel T.

    2010-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a "g" factor in addition to…

  9. Maternal Characteristics Predicting Young Girls' Disruptive Behavior

    Science.gov (United States)

    van der Molen, Elsa; Hipwell, Alison E.; Vermeiren, Robert; Loeber, Rolf

    2011-01-01

    Little is known about the relative predictive utility of maternal characteristics and parenting skills on the development of girls' disruptive behavior. The current study used five waves of parent- and child-report data from the ongoing Pittsburgh Girls Study to examine these relationships in a sample of 1,942 girls from age 7 to 12 years.…

  10. Managing Disruptive Behaviour in the Classroom

    Science.gov (United States)

    Deering, Catherine

    2011-01-01

    Both faculty and students at many colleges and universities report numerous incidents of disruptive and uncivil behaviour. However, studies show that faculty are often reluctant to confront these situations, or they feel ill-equipped to intervene. If the behaviour escalates, a disproportionate amount of time and effort can be spent trying to…

  11. Disrupting Educational Inequalities through Youth Digital Activism

    Science.gov (United States)

    Stornaiuolo, Amy; Thomas, Ebony Elizabeth

    2017-01-01

    This article reviews scholarship on youth and young adult activism in digital spaces, as young users of participatory media sites are engaging in political, civic, social, or cultural action and advocacy online to create social change. The authors argue that youth's digital activism serves as a central mechanism to disrupt inequality, and that…

  12. Development of Disruptive Open Access Journals

    Science.gov (United States)

    Anderson, Terry; McConkey, Brigette

    2009-01-01

    Open access (OA) publication has emerged, with disruptive effects, as a major outlet for scholarly publication. OA publication is usually associated with on-line distribution and provides access to scholarly publications to anyone, anywhere--regardless of their ability to pay subscription fees or their association with an educational institution.…

  13. Is Online Learning a Disruptive Innovation?

    Science.gov (United States)

    Meyer, Katrina A.

    2011-01-01

    In their desire to plan for the future, planners must assess the role of both internal and external influences on the institution. What then should people make of the idea that technology is disruptive? This perception fuels the views of Barone and Hagner (2001), who claimed that technology would "transform" higher education; Duderstadt (2000),…

  14. Hot Super Earths: disrupted young jupiters?

    CERN Document Server

    Nayakshin, Sergei

    2011-01-01

    Recent {\\em Kepler} observations revealed an unexpected abundance of "hot" Earth-size to Neptune-size planets in the inner $0.02-0.2$ AU from their parent stars. We propose that these smaller planets are the remnants of massive giant planets that migrated inward quicker than they could contract. We show that such disruptions naturally occur in the framework of the Tidal Downsizing hypothesis for planet formation. We find that the characteristic planet-star separation at which such "hot disruptions" occur is $R \\approx 0.03-0.2$ AU. This result is independent of the planet's embryo mass but is dependent on the accretion rate in the disc. At high accretion rates, $\\dot M \\simgt 10^{-6}\\msun$ yr$^{-1}$, the embryo is unable to contract quickly enough and is disrupted. At late times, when the accretion rate drops to $\\dot M \\simlt 10^{-8} \\msun$ yr$^{-1}$, the embryos migrate sufficiently slow to not be disrupted. These "late arrivals" may explain the well known population of hot jupiters. If type I migration reg...

  15. Analysis of recent fuel-disruption experiments

    Energy Technology Data Exchange (ETDEWEB)

    Kramer, J.M.; Kraft, T.E.; DiMelfi, R.J.; Fenske, G.R.; Gruber, E.E.

    1982-01-01

    Recent USDOE-sponsored DEH, FGR, and TREAT F series fuel-disruption experiments are analyzed with existing analytical models. The experiments are interpreted and the results used to evaluate the models. Calculations are presented using the FRAS3 fission-gas-behavior code and the DiMelfi-Deitrich fuel-response model.

  16. Perceptual consequences of disrupted auditory nerve activity.

    Science.gov (United States)

    Zeng, Fan-Gang; Kong, Ying-Yee; Michalewski, Henry J; Starr, Arnold

    2005-06-01

    Perceptual consequences of disrupted auditory nerve activity were systematically studied in 21 subjects who had been clinically diagnosed with auditory neuropathy (AN), a recently defined disorder characterized by normal outer hair cell function but disrupted auditory nerve function. Neurological and electrophysical evidence suggests that disrupted auditory nerve activity is due to desynchronized or reduced neural activity or both. Psychophysical measures showed that the disrupted neural activity has minimal effects on intensity-related perception, such as loudness discrimination, pitch discrimination at high frequencies, and sound localization using interaural level differences. In contrast, the disrupted neural activity significantly impairs timing related perception, such as pitch discrimination at low frequencies, temporal integration, gap detection, temporal modulation detection, backward and forward masking, signal detection in noise, binaural beats, and sound localization using interaural time differences. These perceptual consequences are the opposite of what is typically observed in cochlear-impaired subjects who have impaired intensity perception but relatively normal temporal processing after taking their impaired intensity perception into account. These differences in perceptual consequences between auditory neuropathy and cochlear damage suggest the use of different neural codes in auditory perception: a suboptimal spike count code for intensity processing, a synchronized spike code for temporal processing, and a duplex code for frequency processing. We also proposed two underlying physiological models based on desynchronized and reduced discharge in the auditory nerve to successfully account for the observed neurological and behavioral data. These methods and measures cannot differentiate between these two AN models, but future studies using electric stimulation of the auditory nerve via a cochlear implant might. These results not only show the unique

  17. Coastal Structures and Barriers 2012

    Data.gov (United States)

    California Department of Resources — This dataset is a compilation of the UCSC Sand Retention Structures, MC Barriers, and USACE Coastal Structures. UCSC Sand Retention Structures originate from a...

  18. and use of barrier techniques

    African Journals Online (AJOL)

    Attitudes of Nigerian dentists towards hepatitis B vaccination and use of barrier techniques .... tine screening of only high-risk patients has been recommended.“ .... i337-1342. Sote EO. AIDS and infection Control: experiences, attitudes,.

  19. Barriers for recess physical activity

    DEFF Research Database (Denmark)

    Pawlowski, Charlotte Skau; Tjørnhøj-Thomsen, Tine; Schipperijn, Jasper

    2014-01-01

    they would like to have more secluded areas added to the school playground, even in large schoolyards where lack of space was not a barrier. This aligned with girls' requests for more "hanging-out" facilities, whereas boys primarily wanted activity promoting facilities. CONCLUSION: Based on the results from......BACKGROUND: Many children, in particular girls, do not reach the recommended amount of daily physical activity. School recess provides an opportunity for both boys and girls to be physically active, but barriers to recess physical activity are not well understood. This study explores gender....... This was verified by a thematic analysis of transcripts from the open discussions and go-along interviews. RESULTS: The most frequently identified barriers for both boys and girls were weather, conflicts, lack of space, lack of play facilities and a newly-found barrier, use of electronic devices. While boys...

  20. Coastal Structures and Barriers 2012

    Data.gov (United States)

    California Department of Resources — This dataset is a compilation of the UCSC Sand Retention Structures, MC Barriers, and USACE Coastal Structures. UCSC Sand Retention Structures originate from a...

  1. Low Conductivity Thermal Barrier Coatings

    Science.gov (United States)

    Zhu, Dong-Ming

    2005-01-01

    Thermal barrier coatings will be more aggressively designed to protect gas turbine engine hot-section components in order to meet future engine higher fuel efficiency and lower emission goals. In this presentation, thermal barrier coating development considerations and requirements will be discussed. An experimental approach is established to monitor in real time the thermal conductivity of the coating systems subjected to high-heat-flux, steady-state and cyclic temperature gradients. Advanced low conductivity thermal barrier coatings have also been developed using a multi-component defect clustering approach, and shown to have improved thermal stability. The durability and erosion resistance of low conductivity thermal barrier coatings have been improved utilizing advanced coating architecture design, composition optimization, in conjunction with more sophisticated modeling and design tools.

  2. Guided tissue regeneration. Absorbable barriers.

    Science.gov (United States)

    Wang, H L; MacNeil, R L

    1998-07-01

    Over the past 15 years, techniques aimed at regeneration of lost periodontal tissue have become widely used and accepted in clinical practice. Among these techniques are those which use the principles of guided tissue regeneration (GTR), wherein barriers (i.e., membranes) are used to control cell and tissue repopulation of the periodontal wound. A variety of non-absorbable and absorbable barriers have been developed and used for this purpose, with a trend in recent years toward increased use of absorbable GTR materials. This article describes the evolution of absorbable barrier materials and overview materials available for clinical use today. In addition, advantages and disadvantages of these materials are discussed, as well as possible new developments in barrier-based GTR therapy.

  3. Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity.

    Science.gov (United States)

    Deli, Mária A; Veszelka, Szilvia; Csiszár, Boglárka; Tóth, Andrea; Kittel, Agnes; Csete, Mária; Sipos, Aron; Szalai, Anikó; Fülöp, Lívia; Penke, Botond; Abrahám, Csongor S; Niwa, Masami

    2010-01-01

    Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

  4. Therapeutic Potential to Modify the Mucus Barrier in Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Jing Sun

    2016-01-01

    Full Text Available Recently, numerous studies have shown that disruption of the mucus barrier plays an important role in the exacerbation of inflammatory bowel disease, particularly in ulcerative colitis. Alterations in the mucus barrier are well supported by published data and are widely accepted. The use of fluorescence in situ hybridization and Carnoy’s fixation has revealed the importance of the mucus barrier in maintaining a mutualistic relationship between host and bacteria. Studies have raised the possibility that modulation of the mucus barrier may provide therapies for the disease, using agents such as short-chain fatty acids, prebiotics and probiotics. This review describes changes in the mucus barrier of patients with inflammatory bowel disease and in animal models of the disease. We also review the involvement of the mucus barrier in the exacerbation of the disease and explore the therapeutic potential of modifying the mucus barrier with short-chain fatty acids, prebiotics, probiotics, fatty acid synthase, H2S, neutrophil elastase inhibitor and phophatidyl choline.

  5. Nonlocal reflection by photonic barriers

    OpenAIRE

    Vetter, R. -M.; A. Haibel; Nimtz, G.

    2001-01-01

    The time behaviour of microwaves undergoing partial reflection by photonic barriers was measured in the time and in the frequency domain. It was observed that unlike the duration of partial reflection by dielectric layers, the measured reflection duration of barriers is independent of their length. The experimental results point to a nonlocal behaviour of evanescent modes at least over a distance of some ten wavelengths. Evanescent modes correspond to photonic tunnelling in quantum mechanics.

  6. Schooling Inequality and Language Barriers

    OpenAIRE

    Parker, Susan W.; Rubalcava, Luis; Teruel, Graciela

    2005-01-01

    This article estimates the impact of language barriers on school achievement and the potential ameliorating role of bilingual education. Using large household data sets from poor rural communities in Mexico, we find that parental language (failure to speak Spanish) represents an important barrier to the schooling of indigenous children. We provide an empirical test suggesting that this largely reflects parental human capital related to culture/language, rather than unobserved wealth effects. ...

  7. Economic alternatives for containment barriers

    Energy Technology Data Exchange (ETDEWEB)

    Nicholson, P.J.; Jasperse, B.H.; Fisher, M.J. [Geo-Con, Inc., Monroeville, PA (United States)

    1997-12-31

    Fixation, barriers, and containment of existing landfills and other disposal areas are often performed by insitu auger type soil mixing and jet grouting. Cement or other chemical reagents are mixed with soil to form both vertical and horizontal barriers. Immobilization of contaminants can be economically achieved by mixing soil and the contaminants with reagents that solidify or stabilize the contaminated area. Developed in Japan, and relatively new to the United States, the first large scale application was for a vertical barrier at the Jackson Lake Dam project in 1986. This technology has grown in both the civil and environmental field since. The paper describes current United States practice for Deep Soil Mixing (over 12 meters in depth), and Shallow Soil Mixing for vertical barriers and stabilization/solidification, and Jet Grouting for horizontal and vertical barriers. Creating very low permeability barriers at depth with minimal surface return often makes these techniques economical when compared to slurry trenches. The paper will discuss equipment, materials, soil and strength parameters, and quality control.

  8. Barrier function in the peripheral and central nervous system-a review.

    Science.gov (United States)

    Reinhold, A K; Rittner, H L

    2017-01-01

    The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.

  9. Anthropogenic tracers, endocrine disrupting chemicals, and endocrine disruption in Minnesota lakes

    Science.gov (United States)

    Writer, J.H.; Barber, L.B.; Brown, G.K.; Taylor, H.E.; Kiesling, R.L.; Ferrey, M.L.; Jahns, N.D.; Bartell, S.E.; Schoenfuss, H.L.

    2010-01-01

    Concentrations of endocrine disrupting chemicals and endocrine disruption in fish were determined in 11 lakes across Minnesota that represent a range of trophic conditions and land uses (urban, agricultural, residential, and forested) and in which wastewater treatment plant discharges were absent. Water, sediment, and passive polar organic integrative samplers (POCIS) were analyzed for steroidal hormones, alkylphenols, bisphenol A, and other organic and inorganic molecular tracers to evaluate potential non-point source inputs into the lakes. Resident fish from the lakes were collected, and caged male fathead minnows were deployed to evaluate endocrine disruption, as indicated by the biological endpoints of plasma vitellogenin and gonadal histology. Endocrine disrupting chemicals, including bisphenol A, 17??-estradiol, estrone, and 4-nonylphenol were detected in 90% of the lakes at part per trillion concentrations. Endocrine disruption was observed in caged fathead minnows and resident fish in 90% of the lakes. The widespread but variable occurrence of anthropogenic chemicals in the lakes and endocrine disruption in fish indicates that potential sources are diverse, not limited to wastewater treatment plant discharges, and not entirely predictable based on trophic status and land use. ?? 2010.

  10. Longitudinal association between marital disruption and child BMI and obesity.

    Science.gov (United States)

    Arkes, Jeremy

    2012-08-01

    This research examines whether family disruptions (i.e., divorces and separation) contribute to children's weight problems. The sample consists of 7,299 observations for 2,333 children, aged 5-14, over the 1986-2006 period, from a US representative sample from the Child and Young Adult Survey accompanying the National Longitudinal Survey of Youth (NLSY). The study uses individual-fixed-effects models in a longitudinal framework to compare children's BMI and weight problems before and after a disruption. Furthermore, besides doing a before-after comparison for children, the study also estimates the effects at various periods relative to the disruption in order to examine whether children are affected before the disruption and whether any effects change as time passes from the disruption, as some effects may be temporary or slow to develop. Despite having a larger sample than the previous studies, the results provide no evidence that, on average, children's BMI and BMI percentile scores (measured with continuous outcomes) are affected before the disruption, after the disruption, and as time passes from the disruption, relative to a baseline period a few years before the disruption. However, children experiencing a family disruption do have an increased risk of obesity (having a BMI percentile score of 95 or higher) in the two years leading up to the disruption as well as after the disruption, and as time passes from the disruption.

  11. Shigella effector IpaB-induced cholesterol relocation disrupts the Golgi complex and recycling network to inhibit host cell secretion.

    Science.gov (United States)

    Mounier, Joëlle; Boncompain, Gaëlle; Senerovic, Lidija; Lagache, Thibault; Chrétien, Fabrice; Perez, Franck; Kolbe, Michael; Olivo-Marin, Jean-Christophe; Sansonetti, Philippe J; Sauvonnet, Nathalie

    2012-09-13

    Shigella infection causes destruction of the human colonic epithelial barrier. The Golgi network and recycling endosomes are essential for maintaining epithelial barrier function. Here we show that Shigella epithelial invasion induces fragmentation of the Golgi complex with consequent inhibition of both secretion and retrograde transport in the infected host cell. Shigella induces tubulation of the Rab11-positive compartment, thereby affecting cell surface receptor recycling. The molecular process underlying the observed damage to the Golgi complex and receptor recycling is a massive redistribution of plasma membrane cholesterol to the sites of Shigella entry. IpaB, a virulence factor of Shigella that is known to bind cholesterol, is necessary and sufficient to induce Golgi fragmentation and reorganization of the recycling compartment. Shigella infection-induced Golgi disorganization was also observed in vivo, suggesting that this mechanism affecting the sorting of cell surface molecules likely contributes to host epithelial barrier disruption associated with Shigella pathogenesis. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Ultrasound-induced blood-brain barrier opening.

    Science.gov (United States)

    Konofagou, Elisa E; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

    2012-06-01

    Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.

  13. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  14. Filaggrin and Skin Barrier Function.

    Science.gov (United States)

    Kezic, Sanja; Jakasa, Ivone

    2016-01-01

    The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models

  15. Conversion of homothallic yeast to heterothallism trough HO gene disruption

    CSIR Research Space (South Africa)

    Van Zyl, WH

    1993-04-01

    Full Text Available A simple method was developed for the conversion of homothallic Saccharomyces cerevisiae yeaststrains to heterothallism through HO gene disruption. An integrative ho:: neo disrupted allele was constructed by cloning a dominant selectable marker...

  16. Endocrine disrupters. The case of estrogen xenobiotics

    Directory of Open Access Journals (Sweden)

    N. Olea Serrano

    2001-06-01

    Full Text Available Interest of the scientific community in chemical substances able to alter the hormone balance –endocrine disrupters- has grown with increasing evidence of the consequences for animal populations of exposure to these substances. As has occurred on previous occasions, observational data on animal populations have been sufficiently suggestive to cause concerns among clinicians that similar effects may be produced in human populations. Although data on the effects on populations of animals are more easily generated than those on individuals, clinical observations on human individuals alongside the few existing epidemiological studies have shown a certain parallelism. Indeed, in vitro and in vivo models have been able to designate many chemical compounds as hormonal mimics, including both natural and human-produced compounds to which there are exposure risks. The present work reviews the conceptual premises of endocrine disruption and the development of the use of this term.

  17. Minimally Disruptive Medicine for Patients with Diabetes.

    Science.gov (United States)

    Serrano, Valentina; Spencer-Bonilla, Gabriela; Boehmer, Kasey R; Montori, Victor M

    2017-09-23

    Patients with diabetes must deal with the burden of symptoms and complications (burden of illness). Simultaneously, diabetes care demands practical and emotional work from patients and their families, work to access and use healthcare and to enact self-care (burden of treatment). Patient work must compete with the demands of family, job, and community life. Overwhelmed patients may not have the capacity to access care or enact self-care and will thus experience suboptimal diabetes outcomes. Minimally disruptive medicine (MDM) is a patient-centered approach to healthcare that prioritizes patients' goals for life and health while minimizing the healthcare disruption on patients' lives. In patients with diabetes, particularly in those with complex lives and multimorbidity, MDM coordinates healthcare and community responses to improve outcomes, reduce treatment burden, and enable patients to pursue their life's hopes and dreams.

  18. The hexagon hypothesis: Six disruptive scenarios.

    Science.gov (United States)

    Burtles, Jim

    2015-01-01

    This paper aims to bring a simple but effective and comprehensive approach to the development, delivery and monitoring of business continuity solutions. To ensure that the arguments and principles apply across the board, the paper sticks to basic underlying concepts rather than sophisticated interpretations. First, the paper explores what exactly people are defending themselves against. Secondly, the paper looks at how defences should be set up. Disruptive events tend to unfold in phases, each of which invites a particular style of protection, ranging from risk management through to business continuity to insurance cover. Their impact upon any business operation will fall into one of six basic scenarios. The hexagon hypothesis suggests that everyone should be prepared to deal with each of these six disruptive scenarios and it provides them with a useful benchmark for business continuity.

  19. Rotavirus disrupts cytoplasmic P bodies during infection.

    Science.gov (United States)

    Bhowmick, Rahul; Mukherjee, Arpita; Patra, Upayan; Chawla-Sarkar, Mamta

    2015-12-02

    Cytoplasmic Processing bodies (P bodies), the RNA-protein aggregation foci of translationally stalled and potentially decaying mRNA, have been reported to be differentially modulated by viruses. Rotavirus, the causative agent of acute infantile gastroenteritis is a double stranded RNA virus which completes its entire life-cycle exclusively in host cell cytoplasm. In this study, the fate of P bodies was investigated upon rotavirus infection. It was found that P bodies get disrupted during rotavirus infection. The disruption occurred by more than one different mechanism where deadenylating P body component Pan3 was degraded by rotavirus NSP1 and exonuclease XRN1 along with the decapping enzyme hDCP1a were relocalized from cytoplasm to nucleus. Overall the study highlights decay and subcellular relocalization of P body components as novel mechanisms by which rotavirus subverts cellular antiviral responses.

  20. Ultrasonic cavitation for disruption of microalgae.

    Science.gov (United States)

    Greenly, Justin M; Tester, Jefferson W

    2015-05-01

    Challenges with mid-stream fractionation steps in proposed microalgae biofuel pathways arise from the typically dilute cell density in growth media, micron scale cell sizes, and often durable cell walls. For microalgae to be a sustainable source of biofuels and co-products, efficient fractionation by some method will be necessary. This study evaluates ultrasonic cell disruption as a processing step that fractionates microalgae. A range of species types with different sizes and cell wall compositions were treated. The initial seconds of sonication offered the most significant disruption, even for the more durable Nannochloropsis cells. Following this initial period, diminishing effectiveness was attributed, by acoustic measurements, to attenuation of the ultrasound in the ensuing cloud of cavitating bubbles. At longer exposure times, differences between species were more pronounced. Processing higher concentrations of Isochrysis slowed cell disintegration only marginally, making the expenditure of energy more worthwhile.

  1. Diabetes and diet: Managing dietary barriers.

    NARCIS (Netherlands)

    Friele, R.D.

    1989-01-01

    This thesis reports on the barriers diabetic patients experience with their diet, and the ways they cope with these barriers. A dietary barrier is a hinderance to a person's well-being, induced by being advised a diet. First inventories were made of possible dietary barriers and ways of coping with

  2. The mass disruption of Jupiter Family comets

    Science.gov (United States)

    Belton, Michael J. S.

    2015-01-01

    I show that the size-distribution of small scattered-disk trans-neptunian objects when derived from the observed size-distribution of Jupiter Family comets (JFCs) and other observational constraints implies that a large percentage (94-97%) of newly arrived active comets within a range of 0.2-15.4 km effective radius must physically disrupt, i.e., macroscopically disintegrate, within their median dynamical lifetime. Additional observational constraints include the numbers of dormant and active nuclei in the near-Earth object (NEO) population and the slope of their size distributions. I show that the cumulative power-law slope (-2.86 to -3.15) of the scattered-disk TNO hot population between 0.2 and 15.4 km effective radius is only weakly dependent on the size-dependence of the otherwise unknown disruption mechanism. Evidently, as JFC nuclei from the scattered disk evolve into the inner Solar System only a fraction achieve dormancy while the vast majority of small nuclei (e.g., primarily those with effective radius Morbidelli, A., Dones, L., Jedicke, R., Wiegert, P.A., Bottke Jr., W.F. [2002]. Science 296, 2212-2215) suggesting that all types of comet nuclei may have similar structural characteristics even though they may have different source regions and thermal histories. The typical disruption rate for a 1 km radius active nucleus is ∼5 × 10-5 disruptions/year and the dormancy rate is typically 3 times less. We also estimate that average fragmentation rates range from 0.01 to 0.04 events/year/comet, somewhat above the lower limit of 0.01 events/year/comet observed by Chen and Jewitt (Chen, J., Jewitt, D.C. [1994]. Icarus 108, 265-271).

  3. Five disruptive technology directions for 5G

    OpenAIRE

    Boccardi, Federico; W. Heath Jr., Robert; Lozano, Angel; L. Marzetta, Thomas; POPOVSKI, Petar

    2014-01-01

    New research directions will lead to fundamental changes in the design of future fifth generation (5G) cellular networks. This article describes five technologies that could lead to both architectural and component disruptive design changes: device-centric architectures, millimeter wave, massive MIMO, smarter devices, and native support for machine-to-machine communications. The key ideas for each technology are described, along with their potential impact on 5G and the research challenges th...

  4. Subtle sabotage: endocrine disruption in wild populations

    OpenAIRE

    Cheek, Ann Oliver

    2016-01-01

    How important is endocrine disruption as a threat to wildlife populations? This review applies causal criteria to existing studies of wild populations of fish, amphibians, reptiles, birds, and mammals to answer three questions: (1) Have endocrine-mediated effects of contaminant exposure been documented? (2) Have individual adverse effects that could lead to population effects been documented? (3) Have population level effects been documented? In fish, the possibility of population level effec...

  5. Five disruptive technology directions for 5G

    DEFF Research Database (Denmark)

    Boccardi, Federico; W. Heath Jr., Robert; Lozano, Angel

    2014-01-01

    New research directions will lead to fundamental changes in the design of future fifth generation (5G) cellular networks. This article describes five technologies that could lead to both architectural and component disruptive design changes: device-centric architectures, millimeter wave, massive...... MIMO, smarter devices, and native support for machine-to-machine communications. The key ideas for each technology are described, along with their potential impact on 5G and the research challenges that remain....

  6. Identifying and engaging 'disengaged' and 'disruptive' students

    OpenAIRE

    Ted Cole

    2009-01-01

    This paper outlines concerns in the UK about young people who are disruptive in class and/or disengaged from the normal educational process. After discussing who these children are and estimating their numbers, the paper examines recent research on how best to meet their needs. This research indicates the appropriateness of the UK government's recent softening of its position on 'inclusion'. The studies cited indicate that far more can be done in 'normal' school settings to promote engagement...

  7. Policy development for disruptive student behaviors.

    Science.gov (United States)

    Clark, Cynthia M; Farnsworth, Judy; Springer, Pamela J

    2008-01-01

    Nursing students who demonstrate disruptive and at-risk behaviors in the classroom and clinical arena compromise the learning environment and are unable to provide safe, quality client care. They require early and swift identification, consultation, sanctions, or possible referral into treatment to protect themselves and public safety. The authors describe the evolution of a comprehensive policy for faculty intervention with at-risk students and provide an exemplar of a situation illustrating the use of the policy.

  8. Disruptive technologies and networking in telecom industries

    OpenAIRE

    Madsen, Erik Strøjer; Hartington, Simon

    2015-01-01

    This article discuss’ how economics of scale in supply and demand in the telecommunication industry has developed and how this has had great effect on the widespread usage and popularity of smart phones. By using this as a theoretical ground the paper looks into technical innovation in the telecommunication industry and finds significant similarities between the industry development and the literature on disruptive technology, which finds that incumbent companies are not able to react in a su...

  9. Influence of Dynamic Capabilities in Creating Disruptive Innovation

    OpenAIRE

    Čiutienė, R; Thattakath, E

    2015-01-01

    The aim of this paper is to demonstrate the influence of Dynamic Capabilities in creating Disruptive Innovation. For doing so the concepts of Dynamic Capabilities and Disruptive Innovation are reviewed. The criteria of an innovation named Disruptive Innovation are obtained by comparative study between the various innovation types. To demonstrate the role of Dynamic Capabilities in creating Disruptive Innovation, the Innovation Lifecycle is demonstrated with respect to Dynamic Capabilities. Th...

  10. A case for change: disruption in academic medicine.

    Science.gov (United States)

    Kahn, Marc J; Maurer, Ralph; Wartman, Steven A; Sachs, Benjamin P

    2014-09-01

    Disruptive technologies allow less expensive and more efficient processes to eventually dominate a market sector. The academic health center's tripartite mission of education, clinical care, and research is threatened by decreasing revenues and increasing expenses and is, as a result, ripe for disruption. The authors describe current disruptive technologies that threaten traditional operations at academic health centers and provide a prescription not only to survive, but also to prosper, in the face of disruptive forces.

  11. Disruption effects on the beam size measurement

    Energy Technology Data Exchange (ETDEWEB)

    Raimondi, P.; Decker, F.J.; Chen, P.

    1995-06-01

    At the SLC Final Focus with higher currents and smaller beam sizes, the disruption parameter D{sub y} is close to one and so the pinch effect should produce a luminosity enhancement. Since a flat beam-beam function is fit to deflection scan data to measure the beam size, disruption can affect the measurement. Here the authors discuss the quantitative effects of disruption for typical SLC beam parameters. With 3.5 10{sup 10} particles per pulse, bunch length of 0.8 mm and beam sizes of 2.1 {mu}m horizontally and 0.55 {mu}m vertically, the measured vertical size can be as much as 25% bigger than the real one. Furthermore during the collision the spot size actually decrease, producing an enhancement factor H{sub D} of about 1.25. This would yield to a true luminosity which is 1.6 times that which is estimated from the beam-beam deflection fit.

  12. Risk Evaluation of Endocrine-Disrupting Chemicals

    Directory of Open Access Journals (Sweden)

    Laura Gioiosa

    2015-10-01

    Full Text Available We review here our studies on early exposure to low doses of the estrogenic endocrine-disrupting chemical bisphenol A (BPA on behavior and metabolism in CD-1 mice. Mice were exposed in utero from gestation day (GD 11 to delivery (prenatal exposure or via maternal milk from birth to postnatal day 7 (postnatal exposure to 10 µg/kg body weight/d of BPA or no BPA (controls. Bisphenol A exposure resulted in long-term disruption of sexually dimorphic behaviors. Females exposed to BPA pre- and postnatally showed increased anxiety and behavioral profiles similar to control males. We also evaluated metabolic effects in prenatally exposed adult male offspring of dams fed (from GD 9 to 18 with BPA at doses ranging from 5 to 50 000 µg/kg/d. The males showed an age-related significant change in a number of metabolic indexes ranging from food intake to glucose regulation at BPA doses below the no observed adverse effect level (5000 µg/kg/d. Consistent with prior findings, low but not high BPA doses produced significant effects for many outcomes. These findings provide further evidence of the potential risks that developmental exposure to low doses of the endocrine disrupter BPA may pose to human health, with fetuses and infants being highly vulnerable.

  13. Disruptive Innovation Can Prevent the Next Pandemic

    Directory of Open Access Journals (Sweden)

    Affan eShaikh

    2015-09-01

    Full Text Available Public health surveillance (PHS is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet 20th-century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation – used to describe advances in technology and processes that change existing markets, is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet – an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However it is necessary to strengthen and unlock the potential to prevent, detect, and respond.

  14. Natural Hazards and Supply Chain Disruptions

    Science.gov (United States)

    Haraguchi, M.

    2016-12-01

    Natural hazards distress the global economy through disruptions in supply chain networks. Moreover, despite increasing investment to infrastructure for disaster risk management, economic damages and losses caused by natural hazards are increasing. Manufacturing companies today have reduced inventories and streamlined logistics in order to maximize economic competitiveness. As a result, today's supply chains are profoundly susceptible to systemic risks, which are the risk of collapse of an entire network caused by a few node of the network. For instance, the prolonged floods in Thailand in 2011 caused supply chain disruptions in their primary industries, i.e. electronic and automotive industries, harming not only the Thai economy but also the global economy. Similar problems occurred after the Great East Japan Earthquake and Tsunami in 2011, the Mississippi River floods and droughts during 2011 - 2013, and the Earthquake in Kumamoto Japan in 2016. This study attempts to discover what kind of effective measures are available for private companies to manage supply chain disruptions caused by floods. It also proposes a method to estimate potential risks using a Bayesian network. The study uses a Bayesian network to create synthetic networks that include variables associated with the magnitude and duration of floods, major components of supply chains such as logistics, multiple layers of suppliers, warehouses, and consumer markets. Considering situations across different times, our study shows desirable data requirements for the analysis and effective measures to improve Value at Risk (VaR) for private enterprises and supply chains.

  15. Prenatal Testosterone and Preschool Disruptive Behavior Disorders.

    Science.gov (United States)

    Roberts, Bethan A; Martel, Michelle M

    2013-11-01

    Disruptive Behaviors Disorders (DBD), including Oppositional-Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD), are fairly common and highly impairing childhood behavior disorders that can be diagnosed as early as preschool. Prenatal exposure to testosterone may be particularly relevant to these early-emerging DBDs that exhibit a sex-biased prevalence rate favoring males. The current study examined associations between preschool DBD symptom domains and prenatal exposure to testosterone measured indirectly via right 2D:4D finger-length ratios. The study sample consisted of 109 preschool-age children between ages 3 and 6 (64% males;72% with DBD) and their primary caregivers. Primary caregivers completed a semi-structured interview (i.e., Kiddie Disruptive Behavior Disorder Schedule), as well as symptom questionnaires (i.e., Disruptive Behavior Rating Scale, Peer Conflict Scale); teachers and/or daycare providers completed symptom questionnaires and children provided measures of prenatal testosterone exposure, measured indirectly via finger-length ratios (i.e., right 2D:4D). Study results indicated a significant association of high prenatal testosterone (i.e., smaller right 2D:4D) with high hyperactive-impulsive ADHD symptoms in girls but not boys, suggesting that the effect may be driven by, or might only exist in, girls. The present study suggests that prenatal exposure to testosterone may increase risk for early ADHD, particularly hyperactivity-impulsivity, in preschool girls.

  16. Circadian dysregulation disrupts bile acid homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Ma

    Full Text Available BACKGROUND: Bile acids are potentially toxic compounds and their levels of hepatic production, uptake and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-/Per2(-/- (PERDKO mice disrupted normal bile acid control and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST, indicative of liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock output, the transcription factor DBP, which transactivates the promoters of both genes. CONCLUSIONS/SIGNIFICANCE: We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.

  17. Disruptive Innovation Can Prevent the Next Pandemic.

    Science.gov (United States)

    Shaikh, Affan T; Ferland, Lisa; Hood-Cree, Robert; Shaffer, Loren; McNabb, Scott J N

    2015-01-01

    Public health surveillance (PHS) is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet twentieth century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation - used to describe advances in technology and processes that change existing markets - is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet - an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However, it is necessary to strengthen and unlock the potential to prevent, detect, and respond.

  18. Cytokines and the Skin Barrier

    Directory of Open Access Journals (Sweden)

    Jens Malte Baron

    2013-03-01

    Full Text Available The skin is the largest organ of the human body and builds a barrier to protect us from the harmful environment and also from unregulated loss of water. Keratinocytes form the skin barrier by undergoing a highly complex differentiation process that involves changing their morphology and structural integrity, a process referred to as cornification. Alterations in the epidermal cornification process affect the formation of the skin barrier. Typically, this results in a disturbed barrier, which allows the entry of substances into the skin that are immunologically reactive. This contributes to and promotes inflammatory processes in the skin but also affects other organs. In many common skin diseases, including atopic dermatitis and psoriasis, a defect in the formation of the skin barrier is observed. In these diseases the cytokine composition within the skin is different compared to normal human skin. This is the result of resident skin cells that produce cytokines, but also because additional immune cells are recruited. Many of the cytokines found in defective skin are able to influence various processes of differentiation and cornification. Here we summarize the current knowledge on cytokines and their functions in healthy skin and their contributions to inflammatory skin diseases.

  19. Cylindrical air flow reversal barrier

    Energy Technology Data Exchange (ETDEWEB)

    Woznica, C.; Rodziewicz, M.

    1988-06-01

    Describes an innovative design introduced in the ZMP mine in Zory for quick reversal of ventilation air flow. Geologic mining conditions at the 705 m deep horizon, where the barrier was built, are described. According to the design used until now, a reversal system consisted of safety barriers, ventilation air locks, a ventilation bridge and stopping needed in case of a fire when air flow direction must be reversed. Nine air locks and an expensive concrete ventilation bridge were needed and the air locks had to be operated at 8 points of the region to effect reversal. The new design consists of a 2-storey cylindrical barrier which also fulfills the function of a ventilation bridge. It can be manually or remotely operated by a mechanical or pneumatic system. Tests showed that the new barrier permits immediate air flow reversal while retaining 60% of the original air, which is important in the case of fire and methane hazards. It permits improved seam panelling and splitting of pillars and brings an economy of about 40 million zlotys in construction cost. Design and operation of the barrier is illustrated and ventilation air circulation is explained. 7 figs.

  20. Human biological monitoring of suspected endocrine-disrupting compounds

    OpenAIRE

    Moosa Faniband; Lindh, Christian H; Bo AG Jönsson

    2014-01-01

    Endocrine-disrupting compounds are exogenous agents that interfere with the natural hormones of the body. Human biological monitoring is a powerful method for monitoring exposure to endocrine disrupting compounds. In this review, we describe human biological monitoring systems for different groups of endocrine disrupting compounds, polychlorinated biphenyls, brominated flame retardants, phthalates, alkylphenols, pesticides, metals, perfluronated compounds, parabens, ultraviolet filters, and o...