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Sample records for reduced brain edema

  1. Potential of glyburide to reduce intracerebral edema in brain metastases.

    PubMed

    Boggs, Drexell Hunter; Simard, J Marc; Steven, Andrew; Mehta, Minesh P

    2014-04-01

    Metastatic disease to the brain results in significant morbidity because of edema in the central nervous system. Current anti-edema therapies are either expensive or result in unwanted long-term side effects. Sulfonylurea receptor 1 (Sur1) is a transmembrane protein that, when activated in the central nervous system, allows for unregulated sodium influx into cells, a process that has been linked to cytotoxic edema formation in ischemic stroke, subarachnoid hemorrhage, spinal cord injury, traumatic brain injury, and, most recently, brain metastases. In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema. PMID:24552576

  2. Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury.

    PubMed

    Luh, Clara; Kuhlmann, Christoph R; Ackermann, Bianca; Timaru-Kast, Ralph; Luhmann, Heiko J; Behl, Christian; Werner, Christian; Engelhard, Kristin; Thal, Serge C

    2010-02-01

    The role of the endothelial contractile apparatus in the process of brain edema formation after brain trauma is not characterized. Phosphorylation of myosin light chains by myosin light chain kinases (MLCK) activates endothelial contractile elements and results in a rearrangement of the cytoskeleton. This may enhance post-traumatic blood-brain barrier dysfunction. In order to investigate the role of the MLCK on brain edema formation and blood-brain barrier permeability after brain injury, mice were anesthetized and subjected to a controlled cortical impact (CCI). MLCK expression is significantly up-regulated after CCI with a maximum 12 h post-injury. Specific inhibition of MLCK by ML-7 resulted in a reduction of phosphorylation of myosin light chains and improved blood-brain-barrier integrity. Accordingly, ML-7 attenuated post-traumatic brain edema formation and intracranial hypertension 24 h after CCI. Prevention of brain edema formation did not translate into improved neurological outcome or reduced brain lesion. In conclusion, the results confirm that the endothelial contractile apparatus is activated by CCI and opens the endothelial barrier leading to vasogenic brain edema formation. Lack of neurological and histological improvement suggests that specific targeting of vasogenic brain edema at the endothelial level is not sufficient to limit secondary brain damage and has, therefore, to be combined with other potential neuroprotective strategies. PMID:19943851

  3. Hypertonic saline reduces lipopolysaccharide-induced mouse brain edema through inhibiting aquaporin 4 expression

    PubMed Central

    2012-01-01

    Introduction Three percent sodium chloride (NaCl) treatment has been shown to reduce brain edema and inhibited brain aquaporin 4 (AQP4) expression in bacterial meningitis induced by Escherichia coli. Lipopolysaccharide (LPS) is the main pathogenic component of E. coli. We aimed to explore the effect of 3% NaCl in mouse brain edema induced by LPS, as well as to elucidate the potential mechanisms of action. Methods Three percent NaCl was used to treat cerebral edema induced by LPS in mice in vivo. Brain water content, IL-1β, TNFα, immunoglobulin G (IgG), AQP4 mRNA and protein were measured in brain tissues. IL-1β, 3% NaCl and calphostin C (a specific inhibitor of protein kinase C) were used to treat the primary astrocytes in vitro. AQP4 mRNA and protein were measured in astrocytes. Differences in various groups were determined by one-way analysis of variance. Results Three percent NaCl attenuated the increase of brain water content, IL-1β, TNFα, IgG, AQP4 mRNA and protein in brain tissues induced by LPS. Three percent NaCl inhibited the increase of AQP4 mRNA and protein in astrocytes induced by IL-1β in vitro. Calphostin C blocked the decrease of AQP4 mRNA and protein in astrocytes induced by 3% NaCl in vitro. Conclusions Osmotherapy with 3% NaCl ameliorated LPS-induced cerebral edema in vivo. In addition to its osmotic force, 3% NaCl exerted anti-edema effects possibly through down-regulating the expression of proinflammatory cytokines (IL-1β and TNFα) and inhibiting the expression of AQP4 induced by proinflammatory cytokines. Three percent NaCl attenuated the expression of AQP4 through activation of protein kinase C in astrocytes. PMID:23036239

  4. Aquaporin-4 Deletion in Mice Reduces Encephalopathy and Brain Edema in Experimental Acute Liver Failure

    PubMed Central

    Rama Rao, Kakulavarapu V.; Verkman, A. S.; Curtis, Kevin M.; Norenberg, Michael D.

    2014-01-01

    Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6 ± 0.3 and 2.3 ± 0.4 %, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF. PMID:24321433

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

    PubMed Central

    Zeynalov, Emil; Jones, Susan M.; Seo, Jeong-Woo; Snell, Lawrence D.; Elliott, J. Paul

    2015-01-01

    Background 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. Methods 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. Results 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). Conclusion 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. PMID:26275173

  6. Selective inhibition of inducible nitric oxide synthase reduces neurological deficit but not cerebral edema following traumatic brain injury.

    PubMed

    Louin, G; Marchand-Verrecchia, C; Palmier, B; Plotkine, M; Jafarian-Tehrani, M

    2006-02-01

    The role of inducible nitric oxide synthase (iNOS) in cerebral edema and neurological deficit following traumatic brain injury (TBI) is not yet clear-cut. Therefore, the aim of this study was to investigate the effect of three different iNOS inhibitors on cerebral edema and functional outcome after TBI. First, the time courses of blood--brain barrier (BBB) breakdown, cerebral edema, and neurological deficit were studied in a rat model of fluid percussion-induced TBI. The permeability of BBB to Evans blue was increased from 1 h to 24 h after TBI. Consistently, a significant increase in brain water content (BWC) was observed at 6 and 24 h post-TBI. A deficit in sensorimotor neurological functions was also observed from 6 h to 7 days with a maximum 24 h after TBI. Second, a single dose of aminoguanidine (AG; 100 mg/kg, i.p.), L-N-iminoethyl-lysine (L-NIL; 20 mg/kg, i.p.), or N-[3-(aminomethyl)benzyl]acetamide (1400W; 20 mg/kg, s.c.) was administered at 6 h post-TBI. Treatment with AG reduced by 71% the increase in BWC evaluated at 24 h, while L-NIL and 1400W had no effect. In contrast, the three iNOS inhibitors reduced the neurological deficit from 30% to 40%. Third, 1400W (20 mg/kg, s.c.) was administered at 5 min, 8 and 16 h post-TBI. Although this treatment paradigm had no effect on cerebral edema evaluated at 24 h, it significantly reduced the neurological deficit and iNOS activity. In conclusion, iNOS contributes to post-TBI neurological deficit but not to cerebral edema. The beneficial effect of iNOS inhibitors is not due to their anti-edematous effect, and the reduction of cerebral edema by AG is unlikely related to iNOS inhibition. The 6 h therapeutic window of iNOS inhibitors could allow their use in the treatment of functional deficit at the acute phase of TBI. PMID:16242164

  7. NC1900, an Arginine Vasopressin Analogue, Fails to Reduce Brain Edema and Improve Neurobehavioral Deficits in an Intracerebral Hemorrhagic Stroke Mice Model

    PubMed Central

    Manaenko, Anatol; Lekic, Tim; Tang, Jiping; Zhang, John H.

    2013-01-01

    Objective There is mounting evidence suggesting that arginine vasopressin via its V1a receptor interaction is involved in the regulation of the brain water channel, aquaporin-4 (AQP4). The role of AQP4 in brain edema resolution has been thoroughly investigated in knock-out animal studies, which showed that its depletion increases brain water content in models of vasogenic edema. As a result, we tested the hypothesis that the activation of V1a receptor by it selective agonist will decrease brain edema in a mouse intracerebral hemorrhage (ICH) model. Materials and Methods ICH was induced by injection of bacterial collagenase into the right basal ganglia in CD1 male mice (weight 30–35 g). The animals were divided into the following groups: sham, ICH + vehicle, and ICH + AVP V1a receptor agonist. Brain edema and neurological outcomes were evaluated at 24 and 72 h post-ICH. Results We found that collagenase injection increased brain edema and resulted in subsequent neurobehavioral deficits at both time points. Treatment with our agonist had no effect on the ICH outcomes at both time points. Conclusions Our results suggest that the activation of the V1a receptor has no beneficial effect on secondary brain injury following ICH in mice. PMID:21725748

  8. Brain edema in diseases of different etiology.

    PubMed

    Adeva, María M; Souto, Gema; Donapetry, Cristóbal; Portals, Manuel; Rodriguez, Alberto; Lamas, David

    2012-07-01

    Cerebral edema is a potentially life-threatening complication shared by diseases of different etiology, such as diabetic ketoacidosis, acute liver failure, high altitude exposure, dialysis disequilibrium syndrome, and salicylate intoxication. Pulmonary edema is also habitually present in these disorders, indicating that the microcirculatory disturbance causing edema is not confined to the brain. Both cerebral and pulmonary subclinical edema may be detected before it becomes clinically evident. Available evidence suggests that tissue hypoxia or intracellular acidosis is a commonality occurring in all of these disorders. Tissue ischemia induces physiological compensatory mechanisms to ensure cell oxygenation and carbon dioxide removal from tissues, including hyperventilation, elevation of red blood cell 2,3-bisphosphoglycerate content, and capillary vasodilatation. Clinical, laboratory, and necropsy findings in these diseases confirm the occurrence of low plasma carbon dioxide partial pressure, increased erythrocyte 2,3-bisphosphoglycerate concentration, and capillary vasodilatation with increased vascular permeability in all of them. Baseline tissue hypoxia or intracellular acidosis induced by the disease may further deteriorate when tissue oxygen requirement is no longer matched to oxygen delivery resulting in massive capillary vasodilatation with increased vascular permeability and plasma fluid leakage into the interstitial compartment leading to edema affecting the brain, lung, and other organs. Causative factors involved in the progression from physiological adaptation to devastating clinical edema are not well known and may include uncontrolled disease, malfunctioning adaptive responses, or unknown factors. The role of carbon monoxide and local nitric oxide production influencing tissue oxygenation is unclear. PMID:22579570

  9. International brain edema symposia 1967-2011.

    PubMed

    Kuroiwa, Toshihiko

    2013-01-01

    This is a brief review of previous international brain edema symposia. The symposia that took place from 1965 to 1999 were summarized by Igor Klatzo and A. Marmarou in the proceedings Brain Edema XI [1]. In this article the author summarized the symposia, including latest five. Images from previous symposia such as the cover pages of the proceedings and snapshots of organizers were included. The outline and key words of the symposia were summarized in tables. The name of the prize winner and the title of the memorial lectures in recent symposia were also summarized in a table. PMID:23564096

  10. Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

    PubMed Central

    Michinaga, Shotaro; Koyama, Yutaka

    2015-01-01

    Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them. PMID:25941935

  11. Selective Vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury

    PubMed Central

    Marmarou, Christina R.; Liang, Xiuyin; Abidi, Naqeeb H.; Parveen, Shanaz; Taya, Keisuke; Henderson, Scott C.; Young, Harold F.; Filippidis, Aristotelis S.; Baumgarten, Clive M.

    2014-01-01

    A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5 h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm2) versus sham groups (78.3±0.1%; 9.5±0.9 µm2), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8 µm2). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03± 0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema. PMID:24933327

  12. Effects of Gender and Estrogen Receptors on Iron-Induced Brain Edema Formation.

    PubMed

    Xie, Qing; Xi, Guohua; Keep, Richard F; Hua, Ya

    2016-01-01

    Our previous studies have shown that female mice have less brain edema and better recovery in neurological deficits after intracerebral hemorrhage (ICH) and that 17β-estradiol treatment in male mice markedly reduces ICH-induced brain edema. In this study, we investigated the role of gender and the estrogen receptors (ERs) in iron-induced brain edema. There were three parts in this study: (1) either male or female mice received an injection of 10 μL FeCl2 (1 mM) into the right caudate; (2) females received an intracaudate injection of FeCl2 or saline with 1 μg of ICI 182,780 (antagonists of ERs) or vehicle; and (3) males were treated with the ER regulator tamoxifen (5 mg/kg subcutaneously) or vehicle 1 h after FeCl2 injection. Mice were euthanized 24 h later for brain edema determination. FeCl2 induced lower brain edema in females than in males. Co-injection of ICI 182,780 with FeCl2 aggravated iron-induced brain edema in female mice. ICI 182,780 itself did not induce brain edema at the dose of 1 μg. Tamoxifen treatment reduced FeCl2-induced brain edema in male mice. In conclusion, iron induced less brain edema in female mice than in males. ER modification can affect iron-induced brain edema. PMID:26463972

  13. Proton nuclear magnetic resonance studies on brain edema

    SciTech Connect

    Naruse, S.; Horikawa, Y.; Tanaka, C.; Hirakawa, K.; Nishikawa, H.; Yoshizaki, K.

    1982-06-01

    The water in normal and edematous brain tissues of rats was studied by the pulse nuclear magnetic resonance (NMR) technique, measuring the longitudinal relaxation time (T1) and the transverse relaxation time (T2). In the normal brain, T1 and T2 were single components, both shorter than in pure water. Prolongation and separation of T2 into two components, one fast and one slow, were the characteristic findings in brain edema induced by both cold injury and triethyl tin (TET), although some differences between the two types of edema existed in the content of the lesion and in the degree of changes in T1 and T2 values. Quantitative analysis of T1 and T2 values in their time course relating to water content demonstrated that prolongation of T1 referred to the volume of increased water in tissues examined, and that two phases of T2 reflected the distribution and the content of the edema fluid. From the analysis of the slow component of T2 versus water content during edema formation, it was demonstrated that the increase in edema fluid was steady, and its content was constant during formation of TET-induced edema. On the contrary, during the formation of cold-injury edema, water-rich edema fluid increased during the initial few hours, and protein-rich edema fluid increased thereafter. It was concluded that proton NMR relaxation time measurements may provide new understanding in the field of brain edema research.

  14. Activation of NF-κB mediates astrocyte swelling and brain edema in traumatic brain injury.

    PubMed

    Jayakumar, Arumugam R; Tong, Xiao Y; Ruiz-Cordero, Roberto; Bregy, Amade; Bethea, John R; Bramlett, Helen M; Norenberg, Michael D

    2014-07-15

    Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-κB (NF-κB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-κB might also be involved in the mediation of post-traumatic astrocyte swelling/brain edema. Here we show an increase in NF-κB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11-7082, an inhibitor of NF-κB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na(+), K(+), 2Cl(-) cotransporter were also observed in cultured astrocytes after trauma, and BAY 11-7082 reduced these effects. We also examined the role of NF-κB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-κB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-κB Tg mice showed no swelling. We also found increased astrocytic NF-κB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-κB represents a key element in the process by which cytotoxic brain edema occurs after TBI. PMID:24471369

  15. Mathematical modelling of blood-brain barrier failure and edema

    NASA Astrophysics Data System (ADS)

    Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

    2015-11-01

    Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

  16. Drowning stars: Reassessing the role of astrocytes in brain edema

    PubMed Central

    Thrane, Alexander S.; Thrane, Vinita Rangroo; Nedergaard, Maiken

    2014-01-01

    Edema formation frequently complicates brain infarction, tumors and trauma. Despite the significant mortality of this condition, current treatment options are often ineffective or incompletely understood. Recent studies have revealed the existence of a brain-wide paravascular pathway for cerebrospinal (CSF) and interstitial fluid (ISF) exchange. The current review critically examines the contribution of this ‘glymphatic’ system to the main types of brain edema. We propose that in cytotoxic edema, energy depletion enhances glymphatic CSF influx, whilst suppressing ISF efflux. We also argue that paravascular inflammation or ‘paravasculitis’ plays a critical role in vasogenic edema. Finally, recent advances in diagnostic imaging of glymphatic function may hold the key to defining the edema profile of individual patients and thus enable more targeted therapy. PMID:25236348

  17. Dopplersonographic classification of brain edema in infants.

    PubMed

    Deeg, K H; Rupprecht, T; Zeilinger, G

    1990-01-01

    25 infants, 23 newborns and 2 older infants with B-mode sonographic evidence of cerebral edema (gestational age of the newborns 39.1 +/- 2.1 weeks, weight 3270 +/- 672 g) were examined by means of pulsed Doppler sonography. Pulsed Doppler recordings were obtained in the anterior cerebral, internal carotid, basilar, and middle cerebral arteries. In all measured arteries the peak systolic peak endsystolic, peak enddiastolic and the time averaged mean velocities, as well as the resistance index and the pulsatility index were determined. In addition to the flow parameters the pH, pCO2, pO2, oxygen saturation and the blood pressure were measured. The flow velocities were compared with the normal values established by our group. Three different types of flow profiles and velocities could be found: Group 1: 12 infants had normal flow velocities. Group 2: 7 infants showed increased diastolic flow velocities. Group 3: 6 infants demonstrated decreased diastolic flow velocities. There were no significant differences according to gestational age, weight, pH, pCO2, pO2, oxygen saturation and blood pressure in the three groups. The outcome of the 12 children in group 1 was favourable: normal development 10; minor retardation 2. In group 2 only 1 child showed normal development; 2 infants had minor, 1 major handicaps; 2 infants died. Patients in group 3 had the worst outcome: no patient developed normally; 4 infants died; 2 severely handicapped infants showed polycystic leucomalacia and brain atrophy; 1 infant had minor psychomotoric problems. PMID:2216583

  18. [Increased intracranial pressure and brain edema].

    PubMed

    Dietrich, W; Erbguth, F

    2013-03-01

    In primary and secondary brain diseases, increasing volumes of the three compartments of brain tissue, cerebrospinal fluid, or blood lead to a critical increase in intracranial pressure (ICP). A rising ICP is associated with typical clinical symptoms; however, during analgosedation it can only be detected by invasive ICP monitoring. Other neuromonitoring procedures are not as effective as ICP monitoring; they reflect the ICP changes and their complications by other metabolic and oxygenation parameters. The most relevant parameter for brain perfusion is cerebral perfusion pressure (CPP), which is calculated as the difference between the middle arterial pressure (MAP) and the ICP. A mixed body of evidence exists for the different ICP-reducing treatment measures, such as hyperventilation, hyperosmolar substances, hypothermia, glucocorticosteroids, CSF drainage, and decompressive surgery. PMID:23503630

  19. [Increased intracranial pressure and brain edema].

    PubMed

    Dietrich, W; Erbguth, F

    2013-09-01

    In primary and secondary brain diseases, increasing volumes of the three compartments of brain tissue, cerebrospinal fluid, or blood lead to a critical increase in intracranial pressure (ICP). A rising ICP is associated with typical clinical symptoms; however, during analgosedation it can only be detected by invasive ICP monitoring. Other neuromonitoring procedures are not as effective as ICP monitoring; they reflect the ICP changes and their complications by other metabolic and oxygenation parameters. The most relevant parameter for brain perfusion is cerebral perfusion pressure (CPP), which is calculated as the difference between the middle arterial pressure (MAP) and the ICP. A mixed body of evidence exists for the different ICP-reducing treatment measures, such as hyperventilation, hyperosmolar substances, hypothermia, glucocorticosteroids, CSF drainage, and decompressive surgery. PMID:24061872

  20. Evaluation of brain edema using magnetic resonance proton relaxation times

    SciTech Connect

    Fu, Y.; Tanaka, K.; Nishimura, S. )

    1990-01-01

    Experimental and clinical studies on the evaluation of water content in cases of brain edema were performed in vivo, using MR proton relaxation times (longitudinal relaxation time, T1; transverse relaxation time, T2). Brain edema was produced in the white matter of cats by the direct infusion method. The correlations between proton relaxation times obtained from MR images and the water content of white matter were studied both in autoserum-infused cats and in saline-infused cats. The correlations between T1 as well as T2 and the water content in human vasogenic brain edema were also examined and compared with the data obtained from the serum group. T1 and T2 showed good correlations with the water content of white matter not only in the experimental animals but also in the clinical cases. The quality of the edema fluid did not influence relaxation time and T1 seemed to represent almost solely the water content of the tissue. T2, however, was affected by the nature of existence of water and was more sensitive than T1 in detecting extravasated edema fluid. It seems feasible therefore to evaluate the water content of brain edema on the basis of T1 values.

  1. Effects of Chloride Flux Modulators in an in Vitro-model of Brain Edema Formation

    PubMed Central

    Kumar, Vikas; Naik, Runa S.; Hillert, Markus; Klein, Jochen

    2006-01-01

    Brain edema is a serious consequence of hemispheric stroke and traumatic brain injury and contributes significantly to patient mortality. In the present study, we measured water contents in hippocampal slices as an in vitro-model of edema formation. Excitotoxic conditions induced by N-methyl-d-aspartate (NMDA, 300 μM), as well as ischemia induced by oxygen-glucose deprivation (OGD) caused cellular edema formation as indicated by an increase of slice water contents. In the presence of furosemide, an inhibitor of the Na,K,Cl-cotransporter, NMDA-induced edema were reduced by 64% while OGD-induced edema were unaffected. The same observation, i.e. reduction of excitotoxic edema formation but no effect on ischemia-induced edema, was made with chloride transport inhibitors such as DIDS and niflumic acid. Under ischemic conditions, modulation of GABAA receptors by bicuculline, a GABA antagonist, or by diazepam, a GABAergic agonist, did not significantly affect edema formation. Further experiments demonstrated that low chloride conditions prevented NMDA-induced, but not OGD-induced water influx. Omission of calcium ions had no effect. Our results show that NMDA-induced edema formation is highly dependent on chloride influx as it was prevented by low-chloride conditions and by various compounds that interfere with chloride influx. In contrast, OGD-induced edema observed in brain slices were not affected by modulators of chloride fluxes. The results are discussed with reference to ionic changes occurring during tissue ischemia. Section: Neurophysiology, Neuropharmacology and other forms of Intercellular Communication. PMID:17014830

  2. Edema

    MedlinePlus

    Edema means swelling caused by fluid in your body's tissues. It usually occurs in the feet, ankles ... it can involve your entire body. Causes of edema include Eating too much salt Sunburn Heart failure ...

  3. Effect of Small Molecule Vasopressin V1a and V2 Receptor Antagonists on Brain Edema Formation and Secondary Brain Damage following Traumatic Brain Injury in Mice

    PubMed Central

    Krieg, Sandro M.; Sonanini, Sebastian; Trabold, Raimund

    2015-01-01

    Abstract The attenuation of brain edema is a major therapeutic target after traumatic brain injury (TBI). Vasopressin (AVP) is well known to play a major role in the regulation of brain water content and vasoendothelial functions and to be involved in brain edema formation. Therefore, the aim of the current study was to analyze the antiedematous efficacy of a clinically relevant, nonpeptidic AVP V1a and V2 receptor antagonists. C57Bl6 mice were subjected to controlled cortical impact (CCI) and V1a or V2 receptors were inhibited by using the highly selective antagonists SR-49059 or SR-121463A either by systemic (intraperitoneal, IP) or intracerebroventricular (ICV) application. After 24 h, brain edema, intracranial pressure (ICP), and contusion volume were assessed. Systemically applied AVP receptor antagonists could not reduce secondary lesion growth. In contrast, ICV administration of AVP V1a receptor antagonist decreased brain edema formation by 68%, diminished post-traumatic increase of ICP by 46%, and reduced secondary contusion expansion by 43% 24 h after CCI. The ICV inhibition of V2 receptors resulted in significant reduction of post-traumatic brain edema by 41% 24 h after CCI, but failed to show further influence on ICP and lesion growth. Hence, centrally applied vasopressin V1a receptor antagonists may be used to reduce brain edema formation after TBI. PMID:25111427

  4. Brain edema and protein expression of c-Fos and c-Jun in the brain after diffused brain injury

    PubMed Central

    Zheng, Wei; Niu, Lijian; Zhang, Chunpu; Zhu, Chao; Xie, Fangmin; Cao, Chunguang; Li, Gang

    2014-01-01

    Objective: To investigate brain edema and protein expression of c-Fos and c-Jun in brain after diffuse brain injury, and to investigate the pathological change after brain injury, which may provide evidence for the clinical treatment of diffused brain injury. Methods: Marmarou method was used to establish the diffuse brain injury in rats. Results: After diffused brain injury, brain water content increased at 1 h, reached the peak at 1 d and remained at a high level at 7 d when compared with control group. One day after injury, diffuse subarachnoid hemorrhage was observed in the brain. HE staining showed vascular swelling and bleeding at the cortex and corpus callosum at 1 d. β-APP expression was found at the brainstem, hippocampus, thalamus, corpus callosum and periventricular regions. Pathological examination of ultrathin sections showed evidence edema and fracture of axons at 3 d after brain injury. The brain injury caused severe cerebral ischemia. The c-Fos and c-Jun expression increased at 1 h. The c-Fos expression peaked at 3 h (P < 0.05), then reduced, reached a maximal level again at 3 d (P < 0.05), and reduced significantly at 7 d but remained at a higher level when compared with control group (P < 0.05). The number of c-Jun positive cells peaked at 6 h (P < 0.05), then reduced, reached a maximal level again at 3 d and reduced markedly but still remained at a higher level when compared with control group (P < 0.05). Conclusion: After diffuse brain injury, brain water content and c-Fos/c-Jun expression change over time. PMID:25031700

  5. Assessment of the Correlations Between Brain Weight and Brain Edema in Experimental Subarachnoid Hemorrhage.

    PubMed

    Hasegawa, Yu; Suzuki, Hidenori; Nakagawa, Takashi; Uekawa, Ken; Koibuchi, Nobutaka; Kawano, Takayuki; Kim-Mitsuyama, Shokei

    2016-01-01

    Because brain edema is correlated with poor outcome in clinical subarachnoid hemorrhage (SAH), appropriate evaluation methods for brain edema are important in experimental SAH studies. Although brain water content (BWC) is widely used to evaluate brain edema in stroke research, the usefulness of brain weight is undetermined. In this study, we examined the role of brain weight in the evaluation of brain edema in experimental SAH. The endovascular perforation model of SAH was used, and rats were assessed by neurological scoring (NS). The brains were quickly removed at 24 h after the operation, and the weights of wet cerebrum (WWC) and dry cerebrum (WDC) were measured to determine the brain water content (BWC). The correlations of those values with each other and to body weight (BW) were then examined to reveal the significance of brain weight. The rats were assigned to sham-operated (n = 8) and SAH (n = 16) groups. There were no significant differences in WWC between the groups (p = 0.61). WWC was correlated with BWC but not with NS in all rats. In addition, WWC was clearly correlated with BW and WDC, which is thought to substitute for the original brain weight. From these results, we suggest that the measurement of brain weight as an evaluation of brain edema is limited and that BW and original brain volume can be confounding factors in evaluation. PMID:26463928

  6. Increased brain edema following 5-aminolevulinic acid mediated photodynamic in normal and tumor bearing rats

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Angell-Petersen, Even; Spetalen, Signe; Mathews, Marlon; Madsen, Steen J.

    2007-02-01

    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 both tumor cells as well as cerebral blood vessels leading to degradation of the blood brain barrier with subsequent increase of brain edema. The increase in brain edema following ALA-PDT was evaluated in terms of animal survival, histopatological changes in normal brain and tumor tissue and MRI scanning. The effect of steroid treatment, to reduce post-treatment PDT induced edema, was also examined. Methods:Tumors were established in the brains of inbred BD-IX and Fisher rats. At various times following tumor induction the animals were injected with ALA ip. and four hours later light treatment at escalating fluences and fluence rates were given. Nontumor bearing control animals were also exposed to ALA-PDT in a similar manner to evaluate damage to normal brain and degree of blood brain barrier (BBB) disruption. Results: Despite a very low level of PpIX production in normal brain, with a 200:1 tumor to normal tissue selectivity ratio measured at a distance of 2 mm from the tumor border, many animals succumbed shortly after treatment. A total radiant energy of 54 J to non-tumor bearing animals resulted in 50% mortality within 5 days of treatment. Treatment of tumor bearing animals with moderate fluence levels produced similar brain edema compared to higher fluence levels. ALA PDT in nontumor bearing animals produced edema that was light dose dependent. PDT appeared to open the BBB for a period of 24-48 hrs after which it was restored. The addition of post operative steroid treatment reduced the incident of post treatment morbidity and mortality. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and non-evasive modality in following the development of the edema reaction and the degree and time course of BBB dysfunction thus allowing the use of fewer animals.

  7. Treadmill exercise ameliorates ischemia-induced brain edema while suppressing Na(+)/H(+) exchanger 1 expression.

    PubMed

    Nishioka, Ryutaro; Sugimoto, Kana; Aono, Hitomi; Mise, Ayano; Choudhury, Mohammed E; Miyanishi, Kazuya; Islam, Afsana; Fujita, Takahiro; Takeda, Haruna; Takahashi, Hisaaki; Yano, Hajime; Tanaka, Junya

    2016-03-01

    Exercise may be one of the most effective and sound therapies for stroke; however, the mechanisms underlying the curative effects remain unclear. In this study, the effects of forced treadmill exercise with electric shock on ischemic brain edema were investigated. Wistar rats were subjected to transient (90min) middle cerebral artery occlusion (tMCAO). Eighty nine rats with substantially large ischemic lesions were evaluated using magnetic resonance imaging (MRI) and were randomly assigned to exercise and non-exercise groups. The rats were forced to run at 4-6m/s for 10min/day on days 2, 3 and 4. Brain edema was measured on day 5 by MRI, histochemical staining of brain sections and tissue water content determination (n=7, each experiment). Motor function in some rats was examined on day 30 (n=6). Exercise reduced brain edema (P<0.05-0.001, varied by the methods) and ameliorated motor function (P<0.05). The anti-glucocorticoid mifepristone or the anti-mineralocorticoid spironolactone abolished these effects, but orally administered corticosterone mimicked the ameliorating effects of exercise. Exercise prevented the ischemia-induced expression of mRNA encoding aquaporin 4 (AQP4) and Na(+)/H(+) exchangers (NHEs) (n=5 or 7, P<0.01). Microglia and NG2 glia expressed NHE1 in the peri-ischemic region of rat brains and also in mixed glial cultures. Corticosterone at ~10nM reduced NHE1 and AQP4 expression in mixed glial and pure microglial cultures. Dexamethasone and aldosterone at 10nM did not significantly alter NHE1 and AQP4 expression. Exposure to a NHE inhibitor caused shrinkage of microglial cells. These results suggest that the stressful short-period and slow-paced treadmill exercise suppressed NHE1 and AQP4 expression resulting in the amelioration of brain edema at least partly via the moderate increase in plasma corticosterone levels. PMID:26724742

  8. Proton-nuclear magnetic resonance relaxation times in brain edema

    SciTech Connect

    Kamman, R.L.; Go, K.G.; Berendsen, H.J. )

    1990-01-01

    Proton relaxation times of protein solutions, bovine brain, and edematous feline brain tissue were studied as a function of water concentration, protein concentration, and temperature. In accordance with the fast proton exchange model for relaxation, a linear relation could be established between R1 and the inverse of the weight fraction of tissue water. This relation also applied to R2 of gray matter and of protein solutions. No straightforward relation with water content was found for R2 of white matter. Temperature-dependent studies indicated that in this case, the slow exchange model for relaxation had to be applied. The effect of macromolecules in physiological relevant concentrations on the total relaxation behavior of edematous tissue was weak. Total water content changes predominantly affected the relaxation rates. The linear relation may have high clinical potential for assessment of the status of cerebral edema on the basis of T1 and T2 readings from MR images.

  9. Baicalin attenuates brain edema in a rat model of intracerebral hemorrhage.

    PubMed

    Zhou, Qing-Bo; Jin, Yun-Ling; Jia, Qing; Zhang, Yuan; Li, Lu-Yang; Liu, Ping; Liu, Yuan-Tao

    2014-02-01

    Baicalin is a flavonoid compound purified from the roots of Scutellaria baicalensis, which possesses multiple biological activities. Previous studies have shown that baicalin is protective in ischemic cerebral diseases. The aim of the present study was to examine the effects of baicalin on brain injury in a rat model of intracerebral hemorrhage (ICH) and to explore the possible mechanisms. Intracerebral hemorrhage was induced in male Wistar rats by injection of 0.5 U collagenaseVII to the caudate nucleus. Sham operation rats were injected with equal volume of saline. After the induction of ICH, the rats were randomly divided into four groups and administered with different dose of baicalin (0, 25, 50, or 100 mg/kg in saline) through peritoneal injection. The brain tissues around the hemorrhage areas were collected on days 1, 3, and 5 after treatment. Brain edema was analyzed by desiccation method; the metalloproteinase-9 (MMP-9) protein and mRNA expression were determined by western blotting and real time RT-PCR, respectively. Nuclear factor-κB (NF-κB) protein expression was analyzed by western blotting. IL-1β and IL-6 levels were determined by enzyme-linked immunosorbent assay. Blood-brain barrier permeability was determined by Evans blue leakage method. The results showed that baicalin reduced brain edema following ICH in a dose-dependent manner, with concomitant inhibition of NF-κB activation and suppression of MMP-9 expression. In addition, baicalin also reduced IL-1β and IL-6 production, as well as blood-brain barrier permeability. The above results indicated that baicalin prevents against perihematomal edema development after intracerebral hemorrhage possibly through an anti-inflammatory mechanism. PMID:23974988

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

    PubMed Central

    Naderi, Vida; Khaksari, Mohammad; Abbasi, Reza; Maghool, Fatemeh

    2015-01-01

    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<0.01). The brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05). The inhibitory effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content. Conclusion: A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors. PMID:25810887

  11. [Changes in epidural pulse pressure in brain edema following experimental focal ischemia].

    PubMed

    Mase, M

    1990-07-01

    It is well known that epidural pulse pressure (PP) increases with rising intracranial pressure (ICP). However, PP at the same ICP is not always identical in various intracranial pathologies. Many authors have investigated PP at increased states of ICP, but few studies related to brain edema have been done. This study was carried out in order to clarify the changes of PP in brain edema following focal ischemia. ICP and PP were measured in two groups of anesthetized dogs; 1) increased volume of CSF by cisternal saline injection (control, n = 5), 2) brain edema caused by focal ischemia (edema, n = 11). Ischemia was induced by electro-coagulation of the right anterior cerebral artery and by clipping the right middle cerebral artery and right internal carotid artery transorbitaly. The brain was recirculated for 6 hours after 2 hours of ischemia. The ischemic areas were identified by Evans blue, triphenyl tetrazolium chloride (TTC) or histological examination. Water content of the brain was measured by the wet-dry weight method. The canine focal ischemic model showed consistent ischemic damage in the caudate nucleus and produced brain edema successfully. PP increased linearly with rising ICP to 35 mmHg, and PP in the edema group was significantly smaller than that in the control group at the same ICP value. The slopes of the regression equation of ICP and PP were significantly different between the edema and control group (edema: 0.061 +/- 0.030, control: 0.107 +/- 0.015, mean +/- SD, p less than 0.01). These results suggest that PP is easily affected by ischemic brain edema.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2223260

  12. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer

    PubMed Central

    Gerstner, Elizabeth R.; Duda, Dan G.; di Tomaso, Emmanuelle; Ryg, Peter A.; Loeffler, Jay S.; Sorensen, A. Gregory; Ivy, Percy; Jain, Rakesh K.; Batchelor, Tracy T.

    2016-01-01

    Most brain tumors oversecrete vascular endothelial growth factor (VEGF), which leads to an abnormally permeable tumor vasculature. This hyperpermeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites. PMID:19333229

  13. Correlation between subacute sensorimotor deficits and brain edema in two mouse models of intracerebral hemorrhage

    PubMed Central

    Krafft, Paul R.; McBride, Devin W.; Lekic, Tim; Rolland, William B.; Mansell, Charles E.; Ma, Qingyi; Tang, Jiping; Zhang, John H.

    2014-01-01

    Formation of brain edema after intracerebral hemorrhage (ICH) is highly associated with its poor outcome, thus it is clinically important to understand the effect brain edema has on outcome. However, the relationship between cerebral edema and behavioral deficits has not been thoroughly examined in the preclinical setting. Hence, this study aimed to evaluate the ability of common sensorimotor tests to predict the extent of brain edema in two mouse models of ICH. One hundred male CD-1 mice were subjected to sham surgery or ICH induction via intrastriatal injection of either autologous blood (30 μL) or bacterial collagenase (0.0375 U or 0.075 U). At 24 and 72 hours after surgery, animals underwent a battery of behavioral tests, including the modified Garcia neuroscore (Neuroscore), corner turn test (CTT), forelimb placing test (FPT), wire hang task (WHT) and beam walking (BW). Brain edema was evaluated via the wet weight/dry weight method. Intrastriatal injection of autologous blood or bacterial collagenase resulted in a significant increase in brain water content and associated sensorimotor deficits (p<0.05). A significant correlation between brain edema and sensorimotor deficits was observed for all behavioral tests except for WHT and BW. Based on these findings, we recommend implementing the Neuroscore, CTT and/or FPT in preclinical studies of unilateral ICH in mice. PMID:24518201

  14. Expression of Aquaporin 4 and Breakdown of the Blood-Brain Barrier after Hypoglycemia-Induced Brain Edema in Rats

    PubMed Central

    Deng, Jiangshan; Zhao, Fei; Yu, Xiaoyan; Zhao, Yuwu; Li, Dawei; Shi, Hong; Sun, Yongning

    2014-01-01

    Background Hypoglycemia-induced brain edema is a severe clinical event that often results in death. The mechanisms by which hypoglycemia induces brain edema are unclear. Methods In a hypoglycemic injury model established in adult rats, brain edema was verified by measuring brain water content and visualizing water accumulation using hematoxylin and eosin staining. Temporal expression of aquaporin 4 (AQP4) and the integrity of the blood-brain barrier (BBB) were evaluated. We assessed the distribution and expression of AQP4 following glucose deprivation in astrocyte cultures. Results Brain edema was induced immediately after severe hypoglycemia but continued to progress even after recovery from hypoglycemia. Upregulation of AQP4 expression and moderate breakdown of the BBB were observed 24 h after recovery. In vitro, significant redistribution of AQP4 to the plasma membrane was induced following 6 h glucose deprivation. Conclusion Hypoglycemia-induced brain edema is caused by cytotoxic and vasogenic factors. Changes in AQP4 location and expression may play a protective role in edema resolution. PMID:25264602

  15. Near-infrared spectroscopy technique to evaluate the effects of drugs in treating traumatic brain edema

    NASA Astrophysics Data System (ADS)

    Xie, J.; Qian, Z.; Yang, T.; Li, W.; Hu, G.

    2011-01-01

    The aim of this study was to evaluate the effects of several drugs in treating traumatic brain edema (TBE) following traumatic brain injury (TBI) using near-infrared spectroscopy (NIRs) technology. Rats with TBE models were given hypertonic saline (HS), mannitol and mannitol+HS respectively for different groups. Light scattering properties of rat's local cortex was measured by NIRs within the wavelength range from 700 to 850 nm. TBE models were built in rats' left brains. The scattering properties of the right and left target corresponding to the position of normal and TBE tissue were measured and recorded in vivo and real-time by a bifurcated needle probe. The brain water contents (BWC) were measured by the wet and dry weight method after injury and treatment hours 1, 6, 24, 72 and 120. A marked linear relationship was observed between reduced scattering coefficient (μs') and BWC. By recording μs' of rats' brains, the entire progressions of effects of several drugs were observed. The result may suggest that the NIRs techniques have a potential for assessing effects in vivo and real-time on treatment of the brain injury.

  16. Cortical edema in moderate fluid percussion brain injury is attenuated by vagus nerve stimulation.

    PubMed

    Clough, R W; Neese, S L; Sherill, L K; Tan, A A; Duke, A; Roosevelt, R W; Browning, R A; Smith, D C

    2007-06-29

    Development of cerebral edema (intracellular and/or extracellular water accumulation) following traumatic brain injury contributes to mortality and morbidity that accompanies brain injury. Chronic intermittent vagus nerve stimulation (VNS) initiated at either 2 h or 24 h (VNS: 30 s train of 0.5 mA, 20 Hz, biphasic pulses every 30 min) following traumatic brain injury enhances recovery of motor and cognitive function in rats in the weeks following brain injury; however, the mechanisms of facilitated recovery are unknown. The present study examines the effects of VNS on development of acute cerebral edema following unilateral fluid percussion brain injury (FPI) in rats, concomitant with assessment of their behavioral recovery. Two hours following FPI, VNS was initiated. Behavioral testing, using both beam walk and locomotor placing tasks, was conducted at 1 and 2 days following FPI. Edema was measured 48 h post-FPI by the customary method of region-specific brain weights before and after complete dehydration. Results of this study replicated that VNS initiated at 2 h after FPI: 1) effectively facilitated the recovery of vestibulomotor function at 2 days after FPI assessed by beam walk performance (P<0.01); and 2) tended to improve locomotor placing performance at the same time point (P=0.18). Most interestingly, results of this study showed that development of edema within the cerebral cortex ipsilateral to FPI was significantly attenuated at 48 h in FPI rats receiving VNS compared with non-VNS FPI rats (P<0.04). Finally, a correlation analysis between beam walk performance and cerebral edema following FPI revealed a significant inverse correlation between behavior performance and cerebral edema. Together, these results suggest that VNS facilitation of motor recovery following experimental brain injury in rats is associated with VNS-mediated attenuation of cerebral edema. PMID:17543463

  17. Influence of preischemic hyperglycemia on osmolality and early postischemic edema in the rat brain.

    PubMed

    Gisselsson, L; Smith, M L; Siesj, B K

    1992-09-01

    Preischemic hyperglycemia, which raises tissue lactate content during ischemia, is known to aggravate ischemic brain damage. To explore the possibility that the enhanced lactic acidosis gives rise to osmotic damage, we studied the influence of a varied preischemic plasma glucose concentration on the early postischemic edema. Brain edema was measured by the specific-gravity technique. Brain and plasma osmolality were measured with a vapor pressure osmometer. We examined different brain regions in hyperglycemic and moderately hypoglycemic rats subjected to 15 min of forebrain ischemia, followed by recirculation for 5, 15, and 30 min. The decrease in specific gravity was compared with the increase in osmolality, to study whether the edema formation in the different groups correlated to the increase in tissue osmolality. We found edema formation to be most pronounced in frontoparietal cortex. In this structure and in hippocampus, statistically significant decreases of specific gravity were seen at all recirculation times studied. In caudoputamen, significant edema was seen only in the groups with 5 and 15 min of recirculation. Contrary to expectations, no difference was found between hyperglycemic and hyperglycemic animals. Tissue osmolality increased during ischemia in both the low and high glucose groups, but to a higher level in the latter (hypoglycemia 311 +/- 1 mmol kg-1, hyperglycemia 328 +/- 10 mmol kg-1; mean +/- SD, p less than 0.05). In the hyperglycemic group, brain osmolality remained elevated for the first 15 min of recirculation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1506445

  18. Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

    PubMed Central

    Wang, Bao-feng; Cui, Zhen-wen; Zhong, Zhi-hong; Sun, Yu-hao; Sun, Qing-fang; Yang, Guo-yuan; Bian, Liu-guan

    2015-01-01

    Aim: Aquaporins (AQPs) are the water-channels that play important roles in brain water homeostasis and in cerebral edema induced by brain injury. In this study we investigated the relationship between AQPs and a neuroprotective agent curcumin that was effective in the treatment of brain edema in mice with intracerebral hemorrhage (ICH). Methods: ICH was induced in mice by autologous blood infusion. The mice immediately received curcumin (75, 150, 300 mg/kg, ip). The Rotarod test scores, brain water content and brain expression of AQPs were measured post ICH. Cultured primary mouse astrocytes were used for in vitro experiments. The expression of AQP1, AQP4 and AQP9 and NF-κB p65 were detected using Western blotting or immunochemistry staining. Results: Curcumin administration dose-dependently reduced the cerebral edema at d 3 post ICH, and significantly attenuated the neurological deficits at d 5 post ICH. Furthermore, curcumin dose-dependently decreased the gene and protein expression of AQP4 and AQP9, but not AQP1 post ICH. Treatment of the cultured astrocytes with Fe2+ (10–100 μmol/L) dose-dependently increased the expression and nuclear translocation of NF-κB p65 and the expression of AQP4 and AQP9, which were partly blocked by co-treatment with curcumin (20 μmol/L) or the NF-κB inhibitor PDTC (10 μmol/L). Conclusion: Curcumin effectively attenuates brain edema in mice with ICH through inhibition of the NF-κB pathway and subsequently the expression of AQP4 and AQP9. Curcumin may serve as a potential therapeutic agent for ICH. PMID:26119880

  19. Acupuncture and moxibustion reduces neuronal edema in Alzheimer's disease rats

    PubMed Central

    Zhou, Hua; Sun, Guojie; Kong, Lihong; Du, Yanjun; Shen, Feng; Wang, Shuju; Chen, Bangguo; Zeng, Xiaoling

    2014-01-01

    To examine the possible correlation of aberrant Wnt signaling and pathological changes in Alzheimer's disease, we established a rat model of Alzheimer's disease and measured axin and β-catenin expression in the hippocampus. Rats were pretreated with moxibustion or electroacupuncture, or both, at Baihui (GV20) and Shenshu (BL23). Axin expression was lower, β-catenin expression was greater, and neuronal cytoplasmic edema was visibly prevented in the rats that had received the pretreatments. Our results suggest that the mechanism underlying the neuroprotective effect of acupuncture and moxibustion in Alzheimer's disease is associated with axin and β-catenin expression in the Wnt signal transduction pathway. PMID:25206919

  20. Blood Brain Barrier KCa3.1 Channels: Evidence for a Role in Brain Na Uptake and Edema in Ischemic Stroke

    PubMed Central

    Chen, Yi-Je; Wallace, Breanna K.; Yuen, Natalie; Jenkins, David P.; Wulff, Heike; O’Donnell, Martha E.

    2014-01-01

    Background and Purpose KCa3.1, a calcium-activated potassium channel, regulates ion and fluid secretion in the lung and gastrointestinal tract. It is also expressed on vascular endothelium where it participates in blood pressure regulation. However, the expression and physiological role of KCa3.1 in blood-brain barrier (BBB) endothelium has not been investigated. BBB endothelial cells transport Na+ and Cl− from the blood into the brain transcellularly through the cooperation of multiple co-transporters, exchangers, pumps and channels. In the early stages of cerebral ischemia, when the BBB is intact, edema formation occurs by processes involving increased BBB transcellular Na+ transport. This study evaluated whether KCa3.1 is expressed on and participates in BBB ion transport. Methods The expression of KCa3.1 on cultured cerebral microvascular endothelial cells (CMEC), isolated microvessels and brain sections was evaluated by Western blot and immunohistochemistry. Activity of KCa3.1 on CMEC was examined by K+ flux assays and patch-clamp. Magnetic resonance spectroscopy and imaging were used to measure brain Na+ uptake and edema formation in rats with focal ischemic stroke following TRAM-34 treatment. Results KCa3.1 current and channel protein were identified on bovine CMEC and freshly isolated rat microvessels. In situ KCa3.1 expression on BBB endothelium was confirmed in rat and human brain sections. TRAM-34 treatment significantly reduced Na+ uptake, and cytotoxic edema in the ischemic brain. Conclusions BBB endothelial cells exhibit KCa3.1 protein and activity and pharmacological blockade of KCa3.1 appears to provide an effective therapeutic approach for reducing cerebral edema formation in the first 3 hours of ischemic stroke. PMID:25477223

  1. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity.

    PubMed

    Kunze, Reiner; Urrutia, Andrés; Hoffmann, Angelika; Liu, Hui; Helluy, Xavier; Pham, Mirko; Reischl, Stefan; Korff, Thomas; Marti, Hugo H

    2015-04-01

    Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema. PMID:25725349

  2. Inductive phase shift spectroscopy for volumetric brain edema detection: an experimental simulation.

    PubMed

    González, César A; Rojas, Rafael; Villanueva, Cleva; Rubinsky, Boris

    2007-01-01

    This study evaluates experimentally an induction based non-invasive technique for detection of changes of fluid volume through phase shift measurements as a possible method for volumetric brain edema monitoring. An induction coil - spherical head model was build and tested. The model involves two different diameter coils coaxially centered on a two-compartment glass sphere head model centrally placed with respect to the coils. Three different fluid volumes of physiological saline in 20 ml increments were used to simulate different edema levels. Phase shift of the impedance coils as a function of relative fluid volume was measured at five frequencies (40, 50, 100, 200 and 300 MHz) by a commercial vector network analyzer. The results show significant phase shift increase as a function of frequency and fluid volume. The experiments with the coil-spherical head system suggest that the tested technique has the potential to become a practical configuration for non-invasive volumetric brain edema monitoring. PMID:18002463

  3. Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: An in vivo Study

    PubMed Central

    Song, Juhyun; Park, Joohyun; Kim, Jae Hwan; Choi, Ja Yong; Kim, Jae Young; Lee, Kyoung Min

    2015-01-01

    Ischemic stroke results in the diverse phathophysiologies including blood brain barrier (BBB) disruption, brain edema, neuronal cell death, and synaptic loss in brain. Vitamin C has known as the potent anti-oxidant having multiple functions in various organs, as well as in brain. Dehydroascorbic acid (DHA) as the oxidized form of ascorbic acid (AA) acts as a cellular protector against oxidative stress and easily enters into the brain compared to AA. To determine the role of DHA on edema formation, neuronal cell death, and synaptic dysfunction following cerebral ischemia, we investigated the infarct size of ischemic brain tissue and measured the expression of aquaporin 1 (AQP-1) as the water channel protein. We also examined the expression of claudin 5 for confirming the BBB breakdown, and the expression of bcl 2 associated X protein (Bax), caspase-3, inducible nitric oxide synthase (iNOS) for checking the effect of DHA on the neurotoxicity. Finally, we examined postsynaptic density protein-95 (PSD-95) expression to confirm the effect of DHA on synaptic dysfunction following ischemic stroke. Based on our findings, we propose that DHA might alleviate the pathogenesis of ischemic brain injury by attenuating edema, neuronal loss, and by improving synaptic connection. PMID:25792869

  4. Correction of Hyponatremia Improves Cognition, Quality of Life, and Brain Edema in Cirrhosis

    PubMed Central

    Ahluwalia, Vishwadeep; Heuman, Douglas M; Feldman, George; Wade, James B; Thacker, Leroy R; Gavis, Edith; Gilles, HoChong; Unser, Ariel; White, Melanie B; Bajaj, Jasmohan S

    2014-01-01

    Background Hyponatremia in cirrhosis is associated with impaired cognition and poor health-related quality of life(HRQOL). However, the benefit of hyponatremia correction is unclear. Aim To evaluate the effect of tolvaptan on serum sodium, cognition, HRQOL, companion burden, and brain MRI (volumetrics, spectroscopy and diffusion tensor imaging) in cirrhotics with hyponatremia. Methods Cirrhotics with Na<130meq/l were included for a four-week trial. At screening, patients underwent cognitive and HRQOL testing, serum/urine chemistries and companion burden assessment. Patients then underwent fluid restriction and diuretic withdrawal for two weeks after which cognitive tests were repeated. If Na was still<130meq/L, brain MRI was performed & tolvaptan initiated for 14 days with frequent clinical/laboratory monitoring. After 14 days of tolvaptan, all tests were repeated. Comparisons were made between screen, pre and post-drug periods Na, urine/serum laboratories, cognition, HRQOL and companion burden. Results 24 cirrhotics were enrolled; seven normalized Na without tolvaptan with improvement in cognition. The remaining 17 received tolvaptan of which 14 completed the study over 13±2 days (age 58±6 yrs, MELD 17, 55%HCV, median 26mg/day of tolvaptan). Serum Na and urine free water clearance increased with tolvaptan without changes in mental status or liver function. Cognitive function, HRQOL and companion burden only improved in these 14 patients after tolvaptan, along with reduced total brain and white matter volume, increase in choline on MRS, and reduced cytotoxic edema. Conclusions Short-term tolvaptan therapy is well tolerated in cirrhosis. Hyponatremia correction is associated with cognitive, HRQOL, brain MRI and companion burden improvement. PMID:25111174

  5. Quick detection of brain tumors and edemas: a bounding box method using symmetry.

    PubMed

    Saha, Baidya Nath; Ray, Nilanjan; Greiner, Russell; Murtha, Albert; Zhang, Hong

    2012-03-01

    A significant medical informatics task is indexing patient databases according to size, location, and other characteristics of brain tumors and edemas, possibly based on magnetic resonance (MR) imagery. This requires segmenting tumors and edemas within images from different MR modalities. To date, automated brain tumor or edema segmentation from MR modalities remains a challenging, computationally intensive task. In this paper, we propose a novel automated, fast, and approximate segmentation technique. The input is a patient study consisting of a set of MR slices, and its output is a subset of the slices that include axis-parallel boxes that circumscribe the tumors. Our approach is based on an unsupervised change detection method that searches for the most dissimilar region (axis-parallel bounding boxes) between the left and the right halves of a brain in an axial view MR slice. This change detection process uses a novel score function based on Bhattacharya coefficient computed with gray level intensity histograms. We prove that this score function admits a very fast (linear in image height and width) search to locate the bounding box. The average dice coefficients for localizing brain tumors and edemas, over ten patient studies, are 0.57 and 0.52, respectively, which significantly exceeds the scores for two other competitive region-based bounding box techniques. PMID:21719256

  6. Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat.

    PubMed

    Kleindienst, A; Fazzina, G; Dunbar, J G; Glisson, R; Marmarou, A

    2006-01-01

    There exists no pharmacological treatment for fulminating brain edema. Since evidence indicates that brain aquaporin-4 (AQP4) water channels are modulated by vasopressin V1a receptors, we examined the edema-reducing properties of the selective V1a receptor antagonist, SR49059, following middle cerebral artery occlusion (MCAO). Male Sprague-Dawley rats were randomly assigned to sham procedure, vehicle, or SR49059 infusion at different dosages (each n = 6,480 microL/hr, 640 microL/hr, 720 microL/hr) and starting 60 minutes before or after MCAO. After a 2-hour period of ischemia and 2 hours of reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentration. Statistics were performed using an ANOVA followed by a Tukey post hoc analysis. SR049059 treatment reduced brain water content in the infarcted area given at 640 microL/hr (p = 0.036), 720 microL/hr 60 minutes before (p = 0.002) or 60 minutes after (p = 0.005) MCAO. The consecutive sodium shift into the brain was prevented (p = 0.001), while the potassium loss was inhibited only by pre-treatment (p = 0.003). These findings imply that in ischemia-induced brain edema, the selective V1a receptor-antagonist SR49059 inhibits brain edema and the subsequent sodium shift into brain. This substance offers a new avenue in brain edema treatment and prompts further study into AQP4 modulation. PMID:16671476

  7. Activation of P2X7 Promotes Cerebral Edema and Neurological Injury after Traumatic Brain Injury in Mice

    PubMed Central

    Kimbler, Donald E.; Shields, Jessica; Yanasak, Nathan; Vender, John R.; Dhandapani, Krishnan M.

    2012-01-01

    Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7−/− mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1β expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation. PMID:22815977

  8. Cerebral edema following iodine-131 therapy for thyroid carcinoma metastatic to the brain

    SciTech Connect

    Datz, F.L.

    1986-05-01

    Brain metastases are rare in well-differentiated thyroid carcinoma but when present they can lead to the patient's death. Iodine-131 therapy for intracerebral thyroid carcinoma metastases causes radiation-induced acute cerebral edema that can lead to CNS complications and even death. We present a case in which a patient with intracerebral /sup 131/I uptake developed seizures, slurred speech, and muscle weakness 12 hr following /sup 131/I therapy. The patient's CT scan, post-therapy, confirmed an intracranial metastasis with a significant amount of surrounding edema. Radiotherapists, when using external beam radiation to treat intracerebral metastases, commonly place these patients on steroids, glycerol, or mannitol prior to instituting therapy, to prevent complications from radiation-induced cerebral edema. This technique could be applied to /sup 131/I therapy of intracranial thyroid carcinoma metastases as well.

  9. HIGH MOBILITY GROUP BOX PROTEIN-1 PROMOTES CEREBRAL EDEMA AFTER TRAUMATIC BRAIN INJURY VIA ACTIVATION OF TOLL-LIKE RECEPTOR 4

    PubMed Central

    Laird, Melissa D.; Shields, Jessica S.; Sukumari-Ramesh, Sangeetha; Kimbler, Donald E.; Fessler, R. David; Shakir, Basheer; Youssef, Patrick; Yanasak, Nathan; Vender, John R.; Dhandapani, Krishnan M.

    2015-01-01

    Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor-4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI. PMID:24166800

  10. Antagonists of the Vasopressin V1 Receptor and of the β1-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes – but the Mechanisms Differ

    PubMed Central

    Hertz, Leif; Xu, Junnan; Chen, Ye; Gibbs, Marie E; Du, Ting; Hertz, Leif; Xu, Junnan; Chen, Ye; Gibbs, Marie E; Du, Ting

    2014-01-01

    Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na+, K+, 2Cl- and water and its activation by highly increased extracellular K+ concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na+ release and K+ uptake by the Na+,K+-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the blood-brain barrier, essential for development of edema. It shows that brain edema does not develop until during reperfusion, which can be explained by lack of metabolic energy during ischemia. V1 antagonists are likely to protect against cytotoxic edema formation by inhibiting AVP enhancement of NKCC1-mediated uptake of ions and water, whereas β1-adrenergic antagonists prevent edema formation because β1-adrenergic stimulation alone is responsible for stimulation of the Na+,K+-ATPase driving NKCC1, first and foremost due to decrease in extracellular Ca2+ concentration. Inhibition of NKCC1 also has adverse effects, e.g. on memory and the treatment should probably be of shortest possible duration. PMID:25342939

  11. Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice.

    PubMed

    Li, Lihua; Weng, Zhiyong; Yao, Chenjuan; Song, Yuanlin; Ma, Tonghui

    2015-01-01

    Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1-/- mice were used to create the MI model. Under physiological conditions, AQP1-/- mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays, and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1? in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1? levels in endothelial cells and decreased cellular apoptosis following MI. PMID:26348407

  12. Segmentation of tumor and edema along with healthy tissues of brain using wavelets and neural networks.

    PubMed

    Demirhan, Ayşe; Toru, Mustafa; Guler, Inan

    2015-07-01

    Robust brain magnetic resonance (MR) segmentation algorithms are critical to analyze tissues and diagnose tumor and edema in a quantitative way. In this study, we present a new tissue segmentation algorithm that segments brain MR images into tumor, edema, white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). The detection of the healthy tissues is performed simultaneously with the diseased tissues because examining the change caused by the spread of tumor and edema on healthy tissues is very important for treatment planning. We used T1, T2, and FLAIR MR images of 20 subjects suffering from glial tumor. We developed an algorithm for stripping the skull before the segmentation process. The segmentation is performed using self-organizing map (SOM) that is trained with unsupervised learning algorithm and fine-tuned with learning vector quantization (LVQ). Unlike other studies, we developed an algorithm for clustering the SOM instead of using an additional network. Input feature vector is constructed with the features obtained from stationary wavelet transform (SWT) coefficients. The results showed that average dice similarity indexes are 91% for WM, 87% for GM, 96% for CSF, 61% for tumor, and 77% for edema. PMID:25265636

  13. Electron microscopic study of perivascular structure associated with experimentally induced brain edema in cats.

    PubMed

    Ohata, K; Tanaka, K; Katsuyama, J; Nishimura, S

    1990-01-01

    The fine structural features and water content of white matter associated with the resolution process of brain edema were sequentially investigated in the model produced by infusion of autoserum, mock CSF, or ferritin into the centrum semiovale of cats. The correlation between water content and morphological features was good. Mock CSF-infused edema disappeared within 3 days, serum infused edema within 6 days. In a fine structural study of serum-infused white matter, the distended extracellular spaces were found to be occupied with electron-dense materials, active phagocytosis of the dense materials being observed in the macrophages. Around the postcapillary venules, edematous changes were characterized by wide expansion of the perivascular spaces between endothelial cells and astrocytic endfeet. In some instances, the dense materials in the cytoplasm or in the membrane-bound vacuoles of the astrocytic endfeet were continuous with those in the perivascular space, through the hiatuses of the perivascular astrocytic endfeet being separated at their margins. At 3 days after infusion, wide distension of the extracellular space persisted, but the dense materials had markedly diminished. These results strongly suggest that water clearance of vasogenic brain edema does not commence until proteinaceous macromolecules are degraded and removed from the extracellular space. Perivascular channels around the postcapillary venules might also have some role on the movement of edematous fluid. PMID:2396518

  14. Central Role of Maladapted Astrocytic Plasticity in Ischemic Brain Edema Formation

    PubMed Central

    Wang, Yu-Feng; Parpura, Vladimir

    2016-01-01

    Brain edema formation and the ensuing brain damages are the major cause of high mortality and long term disability following the occurrence of ischemic stroke. In this process, oxygen and glucose deprivation and the resulting reperfusion injury play primary roles. In response to the ischemic insult, the neurovascular unit experiences both intracellular and extracellular edemas, associated with maladapted astrocytic plasticity. The astrocytic plasticity includes both morphological and functional plasticity. The former involves a reactive gliosis and the subsequent glial retraction. It relates to the capacity of astrocytes to buffer changes in extracellular chemical levels, particularly K+ and glutamate, as well as the integrity of the blood-brain barrier (BBB). The latter involves the expression and activity of a series of ion and water transport proteins. These molecules are grouped together around glial fibrillary acidic protein (GFAP) and water channel protein aquaporin 4 (AQP4) to form functional networks, regulate hydromineral balance across cell membranes and maintain the integrity of the BBB. Intense ischemic challenges can disrupt these capacities of astrocytes and result in their maladaptation. The maladapted astrocytic plasticity in ischemic stroke cannot only disrupt the hydromineral homeostasis across astrocyte membrane and the BBB, but also leads to disorders of the whole neurovascular unit. This review focuses on how the maladapted astrocytic plasticity in ischemic stroke plays the central role in the brain edema formation.

  15. The role of extracellular-5'-nucleotidase/CD73 in glioma peritumoural brain edema.

    PubMed

    Wang, Bo; Wang, Dong; Zhu, ZhiZhong; Wang, Wei; Zhang, XueBin; Tang, Fan; Zhou, Yu; Wang, HongGuang; Liu, MengYuan; Yao, Xin; Yan, XiaoLing

    2016-04-01

    During pathological conditions, extracellular-5'-nucleotidase/CD73 can protect neurons by reducing the permeability of the blood brain barrier. In recent years, it has been demonstrated that CD73 can negatively contribute to the growth of gliomas; however, the function of CD73 in glioma blood vessels is not clear. We analysed the expression of CD73 in 72 glioma patients using immunohistochemistry and correspondingly compared the results with the Edema index (EI). We established an in vitro model of the blood-tumour barrier and analysed the expression of CD73 in vascular endothelial cells. Lastly, CD73 expression was inhibited in endothelial cells, and the effects of this inhibition on tight junction structure and transendothelial resistance were observed. Compared to normal brains, the expression of CD73 in blood vessels of glioma patients was significantly decreased, and the amount was lower in the centre of the tumour than the periphery. The proportion of CD73-positive blood vessels had a positive correlation with the EI. The expression of CD73 in the in vitro endothelial cell blood-tumour barrier model was decreased. Lastly, inhibiting CD73 was found to decrease the expression of tight junction related proteins in endothelial cells and to decrease the value of transendothelial electric resistance. The expression of CD73 in glioma blood vessels was significantly decreased, which may play a multi-functional role in decreasing the expression of tight junction related proteins of brain microvascular endothelial cells and may also increase blood-tumour barrier permeability and accelerate the formation of PTBE. PMID:26884147

  16. Ability of eugenol to reduce tongue edema induced by Dieffenbachia picta Schott in mice.

    PubMed

    Dip, Etyene Castro; Pereira, Nuno Alvarez; Fernandes, Patricia Dias

    2004-05-01

    Dieffenbachia picta Schott (Araceae), known in Brazil as "comigo-ninguém-pode" is an ornamental plant with toxic properties. Its juice, when chewed, causes a painful edema of the oral mucous membranes, buccal ulcerations and tongue hypertrophy. This acute inflammation sometimes becomes severe enough to produce glottis obstruction, respiratory compromise and death. Eugenol (4-alil-2-metoxiphenol), the essential oil extracted from Caryophyllus aromaticus (Myrtaceae) is widely used in odontology. In this study, our objective was to standardize, in mice, a measurable methodology for the tongue edema induced by the topical application of the D. picta stem juice; evaluate the effects of eugenol in this model and compare the results with emergency treatment used in hospitals. Our results show that in spite of a small increase in edema a few minutes after administration, emergency treatment reduced by 70% the overall edema. When compared with the combination of the above drugs, eugenol, even at the smallest dose of 5 microg/kg, regardless of the chosen administration route, or the moment the treatment began, presents better results in the reduction and inhibition of the tongue edema induced by the D. picta juice. PMID:15109894

  17. Perilesional brain edema and seizure activity in patients with calcified neurocysticercosis

    PubMed Central

    Nash, Theodore E.; Pretell, E. Javier; Lescano, Andres. G.; Bustos, Javier A.; Gilman, Robert H.; Gonzalez, Armando E.; Garcia, Héctor H.

    2013-01-01

    Background Cysticercosis due to Taenia solium is a leading cause of adult acquired seizures and epilepsy that frequently occurs in patients with only calcified larval cysts. Transient episodes of perilesional brain edema occur around calcified foci but its importance, association with seizures, incidence, and pathophysiology are unknown. Methods One hundred and ten persons with only calcified lesions and a history of seizures or severe headaches were followed prospectively in a cohort design to assess the incidence of seizure relapses. In a nested case-control sub study, perilesional edema was assessed by MRI at the time a seizure occurred in the symptomatic patient and in a matched asymptomatic control, amongst the 110 followed. Results Median follow up was 32.33 months (SD 19.99). Twenty-nine people had an incident seizure with an estimated 5 year seizure incidence of 36%. Twenty-four patients of the 29 with seizure relapse had an MRI evaluation within five days of the event. Perilesional edema was found in 12 (50.0%) compared to 2 of 23 asymptomatic matched controls (8.7%). Conclusions Perilesional edema occurs frequently and is associated with episodic seizure activity in calcified neurocysticercosis. Our findings are likely representative of symptomatic patients in endemic regions and suggest a unique and possibly preventable cause of seizures in this population. PMID:18986841

  18. Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.

    PubMed

    Butterworth, Roger F

    2015-03-01

    Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. PMID:26041966

  19. Multi-fractal texture features for brain tumor and edema segmentation

    NASA Astrophysics Data System (ADS)

    Reza, S.; Iftekharuddin, K. M.

    2014-03-01

    In this work, we propose a fully automatic brain tumor and edema segmentation technique in brain magnetic resonance (MR) images. Different brain tissues are characterized using the novel texture features such as piece-wise triangular prism surface area (PTPSA), multi-fractional Brownian motion (mBm) and Gabor-like textons, along with regular intensity and intensity difference features. Classical Random Forest (RF) classifier is used to formulate the segmentation task as classification of these features in multi-modal MRIs. The segmentation performance is compared with other state-of-art works using a publicly available dataset known as Brain Tumor Segmentation (BRATS) 2012 [1]. Quantitative evaluation is done using the online evaluation tool from Kitware/MIDAS website [2]. The results show that our segmentation performance is more consistent and, on the average, outperforms other state-of-the art works in both training and challenge cases in the BRATS competition.

  20. A fatal adverse effect of cefazolin administration: severe brain edema in a patient with multiple meningiomas

    PubMed Central

    Tribuddharat, Sirirat; Sathitkarnmanee, Thepakorn; Kitkhuandee, Amnat; Theerapongpakdee, Sunchai; Ngamsaengsirisup, Kriangsak; Chanthawong, Sarinya

    2016-01-01

    Cefazolin is commonly administered before surgery as a prophylactic antibiotic. Hypersensitivity to cefazolin is not uncommon, and the symptoms mostly include urticaria, skin reaction, diarrhea, vomiting, and transient neutropenia, which are rarely life threatening. We present a rare case of fatal cefazolin hypersensitivity in a female who was diagnosed with multiple meningiomas and scheduled for craniotomy and tumor removal. Immediately after cefazolin IV administration, the patient developed acute hypertensive crisis, which resolved within 10 minutes after the treatment. This was followed by unexplained metabolic acidosis. The patient then developed severe brain edema 100 minutes later. The patient had facial edema when her face was exposed for the next 30 minutes. A computed tomography scan revealed global brain edema with herniation. She was admitted to the intensive care unit for symptomatic treatment and died 10 days after surgery from multiorgan failure. The serum IgE level was very high (734 IU/mL). Single-dose administration of cefazolin for surgical prophylaxis may lead to rare, fatal adverse reaction. The warning signs are sudden, unexplained metabolic acidosis, hypertensive crisis, tachycardia, and facial angioedema predominating with or without cutaneous symptoms like urticaria. PMID:26929668

  1. 3D multimodal MRI brain glioma tumor and edema segmentation: a graph cut distribution matching approach.

    PubMed

    Njeh, Ines; Sallemi, Lamia; Ayed, Ismail Ben; Chtourou, Khalil; Lehericy, Stephane; Galanaud, Damien; Hamida, Ahmed Ben

    2015-03-01

    This study investigates a fast distribution-matching, data-driven algorithm for 3D multimodal MRI brain glioma tumor and edema segmentation in different modalities. We learn non-parametric model distributions which characterize the normal regions in the current data. Then, we state our segmentation problems as the optimization of several cost functions of the same form, each containing two terms: (i) a distribution matching prior, which evaluates a global similarity between distributions, and (ii) a smoothness prior to avoid the occurrence of small, isolated regions in the solution. Obtained following recent bound-relaxation results, the optima of the cost functions yield the complement of the tumor region or edema region in nearly real-time. Based on global rather than pixel wise information, the proposed algorithm does not require an external learning from a large, manually-segmented training set, as is the case of the existing methods. Therefore, the ensuing results are independent of the choice of a training set. Quantitative evaluations over the publicly available training and testing data set from the MICCAI multimodal brain tumor segmentation challenge (BraTS 2012) demonstrated that our algorithm yields a highly competitive performance for complete edema and tumor segmentation, among nine existing competing methods, with an interesting computing execution time (less than 0.5s per image). PMID:25467804

  2. A fatal adverse effect of cefazolin administration: severe brain edema in a patient with multiple meningiomas.

    PubMed

    Tribuddharat, Sirirat; Sathitkarnmanee, Thepakorn; Kitkhuandee, Amnat; Theerapongpakdee, Sunchai; Ngamsaengsirisup, Kriangsak; Chanthawong, Sarinya

    2016-01-01

    Cefazolin is commonly administered before surgery as a prophylactic antibiotic. Hypersensitivity to cefazolin is not uncommon, and the symptoms mostly include urticaria, skin reaction, diarrhea, vomiting, and transient neutropenia, which are rarely life threatening. We present a rare case of fatal cefazolin hypersensitivity in a female who was diagnosed with multiple meningiomas and scheduled for craniotomy and tumor removal. Immediately after cefazolin IV administration, the patient developed acute hypertensive crisis, which resolved within 10 minutes after the treatment. This was followed by unexplained metabolic acidosis. The patient then developed severe brain edema 100 minutes later. The patient had facial edema when her face was exposed for the next 30 minutes. A computed tomography scan revealed global brain edema with herniation. She was admitted to the intensive care unit for symptomatic treatment and died 10 days after surgery from multiorgan failure. The serum IgE level was very high (734 IU/mL). Single-dose administration of cefazolin for surgical prophylaxis may lead to rare, fatal adverse reaction. The warning signs are sudden, unexplained metabolic acidosis, hypertensive crisis, tachycardia, and facial angioedema predominating with or without cutaneous symptoms like urticaria. PMID:26929668

  3. Relationship between apathy and tumor location, size, and brain edema in patients with intracranial meningioma

    PubMed Central

    Peng, Yihua; Shao, Chunhong; Gong, Ye; Wu, Xuehai; Tang, Weijun; Shi, Shenxun

    2015-01-01

    Background The purpose of this study is to assess the relationship between apathy and tumor location, size, and brain edema in patients with intracranial meningioma. Methods We enrolled 65 consecutive patients with meningioma and 31 normal controls matched for age, gender, and education. The patients were divided into frontal or non-frontal (NF) meningioma groups based on magnetic resonance imaging; the frontal group was then subdivided to dorsolateral frontal (DLF), medial frontal (MF), and ventral frontal (VF) groups. Tumor size and brain edema were also recorded. Apathy was assessed by the Apathy Evaluation Scale (AES). Assessments were carried out 1 week before and 3 months after surgery, respectively. Logistic regression analysis was performed to identify the predictive effect of tumor size, location, and brain edema on apathy. Analysis of variance and chi-square analysis were applied to compare apathy scores and apathy rates among the frontal, NF, and normal control groups, and all subgroups within the frontal group. Results Compared with the NF and control groups, the mean AES score was much higher in the frontal group (34.08.3 versus 28.636.0, P=0.008, and 26.84.2, P<0.001). Subgroup analysis showed that AES scores in the MF group (42.16.6) and VF group (34.78.0) were higher than in the DLF group (28.54.36), NF group, and control group (P<0.05). The apathy rate was 63.6% in the MF group and 25% in the VF group, and significantly higher than in the DLF (5.6%), NF (5.3%), and control (0%) groups (P<0.001). A moderate correlation was found between AES score and mean diameter of the meningioma in all patient groups. Further analysis demonstrated that the correlation existed in the DLF (r=0.52, P=0.032), MF (r=0.84, P<0.001), and VF (r=0.64, P=0.008) groups, but not in the NF group (r=0.19, P=0.448). The AES score was much higher in patients with brain edema than in those without brain edema (34.738.28 versus 28.774.20, t=3.545, P=0.001). In subgroups within frontal meningioma patients, the statistical significance above only existed in the MF group (43.505.26 versus 25.676.03, P=0.001). Also, we examined the effect of related factors, such as age, sex, education, tumor size, tumor location and edema on the occurrence of apathy. The binary logistic regression analysis showed that MF [P=0.023, Exp(B) =145.6] and size [P=0.012, Exp(B) =1.20] got into the regression equation. Thirty-two patients underwent follow-up post-surgery. A significant reduction in AES was found in the MF group (AES1 AES2 =6.866.82, t=2.68, P=0.04), but not in any of the other groups. Conclusion Apathy occurs frequently in patients with frontal meningioma, and is more severe, especially in the MF region. Apathy is probably correlated with tumor location and size. Brain edema might increase the severity of apathy. PMID:26203250

  4. Peritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy.

    PubMed

    Hou, Jack; Kshettry, Varun R; Selman, Warren R; Bambakidis, Nicholas C

    2013-12-01

    Meningioma is the second most common type of adult intracranial neoplasm. A substantial subset of patients present with peritumoral brain edema (PTBE), which can cause significant morbidity via mass effect, complicate surgical management, and impact the safety of stereotactic radiosurgery. Recent studies suggest a close relationship between vascular endothelial growth factor-A (VEGF-A) expression and PTBE development in meningiomas. The authors performed a systematic review of the literature on the pathogenesis of PTBE in meningiomas, the effectiveness of steroid therapy, the role played by VEGF-A, and the current clinical evidence for antiangiogenic therapy to treat peritumoral brain edema. Mounting evidence suggests VEGF-A is secreted directly by meningioma cells to induce angiogenesis and edemagenesis of tumoral as well as peritumoral brain tissue. The VEGF-A cascade results in recruitment of cerebral-pial vessels and disruption of the tumor-brain barrier, which appear to be requisite for VEGF-A to have an edemagenic effect. Results of preliminary clinical studies suggest VEGF-directed therapy has modest activity against recurrent and progressive meningioma growth but can alleviate PTBE in some patients. A comprehensive understanding of the VEGF-A pathway and its modulators may hold the key to an effective therapeutic approach to treating PTBE associated with meningiomas. Further clinical trials with larger patient cohorts and longer follow-up periods are warranted to confirm the efficacy of VEGF-directed therapy. PMID:24289127

  5. Blood–brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edema

    PubMed Central

    Marchi, Nicola; Betto, Giulia; Fazio, Vincent; Fan, Quinyuan; Ghosh, Chaitali; Machado, Andre; Janigro, Damir

    2009-01-01

    SUMMARY Purpose: Increased blood–brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods: In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results: BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion: After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. PMID:19175391

  6. The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor.

    PubMed Central

    Criscuolo, G. R.

    1993-01-01

    Cerebral edema and fluid-filled cysts are common accompaniments of brain tumors. They contribute to the mass effect imposed by the primary tumor and are often responsible for a patient's signs and symptoms. Cerebral edema significantly increases the morbidity associated with tumor biopsy, excision, radiation therapy, and chemotherapy. Both edema and cyst formation are thought to result from a deficiency in the blood-brain barrier, with consequent extravasation of water, electrolytes, and plasma proteins from altered tumor microvessels. The resultant expansion of the cerebral interstitial space contributes to the elevated intracranial pressure observed with brain tumors. Departure from the typical blood-brain barrier microvascular architecture may only partially explain the occurrence of edema and tumor cyst formation. Biochemical mediators have also been implicated in vascular extravasation. Vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) is a protein that has recently been isolated from a variety of tumors including human brain tumors. VPFb is an extraordinarily potent inducer of both microvascular extravasation (edemagenesis) and the formation of new blood vessels (angiogenesis). Its role in tumor growth and progression would therefore appear pivotal. Herein, the author presents an updated account of the investigation of VPF. Historical and clinical perspectives of the study and treatment of tumor associated edema are provided. The efficacy of high-dose dexamethasone in the treatment of neoplastic brain edema is discussed. A hypothetical role for VPF in edemagenesis is presented and discussed. It is hoped that an expanded understanding of the mechanisms responsible for the genesis of edema will ultimately facilitate therapeutic intervention. Images Figure 1 Figure 2 Figure 3 PMID:7516104

  7. Amelioration of Cold Injury-Induced Cortical Brain Edema Formation by Selective Endothelin ETB Receptor Antagonists in Mice

    PubMed Central

    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults. PMID:25000290

  8. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

    PubMed

    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults. PMID:25000290

  9. A Peptide to Reduce Pulmonary Edema in a Rat Model of Lung Transplantation

    PubMed Central

    Finsterwalder, Richard; Friedl, Heinz P.; Rauscher, Sabine; Gröger, Marion; Kocher, Alfred; Wagner, Christine; Wagner, Stephan N.; Fischer, Gottfried; Schultz, Marcus J.; Wiedemann, Dominik; Petzelbauer, Peter

    2015-01-01

    Background Despite significant advances in organ preservation, surgical techniques and perioperative care, primary graft dysfunction is a serious medical problem in transplantation medicine in general and a specific problem in patients undergoing lung transplantation. As a result, patients develop lung edema, causing reduced tissue oxygenation capacity, reduced lung compliance and increased requirements for mechanical ventilatory support. Yet, there is no effective strategy available to protect the grafted organ from stress reactions induced by ischemia/reperfusion and by the surgical procedure itself. Methods We assessed the effect of a cingulin-derived peptide, XIB13 or a random peptide in an established rat model of allogeneic lung transplantation. Donor lungs and recipients received therapeutic peptide at the time of transplantation and outcome was analyzed 100min and 28 days post grafting. Results XIB13 improved blood oxygenation and reduced vascular leak 100min post grafting. Even after 28 days, lung edema was significantly reduced by XIB13 and lungs had reduced fibrotic or necrotic zones. Moreover, the induction of an allogeneic T cell response was delayed indicating a reduced antigen exchange between the donor and the host. Conclusions In summary, we provide a new tool to strengthen endothelial barrier function thereby improving outcomes in lung transplantation. PMID:26536466

  10. Expression of MMP-9 and VEGF in Meningiomas and Their Correlation with Peritumoral Brain Edema

    PubMed Central

    Rutkowski, Robert; Turek, Grzegorz; Mariak, Zenon; Chyczewski, Lech

    2015-01-01

    Meningiomas constitute up to 13% of all intracranial tumors. The predictive factors for meningioma have not been unambiguously defined; however some limited data suggest that the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) may be associated with the presence of peritumoral brain edema (PTBE) and worse clinical outcome. The aim of this study was to analyze the expressions of MMP-9 and VEGF in a group of meningiomas of various grades and to study associations between these two markers and PTBE. The study included patients with supratentorial meningiomas. The patients were divided into low- (G1) and high-grade meningiomas (G2 and G3). PTBE was assessed on MRI. The expressions of VEGF and MMP-9 were determined immunohistochemically. The expression of MMP-9 was observed significantly more often in G3 meningiomas than in lower grade tumors. The presence of stage II or III PTBE was associated with a significant increase in MMP-9 expression. The expression of VEGF did not differ across the PTBE stages. Our findings point to a significant role of MMP-9 and VEGF in the pathogenesis of peritumoral brain edema in low- and high-grade meningiomas. PMID:25821815

  11. Partial IGF-1 deficiency induces brain oxidative damage and edema, which are ameliorated by replacement therapy.

    PubMed

    Puche, Juan E; Muñoz, Úrsula; García-Magariño, Mariano; Sádaba, María C; Castilla-Cortázar, Inma

    2016-01-01

    Insulin-like growth factor 1 (IGF-1) induces multiple cytoprotective effects on every tissue, including the brain. Since the mechanisms by which IGF-1 produces neuroprotection are not fully understood, the aim of this work was to delve into the underlying mechanisms. IGF-1 deficient mice (Hz) were compared with wild type (WT) and Hz mice treated with low doses of IGF-1 (2 µg/100 g body weight/day) for 10 days (Hz + IGF). Gene expression, quantitative PCR, histology, and magnetic resonance imaging were performed in the three groups. IGF-1 deficiency induced increased oxidative damage determined by markers of lipid peroxidation and hypoxia, as well as gene expression of heat shock proteins, antioxidant enzymes, and molecules involved in inflammation, apoptosis, and mitochondrial protection. These changes correlated with edema and learning impairment in Hz mice. IGF-1 therapy improved all these alterations. In conclusion, IGF-1 deficiency is responsible for increased brain oxidative damage, edema, and impaired learning and memory capabilities which are rescued by IGF-1 replacement therapy. © 2016 BioFactors, 42(1):60-79, 2016. PMID:26891019

  12. Computer aided detection of tumor and edema in brain FLAIR magnetic resonance image using ANN

    NASA Astrophysics Data System (ADS)

    Pradhan, Nandita; Sinha, A. K.

    2008-03-01

    This paper presents an efficient region based segmentation technique for detecting pathological tissues (Tumor & Edema) of brain using fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. This work segments FLAIR brain images for normal and pathological tissues based on statistical features and wavelet transform coefficients using k-means algorithm. The image is divided into small blocks of 4×4 pixels. The k-means algorithm is used to cluster the image based on the feature vectors of blocks forming different classes representing different regions in the whole image. With the knowledge of the feature vectors of different segmented regions, supervised technique is used to train Artificial Neural Network using fuzzy back propagation algorithm (FBPA). Segmentation for detecting healthy tissues and tumors has been reported by several researchers by using conventional MRI sequences like T1, T2 and PD weighted sequences. This work successfully presents segmentation of healthy and pathological tissues (both Tumors and Edema) using FLAIR images. At the end pseudo coloring of segmented and classified regions are done for better human visualization.

  13. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

    PubMed

    Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

    2016-04-01

    Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes. PMID:25833102

  14. A Randomized Trial of the Effects of Nebulized Albuterol on Pulmonary Edema in Brain Dead Organ Donors

    PubMed Central

    Ware, Lorraine B.; Landeck, Megan; Koyama, Tatsuki; Zhao, Zhiguo; Singer, Jonathan; Kern, Ryan; Neidlinger, Nikole; Nguyen, John; Johnson, Elizabeth; Janz, David R.; Bernard, Gordon R.; Lee, Jae W.; Matthay, Michael A.

    2013-01-01

    Donor lung utilization rates are persistently low primarily due to donor lung dysfunction. We hypothesized that a treatment that enhances the resolution of pulmonary edema by stimulating the rate of alveolar fluid clearance would improve donor oxygenation and increase donor lung utilization. We conducted a randomized, blinded, placebo-controlled trial of aerosolized albuterol (5 mg q4h) versus saline placebo during active donor management in 506 organ donors. The primary outcome was change in oxygenation (PaO2/FiO2) from enrollment to organ procurement. The albuterol (n=260) and placebo (n=246) groups were well matched for age, gender, ethnicity, smoking, and cause of brain death. The change in PaO2/FiO2 from enrollment to organ procurement did not differ between treatment groups (p=0.54) nor did donor lung utilization (albuterol 29% vs. placebo 32%, p=0.44). Donors in the albuterol vs. placebo group were more likely to have the study drug dose reduced (13% vs. 1%, p<0.001) or stopped (8% vs. 0%, p<0.001) for tachycardia. In summary, treatment with high dose inhaled albuterol during the donor management period did not improve donor oxygenation or increase donor lung utilization but did cause tachycardia. High dose aerosolized albuterol should not be used in donors to enhance the resolution of pulmonary edema. PMID:24730050

  15. Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: Possible association with AQP4 modulation.

    PubMed

    Sadana, Prabodh; Coughlin, Lucy; Burke, Jamie; Woods, Robert; Mdzinarishvili, Alexander

    2015-07-15

    The use of neuroprotective strategies to mitigate the fatal consequences of ischemic brain stroke is a focus of robust research activity. We have previously demonstrated that thyroid hormone (T3; 3,3',5-triiodo-l-thyronine) possesses neuroprotective and anti-edema activity in pre-stroke treatment regimens when administered as a solution or as a nanoparticle formulation. In this study we have extended our evaluation of thyroid hormone use in animal models of brain stroke. We have used both transient middle cerebral artery occlusion (t-MCAO) and permanent (p-MCAO) models of ischemic brain stroke. A significant reduction of tissue infarction and a concurrent decrease in edema were observed in the t-MCAO model of brain stroke. However, no benefit of T3 was observed in p-MCAO stroke setting. Significant improvement of neurological outcomes was observed upon T3 treatment in t-MCAO mice. Further, we tested T2 (3,5-diiodo-l-thyronine) a natural deiodination metabolite of T3 in MCAO model of brain stroke. T2 potently decreased infarct size as well as edema formation. Additionally, we report here that T3 suppresses the expression of aquaporin-4 (AQP4) water channels which could be a likely mechanism of its anti-edema activity. Our studies provide evidence to stimulate clinical development of thyroid hormones for use in ischemic brain stroke. PMID:25963308

  16. Cannabinoid CB2 receptor stimulation attenuates brain edema and neurological deficits in a germinal matrix hemorrhage rat model.

    PubMed

    Tao, Yihao; Tang, Jun; Chen, Qianwei; Guo, Jing; Li, Lin; Yang, Liming; Feng, Hua; Zhu, Gang; Chen, Zhi

    2015-03-30

    Germinal matrix hemorrhage (GMH) is one of the most common and devastating cerebrovascular events that affect premature infants, resulting in a significant socioeconomic burden. However, GMH has been largely unpreventable, and clinical treatments are mostly inadequate. In the present study, we tested the hypothesis that JWH133, a selective CB2 receptor agonist, could attenuate brain injury and neurological deficits in a clostridial collagenase VII induced GMH model in seven-day-old (P7) S-D rat pups. Up to 1h post-injury, the administration of JWH133 (1mg/kg, intraperitoneal injection) significantly attenuated brain edema at 24h post-GMH, which was reversed by a selective CB2R antagonist, SR144528 (3mg/kg, intraperitoneal injection). Long-term brain morphology and neurofunctional outcomes were also improved. In contrast, JWH133 did not have a noticeable effect on the hematoma volume during the acute phase. These data also showed that microglia activation and inflammatory cytokine (TNF-α) release were significantly inhibited by JWH133 after GMH. This current study suggests a potential clinical utility for CB2R agonists as a potential therapy to reduce neurological injury and improve patient outcomes after GMH. PMID:25625355

  17. Absence of Glial α-Dystrobrevin Causes Abnormalities of the Blood-Brain Barrier and Progressive Brain Edema*

    PubMed Central

    Lien, Chun Fu; Mohanta, Sarajo Kumar; Frontczak-Baniewicz, Malgorzata; Swinny, Jerome D.; Zablocka, Barbara; Górecki, Dariusz C.

    2012-01-01

    The blood-brain barrier (BBB) plays a key role in maintaining brain functionality. Although mammalian BBB is formed by endothelial cells, its function requires interactions between endotheliocytes and glia. To understand the molecular mechanisms involved in these interactions is currently a major challenge. We show here that α-dystrobrevin (α-DB), a protein contributing to dystrophin-associated protein scaffolds in astrocytic endfeet, is essential for the formation and functioning of BBB. The absence of α-DB in null brains resulted in abnormal brain capillary permeability, progressively escalating brain edema, and damage of the neurovascular unit. Analyses in situ and in two-dimensional and three-dimensional in vitro models of BBB containing α-DB-null astrocytes demonstrated these abnormalities to be associated with loss of aquaporin-4 water and Kir4.1 potassium channels from glial endfeet, formation of intracellular vacuoles in α-DB-null astrocytes, and defects of the astrocyte-endothelial interactions. These caused deregulation of tight junction proteins in the endothelia. Importantly, α-DB but not dystrophins showed continuous expression throughout development in BBB models. Thus, α-DB emerges as a central organizer of dystrophin-associated protein in glial endfeet and a rare example of a glial protein with a role in maintaining BBB function. Its abnormalities might therefore lead to BBB dysfunction. PMID:23043099

  18. The neuroprotective effect of olive leaf extract is related to improved blood-brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia.

    PubMed

    Mohagheghi, Fatemeh; Bigdeli, Mohammad Reza; Rasoulian, Bahram; Hashemi, Payman; Pour, Marzyeh Rashidi

    2011-01-15

    Recent studies suggest that olive extracts suppress inflammation and reduce stress oxidative injury. We sought to extend these observations in an in vivo study of rat cerebral ischemia-reperfusion injury. Four groups, each of 18 Wister rats, were studied. One (control) group received distilled water, while three treatment groups received oral olive leaf extract (50, 75 and 100mg/kg/day respectively). After 30 days, blood lipid profiles were determined, before a 60 min period of middle cerebral artery occlusion (MCAO). After 24h reperfusion, neurological deficit scores, infarct volume, brain edema, and blood-brain barrier permeability were each assessed in subgroups of six animals drawn from each main group. Olive leaf extract reduced the LDL/HDL ratio in doses 50, 75, and 100mg/kg/day in comparison to the control group (P<0.001), and offered cerebroprotection from ischemia-reperfusion. For controls vs. doses of 50mg/kg/day vs. 75 mg/kg/day vs. 100mg/kg/day, attenuated corrected infarct volumes were 209.79 ± 33.05 mm(3) vs. 164.36 ± 13.44 mm(3) vs. 123.06 ± 28.83 mm(3) vs. 94.71 ± 33.03 mm(3); brain water content of the infarcted hemisphere 82.33 ± 0.33% vs. 81.33 ± 0.66% vs. 80.75 ± 0.6% vs. 80.16 ± 0.47%, and blood-brain barrier permeability of the infarcted hemisphere 11.22 ± 2.19 μg/g vs. 9.56 ± 1.74 μg/g vs. 6.99 ± 1.48 μg/g vs. 5.94 ± 1.73 μg/g tissue (P<0.05 and P<0.01 for measures in doses 75 and 100mg/kg/day vs. controls respectively). Oral administration of olive leaf extract reduces infarct volume, brain edema, blood-brain barrier permeability, and improves neurologic deficit scores after transient middle cerebral artery occlusion in rats. PMID:21183324

  19. Histochemical characteristic of perivascular space in the brain with an advanced edema.

    PubMed

    Nishi, Katsuji; Tanegashima, Akio; Yamamoto, Yoshio; Ushiyama, Ikuko; Yamazaki, Shigeru; Nishikawa, Yoshinari; Ohkubo, Iwao

    2003-03-01

    Amorphorous and colorless spaces, Virchow-Robin spaces (VRS), were often found by HE stain around blood vessels in the edematous brain. Histochemical characteristic of the enlarged VRS caused by an advanced edema and detected by lectin stain using Griffonia simplicifolia I agglutinin in the brain stem, the occipital lobe and/or the cerebellum was examined by means of immunohistochemical method. After pretreatment with formic acid or proteinase K, formalin fixed-paraffin embedded tissue sections were incubated with antibodies (ABs) against plasma proteins such as amyloid P component, Ig G, albumin (Al), apolipoprotein E (Apo E), and lactotransferrin (Lf), and cellular proteins such as ubiquitin (Ubt), Tau-protein (Tau), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), CD68 (KP-1) and heparansulfate proteoglycan (HSG). The tissue sections were also incubated with antibodies against alanyl aminopeptidase-S (AAP-S) and alanyl aminopeptidase-N (AAP-N) without pretreatment. The VRS showed intensive reactivity with ABs against Amy P, AAP-S and AAP-N, moderate with ABs against Apo E and HSG, weak with ABs against Ig G, Al and Lf, feeble with ABs against Ubt, Tau and CD 68, and no with ABs against GFAP and MBP, respectively. Although the substances detected in VRS might be of blood plasma origin resulting from abnormalities in the blood-brain barrier, the mechanisms whereby the serum proteins and/or other substances are enriched in VRS remain incompletely understood. PMID:12935611

  20. Brain natriuretic peptide levels in six basic underwater demolitions/SEAL recruits presenting with swimming induced pulmonary edema (SIPE).

    PubMed

    Shearer, Damon; Mahon, Richard

    2009-01-01

    Swimming induced pulmonary edema (SIPE) is associated with both SCUBA diving and strenuous surface swimming; however, the majority of reported cases and clinically observed cases tend to occur during or after aggressive surface swimming. Capillary stress failure appears to be central to the pathophysiology of this disorder. Regional pulmonary capillaries are exposed to relatively high pressures secondary to increased vascular volume, elevation of pulmonary vascular resistance, and regional differences in perfusion secondary to forces of gravity and high cardiac output. Acute pulmonary edema can be classified as either cardiogenic or noncardiogenic or both. Cardiogenic pulmonary edema occurs when the pulmonary capillary hydrostatic pressure exceeds plasma oncotic pressure. Noncardiogenic pulmonary edema occurs when pulmonary capillary permeability is increased. Given the pathophysiology noted above, SIPE can be described as a cardiogenic pulmonary edema, at least in part, since an increased transalveolar pressure gradient has been implicated in the pathogenesis of SIPE. Brain natriuretic peptide (BNP) is used in the clinical setting to differentiate cardiac from pulmonary sources of dyspnea, specifically to diagnose cardiogenic pulmonary edema. During clinical management, BNP levels were drawn on six BUD/S recruits simultaneously presenting with pulmonary complaints consistent with SIPE, after an extended surface bay swim. This paper analyzes that data after de-identification and reviews the pathophysiology and clinical management of SIPE. PMID:19739476

  1. Imaging ¹⁸F-fluorodeoxy glucose/¹¹C-methionine uptake decoupling for identification of tumor cell infiltration in peritumoral brain edema.

    PubMed

    Kinoshita, Manabu; Goto, Tetsu; Arita, Hideyuki; Okita, Yoshiko; Isohashi, Kayako; Kagawa, Naoki; Fujimoto, Yasunori; Kishima, Haruhiko; Shimosegawa, Eku; Saitoh, Youichi; Hatazawa, Jun; Hashimoto, Naoya; Yoshimine, Toshiki

    2012-01-01

    Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of (18)F-fluorodeoxy glucose (FDG) and (11)C-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and (11)C-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and (11)C-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher (11)C-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/(11)C-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up. PMID:21847706

  2. Curcumin alleviates brain edema by lowering AQP4 expression levels in a rat model of hypoxia-hypercapnia-induced brain damage

    PubMed Central

    YU, LIN-SHENG; FAN, YAN-YAN; YE, GUANGHUA; LI, JUNLI; FENG, XIANG-PING; LIN, KEZHI; DONG, MIUWU; WANG, ZHENYUAN

    2016-01-01

    The present study aimed to investigate the therapeutic effects of curcumin (CU) against brain edema in a rat model of hypoxia-hypercapnia (HH)-induced brain damage (HHBD). Male Sprague-Dawley rats were divided into five groups, including a control group and four treatment groups. The rats in the control group were raised under normal laboratory conditions and were injected with water, whereas the rats in the treatment groups were exposed to a low O2/high CO2 environment simulating HH conditions, and were injected with water, CU, dimethyl sulfoxide (solvent control) or monosialoganglioside GM1. After 2 weeks, the morphological characteristics of the brain tissues were analyzed using optical and electron microscopy. In addition, aquaporin (AQP)-4 protein expression levels in brain tissue samples were analyzed using streptavidin-biotin complex immunohistochemistry and western blotting, and mRNA expression levels were detected using reverse transcription-quantitative polymerase chain reaction. Severe brain edema, tissue structure disruption and increased AQP4 expression levels were detected in the brain tissues of the HH rats. Conversely, the rats treated with CU or GM1 exhibited attenuated HHBD-induced brain edema and tissue structure disruption, and decreased mRNA and protein expression levels of AQP4. The results of the present study suggested that CU treatment was able to attenuate HHBD-induced brain edema by downregulating the expression levels of AQP4 in a rat model. Therefore, CU may be considered a potential therapeutic drug for the treatment of patients with brain edema. PMID:26997983

  3. What predicts early volumetric edema increase following stereotactic radiosurgery for brain metastases?

    PubMed

    Hanna, Andrew; Boggs, D Hunter; Kwok, Young; Simard, Marc; Regine, William F; Mehta, Minesh

    2016-04-01

    A volumetric analysis of pre- and post-radiosurgery (PreSRS and PostSRS) edema in patients with cerebral metastases was performed to determine factors of a predictive model assessing the risk of developing increased edema relatively early after SRS. One-hundred-fourteen metastases in 55 patients were analyzed. Selection for this analysis required an MRI ≤ 30 days before SRS and an MRI ≤ 100 days after SRS. Tumor volumes were calculated on PreSRS, SRS, and PostSRS T1-weighted postgadolinium images while edema volumes were calculating using PreSRS and PostSRS fluid-attenuated inversion recovery MR images. An increase in edema was defined as an increase in measurable edema of at least 5 %. We developed and evaluated a model predicting the relative risk (RR) of increased edema after SRS. Peritumoral edema increased in 18 % (21/114) of the analyzed lesions. Melanoma/renal histology, recursive partitioning analysis class III, and prior WBRT carried RRs of developing postSRS edema increase of 2.45, 2.48, and 3.16, respectively (all P values <0.05). The PreSRS edema/tumor ratio predicted for a RR of 1.007/ratio unit, and steroid dose at time of SRS predicted for a RR of 0.89/mg (all P values <0.05). A predictive model for assessing the RR of increased edema after SRS was developed based from these data and may be useful in identifying patients who might benefit from prophylactic anti-edema therapies before, during, or after SRS. This model could be used as the basis of inclusion criteria for prospective trials investigating novel anti-edema therapies. PMID:26721241

  4. Electron microscopic features of brain edema in rodent cerebral malaria in relation to glial fibrillary acidic protein expression

    PubMed Central

    Ampawong, Sumate; Chaisri, Urai; Viriyavejakul, Parnpen; Nontprasert, Apichart; Grau, Georges E; Pongponratn, Emsri

    2014-01-01

    The mechanisms leading to cerebral malaria (CM) are not completely understood. Brain edema has been suggested as having an important role in experimental CM. In this study, CBA/CaH mice were infected with Plasmodium berghei ANKA blood-stage and when typical symptoms of CM developed on day 7, brain tissues were processed for electron-microscopic and immunohistochemical studies. The study demonstrated ultrastructural hallmarks of cerebral edema by perivascular edema and astroglial dilatation confirming existing evidence of vasogenic and cytogenic edema. This correlates closely with the clinical features of CM. An adaptive response of astrocytic activity, represented by increasing glial fibrillary acidic protein (GFAP) expression in the perivascular area and increasing numbers of large astrocyte clusters were predominately found in the CM mice. The presence of multivesicular and lamellar bodies indicates the severity of cerebral damage in experimental CM. Congestion of the microvessels with occluded white blood cells (WBCs), parasitized red blood cells (PRBCs) and platelets is also a crucial covariate role for CM pathogenesis. PMID:24966914

  5. Electron microscopic features of brain edema in rodent cerebral malaria in relation to glial fibrillary acidic protein expression.

    PubMed

    Ampawong, Sumate; Chaisri, Urai; Viriyavejakul, Parnpen; Nontprasert, Apichart; Grau, Georges E; Pongponratn, Emsri

    2014-01-01

    The mechanisms leading to cerebral malaria (CM) are not completely understood. Brain edema has been suggested as having an important role in experimental CM. In this study, CBA/CaH mice were infected with Plasmodium berghei ANKA blood-stage and when typical symptoms of CM developed on day 7, brain tissues were processed for electron-microscopic and immunohistochemical studies. The study demonstrated ultrastructural hallmarks of cerebral edema by perivascular edema and astroglial dilatation confirming existing evidence of vasogenic and cytogenic edema. This correlates closely with the clinical features of CM. An adaptive response of astrocytic activity, represented by increasing glial fibrillary acidic protein (GFAP) expression in the perivascular area and increasing numbers of large astrocyte clusters were predominately found in the CM mice. The presence of multivesicular and lamellar bodies indicates the severity of cerebral damage in experimental CM. Congestion of the microvessels with occluded white blood cells (WBCs), parasitized red blood cells (PRBCs) and platelets is also a crucial covariate role for CM pathogenesis. PMID:24966914

  6. PGJ2 Provides Prolonged CNS Stroke Protection by Reducing White Matter Edema

    PubMed Central

    Nicholson, James D.; Puche, Adam C.; Guo, Yan; Weinreich, Daniel; Slater, Bernard J.; Bernstein, Steven L.

    2012-01-01

    Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), an analog of the metabolically active PGD2 metabolite. We evaluated PGJ2's effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ2 administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ2 improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ2 acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ2 showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ2 may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention. PMID:23284631

  7. YiQiFuMai powder injection ameliorates blood–brain barrier dysfunction and brain edema after focal cerebral ischemia–reperfusion injury in mice

    PubMed Central

    Cao, Guosheng; Ye, Xinyi; Xu, Yingqiong; Yin, Mingzhu; Chen, Honglin; Kou, Junping; Yu, Boyang

    2016-01-01

    YiQiFuMai powder injection (YQFM) is a modern preparation derived from the traditional Chinese medicine Sheng-Mai-San. YQFM is widely used in clinical practice in the People’s Republic of China, mainly for the treatment of microcirculatory disturbance-related diseases. However, little is known about its role in animals with ischemic stroke. The aim of this study was to examine the effect of YQFM on brain edema and blood–brain barrier (BBB) dysfunction induced by cerebral ischemia–reperfusion (I/R) injury. Male C57BL/6J mice underwent right middle cerebral artery occlusion for 1 hour with a subsequent 24-hour reperfusion to produce I/R injury. YQFM (three doses: 0.336, 0.671, and 1.342 g/kg) was then given intraperitoneally (IP). The results demonstrated that YQFM significantly decreased infarct size, improved neurological deficits, reduced brain water content, and increased cerebral blood flow after I/R injury. 18F-fluorodeoxyglucose micro-positron emission tomography imaging and hematoxylin and eosin staining results indicated that YQFM is able to ameliorate brain metabolism and histopathological damage after I/R. Moreover, YQFM administration reduced BBB leakage and upregulated the expression of zona occludens-1 (ZO-1) and occludin, which was confirmed by Evans Blue extravasation, Western blotting, and immunofluorescence assay. Our findings suggest that YQFM provides protection against focal cerebral I/R injury in mice, possibly by improving BBB dysfunction via upregulation of the expression of tight junction proteins. PMID:26834461

  8. YiQiFuMai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice.

    PubMed

    Cao, Guosheng; Ye, Xinyi; Xu, Yingqiong; Yin, Mingzhu; Chen, Honglin; Kou, Junping; Yu, Boyang

    2016-01-01

    YiQiFuMai powder injection (YQFM) is a modern preparation derived from the traditional Chinese medicine Sheng-Mai-San. YQFM is widely used in clinical practice in the People's Republic of China, mainly for the treatment of microcirculatory disturbance-related diseases. However, little is known about its role in animals with ischemic stroke. The aim of this study was to examine the effect of YQFM on brain edema and blood-brain barrier (BBB) dysfunction induced by cerebral ischemia-reperfusion (I/R) injury. Male C57BL/6J mice underwent right middle cerebral artery occlusion for 1 hour with a subsequent 24-hour reperfusion to produce I/R injury. YQFM (three doses: 0.336, 0.671, and 1.342 g/kg) was then given intraperitoneally (IP). The results demonstrated that YQFM significantly decreased infarct size, improved neurological deficits, reduced brain water content, and increased cerebral blood flow after I/R injury. 18F-fluorodeoxyglucose micro-positron emission tomography imaging and hematoxylin and eosin staining results indicated that YQFM is able to ameliorate brain metabolism and histopathological damage after I/R. Moreover, YQFM administration reduced BBB leakage and upregulated the expression of zona occludens-1 (ZO-1) and occludin, which was confirmed by Evans Blue extravasation, Western blotting, and immunofluorescence assay. Our findings suggest that YQFM provides protection against focal cerebral I/R injury in mice, possibly by improving BBB dysfunction via upregulation of the expression of tight junction proteins. PMID:26834461

  9. Improvement of cold injury-induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor-A.

    PubMed

    Michinaga, Shotaro; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Minami, Shizuho; Kimura, Akimasa; Hatanaka, Shunichi; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Koyama, Yutaka

    2015-09-01

    Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ETB antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)-A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5-6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF-A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF-A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 μg) or IRL-2500 (10 μg) (selective ETB antagonists) attenuated brain edema and disruption of the blood-brain barrier after cold injury. BQ788 and IRL-2500 reversed the cold injury-induced increases in MMP9 and VEGF-A expression. The induction of reactive astrocytes producing MMP9 and VEGF-A in the damaged cerebrum was attenuated by BQ788 and IRL-2500. These results suggest that attenuations of astrocytic MMP9 and VEGF-A expression by ETB antagonists may be involved in the amelioration of vasogenic brain edema. PMID:26174228

  10. Photobiostimulation reduces edema formation induced in mice by Lys-49 phospholipases A2 isolated from Bothrops moojeni venom.

    PubMed

    Nadur-Andrade, Nikele; Dale, Camila Squarzone; Santos, Adriano Silvio Dos; Soares, Andreimar M; de Lima, Carlos J; Zamuner, Stella Regina

    2014-11-01

    The prominent local myotoxic effects induced by Bothrops snake venom are due, in part, to myotoxins. This effect is not neutralized by antivenom, which is the main therapy for victims of snakebite. Two basic myotoxins named MjTX-I and MjTX-II were isolated from Bothrops moojeni venom. Both myotoxins have a Lys-49 phospholipase A2 structure devoid of enzymatic activity, but are highly myonecrotic and edema-inducing. In this study, we analyzed the effect of a low-level laser (LLL) at 685 nm, an energy density of 2.2 J cm(-2), and the irradiation time of 15 s, and a light emitting diode (LED) at 635 or 945 nm at energy densities of 4 and 3.8 J cm(-2), and irradiation times of 41 and 38 s, respectively, applied 30 min and 3 h after edema formation in mice caused by MjTX-I or MjTX-II. MjTX-I or MjTX-II caused a significant edema formation in envenomed paws. LLL and LED irradiation significantly reduced the edema formation by both myotoxins from 1 up to 6 hours after the injection. Both LLL and LEDs were similar in reducing the edema formation induced by myotoxins. The combined photobiostimulation with antivenom had the same effect in reducing edema as treatment with the LLL or LEDs alone. In conclusion, the results of this study indicate that photobiostimulation could be used in association with antivenom therapy for treatment of local effects of Bothrops species venom. PMID:25232894

  11. Imatinib treatment reduces brain injury in a murine model of traumatic brain injury

    PubMed Central

    Su, Enming J.; Fredriksson, Linda; Kanzawa, Mia; Moore, Shannon; Folestad, Erika; Stevenson, Tamara K.; Nilsson, Ingrid; Sashindranath, Maithili; Schielke, Gerald P.; Warnock, Mark; Ragsdale, Margaret; Mann, Kris; Lawrence, Anna-Lisa E.; Medcalf, Robert L.; Eriksson, Ulf; Murphy, Geoffrey G.; Lawrence, Daniel A.

    2015-01-01

    Current therapies for Traumatic brain injury (TBI) focus on stabilizing individuals and on preventing further damage from the secondary consequences of TBI. A major complication of TBI is cerebral edema, which can be caused by the loss of blood brain barrier (BBB) integrity. Recent studies in several CNS pathologies have shown that activation of latent platelet derived growth factor-CC (PDGF-CC) within the brain can promote BBB permeability through PDGF receptor α (PDGFRα) signaling, and that blocking this pathway improves outcomes. In this study we examine the efficacy for the treatment of TBI of an FDA approved antagonist of the PDGFRα, Imatinib. Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction. This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function. Finally, analysis of cerebrospinal fluid (CSF) from human TBI patients suggests a possible correlation between high PDGF-CC levels and increased injury severity. Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα. PMID:26500491

  12. Effects of Different Doses of Levetiracetam on Aquaporin 4 Expression in Rats with Brain Edema Following Fluid Percussion Injury.

    PubMed

    Jin, Hongbo; Li, Wenling; Dong, Changzheng; Ma, Li; Wu, Jiang; Zhao, Wenqing

    2016-01-01

    BACKGROUND This study was designed to investigate the effects of different doses of levetiracetam on aquaporin 4 (AQP4) expression in rats after fluid percussion injury. MATERIAL AND METHODS Sprague-Dawley rats were randomly divided into 4 groups: sham operation group, traumatic brain injury group, low-dose levetiracetam group, and high-dose levetiracetam group. Brain edema models were established by fluid percussion injury, and intervened by the administration of levetiracetam. Samples from the 4 groups were collected at 2, 6, 12, and 24 h, and at 3 and 7 days after injury. Histological observation was performed using hematoxylin-eosin staining and immunohistochemical staining. AQP4 and AQP4 mRNA expression was detected using Western blot assay and RT-PCR. Brain water content was measured by the dry-wet method. RESULTS Compared with the traumatic brain injury group, brain water content, AQP4 expression, and AQP4 mRNA expression were lower in the levetiracetam groups at each time point and the differences were statistically significant (P<0.05). The intervention effects of high-dose levetiracetam were more apparent. CONCLUSIONS Levetiracetam can lessen brain edema from fluid percussion injury by down-regulating AQP4 and AQP4 mRNA expression. There is a dose-effect relationship in the preventive effect of levetiracetam within a certain extent. PMID:26927633

  13. Effects of Different Doses of Levetiracetam on Aquaporin 4 Expression in Rats with Brain Edema Following Fluid Percussion Injury

    PubMed Central

    Jin, Hongbo; Li, Wenling; Dong, Changzheng; Ma, Li; Wu, Jiang; Zhao, Wenqing

    2016-01-01

    Background This study was designed to investigate the effects of different doses of levetiracetam on aquaporin 4 (AQP4) expression in rats after fluid percussion injury. Material/Methods Sprague-Dawley rats were randomly divided into 4 groups: sham operation group, traumatic brain injury group, low-dose levetiracetam group, and high-dose levetiracetam group. Brain edema models were established by fluid percussion injury, and intervened by the administration of levetiracetam. Samples from the 4 groups were collected at 2, 6, 12, and 24 h, and at 3 and 7 days after injury. Histological observation was performed using hematoxylin-eosin staining and immunohistochemical staining. AQP4 and AQP4 mRNA expression was detected using Western blot assay and RT-PCR. Brain water content was measured by the dry-wet method. Results Compared with the traumatic brain injury group, brain water content, AQP4 expression, and AQP4 mRNA expression were lower in the levetiracetam groups at each time point and the differences were statistically significant (P<0.05). The intervention effects of high-dose levetiracetam were more apparent. Conclusions Levetiracetam can lessen brain edema from fluid percussion injury by down-regulating AQP4 and AQP4 mRNA expression. There is a dose-effect relationship in the preventive effect of levetiracetam within a certain extent. PMID:26927633

  14. Lipophilic amino alcohols reduces carrageenan-induced paw edema and anti-OVA DTH in BALB/c mice.

    PubMed

    Reis, Elaine F C; Castro, Sandra B R; Alves, Caio Cesar S; Oliveira, Erick E; Corrêa, Tais A; Almeida, Mauro V; Ferreira, Ana Paula

    2013-11-01

    The inflammation process is a coordinated response of the organism related to immune response with release of pro-inflammatory substances, as nitric oxide, TNF-α and IL-1β. In this work, a series of lipophilic amino alcohols were evaluated on RAW264.7 and primary macrophages for the modulation of nitric oxide and TNF-α. The most potent compounds were submitted to the treatment of BALB/c mice and evaluation of the carrageenan-induced paw edema and TNF-α and IL1-β release in the paws and anti-OVA delayed type hypersensitivity reaction. RAW264.7 and primary macrophages were incubated in the presence of amino alcohols at different concentrations (1, 0.5, 0.05 and 0.005 μg mL(-1)). All tested compounds were not cytotoxic, however the inhibition of NO and TNF-α were observed only in RAW264.7 cultures. The NO production were reduced in 100% for all compounds, but only the compounds 4a and 4b expressively reduced the TNF-α release (67% and 92% respectively). On the carrageenan-induced paw edema, the compound 4b treatment showed reduction of edema, TNF-α and IL-1β as efficient as dexamethasone treatment. Meanwhile, the compound 4a treatment showed only slight reduction of paw edema. In the anti-OVA DTH reaction, both compounds showed reduction in the paw edema as effective as dexamethasone. In function of the observed results in vitro and in the acute and anti-OVA inflammation of mice paw edema compound 4b showed promissory anti-inflammatory properties. PMID:24035232

  15. Radiation brain injury is reduced by the polyamine inhibitor [alpha]-difluoromethylornithine

    SciTech Connect

    Fike, J.R.; Seilhan, T.M.; Gobbel, G.T. ); Marton, L.J. )

    1994-04-01

    [alpha]-difluoromethylornithine (DFMO) was used to reduce [sup 125]I-induced brain injury in normal beagle dogs. Different DFMO doses and administration schedules were used to determine if the reduction in brain injury was dependent on dose and/or dependent upon when the drug was administered relative to the radiation treatment. Doses of DMFO of 75 mg/kg/day and 37.5 mg/kg/day given 2 days before, during and for 14 days after irradiation reduced levels of putrescine (PU) in the cerebrospinal fluid relative to controls. Volume of edema was significantly reduced by 75 mg/kg/day of DFMO before, during and after irradiation and by the same dose when the drug was started immediately after irradiation. A reduction in edema volume after 37.5 mg/kg/day of DFMO before, during and after irradiation was very near significance. Ultrafast CT studies performed on dogs that received a DFMO dose of 75 mg/kg/day before, during and after irradiation suggested that the reduce edema volume was associated with reduced vascular permeability. Volume of necrosis and volume of contrast enhancement (breakdown of the blood-brain barrier) were significantly lower than controls only after a DFMO dose of 75 mg/kg/day before, during and after irradiation. These latter data, coupled with the findings relative to edema, suggest that different mechanisms may be involved with respect to the effects of DFMO on brain injury, or that the extents of edema, necrosis and breakdown of the blood-brain barrier may depend upon different levels of polyamine depletion. The precise mechanisms by which DFMO exerts the effects observed here need to be determined. 41 refs., 5 figs.

  16. Inositol-trisphosphate reduces alveolar apoptosis and pulmonary edema in neonatal lung injury.

    PubMed

    Preuss, Stefanie; Stadelmann, Sabrina; Omam, Friede D; Scheiermann, Julia; Winoto-Morbach, Supandi; von Bismarck, Philipp; Knerlich-Lukoschus, Friederike; Lex, Dennis; Adam-Klages, Sabine; Wesch, Daniela; Held-Feindt, Janka; Uhlig, Stefan; Schtze, Stefan; Krause, Martin F

    2012-08-01

    D-myo-inositol-1,2,6-trisphosphate (IP3) is an isomer of the naturally occurring second messenger D-myo-inositol-1,4,5-trisphosphate, and exerts anti-inflammatory and antiedematous effects in the lung. Myo-inositol (Inos) is a component of IP3, and is thought to play an important role in the prevention of neonatal pulmonary diseases such as bronchopulmonary dysplasia and neonatal acute lung injury (nALI). Inflammatory lung diseases are characterized by augmented acid sphingomyelinase (aSMase) activity leading to ceramide production, a pathway that promotes increased vascular permeability, apoptosis, and surfactant alterations. A novel, clinically relevant triple-hit model of nALI was developed, consisting of repeated airway lavage, injurious ventilation, and lipopolysaccharide instillation into the airways, every 24 hours. Thirty-five piglets were randomized to one of four treatment protocols: control (no intervention), surfactant alone, surfactant + Inos, and surfactant + IP3. After 72 hours of mechanical ventilation, lungs were excised from the thorax for subsequent analyses. Clinically, oxygenation and ventilation improved, and extravascular lung water decreased significantly with the S + IP3 intervention. In pulmonary tissue, we observed decreased aSMase activity and ceramide concentrations, decreased caspase-8 concentrations, reduced alveolar epithelial apoptosis, the reduced expression of interleukin-6, transforming growth factor-?1, and amphiregulin (an epithelial growth factor), reduced migration of blood-borne cells and particularly of CD14(+)/18(+) cells (macrophages) into the airspaces, and lower surfactant surface tensions in S + IP3-treated but not in S + Inos-treated piglets. We conclude that the admixture of IP3 to surfactant, but not of Inos, improves gas exchange and edema in our nALI model by the suppression of the governing enzyme aSMase, and that this treatment deserves clinical evaluation. PMID:22403805

  17. [Postoperative cerebral edema. Physiopathology of the edema and medical therapy].

    PubMed

    Tommasino, C

    1992-04-01

    Cerebral edema complicates many neurosurgical conditions, such as head injuries, neoplasms and infections, and is the direct result of operative trauma. The recognition and the treatment of brain edema are of great practical importance, particularly in those conditions leading to brain herniations and/or intracranial hypertension. Brain edema can be distinguished into two major categories, based on the integrity of the blood brain-barrier (BBB). With intact BBB edema, the crucial pathogenic event is related to disturbances of cellular metabolism and ionic transport. All the cellular elements of brain may undergo swelling, with a concomitant reduction of the extracellular-fluid space of the brain. Open BBB edema, the most common form of brain edema, is characterized by increased permeability of the brain endothelial cells. Brain edema results from the oncotic forces generated from a serum protein influx into the nervous tissue, and edema fluid accumulates primarily in the extracellular space. The non-operative management of brain edema requires attention to the causes that have induced brain edema. Specific pharmacologic therapy with corticosteroids, hyperosmolar agents and furosemide or acetazolamide depend upon accurate assessment of BBB integrity. PMID:1620460

  18. Melatonin reduces acute lung inflammation, edema, and hemorrhage in heatstroke rats

    PubMed Central

    Wu, Wen-shiann; Chou, Ming-ting; Chao, Chien-ming; Chang, Chen-kuei; Lin, Mao-tsun; Chang, Ching-ping

    2012-01-01

    Aim: To assess the therapeutic effect of melatonin on heat-induced acute lung inflammation and injury in rats. Methods: Heatstroke was induced by exposing anesthetized rats to heat stress (36 °C, 100 min). Rats were treated with vehicle or melatonin (0.2, 1, 5 mg/kg) by intravenous administration 100 min after the initiatioin of heatstroke and were allowed to recover at room temperature (26 °C). The acute lung injury was quantified by morphological examination and by determination of the volume of pleural exudates, the number of polymorphonuclear (PMN) cells, and the myeloperoxidase (MPO) activity. The concentrations of tumor necrosis factor, interleukin (IL)-1β, IL-6, and IL-10 in bronchoalveolar fluid (BALF) were measured by ELISA. Nitric oxide (NO) level was determined by Griess method. The levels of glutamate and lactate-to-pyruvate ratio were analyzed by CMA600 microdialysis analyzer. The concentrations of hydroxyl radicals were measured by a procedure based on the hydroxylation of sodium salicylates leading to the production of 2,3-dihydroxybenzoic acid (DHBA). Results: Melatonin (1 and 5 mg/kg) significantly (i) prolonged the survival time of heartstroke rats (117 and 186 min vs 59 min); (ii) attenuated heatstroke-induced hyperthermia and hypotension; (iii) attenuated acute lung injury, including edema, neutrophil infiltration, and hemorrhage scores; (iv) down-regulated exudate volume, BALF PMN cell number, and MPO activity; (v) decreased the BALF levels of lung inflammation response cytokines like TNF-alpha, interleukin (IL)-1β, and IL-6 but further increased the level of an anti-inflammatory cytokine IL-10; (vi) reduced BALF levels of glutamate, lactate-to-pyruvate ratio, NO, 2,3-DHBA, and lactate dehydrogenase. Conclusion: Melatonin may improve the outcome of heatstroke in rats by attenuating acute lung inflammation and injury. PMID:22609835

  19. Novel treatment targets for cerebral edema.

    PubMed

    Walcott, Brian P; Kahle, Kristopher T; Simard, J Marc

    2012-01-01

    Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) and the SUR1-regulated NC(Ca-ATP) (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A- and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis. PMID:22125096

  20. Modeling the Presence of Myelin and Edema in the Brain Based on Multi-Parametric Quantitative MRI.

    PubMed

    Warntjes, Marcel; Engström, Maria; Tisell, Anders; Lundberg, Peter

    2016-01-01

    The aim of this study was to present a model that uses multi-parametric quantitative MRI to estimate the presence of myelin and edema in the brain. The model relates simultaneous measurement of R1 and R2 relaxation rates and proton density to four partial volume compartments, consisting of myelin partial volume, cellular partial volume, free water partial volume, and excess parenchymal water partial volume. The model parameters were obtained using spatially normalized brain images of a group of 20 healthy controls. The pathological brain was modeled in terms of the reduction of myelin content and presence of excess parenchymal water, which indicates the degree of edema. The method was tested on spatially normalized brain images of a group of 20 age-matched multiple sclerosis (MS) patients. Clear differences were observed with respect to the healthy controls: the MS group had a 79 mL smaller brain volume (1069 vs. 1148 mL), a 38 mL smaller myelin volume (119 vs. 157 mL), and a 21 mL larger excess parenchymal water volume (78 vs. 57 mL). Template regions of interest of various brain structures indicated that the myelin partial volume in the MS group was 1.6 ± 1.5% lower for gray matter (GM) structures and 2.8 ± 1.0% lower for white matter (WM) structures. The excess parenchymal water partial volume was 9 ± 10% larger for GM and 5 ± 2% larger for WM. Manually placed ROIs indicated that the results using the template ROIs may have suffered from loss of anatomical detail due to the spatial normalization process. Examples of the application of the method on high-resolution images are provided for three individual subjects: a 45-year-old healthy subject, a 72-year-old healthy subject, and a 45-year-old MS patient. The observed results agreed with the expected behavior considering both age and disease. In conclusion, the proposed model may provide clinically important parameters, such as the total brain volume, degree of myelination, and degree of edema, based on a single qMRI acquisition with a clinically acceptable scan time. PMID:26925030

  1. Modeling the Presence of Myelin and Edema in the Brain Based on Multi-Parametric Quantitative MRI

    PubMed Central

    Warntjes, Marcel; Engström, Maria; Tisell, Anders; Lundberg, Peter

    2016-01-01

    The aim of this study was to present a model that uses multi-parametric quantitative MRI to estimate the presence of myelin and edema in the brain. The model relates simultaneous measurement of R1 and R2 relaxation rates and proton density to four partial volume compartments, consisting of myelin partial volume, cellular partial volume, free water partial volume, and excess parenchymal water partial volume. The model parameters were obtained using spatially normalized brain images of a group of 20 healthy controls. The pathological brain was modeled in terms of the reduction of myelin content and presence of excess parenchymal water, which indicates the degree of edema. The method was tested on spatially normalized brain images of a group of 20 age-matched multiple sclerosis (MS) patients. Clear differences were observed with respect to the healthy controls: the MS group had a 79 mL smaller brain volume (1069 vs. 1148 mL), a 38 mL smaller myelin volume (119 vs. 157 mL), and a 21 mL larger excess parenchymal water volume (78 vs. 57 mL). Template regions of interest of various brain structures indicated that the myelin partial volume in the MS group was 1.6 ± 1.5% lower for gray matter (GM) structures and 2.8 ± 1.0% lower for white matter (WM) structures. The excess parenchymal water partial volume was 9 ± 10% larger for GM and 5 ± 2% larger for WM. Manually placed ROIs indicated that the results using the template ROIs may have suffered from loss of anatomical detail due to the spatial normalization process. Examples of the application of the method on high-resolution images are provided for three individual subjects: a 45-year-old healthy subject, a 72-year-old healthy subject, and a 45-year-old MS patient. The observed results agreed with the expected behavior considering both age and disease. In conclusion, the proposed model may provide clinically important parameters, such as the total brain volume, degree of myelination, and degree of edema, based on a single qMRI acquisition with a clinically acceptable scan time. PMID:26925030

  2. Inhibition of PKCβ Reverses Increased Blood-brain Barrier Permeability during Hyperglycemic Stroke and Prevents Edema Formation In Vivo

    PubMed Central

    Cipolla, Marilyn J.; Huang, Quillan; Sweet, Julie G.

    2011-01-01

    Purpose We investigated the effect of circulating factors and protein kinase Cβ (PKCβ) on blood-brain barrier permeability and edema during hyperglycemic stroke. Methods Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5–6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in MCAs that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the PKCβ inhibitor CGP53353 (0.5 μmol/L) and permeability measured. Lastly, hyperglycemic rats were treated i.v. with CGP53353 (10 or 100 μg/kg or vehicle 15 minutes prior to reperfusion and edema formation measured by wet:dry weights (n=6/group). Results MCAO vessels had increased permeability compared to controls, regardless of the plasma perfusate. Permeability (water flux, μm3 × 108) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6) and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06; p<0.01). Inhibition of PKCβ in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1; p<0.01). In vivo, hyperglycemia increased edema vs. normoglycemia after MCAO (water content = 78.84±0.11% vs. 81.38±0.21%; p<0.01). Inhibition of PKCβ with 10 or 100 μg/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content = 79.54±0.56% and 79.99±0.43%; p<0.01 vs. vehicle). Conclusions These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of PKCβ. PMID:21852606

  3. [The effects of a benzopyrone derivative in experimental brain edema due to cold in the rabbit].

    PubMed

    Góngora Castillo, C; Gómez de Segura, I A; López Bravo, A; de Miguel del Campo, E

    1993-01-01

    On this study, parenchymal changes during a cerebral edema caused by thermic injury (cool) on the rabbit, are analyzed. The work was based on the ultrastructural findings obtained by transmission electronic microscopy and on the effects produced by a benzopironic derived (F-117 Hydrosmina). The injury was produced with solid CO2, previous a craniectomy, on the dura mater of the left hemisphere. Forty rabbits were included into the study, the animals were distributed into five groups (n = 8): a control group and 4 treatment groups. One of the groups received treatment without previous cerebral injury. The group of rabbits with doses of 50 mg/Kg of weight showed focal and diffuse areas of edema alternating with less damaged areas, the edema was evident on the white substance. This group also showed a dissociation of the myelinic fibers and an intracytoplasmatic tumefaction into the glial cells. These findings contrast with the histopathological findings obtained from the rabbits (V), the extracellular edema was poor, the myelinic fiber disorganization was minimal with no vacuolar degeneration and no structural mitochondrial changes had been showed. The discontinuance of the hematoencephalic barrier caused by the cool could be a possible mechanism that causes the opening of the endothelial unions from the capillary vessels, changing their membranes and resulting in a free penetration of the molecule into the cerebral parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8338248

  4. Epigallocatechin-3-Gallate (EGCG) Attenuates Traumatic Brain Injury by Inhibition of Edema Formation and Oxidative Stress

    PubMed Central

    Zhang, Bo; Wang, Bing; Cao, Shuhua

    2015-01-01

    Traumatic brain injury (TBI) is a major cause of mortality and long-term disability, which can decrease quality of life. In spite of numerous studies suggesting that Epigallocatechin-3-gallate (EGCG) has been used as a therapeutic agent for a broad range of disorders, the effect of EGCG on TBI remains unknown. In this study, a weight drop model was established to evaluate the therapeutic potential of EGCG on TBI. Rats were administered with 100 mg/kg EGCG or PBS intraperitoneally. At different times following trauma, rats were sacrificed for analysis. It was found that EGCG (100 mg/kg, i.p.) treatment significantly reduced brain water content and vascular permeability at 12, 24, 48, 72 hour after TBI. Real-time PCR results revealed that EGCG inhibited TBI-induced IL-1β and TNF-α mRNA expression. Importantly, CD68 mRNA expression decreasing in the brain suggested that EGCG inhibited microglia activation. Western blotting and immunohistochemistry results showed that administering of EGCG significantly inhibited the levels of aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) expression. TBI-induced oxidative stress was remarkably impaired by EGCG treatment, which elevated the activities of SOD and GSH-PX. Conversely, EGCG significantly reduced the contents of MDA after TBI. In addition, EGCG decreased TBI-induced NADPH oxidase activation through inhibition of p47phox translocation from cytoplasm to plasma membrane. These data demonstrate that EGCG treatment may be an effective therapeutic strategy for TBI and the underlying mechanism involves inhibition of oxidative stress. PMID:26557015

  5. Changes in Cannabinoid Receptors, Aquaporin 4 and Vimentin Expression after Traumatic Brain Injury in Adolescent Male Mice. Association with Edema and Neurological Deficit

    PubMed Central

    Lopez-Rodriguez, Ana Belen; Acaz-Fonseca, Estefania; Viveros, Maria-Paz; Garcia-Segura, Luis M.

    2015-01-01

    Traumatic brain injury (TBI) incidence rises during adolescence because during this critical neurodevelopmental period some risky behaviors increase. The purpose of this study was to assess the contribution of cannabinoid receptors (CB1 and CB2), blood brain barrier proteins (AQP4) and astrogliosis markers (vimentin) to neurological deficit and brain edema formation in a TBI weight drop model in adolescent male mice. These molecules were selected since they are known to change shortly after lesion. Here we extended their study in three different timepoints after TBI, including short (24h), early mid-term (72h) and late mid-term (two weeks). Our results showed that TBI induced an increase in brain edema up to 72 h after lesion that was directly associated with neurological deficit. Neurological deficit appeared 24 h after TBI and was completely recovered two weeks after trauma. CB1 receptor expression decreased after TBI and was negatively correlated with edema formation and behavioral impairments. CB2 receptor increased after injury and was associated with high neurological deficit whereas no correlation with edema was found. AQP4 increased after TBI and was positively correlated with edema and neurological impairments as occurred with vimentin expression in the same manner. The results suggest that CB1 and CB2 differ in the mechanisms to resolve TBI and also that some of their neuroprotective effects related to the control of reactive astrogliosis may be due to the regulation of AQP4 expression on the end-feet of astrocytes. PMID:26039099

  6. Effect of estrogen and/or progesterone administration on traumatic brain injury-caused brain edema: the changes of aquaporin-4 and interleukin-6.

    PubMed

    Soltani, Zahra; Khaksari, Mohammad; Shahrokhi, Nader; Mohammadi, Gholamabbas; Mofid, Behshad; Vaziri, Ali; Amiresmaili, Sedigheh

    2016-03-01

    The role of aquaporin-4 (AQP4) and interleukin-6 (IL-6) in the development of brain edema post-traumatic brain injury (TBI) has been indicated. The present study was designed to investigate the effect(s) of administration of progesterone (P) and/or estrogen (E) on brain water content, AQP4 expression, and IL-6 levels post-TBI. The ovariectomized rats were divided into 11 groups: sham, one vehicle, two vehicles, E1, E2, P1, P2, E1 + P1, E1 + P2, E2 + P1, and E2 + P2. The brain AQP4 expression, IL-6 levels, and water content were evaluated 24 h after TBI induced by Marmarou's method. The low (E1 and P1) and high (E2 and P2) doses of estrogen and progesterone were administered 30 min post-TBI. The results showed that brain water content and AQP4 expression decreased in the E1, E2, P1, and P2-treated groups. The administration of E1 decreased IL-6 levels. Addition of progesterone decreased the inhibitory effect of E1 and E2 on the accumulation of water in the brain. Administration of E1 + P1 and E1 + P2 decreased the inhibitory effect of E1 on the IL-6 levels and AQP4 protein expression. Our findings suggest that estrogen or progesterone by itself has more effective roles in decrease of brain edema than combination of both. Possible mechanism may be mediated by the alteration of AQP4 and IL-6 expression. However, further studies are required to verify the exact mechanism. PMID:26638215

  7. The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury.

    PubMed

    Rodriguez-Grande, Beatriz; Swana, Matimba; Nguyen, Loan; Englezou, Pavlos; Maysami, Samaneh; Allan, Stuart M; Rothwell, Nancy J; Garlanda, Cecilia; Denes, Adam; Pinteaux, Emmanuel

    2014-03-01

    Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin-1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood-brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders. PMID:24346689

  8. β-Dystroglycan cleavage by matrix metalloproteinase-2/-9 disturbs aquaporin-4 polarization and influences brain edema in acute cerebral ischemia.

    PubMed

    Yan, W; Zhao, X; Chen, H; Zhong, D; Jin, J; Qin, Q; Zhang, H; Ma, S; Li, G

    2016-06-21

    Dystroglycan (DG) is widely expressed in various tissues, and throughout the cerebral microvasculature. It consists of two subunits, α-DG and β-DG, and the cleavage of the latter by matrix metalloproteinase (MMP)-2 and -9 underlies a number of physiological and pathological processes. However, the involvement of MMP-2/-9-mediated β-DG cleavage in cerebral ischemia remains uncertain. In astrocytes, DG is crucial for maintaining the polarization of aquaporin-4 (AQP4), which plays a role in the regulation of cytotoxic and vasogenic edema. The present study aimed to explore the effects of MMP-2/-9-mediated β-DG cleavage on AQP4 polarization and brain edema in acute cerebral ischemia. A model of cerebral ischemia was established via permanent middle cerebral artery occlusion (pMCAO) in male C57BL/6 mice. Western blotting, real-time polymerase chain reaction (PCR), immunohistochemical staining, immunofluorescent staining, electron microscopy, and light microscopy were used. Captopril was applied as a selective MMP-2/-9 inhibitor. Recombinant mouse MMP (rmMMP)-2 and -9 were used in an in vitro cleavage experiment. The present study demonstrated evidence of β-DG cleavage by MMP-2/-9 in pMCAO mouse brains; this cleavage was implicated in AQP4 redistribution and brain edema in cerebral ischemia. In addition, captopril exacerbated cytotoxic edema and ameliorated vasogenic edema at 24h after pMCAO, and alleviated brain edema and neurological deficit at 48h and 72h. In conclusion, this study provides novel insight into the effects of MMP-2/-9-mediated β-DG cleavage in acute cerebral ischemia. Such findings might facilitate the development of a therapeutic strategy for the optimization of MMP-2/-9 targeted treatment in cerebral ischemia. PMID:27038751

  9. Pulmonary edema

    MedlinePlus

    Pulmonary edema is an abnormal buildup of fluid in the lungs. This buildup of fluid leads to shortness of ... Pulmonary edema is often caused by congestive heart failure . When the heart is not able to pump efficiently, blood ...

  10. Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.

    PubMed

    Su, Wei-Shen; Tsai, Min-Lan; Huang, Sin-Luo; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-12-01

    It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain. PMID:26517350

  11. Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation

    PubMed Central

    Huang, Sin-Luo; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-01-01

    It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain. PMID:26517350

  12. Massive cerebral edema resulting in brain death as a complication of Cryptococcus neoformans meningitis

    PubMed Central

    Orsini, Jose; Blaak, Christa; Mahmoud, Dalia; Young-Gwang, Jeong

    2015-01-01

    Despite the widespread use of highly active antiretroviral therapy, cryptococcal meningoencephalitis has emerged as the second leading cause of infectious morbidity and mortality in HIV-infected patients worldwide. It presents usually as subacute or chronic disease but occasionally may be fulminant. Common clinical presentations included headache, fever, and depressed level of consciousness. The infection affects both the subarachnoid space and brain parenchyma, and is characterized by a paucity of inflammation and a large fungal burden in the cerebrospinal fluid at the time of diagnosis. Infection is usually lethal without treatment, thus the prompt diagnosis and therapy might improve the outcome. We report a case of brain death caused by Cryptococcus neoformans meningitis that was diagnosed based on clinical neurological examinations and supported by the absence of cerebral blood flow on brain angiography. PMID:25656669

  13. Symmetrical Curvilinear Cytotoxic Edema Along the Surface of the Brain Stem: A Probable New Magnetic Resonance Imaging Finding of Leptomeningeal Carcinomatosis.

    PubMed

    Khil, Eun Kyung; Lee, A Leum; Chang, Kee-Hyun; Yun, Tae Jin; Hong, Hyun Sook

    2015-07-01

    Lung cancer is one of the most common neoplasms to appear leptomeningeal metastasis (LM). Contrast-enhanced magnetic resonance imaging (MRI) is better diagnostic choice for LM and usually shows focal nodular or diffuse linear enhancement on the leptomeninges along the sulci and tentorium in the brain. We experienced atypical 2 cases of lung cancer in patients who showed unusual brain MRI finding of symmetrical curvilinear or band-like, nonenhancing cytotoxic edema along the surface of the brain stem. This finding is unique and different from the general findings of leptomeningeal metastasis. This unique imaging finding of symmetric curvilinear nonenhancing cytotoxic edema along the brainstem is extremely rare and represents a new presentation of leptomeningeal carcinomatosis. PMID:26200611

  14. Curcumin reduces brain-infiltrating T lymphocytes after intracerebral hemorrhage in mice.

    PubMed

    Liu, Wei; Yuan, Jichao; Zhu, Haitao; Zhang, Xuan; Li, Lan; Liao, Xiaojun; Wen, Zexian; Chen, Yaxing; Feng, Hua; Lin, Jiangkai

    2016-05-01

    T lymphocytes contribute to inflammation, thereby exacerbating neuronal injury after cerebral ischemia. An increasing amount of evidence indicates that inflammation is a key contributor to intracerebral hemorrhage (ICH)-induced secondary brain injury. Curcumin, a low-molecular-weight curry spice that is derived from the Curcuma longa plant, suppresses T lymphocyte proliferation and migration. Based on these findings, we investigated whether treatment with curcumin would reduce the number of cerebral T lymphocytes in mice with experimentally induced ICH. We found that a large number of T lymphocytes infiltrated the brain at 3days post-ICH. Curcumin significantly improved neurological scores and reduced brain edema in mice with ICH, consistent with a role in reducing neuroinflammation and neurovascular injury. Using flow cytometry, we observed significantly fewer T lymphocytes in brain samples obtained from the curcumin-treated group than in samples obtained from the vehicle-treated group. Moreover, Western blot analysis and immunostaining indicated that treatment with curcumin significantly reduced the expression of a vascular cell adhesion molecule-1 (VCAM-1), interferon-γ (INF-γ) and interleukin-17 (IL-17) in the mouse brain at 72h post-ICH. Our results suggest that administering curcumin may alleviate cerebral inflammation resulting from ICH, at least in part by reducing the infiltration of T lymphocytes into the brain. Therefore, preventing T lymphocytes from infiltrating the brain may become a new strategy for treating clinical ICH. PMID:27026486

  15. Deep brain stimulation to reduce sexual drive

    PubMed Central

    Fuss, Johannes; Auer, Matthias K.; Biedermann, Sarah V.; Briken, Peer; Hacke, Werner

    2015-01-01

    To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID:26057198

  16. An aqueous extract of Ilex paraguariensis reduces carrageenan-induced edema and inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase in animal models of inflammation.

    PubMed

    Schinella, Guillermo; Neyret, Elisa; Cónsole, Gloria; Tournier, Horacio; Prieto, José M; Ríos, José-Luis; Giner, Rosa María

    2014-08-01

    Mate (Ilex paraguariensis) is a highly popular herbal beverage in South America due to its high content of caffeine. Its hypolipidemic and antioxidant properties are of increasing interest in the treatment of cardiovascular disorders and for weight control. In the present study, we show for the first time both the local and systemic anti-inflammatory effects of an aqueous extract of mate in three classic in vivo models, namely acute and chronic 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema and acute carrageenan-induced mouse paw edema. Caffeine, rutin, chlorogenic acid, 3,5-dicafeoyl quinic acid, and 4,5-dicafeoyl quinic acid, accompanied by a complex mixture of other simple phenolic acids, were identified in the extract by HPLC-UV analyses. In the acute edema model, mate extract applied topically (1 mg/ear) halved the 12-O-tetradecanoylphorbol 13-acetate-induced acute edema (50 %) and almost suppressed neutrophil infiltration (93 %), while in the 12-O-tetradecanoylphorbol 13-acetate-induced subchronic inflammation, the edema was significantly reduced by 62 % (1 mg/ear/day × seven doses). The oral administration of the mate extract (250 mg/kg) significantly reduced the carrageenan-induced edema at all time points, an effect which was accompanied by a 43 % and 53 % reduction of the expression of cyclooxygenase-2 and inducible nitric oxide synthase, respectively. Histological analyses confirmed a reduction of epithelium thickness, dermis with mild inflammation, hair follicles with some secretory cells of sebaceous glands, and hypodermic adipocytes. In conclusion, mate is endowed with in vivo preventative or therapeutic anti-inflammatory effects in both local and systemic inflammatory processes. PMID:25089736

  17. Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: edema or apoptosis?

    PubMed

    Malheiros, Jackeline Moraes; Persike, Daniele Suzete; Castro, Leticia Urbano Cardoso de; Sanches, Talita Rojas Cunha; Andrade, Lúcia da Conceição; Tannús, Alberto; Covolan, Luciene

    2014-05-01

    Manganese-enhanced MRI (MEMRI) has been considered a surrogate marker of Ca(+2) influx into activated cells and tracer of neuronal active circuits. However, the induction of status epilepticus (SE) by kainic acid does not result in hippocampal MEMRI hypersignal, in spite of its high cell activity. Similarly, short durations of status (5 or 15min) induced by pilocarpine did not alter the hippocampal MEMRI, while 30 min of SE even reduced MEMRI signal Thus, this study was designed to investigate possible explanations for the absence or decrease of MEMRI signal after short periods of SE. We analyzed hippocampal caspase-3 activation (to evaluate apoptosis), T2 relaxometry (tissue water content) and aquaporin 4 expression (water-channel protein) of rats subjected to short periods of pilocarpine-induced SE. For the time periods studied here, apoptotic cell death did not contribute to the decrease of the hippocampal MEMRI signal. However, T2 relaxation was higher in the group of animals subjected to 30min of SE than in the other SE or control groups. This result is consistent with higher AQP-4 expression during the same time period. Based on apoptosis and tissue water content analysis, the low hippocampal MEMRI signal 30min after SE can potentially be attributed to local edema rather than to cell death. PMID:24630048

  18. Molecular pathophysiology of cerebral edema

    PubMed Central

    Gerzanich, Volodymyr; Simard, J Marc

    2015-01-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  19. Molecular pathophysiology of cerebral edema.

    PubMed

    Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc

    2016-03-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  20. Elevated pulmonary artery pressure and brain natriuretic peptide in high altitude pulmonary edema susceptible non-mountaineers

    PubMed Central

    Gupta, Rajinder K.; Himashree, G.; Singh, Krishan; Soree, Poonam; Desiraju, Koundinya; Agrawal, Anurag; Ghosh, Dishari; Dass, Deepak; Reddy, Prassana K.; Panjwani, Usha; Singh, Shashi Bala

    2016-01-01

    Exaggerated pulmonary pressor response to hypoxia is a pathgonomic feature observed in high altitude pulmonary edema (HAPE) susceptible mountaineers. It was investigated whether measurement of basal pulmonary artery pressure (Ppa) and brain natriuretic peptide (BNP) could improve identification of HAPE susceptible subjects in a non-mountaineer population. We studied BNP levels, baseline hemodynamics and the response to hypoxia (FIo2 = 0.12 for 30 min duration at sea level) in 11 HAPE resistant (no past history of HAPE, Control) and 11 HAPE susceptible (past history of HAPE, HAPE-S) subjects. Baseline Ppa (19.31 ± 3.63 vs 15.68 ± 2.79 mm Hg, p < 0.05) and plasma BNP levels (52.39 ± 32.9 vs 15.05 ± 9.6 pg/ml, p < 0.05) were high and stroke volume was less (p < 0.05) in HAPE-S subjects compared to control. Acute hypoxia produced an exaggerated increase in heart rate (p < 0.05), mean arterial pressure (p < 0.05) and Ppa (28.2 ± 5.8 vs 19.33 ± 3.74 mm Hg, p < 0.05) and fall in peripheral oxygen saturation (p < 0.05) in HAPE-S compared to control. Receiver operating characteristic (ROC) curves showed that Ppa response to acute hypoxia was the best variable to identify HAPE susceptibility (AUC 0.92) but BNP levels provided comparable information (AUC 0.85). BNP levels are easy to determine and may represent an important marker for the determination of HAPE susceptibility. PMID:26892302

  1. Elevated pulmonary artery pressure and brain natriuretic peptide in high altitude pulmonary edema susceptible non-mountaineers.

    PubMed

    Gupta, Rajinder K; Himashree, G; Singh, Krishan; Soree, Poonam; Desiraju, Koundinya; Agrawal, Anurag; Ghosh, Dishari; Dass, Deepak; Reddy, Prassana K; Panjwani, Usha; Singh, Shashi Bala

    2016-01-01

    Exaggerated pulmonary pressor response to hypoxia is a pathgonomic feature observed in high altitude pulmonary edema (HAPE) susceptible mountaineers. It was investigated whether measurement of basal pulmonary artery pressure (Ppa) and brain natriuretic peptide (BNP) could improve identification of HAPE susceptible subjects in a non-mountaineer population. We studied BNP levels, baseline hemodynamics and the response to hypoxia (FIo2?=?0.12 for 30?min duration at sea level) in 11 HAPE resistant (no past history of HAPE, Control) and 11 HAPE susceptible (past history of HAPE, HAPE-S) subjects. Baseline Ppa (19.31??3.63 vs 15.68??2.79?mm Hg, p?

  2. Clinical Outcomes of Wulingsan Subtraction Decoction Treatment of Postoperative Brain Edema and Fever as a Complication of Glioma Neurosurgery

    PubMed Central

    Jin, Wei-rong; Zhang, Feng-e; Diao, Bao-zhong; Zhang, Yue-ying

    2016-01-01

    Objective. To evaluate the efficacy of Wulingsan subtraction (五苓散加减 WLSS) decoction in the treatment of postoperative brain edema and fever as a complication of glioma neurosurgery. Methods. This retrospective study was conducted at the Department of Neurosurgery of Liaocheng People's Hospital. Patients hospitalized between March 2011 and December 2014 were divided into three groups: Group A received WLSS oral liquid (50 mL), twice a day; Group B received an intravenous infusion of mannitol; and Group C received WLSS combined with mannitol (n = 30 patients per group). All patients were treated for 10 days continuously. Therapeutic efficacy was evaluated by measuring body temperature and indicators of renal function before and 3, 5, and 10 days after treatment. Results. Compared to the other two groups, significantly greater clinical efficacy was observed in the patients treated with mannitol (Group B; P < 0.05), although marked clinical efficacy was also observed over time in patients treated with WLSS (Group A). After 5 days, the quantifiable effects of the WLSS and mannitol combination group (Group C) were substantial (P < 0.05). The renal damage in Group B was more obvious after 5 days and 10 days. Conclusion. Compared with mannitol treatment alone, WLSS combined with mannitol induced a more rapid reduction in body temperature. Our findings suggest that patients should be started on mannitol for 3 days and then switched to WLSS to achieve obvious antipyretic effects and protect renal function. This method of treatment should be considered for clinical applications. PMID:27019661

  3. Scientists Reduce Alzheimer's-Linked Brain Plaques in Mice

    MedlinePlus

    ... html Scientists Reduce Alzheimer's-Linked Brain Plaques in Mice Team used gene therapy, but there's no guarantee ... March 31, 2016 (HealthDay News) -- Scientists working with mice report preliminary progress in efforts to eliminate brain- ...

  4. Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats.

    PubMed

    Ren, Xiaoyan; Ma, Hong; Zuo, Zhiyi

    2016-06-01

    Perinatal asphyxia can lead to death and severe disability. Brain hypoxia-ischemia (HI) injury is the major pathophysiology contributing to death and severe disability after perinatal asphyxia. Here, seven-day old Sprague-Dawley rats were subjected to left brain HI. Dexmedetomidine was given intraperitoneally after the brain HI. Yohimbine or atipamezole, two α2 adrenergic receptor antagonists, were given 10 min before the dexmedetomidine injection. Neurological outcome was evaluated 7 or 28 days after the brain HI. Frontal cerebral cortex was harvested 6 h after the brain HI. Left brain HI reduced the left cerebral hemisphere weight assessed 7 days after the brain HI. This brain tissue loss was dose-dependently attenuated by dexmedetomidine. Dexmedetomidine applied within 1 h after the brain HI produced this effect. Dexmedetomidine attenuated the brain HI-induced brain tissue and cell loss as well as neurological and cognitive dysfunction assessed from 28 days after the brain HI. Dexmedetomidine postconditioning-induced neuroprotection was abolished by yohimbine or atipamezole. Brain HI increased tumor necrosis factor α and interleukin 1β in the brain tissues. This increase was attenuated by dexmedetomidine. Atipamezole inhibited this dexmedetomidine effect. Our results suggest that dexmedetomidine postconditioning reduces HI-induced brain injury in the neonatal rats. This effect may be mediated by α2 adrenergic receptor activation that inhibits inflammation in the ischemic brain tissues. PMID:26932203

  5. Taurine improves functional and histological outcomes and reduces inflammation in traumatic brain injury.

    PubMed

    Su, Y; Fan, W; Ma, Z; Wen, X; Wang, W; Wu, Q; Huang, H

    2014-04-25

    We investigated the effect of taurine on inflammatory cytokine expression, on astrocyte activity and cerebral edema and functional outcomes, following traumatic brain injury (TBI) in rats. 72 rats were randomly divided into sham, TBI and Taurine groups. Rats subjected to moderate lateral fluid percussion injury were injected intravenously with taurine (200mg/kg) or saline immediately after injury or daily for 7days. Functional outcome was evaluated using Modified Neurological Severity Score (mNSS). Glial fibrillary acidic protein (GFAP) of the brain was measured using immunofluorescence. Concentration of 23 cytokines and chemokines in the injured cortex at 1 and 7days after TBI was assessed by Luminex xMAP technology. The results showed that taurine significantly improved functional recovery except 1day, reduced accumulation of GFAP and water content in the penumbral region at 7days after TBI. Compared with the TBI group, taurine significantly suppressed growth-related oncogene (GRO/KC) and interleukin (IL)-1β levels while elevating the levels of regulated on activation, normal T cell expressed and secreted (RANTES) at 1day. And taurine markedly decreased the level of 17 cytokine: eotaxin, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17, leptin, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and only increased the level of MIP-1α in a week. The results suggest that taurine effectively mitigates the severity of brain damage in TBI by attenuating the increase of astrocyte activity and edema as well as pro-inflammatory cytokines. PMID:24530657

  6. Correlation of high delta-like ligand 4 expression with peritumoral brain edema and its prediction of poor prognosis in patients with primary high-grade gliomas.

    PubMed

    Qiu, Xian-Xin; Wang, Chen-Hong; Lin, Zhi-Xiong; You, Na; Wang, Xing-Fu; Chen, Yu-Peng; Chen, Long; Liu, Shui-Yuan; Kang, De-Zhi

    2015-12-01

    OBJECT Peritumoral brain edema (PTBE) is a common phenomenon associated with high-grade gliomas (HGGs). In this study, the authors investigated the expression of Notch delta-like ligand 4 (DLL4) and its correlation with PTBE and prognosis in patients with an HGG. METHODS Tumors from 99 patients with HGG were analyzed for DLL4 expression using immunohistochemistry. PTBE on preoperative MR images and the relationship between PTBE and DLL4 expression were evaluated. The effect of DLL4 on patient prognosis was assessed by using Kaplan-Meier survival and Cox proportional hazard models. RESULTS Immunohistochemistry results revealed that the expression of DLL4 was distributed primarily within the cytoplasm of tumor vascular endothelial cells and seldom detected in tumor cells. DLL4 expression was correlated positively with the degree of edema (r = 0.845 and p < 0.001, Spearman's test). In addition, DLL4 was an independent predictor of prognosis in patients with HGGs (p = 0.001). CONCLUSIONS DLL4 expression was correlated positively with the degree of PTBE and was an independent unfavorable prognostic indicator in patients with HGG. PMID:26047413

  7. Hydrogen Sulfide Offers Neuroprotection on Traumatic Brain Injury in Parallel with Reduced Apoptosis and Autophagy in Mice

    PubMed Central

    Wang, Tao; Dong, Wenwen; Chen, Xiping; Tao, Luyang

    2014-01-01

    Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. The present study was undertaken to study the effects of exogenous H2S on traumatic brain injury (TBI) and the underlying mechanisms. The effects of exogenous H2S on TBI were examined by using measurement of brain edema, behavior assessment, propidium iodide (PI) staining, and Western blotting, respectively. Compared to TBI groups, H2S pretreatment had reduced brain edema, improved motor performance and ameliorated performance in Morris water maze test after TBI. Immunoblotting results showed that H2S pretreatment reversed TBI-induced cleavage of caspase-3 and decline of Bcl-2, suppressed LC3-II, Beclin-1 and Vps34 activation and maintained p62 level in injured cortex and hippocampus post TBI. The results suggest a protective effect and therapeutic potential of H2S in the treatment of brain injury and the protective effect against TBI may be associated with regulating apoptosis and autophagy. PMID:24466346

  8. Astaxanthin reduces matrix metalloproteinase-9 expression and activity in the brain after experimental subarachnoid hemorrhage in rats.

    PubMed

    Zhang, Xiang-Sheng; Zhang, Xin; Zhang, Qing-Rong; Wu, Qi; Li, Wei; Jiang, Tian-Wei; Hang, Chun-Hua

    2015-10-22

    We have previously shown that astaxanthin (ATX) reduces the blood-brain barrier (BBB) disruption and neurovascular dysfunction following subarachnoid hemorrhage (SAH) insults. However, the underlying mechanisms remain unclear. It is known that the matrix metalloproteinases (MMPs), especially matrix metalloproteinase-9 (MMP-9) plays a crucial role in the pathogenesis of secondary brain injury after SAH. And ATX has the ability to regulate MMP-9 in other models. Herein, we investigated whether ATX could ameliorate MMP-9 activation and expression in a rat model of SAH. A total of 144 rats were randomly divided into the following groups: control group (n=36), SAH group (n=36), SAH+vehicle group (n=36), and SAH+ATX group (n=36). The SAH model was induced by injection of 0.3 ml autologous blood into the prechiasmatic cistern. ATX (20 μl of 0.1 mmol) or vehicle was administered intracerebroventricularly 30 min after SAH induction. Mortality, neurological function, brain edema and blood-brain barrier (BBB) permeability were measured at 24 and 72 h after SAH. Biochemical and zymographic methods were used to analyze MMP-9 expression and activity in brain samples. Immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining were also evaluated at 24h. Our data indicated that ATX could significantly reduce the expression and activity of MMP-9, leading to the amelioration of brain edema, BBB impairment, neurological deficits and TUNEL-positive cells at 24h but not 72 h after SAH. The ATX-mediated down-regulation of MMP-9 was correlated with the decreased levels of IL-1β, TNF-α, oxidative stress, activated microglia and infiltrating neutrophils. These results suggest that the neurovascular protection of ATX in SAH is partly associated with the inhibition of MMP-9 expression and activity. PMID:26210617

  9. Reduced GABAergic Action in the Autistic Brain.

    PubMed

    Robertson, Caroline E; Ratai, Eva-Maria; Kanwisher, Nancy

    2016-01-11

    An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1], inspired in part by the striking prevalence of seizures among individuals with the disorder [2]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [3-7], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8, 9], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [11], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12-15]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition. PMID:26711497

  10. Over-expression of laminin correlates to recovery of vasogenic edema following status epilepticus.

    PubMed

    Kim, Y-J; Kim, J-Y; Ko, A-R; Kang, T-C

    2014-09-01

    In the present study, we addressed the question of whether the up-regulation of laminin expression represents the astroglio-vascular responses to status epilepticus (SE) in the rat brain to better understand the role of vasogenic edema in epileptogenic insult. In the hippocampus, vasogenic edema was observed in the hippocampus 12h after SE when astroglial degeneration was undetected. Vasogenic edema in the hippocampus was more severe in the CA1 region where astroglial loss was absent than in the dentate gyrus showing astroglial degeneration. In the piriform cortex (PC), vasogenic edema was accompanied by appearance of astroglial degeneration 12h after SE. Laminin expression in the hippocampus and the PC was increased 3 days and 4 days after SE, respectively. Laminin expression was up-regulated in the hippocampus and the PC with concomitant reduction of SMI-71 (the endothelial barrier antigen) expression. Four weeks after SE, laminin expression was reduced in vessels showing strong SMI-71 expression within vasogenic edema lesion. Inhibition of SE-induced vasogenic edema formation by BQ788 effectively prevented laminin over-expression. Therefore, our findings indicate that laminin over-expression may be one of consequences from vasogenic edema rather than astroglial loss, and that laminin over-expression may promote migration of astrocytes to damaged or newly generated vessels to repair brain-blood barrier (BBB) disruption accompanied by the reconstruction of endothelial barrier. PMID:24931765

  11. Diosmin Alleviates Retinal Edema by Protecting the Blood-Retinal Barrier and Reducing Retinal Vascular Permeability during Ischemia/Reperfusion Injury

    PubMed Central

    Tong, Nianting; Zhang, Zhenzhen; Zhang, Wei; Qiu, Yating; Gong, Yuanyuan; Yin, Lili; Qiu, Qinghua; Wu, Xingwei

    2013-01-01

    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. PMID:23637907

  12. Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury.

    PubMed

    Schober, Michelle E; Requena, Daniela F; Abdullah, Osama M; Casper, T Charles; Beachy, Joanna; Malleske, Daniel; Pauly, James R

    2016-02-15

    Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children. Specific therapies to treat acute TBI are lacking. Cognitive impairment from TBI may be blunted by decreasing inflammation and oxidative damage after injury. Docosahexaenoic acid (DHA) decreases cognitive impairment, oxidative stress, and white matter injury in adult rats after TBI. Effects of DHA on cognitive outcome, oxidative stress, and white matter injury in the developing rat after experimental TBI are unknown. We hypothesized that DHA would decrease early inflammatory markers and oxidative stress, and improve cognitive, imaging and histologic outcomes in rat pups after controlled cortical impact (CCI). CCI or sham surgery was delivered to 17 d old male rat pups exposed to DHA or standard diet for the duration of the experiments. DHA was introduced into the dam diet the day before CCI to allow timely DHA delivery to the pre-weanling pups. Inflammatory cytokines and nitrates/nitrites were measured in the injured brains at post-injury Day (PID) 1 and PID2. Morris water maze (MWM) testing was performed at PID41-PID47. T2-weighted and diffusion tensor imaging studies were obtained at PID12 and PID28. Tissue sparing was calculated histologically at PID3 and PID50. DHA did not adversely affect rat survival or weight gain. DHA acutely decreased oxidative stress and increased anti-inflammatory interleukin 10 in CCI brains. DHA improved MWM performance and lesion volume late after injury. At PID12, DHA decreased T2-imaging measures of cerebral edema and decreased radial diffusivity, an index of white matter injury. DHA improved short- and long-term neurologic outcomes after CCI in the rat pup. Given its favorable safety profile, DHA is a promising candidate therapy for pediatric TBI. Further studies are needed to explore neuroprotective mechanisms of DHA after developmental TBI. PMID:26247583

  13. [Uveitic macular edema].

    PubMed

    Fardeau, C; Champion, E; Massamba, N; LeHoang, P

    2015-01-01

    Macular edema may complicate anterior, intermediate, and posterior uveitis, which may be due to various infectious, tumoral, or autoimmune etiologies. Breakdown of the internal or external blood-retinal barrier is involved in the pathogenesis of inflammatory macular edema. Optical coherence tomography has become standard in confirming the diagnosis of macular thickening, due to its non-invasive, reproducible and sensitivity characteristics. Fluorescein and indocyanine green angiography allows for, in addition to study of the macula, screening for associated vasculitis, detection of ischemic areas, easy diagnosis of preretinal, prepaillary or choroidal neovascular complications, and it can provide etiological information and may be required to evaluate the therapeutic response. Treatment of inflammatory macular edema requires specific treatment in cases of infectious or tumoral etiologies. If it remains persistent, or occurs in other etiologies, anti-inflammatory treatments are needed. Steroid treatment, available in intravitreal, subconjunctival and sub-Tenon's routes, are widely used. Limitations of local use include induced cataract and glaucoma, and their short-lasting action. Such products may reveal retinal infection. Thus, bilateral chronic sight-threatening posterior uveitis often requires systemic treatment, and steroids represent the classic first-line therapy. In order to reduce the daily steroid dose, immunosuppressant or immunomodulatory drugs may be added. Certain of these compounds are now available intravitreally. PMID:25547721

  14. Astaxanthin reduces ischemic brain injury in adult rats

    PubMed Central

    Shen, Hui; Kuo, Chi-Chung; Chou, Jenny; Delvolve, Alice; Jackson, Shelley N.; Post, Jeremy; Woods, Amina S.; Hoffer, Barry J.; Wang, Yun; Harvey, Brandon K.

    2009-01-01

    Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events.—Shen, H., Kuo, C.-C., Chou, J., Delvolve, A., Jackson, S. N., Post, J., Woods, A. S., Hoffer, B. J., Wang, Y., Harvey, B. K. Astaxanthin reduces ischemic brain injury in adult rats. PMID:19218497

  15. Effect of Decompressive Craniectomy on Perihematomal Edema in Patients with Intracerebral Hemorrhage

    PubMed Central

    Klinger-Gratz, Pascal P.; Fiechter, Michael; Z’Graggen, Werner J.; Gautschi, Oliver P.; El-Koussy, Marwan; Gralla, Jan; Schaller, Karl; Zbinden, Martin; Arnold, Marcel; Fischer, Urs; Mattle, Heinrich P.; Raabe, Andreas; Beck, Jürgen

    2016-01-01

    Background Perihematomal edema contributes to secondary brain injury in the course of intracerebral hemorrhage. The effect of decompressive surgery on perihematomal edema after intracerebral hemorrhage is unknown. This study analyzed the course of PHE in patients who were or were not treated with decompressive craniectomy. Methods More than 100 computed tomography images from our published cohort of 25 patients were evaluated retrospectively at two university hospitals in Switzerland. Computed tomography scans covered the time from admission until day 100. Eleven patients were treated by decompressive craniectomy and 14 were treated conservatively. Absolute edema and hematoma volumes were assessed using 3-dimensional volumetric measurements. Relative edema volumes were calculated based on maximal hematoma volume. Results Absolute perihematomal edema increased from 42.9 ml to 125.6 ml (192.8%) after 21 days in the decompressive craniectomy group, versus 50.4 ml to 67.2 ml (33.3%) in the control group (Δ at day 21 = 58.4 ml, p = 0.031). Peak edema developed on days 25 and 35 in patients with decompressive craniectomy and controls respectively, and it took about 60 days for the edema to decline to baseline in both groups. Eight patients (73%) in the decompressive craniectomy group and 6 patients (43%) in the control group had a good outcome (modified Rankin Scale score 0 to 4) at 6 months (P = 0.23). Conclusions Decompressive craniectomy is associated with a significant increase in perihematomal edema compared to patients who have been treated conservatively. Perihematomal edema itself lasts about 60 days if it is not treated, but decompressive craniectomy ameliorates the mass effect exerted by the intracerebral hemorrhage plus the perihematomal edema, as reflected by the reduced midline shift. PMID:26872068

  16. Could Cord Blood Cell Therapy Reduce Preterm Brain Injury?

    PubMed Central

    Li, Jingang; McDonald, Courtney A.; Fahey, Michael C.; Jenkin, Graham; Miller, Suzanne L.

    2014-01-01

    Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matter of the developing brain. Nearly 90% of preterm infants who later develop spastic CP have evidence of periventricular white matter injury. There are currently no treatments targeted at protecting the immature preterm brain. Umbilical cord blood (UCB) contains a diverse mix of stem and progenitor cells, and is a particularly promising source of cells for clinical applications, due to ethical and practical advantages over other potential therapeutic cell types. Recent studies have documented the potential benefits of UCB cells in reducing brain injury, particularly in rodent models of term neonatal hypoxia–ischemia. These studies indicate that UCB cells act via anti-inflammatory and immuno-modulatory effects, and release neurotrophic growth factors to support the damaged and surrounding brain tissue. The etiology of brain injury in preterm-born infants is less well understood than in term infants, but likely results from episodes of hypoperfusion, hypoxia–ischemia, and/or inflammation over a developmental period of white matter vulnerability. This review will explore current knowledge about the neuroprotective actions of UCB cells and their potential to ameliorate preterm brain injury through neonatal cell administration. We will also discuss the characteristics of UCB-derived from preterm and term infants for use in clinical applications. PMID:25346720

  17. Cytotoxic edema: mechanisms of pathological cell swelling

    PubMed Central

    Liang, Danny; Bhatta, Sergei; Gerzanich, Volodymyr; Simard, J. Marc

    2009-01-01

    Cerebral edema is caused by a variety of pathological conditions that affect the brain. It is associated with two separate pathophysiological processes with distinct molecular and physiological antecedents: those related to cytotoxic (cellular) edema of neurons and astrocytes, and those related to transcapillary flux of Na+ and other ions, water, and serum macromolecules. In this review, the authors focus exclusively on the first of these two processes. Cytotoxic edema results from unchecked or uncompensated influx of cations, mainly Na+, through cation channels. The authors review the different cation channels that have been implicated in the formation of cytotoxic edema of astrocytes and neurons in different pathological states. A better understanding of these molecular mechanisms holds the promise of improved treatments of cerebral edema and of the secondary injury produced by this pathological process. PMID:17613233

  18. Diffuse Interstitial Brain Edema in Patients With End-Stage Renal Disease Undergoing Hemodialysis: A Tract-Based Spatial Statistics Study

    PubMed Central

    Kong, Xiang; Wen, Ji-qiu; Qi, Rong-feng; Luo, Song; Zhong, Jian-hui; Chen, Hui-juan; Ji, Gong-jun; Lu, Guang Ming; Zhang, Long Jiang

    2014-01-01

    Abstract To investigate white matter (WM) alterations and their correlation with cognition function in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) using diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) approach. This prospective HIPAA-complaint study was approved by our institutional review board. Eighty HD ESRD patients and 80 sex- and age-matched healthy controls were included. Neuropsychological (NP) tests and laboratory tests, including serum creatinine and urea, were performed. DTI data were processed to obtain fractional anisotropy (FA) and mean diffusivity (MD) maps with TBSS. FA and MD difference between the 2 groups were compared. We also explored the associations of FA values in WM regions of lower FA with ages, NP tests, disease, and dialysis durations, serum creatinine and urea levels of ESRD patients. Compared with controls, HD ESRD patients had lower FA value in the corpus callosum, bilateral corona radiate, posterior thalamic radiation, left superior longitudinal fasciculus, and right cingulum (P < 0.05, FWE corrected). Almost all WM regions had increased MD in HD ESRD patients compared with controls (P < 0.05, FWE corrected). In some regions with lower FA, FA values showed moderate correlations with ages, NP tests, and serum urea levels. There was no correlation between FA values and HD durations, disease durations, and serum creatinine levels of ESRD patients (all P > 0.05). Diffuse interstitial brain edema and moderate WM integrity disruption occurring in HD ESRD patients, which correlated with cognitive dysfunction, and serum urea levels might be a risk factor for these WM changes. PMID:25526483

  19. Mechanisms of Astrocyte-Mediated Cerebral Edema

    PubMed Central

    Stokum, Jesse A.; Kurland, David B.; Gerzanich, Volodymyr; Simard, J. Marc

    2014-01-01

    Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4- dependent edema formation. PMID:24996934

  20. Reduced predictable information in brain signals in autism spectrum disorder

    PubMed Central

    Gómez, Carlos; Lizier, Joseph T.; Schaum, Michael; Wollstadt, Patricia; Grützner, Christine; Uhlhaas, Peter; Freitag, Christine M.; Schlitt, Sabine; Bölte, Sven; Hornero, Roberto; Wibral, Michael

    2014-01-01

    Autism spectrum disorder (ASD) is a common developmental disorder characterized by communication difficulties and impaired social interaction. Recent results suggest altered brain dynamics as a potential cause of symptoms in ASD. Here, we aim to describe potential information-processing consequences of these alterations by measuring active information storage (AIS)—a key quantity in the theory of distributed computation in biological networks. AIS is defined as the mutual information between the past state of a process and its next measurement. It measures the amount of stored information that is used for computation of the next time step of a process. AIS is high for rich but predictable dynamics. We recorded magnetoencephalography (MEG) signals in 10 ASD patients and 14 matched control subjects in a visual task. After a beamformer source analysis, 12 task-relevant sources were obtained. For these sources, stationary baseline activity was analyzed using AIS. Our results showed a decrease of AIS values in the hippocampus of ASD patients in comparison with controls, meaning that brain signals in ASD were either less predictable, reduced in their dynamic richness or both. Our study suggests the usefulness of AIS to detect an abnormal type of dynamics in ASD. The observed changes in AIS are compatible with Bayesian theories of reduced use or precision of priors in ASD. PMID:24592235

  1. Traumatic Brain Injury Reduces Soluble Extracellular Amyloid-β in Mice: A Methodologically Novel Combined Microdialysis- Controlled Cortical Impact Study

    PubMed Central

    Schwetye, Katherine E.; Cirrito, John R.; Esparza, Thomas J.; Mac Donald, Christine L.; Holtzman, David M.; Brody, David L.

    2010-01-01

    Acute amyloid-β peptide (Aβ) deposition has been observed in young traumatic brain injury (TBI) patients, leading to the hypothesis that elevated extracellular Aβ levels could underlie the increased risk of dementia following TBI. However, a recent microdialysis-based study in human brain injury patients found that extracellular Aβ dynamics correlate with changes in neurological status. Because neurological status is generally diminished following injury, this correlation suggested the alternative hypothesis that soluble extracellular Aβ levels may instead be reduced after TBI relative to baseline. We have developed a methodologically novel mouse model that combines experimental controlled cortical impact TBI with intracerebral microdialysis. In this model, we found that Aβ levels in microdialysates were immediately decreased by 25–50% in the ipsilateral hippocampus following TBI. This result was found in PDAPP, Tg2576, and Tg2576-ApoE2 transgenic mice producing human Aβ plus wild-type animals. Changes were not due to altered probe function, edema, changes in APP levels, or Aβ deposition. Similar decreases in Aβ were observed in phosphate buffered saline-soluble tissue extracts. Hippocampal electroencephalographic activity was also decreased up to 40% following TBI, and correlated with reduced microdialysate Aβ levels. These results support the alternative hypothesis that post-injury extracellular soluble Aβ levels are acutely decreased relative to baseline. Reduced neuronal activity may contribute, though the underlying mechanisms have not been definitively determined. Further work will be needed to assess the dynamics of insoluble and oligomeric Aβ after TBI. PMID:20682338

  2. Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor–Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice

    PubMed Central

    Kamoun, Walid S.; Ley, Carsten D.; Farrar, Christian T.; Duyverman, Annique M.; Lahdenranta, Johanna; Lacorre, Delphine A.; Batchelor, Tracy T.; di Tomaso, Emmanuelle; Duda, Dan G.; Munn, Lance L.; Fukumura, Dai; Sorensen, A. Gregory; Jain, Rakesh K.

    2009-01-01

    Purpose Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. Methods We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers. Results We show by intravital microscopy that cediranib significantly decreased tumor vessel permeability and diameter. Moreover, cediranib treatment induced normalization of perivascular cell coverage and thinning of the basement membrane, as mirrored by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation—as measured by MRI and by dry/wet weight measurement of water content—but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4+CD45+ cells. However, by controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth. Conclusion Anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth. PMID:19332720

  3. Reduced brain activation in violent adolescents during response inhibition

    PubMed Central

    Qiao, Yi; Mei, Yi; Du, XiaoXia; Xie, Bin; Shao, Yang

    2016-01-01

    Deficits in inhibitory control have been linked to aggression and violent behaviour. This study aimed to observe whether violent adolescents show different brain activation patterns during response inhibition and to ascertain the roles these brain regions play. A self-report method and modified overt aggression scale (MOAS) were used to evaluate violent behaviour. Functional magnetic resonance imaging was performed in 22 violent adolescents and 17 matched healthy subjects aged 12 to 18 years. While scanning, a go/no-go task was performed. Between-group comparisons revealed that activation in the bilateral middle and superior temporal gyrus, hippocampus, and right orbitofrontal area (BA11) regions were significantly reduced in the violent group compared with the control group. Meanwhile, the violent group had more widespread activation in the prefrontal cortex than that observed in the control group. Activation of the prefrontal cortex in the violent group was widespread but lacking in focus, failing to produce intensive activation in some functionally related regions during response inhibition. PMID:26888566

  4. Intravenous anesthetic propofol suppresses prostaglandin E2 and cysteinyl leukotriene production and reduces edema formation in arachidonic acid-induced ear inflammation.

    PubMed

    Inada, Takefumi; Hirota, Kiichi; Shingu, Koh

    2015-01-01

    Propofol is an intravenous drug widely used for anesthesia and sedation. Previously, propofol was shown to inhibit cyclo-oxygenase (COX) and 5-lipoxygenase (5-LOX) activities. Because these enzyme-inhibiting effects have only been demonstrated in vitro, this study sought to ascertain whether similar effects might also be observed in vivo. In the current studies, effects of propofol were tested in a murine model of arachidonic acid-induced ear inflammation. Specifically, propofol - as a pre-treatment -- was intraperitoneally and then topical application of arachidonic acid was performed. After 1 h, tissue biopsies were collected and tested for the presence of edema and for levels of inflammatory mediators. The results indicated that the administration of propofol significantly suppressed ear edema formation, tissue myeloperoxidase activity, and tissue production of both prostaglandin E2 and cysteinyl leukotrienes. From the data, it can be concluded that propofol could exert anti-COX and anti-5-LOX activities in an in vivo model and that these activities in turn could have, at least in part, suppressed arachidonic acid-induced edema formation in the ear. PMID:25046027

  5. Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward.

    PubMed

    Macoveanu, Julian; Henningsson, Susanne; Pinborg, Anja; Jensen, Peter; Knudsen, Gitte M; Frokjaer, Vibe G; Siebner, Hartwig R

    2016-03-01

    Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women. PMID:26245498

  6. Reduced Regional Brain Cortical Thickness in Patients with Heart Failure

    PubMed Central

    Kumar, Rajesh; Yadav, Santosh K.; Palomares, Jose A.; Park, Bumhee; Joshi, Shantanu H.; Ogren, Jennifer A.; Macey, Paul M.; Fonarow, Gregg C.; Harper, Ronald M.; Woo, Mary A.

    2015-01-01

    Aims Autonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects, and these compromised functions depend on cerebral cortex integrity in addition to that of subcortical and brainstem sites. Impaired autoregulation, low cardiac output, sleep-disordered-breathing, hypertension, and diabetic conditions in HF offer considerable potential to affect cortical areas by loss of neurons and glia, which would be expressed as reduced cortical thicknesses. However, except for gross descriptions of cortical volume loss/injury, regional cortical thickness integrity in HF is unknown. Our goal was to assess regional cortical thicknesses across the brain in HF, compared to control subjects. Methods and Results We examined localized cortical thicknesses in 35 HF and 61 control subjects with high-resolution T1-weighted images (3.0-Tesla MRI) using FreeSurfer software, and assessed group differences with analysis-of-covariance (covariates; age, gender; p<0.05; FDR). Significantly-reduced cortical thicknesses appeared in HF over controls in multiple areas, including the frontal, parietal, temporal, and occipital lobes, more markedly on the left side, within areas that control autonomic, cognitive, affective, language, and visual functions. Conclusion Heart failure subjects show reduced regional cortical thicknesses in sites that control autonomic, cognitive, affective, language, and visual functions that are deficient in the condition. The findings suggest chronic tissue alterations, with regional changes reflecting loss of neurons and glia, and presumably are related to earlier-described axonal changes. The pathological mechanisms contributing to reduced cortical thicknesses likely include hypoxia/ischemia, accompanying impaired cerebral perfusion from reduced cardiac output and sleep-disordered-breathing and other comorbidities in HF. PMID:25962164

  7. High-fat diet transition reduces brain DHA levels associated with altered brain plasticity and behaviour

    PubMed Central

    Sharma, Sandeep; Zhuang, Yumei; Gomez-Pinilla, Fernando

    2012-01-01

    To assess how the shift from a healthy diet rich in omega-3 fatty acids to a diet rich in saturated fatty acid affects the substrates for brain plasticity and function, we used pregnant rats fed with omega-3 supplemented diet from their 2nd day of gestation period as well as their male pups for 12 weeks. Afterwards, the animals were randomly assigned to either a group fed on the same diet or a group fed on a high-fat diet (HFD) rich in saturated fats for 3 weeks. We found that the HFD increased vulnerability for anxiety-like behavior, and that these modifications harmonized with changes in the anxiety-related NPY1 receptor and the reduced levels of BDNF, and its signalling receptor pTrkB, as well as the CREB protein. Brain DHA contents were significantly associated with the levels of anxiety-like behavior in these rats. PMID:22666534

  8. Selective Brain Cooling Reduces Water Turnover in Dehydrated Sheep

    PubMed Central

    Strauss, W. Maartin; Hetem, Robyn S.; Mitchell, Duncan; Maloney, Shane K.; Meyer, Leith C. R.; Fuller, Andrea

    2015-01-01

    In artiodactyls, arterial blood destined for the brain can be cooled through counter-current heat exchange within the cavernous sinus via a process called selective brain cooling. We test the hypothesis that selective brain cooling, which results in lowered hypothalamic temperature, contributes to water conservation in sheep. Nine Dorper sheep, instrumented to provide measurements of carotid blood and brain temperature, were dosed with deuterium oxide (D2O), exposed to heat for 8 days (40◦C for 6-h per day) and deprived of water for the last five days (days 3 to 8). Plasma osmolality increased and the body water fraction decreased over the five days of water deprivation, with the sheep losing 16.7% of their body mass. Following water deprivation, both the mean 24h carotid blood temperature and the mean 24h brain temperature increased, but carotid blood temperature increased more than did brain temperature resulting in increased selective brain cooling. There was considerable inter-individual variation in the degree to which individual sheep used selective brain cooling. In general, sheep spent more time using selective brain cooling, and it was of greater magnitude, when dehydrated compared to when they were euhydrated. We found a significant positive correlation between selective brain cooling magnitude and osmolality (an index of hydration state). Both the magnitude of selective brain cooling and the proportion of time that sheep spent selective brain cooling were negatively correlated with water turnover. Sheep that used selective brain cooling more frequently, and with greater magnitude, lost less water than did conspecifics using selective brain cooling less efficiently. Our results show that a 50kg sheep can save 2.6L of water per day (~60% of daily water intake) when it employs selective brain cooling for 50% of the day during heat exposure. We conclude that selective brain cooling has a water conservation function in artiodactyls. PMID:25675092

  9. Selective brain cooling reduces water turnover in dehydrated sheep.

    PubMed

    Strauss, W Maartin; Hetem, Robyn S; Mitchell, Duncan; Maloney, Shane K; Meyer, Leith C R; Fuller, Andrea

    2015-01-01

    In artiodactyls, arterial blood destined for the brain can be cooled through counter-current heat exchange within the cavernous sinus via a process called selective brain cooling. We test the hypothesis that selective brain cooling, which results in lowered hypothalamic temperature, contributes to water conservation in sheep. Nine Dorper sheep, instrumented to provide measurements of carotid blood and brain temperature, were dosed with deuterium oxide (D2O), exposed to heat for 8 days (40 ◦C for 6-h per day) and deprived of water for the last five days (days 3 to 8). Plasma osmolality increased and the body water fraction decreased over the five days of water deprivation, with the sheep losing 16.7% of their body mass. Following water deprivation, both the mean 24h carotid blood temperature and the mean 24h brain temperature increased, but carotid blood temperature increased more than did brain temperature resulting in increased selective brain cooling. There was considerable inter-individual variation in the degree to which individual sheep used selective brain cooling. In general, sheep spent more time using selective brain cooling, and it was of greater magnitude, when dehydrated compared to when they were euhydrated. We found a significant positive correlation between selective brain cooling magnitude and osmolality (an index of hydration state). Both the magnitude of selective brain cooling and the proportion of time that sheep spent selective brain cooling were negatively correlated with water turnover. Sheep that used selective brain cooling more frequently, and with greater magnitude, lost less water than did conspecifics using selective brain cooling less efficiently. Our results show that a 50 kg sheep can save 2.6L of water per day (~60% of daily water intake) when it employs selective brain cooling for 50% of the day during heat exposure. We conclude that selective brain cooling has a water conservation function in artiodactyls. PMID:25675092

  10. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats.

    PubMed

    Ma, Daqing; Hossain, Mahmuda; Pettet, Garry K J; Luo, Yan; Lim, Ta; Akimov, Stanislav; Sanders, Robert D; Franks, Nicholas P; Maze, Mervyn

    2006-02-01

    Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury. PMID:16034370

  11. [Edema and the tropics].

    PubMed

    Holzer, B R

    2004-11-01

    People visiting or living in tropical or subtropical regions are exposed to various factors, which can lead to edema. Tourists staying for only a short time in the tropics are exposed to different risks, with other disease patterns, than people living in the tropics or immigrants from tropical regions. The differential diagnosis of edema and swelling is extensive and it can sometimes be difficult to distinguish classical edema with fluid retention in the extravascular interstitial space, from lymphedema or swelling due to other aetiologies. The patients often connect the edema to their stay in the tropics although it may have been pre-existing with no obvious relation to their travels. Already the long trip in the plane can lead to an "economy class syndrome" due to deep venous thrombosis. Contacts with animal or plant toxins, parasites or parasitic larvae can produce peripheral edema. The diagnosis can often only be made by taking a meticulous history, checking for eosinophilia and with the help of serological investigations. Chronic lymphedema or elephantiasis of the limbs is often due to blocked lymph vessels by filarial worms. It has to be distinguished from other forms as e.g. podoconiosis due to blockage by mineral particles in barefoot walking people. The trend to book adventure and trekking holidays at high altitude leads to high altitude peripheral edema or non-freezing cold injuries such as frostbites and trench foot. Edema can be an unwanted side effect of a range of drugs e.g. nifedipine, which is used to prevent and treat high altitude pulmonary edema. Protein malnutrition, (Kwashiorkor), and vitamin B6 deficiency, (Beri-Beri) are very rarely observed in immigrants and almost never in tourists. A very painful swelling of fingers and hands in children and young adults of African origin can be observed during a sickle cell crisis. Many protein loosing nephropathies connected with plant and animal toxins but also bacterial, viral or parasitic agents, can lead to edema. But very often edema in tourists or immigrants from the tropics is not related to their stay abroad. To take an accurate history of the itinerary, eating habits and exposure to water etc. is very important. Knowledge of the precise epidemiology and geographic distribution of diseases are essential. PMID:15605460

  12. Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model.

    PubMed

    Min, Jia-Wei; Hu, Jiang-Jian; He, Miao; Sanchez, Russell M; Huang, Wen-Xian; Liu, Yu-Qiang; Bsoul, Najeeb Bassam; Han, Song; Yin, Jun; Liu, Wan-Hong; He, Xiao-Hua; Peng, Bi-Wen

    2015-12-01

    Previous studies have demonstrated that the early suppression of HIF-1α after hypoxia-ischemia (HI) injury provides neuroprotection. Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), an HIF-1α inhibitor, is a c-glycosylated flavone that has been identified in medicinal plants. Therefore, we hypothesized that treatment with vitexin would protect against HI brain injury. Newborn rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2 at 37 °C). Vitexin (30, 45 or 60 mg/kg) was administered intraperitoneally at 5 min or 3 h after HI. Vitexin, administered 5 min after HI, was neuroprotective as seen by decreased infarct volume evaluated at 48 h post-HI. This neuroprotection was removed when vitexin was administered 3 h after HI. Neuronal cell death, blood-brain barrier (BBB) integrity, brain edema, HIF-1α and VEGF protein levels were evaluated using a combination of Nissl staining, IgG staining, brain water content, immunohistochemistry and Western blot at 24 and 48 h after HI. The long-term effects of vitexin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests. Vitexin (45 mg/kg) ameliorated brain edema, BBB disruption and neuronal cell death; Upregulation of HIF-1α by dimethyloxalylglycine (DMOG) increased the BBB permeability and brain edema compared to HI alone. Vitexin attenuated the increase in HIF-1α and VEGF. Vitexin also had long-term effects of protecting against the loss of ipsilateral brain and improveing neurobehavioral outcomes. In conclusion, our data indicate early HIF-1α inhibition with vitexin provides both acute and long-term neuroprotection in the developing brain after neonatal HI injury. PMID:26187393

  13. [Neurogenic pulmonary edema. Report of 2 cases].

    PubMed

    Dragosavac, D; Falcão, A L; Araújo, S; Terzi, R G

    1997-06-01

    Neurogenic pulmonary edema is a rare and serious complication in patients with head injury. It also may develop after a variety of cerebral insults such as subarachnoid hemorrhage, brain tumors and after epileptic seizures. Thirty six patients with severe head injury and four patients with cerebrovascular insults treated in Intensive Care Unit of HC-UNICAMP from January to September 1995 were evaluated. In this period there were two patients with neurogenic pulmonary edema, one with head injury and other with intracerebral hemorrhage. Diagnosis was made by rapid onset of pulmonary edema, severe hypoxemia, decrease of pulmonary complacence and diffuse pulmonary infiltrations, without previous history of tracheal aspiration or any other risk factor for development of adult respiratory distress syndrome. In the first case, with severe head trauma, neurogenic pulmonary edema was diagnosed at admission one hour after trauma, associated with severe systemic inflammatory reaction, and good outcome in three days. The second case, with hemorrhagic vascular insult, developed neurogenic pulmonary edema the fourth day after drainage of intracerebral hematoma and died. PMID:9629392

  14. Latest advances in edema

    NASA Technical Reports Server (NTRS)

    Villavicencio, J. L.; Hargens, A. R.; Pikoulicz, E.

    1996-01-01

    Basic concepts in the physiopathology of edema are reviewed. The mechanisms of fluid exchange across the capillary endothelium are explained. Interstitial flow and lymph formation are examined. Clinical disorders of tissue and lymphatic transport, microcirculatory derangements in venous disorders, protein disorders, and lymphatic system disorders are explored. Techniques for investigational imaging of the lymphatic system are explained.

  15. Tracheal mucosal edema in hydrostatic pulmonary edema.

    PubMed

    Baier, H; Onorato, D; Barker, J; Wanner, A

    1994-07-01

    Airway edema has been described in heart failure, and, in animal experiments, airway narrowing was observed with elevated left atrial pressure (Pla). On the basis of double-indicator-dilution principles using helium and dimethylether, we were able to measure a water compartment of the tracheal mucosa (VH2O) in dogs. Hypervolemia with an attendant increase in Pla caused by infusion of 2 liters of dextran increased VH2O from 368 +/- 71 (SE) to 794 +/- 177 microliters (P < 0.01). Pulmonary arterial wedge and central venous pressures (Pcv) rose concomitantly. Increases in pulmonary arterial wedge and Pcv by a left atrial balloon catheter produced similar increases in VH2O, whereas increases in Pcv alone by a right atrial balloon did not increase VH2O. Increasing VH2O by dextran infusion was associated with an increase in pulmonary resistance from 1.16 +/- 0.19 to 2.15 +/- 0.24 cmH2O.l-1.s (P < 0.01). These observations show that fluid accumulation in the lung during pulmonary congestion also involves extraparenchymal airways and is related to Pla rather than right atrial pressure. This indicates that sufficient collateral drainage exists during right-sided but not left-sided pressure elevations. PMID:7961256

  16. Reperfusion pulmonary edema

    SciTech Connect

    Klausner, J.M.; Paterson, I.S.; Mannick, J.A.; Valeri, C.R.; Shepro, D.; Hechtman, H.B. )

    1989-02-17

    Reperfusion following lower-torso ischemia in humans leads to respiratory failure manifest by pulmonary hypertension, hypoxemia, and noncardiogenic pulmonary edema. The mechanism of injury has been studied in the sheep lung lymph preparation, where it has been demonstrated that the reperfusion resulting in pulmonary edema is due to an increase in microvascular permeability of the lung to protein. This respiratory failure caused by reperfusion appears to be an inflammatory reaction associated with intravascular release of the chemoattractants leukotriene B{sub 4} and thromboxane. Histological studies of the lung in experimental animals revealed significant accumulation of neutrophils but not platelets in alveolar capillaries. The authors conclude that thromboxane generated and released from the ischemic tissue is responsible for the transient pulmonary hypertension. Second, it is likely that the chemoattractants are responsible for leukosequestration, and third, neutrophils, oxygen-derived free radicals, and thromboxane moderate the altered lung permeability.

  17. Agents for cerebral edema.

    PubMed

    de los Reyes, R A; Ausman, J I; Diaz, F G

    1981-01-01

    Hyperventilation, ventricular drainage, and mannitol remain the mainstays of the treatment of cerebral edema not amenable to or following surgical therapy. There appears to be good therapeutic rationale for the use of "low-dose" mannitol in more prolonged treatment of intracranial hypertension (Table 5.1). The beneficial effects of steroids, either in "standard" or "high" doses, is less clear but, pending evidence to the contrary, we favor the use of "high-dose" corticosteroid therapy. Barbiturates appear to hold promise, but pending controlled, randomized trials to confirm or refute their efficacy, the logistics of their use, as well as their potential complications, precludes their widespread use outside of major centers. Certainly, the "ideal" agent for the treatment of cerebral edema, one that would selectively mobilize and/or prevent the formation of edema fluid with a rapid onset and prolonged duration of action, and with minimal side effects, remains to be discovered. In the meantime, research to refine the use of the older agents and determine the usefulness of the newer ones should be encouraged. PMID:6797771

  18. Regression of bilateral optic disc edema after discontinuation of amiodarone.

    PubMed

    Shinder, Roman; Frohman, Larry P; Turbin, Roger E

    2006-09-01

    A 54-year-old non-obese woman treated with amiodarone reported blurred vision and had bilateral optic disc edema with relative preservation of visual function. Neurologic examination, brain imaging, and lumbar puncture opening pressures were normal, effectively ruling out increased intracranial pressure. Amiodarone was discontinued and the optic disc edema completely resolved over 15 months. In the absence of alternative explanations for the optic disc findings, amiodarone toxicity is suggested. PMID:16966939

  19. The antioxidative, non-psychoactive tricyclic phenothiazine reduces brain damage after experimental traumatic brain injury in mice.

    PubMed

    Songarj, Phuriphong; Luh, Clara; Staib-Lasarzik, Irina; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

    2015-01-01

    Oxidative stress due to free radical formation is an important mechanism of secondary brain damage following traumatic brain injury (TBI). Phenothiazine has been found to be a strong antioxidant in eukaryotic cells in vitro and in invertebrates in vivo. The present study was designed to determine the neuroprotective potency of unsubstituted phenothiazine in a paradigm of acute brain injury. Thirty minutes after pneumatic, controlled cortical impact (CCI) injury, C57BI6 mice were randomly assigned to "low dose" (3 mg/kg, LD) or "high dose" (30 mg/kg, HD) s.c. phenothiazine or vehicle treatment. Brain lesion, neurofunctional impairment, body weight, and markers of cerebral inflammation were determined 24h after the insult. Phenothiazine treatment dose-dependently reduced brain lesion volume (LD: -19.8%; HD: -26.1%) and posttraumatic body weight loss. There were no significant differences in the neurological function score and in markers of cerebral inflammation (Iba-1 positive cells, TNFα expression), whereas iNOS expression was significantly lower compared to vehicle-treated animals. Phenothiazine appears to modify in a post-treatment protocol certain aspects of secondary brain damage in vivo at unusually low concentrations, in particular the cortical contusion volume after TBI. The potential role of the reduced iNOS expression is unclear at present. PMID:25449871

  20. Brain-computer interfaces and disability: extending embodiment, reducing stigma?

    PubMed

    Aas, Sean; Wasserman, David

    2016-01-01

    Brain-Computer Interfaces (BCIs) now enable an individual without limb function to "move" a detached mechanical arm to perform simple actions, such as feeding herself. This technology may eventually offer almost everyone a way to move objects at a distance, by exercising cognitive control of a mechanical device. At that point, BCIs may be seen less as an assistive technology for disabled people, and more as a tool, like the internet, which can benefit all users. We will argue that BCIs will have a significant but uncertain impact on attitudes toward disabilities and on norms of bodily form and function. It may be liberating, oppressive, or both. Its impact, we argue, will depend - though not in any simple way - on whether BCIs come to be seen as parts of the body itself or as external tools. PMID:26336895

  1. Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report.

    PubMed

    Senda, Noriko; Yamaguchi, Ayane; Nishimura, Hideaki; Shiozaki, Toshiki; Tsuyuki, Shigeru

    2016-03-01

    The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases. PMID:26116144

  2. Luteolin reduces Alzheimer's disease pathologies induced by traumatic brain injury.

    PubMed

    Sawmiller, Darrell; Li, Song; Shahaduzzaman, Md; Smith, Adam J; Obregon, Demian; Giunta, Brian; Borlongan, Cesar V; Sanberg, Paul R; Tan, Jun

    2014-01-01

    Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer's disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI. PMID:24413756

  3. Diabetic Macular Edema

    NASA Astrophysics Data System (ADS)

    Lobo, Conceição; Pires, Isabel; Cunha-Vaz, José

    The optical coherence tomography (OCT), a noninvasive and noncontact diagnostic method, was introduced in 1995 for imaging macular diseases. In diabetic macular edema (DME), OCT scans show hyporeflectivity, due to intraretinal and/or subretinal fluid accumulation, related to inner and/or outer blood-retinal barrier breakdown. OCT tomograms may also reveal the presence of hard exudates, as hyperreflective spots with a shadow, in the outer retinal layers, among others. In conclusion, OCT is a particularly valuable diagnostic tool in DME, helpful both in the diagnosis and follow-up procedure.

  4. Diabetic Macular Edema

    PubMed Central

    Gundogan, Fatih C.; Yolcu, Umit; Akay, Fahrettin; Ilhan, Abdullah; Ozge, Gokhan; Uzun, Salih

    2016-01-01

    Diabetic macular edema (DME), one the most prevalent causes of visual loss in industrialized countries, may be diagnosed at any stage of diabetic retinopathy. The diagnosis, treatment, and follow up of DME have become straightforward with recent developments in fundus imaging, such as optical coherence tomography. Laser photocoagulation, intravitreal injections, and pars plana vitrectomy surgery are the current treatment modalities; however, the positive effects of currently available intravitreally injected agents are temporary. At this point, further treatment choices are needed for a permanent effect. Sources of data selection: The articles published between 1985-2015 years on major databases were searched and most appropriate 40 papers were used to write this review article.

  5. Caspase 1 deficiency reduces inflammation-induced brain transcription

    PubMed Central

    Mastronardi, Claudio; Whelan, Fiona; Yildiz, Ozlem A.; Hannestad, Jonas; Elashoff, David; McCann, Samuel M.; Licinio, Julio; Wong, Ma-Li

    2007-01-01

    The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The CNS regulates many features of SIRS such as fever, cardiovascular, and neuroendocrine responses. Central and systemic manifestations of SIRS can be induced by LPS or IL-1β administration. The crucial role of IL-1β in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1β convertase), a protease that cleaves pro-IL-1β into mature IL-1β. Indeed, casp1 knockout (casp1−/−) mice survive lethal doses of LPS. The key role of IL-1β in sickness behavior and its de novo expression in the CNS during inflammation led us to test the hypothesis that IL-1β plays a major role modulating the brain transcriptome during SIRS. We show a gene–environment effect caused by LPS administration in casp1−/− mice. During SIRS, the expression of several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase, and cyclooxygenase-2, was differentially increased in casp1−/− mice. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders. PMID:17409187

  6. [Differential diagnosis of leg edema].

    PubMed

    Fries, R

    2004-04-15

    Both generalized and localized edema needs to be submitted to a differential diagnostic investigation. In the case of edema affecting the lower extremities, in particular the Stemmer sign which is the inability to tent the skin at the dorsum of the toes is a useful distinguishing aid. If there is acute unilateral swelling of a leg, other processes with diffuse space-consuming processes need to be distinguished from deep venous thrombosis and secondary lymphedema. Chronic bilateral leg edema is usually due to a venous flowoff obstruction (stasis edema). Less commonly, lipedema or a primary lymphedema may be responsible for the swelling. PMID:15222499

  7. Lung injury edema in dogs. Influence of sympathetic ablation.

    PubMed Central

    Dauber, I M; Weil, J V

    1983-01-01

    Increased vascular permeability characterizes lung injury pulmonary edema and renders fluid balance in the injured lung especially sensitive to changes in hydrostatic pressure. Pulmonary edema is often associated with increased sympathetic nervous system activity which can lead to pulmonary venoconstriction. This postcapillary venoconstriction could raise microvascular pressure and might therefore increase edema in the injured lung. We produced lung injury edema in dogs with oleic acid and directly measured small (less than 2 mm) pulmonary vein pressure. We found that the small pulmonary vein pressure was increased from 9.8 +/- 0.5 mmHg to 12.6 +/- 0.5 mmHg (n = 10) by oleic acid injury edema. The increase was not due to a rise in left atrial pressure since the small pulmonary vein-left atrial pressure gradient also increased. To test if this increase in the postcapillary pressure gradient was sympathetically mediated, we either unilaterally ablated the stellate ganglion or produced unilateral alpha adrenergic blockade with phenoxybenzamine before giving oleic acid. Both of these "antisympathetic" interventions prevented the increase in pulmonary vein pressure caused by oleic acid edema in the protected lung but not in the intact contralateral lung. These interventions produced a 30 +/- 6.8% reduction in the amount of edema caused by oleic acid. Restoring the increase in small vein pressure by inflating a balloon in the left atrium of dogs with bilateral stellate ganglion ablations abolished the reduction in edema produced by antisympathetic treatment. However, the decrease in edema was not significantly correlated with the reduction in pulmonary vein pressure. Thus, the mechanism of the effects of these antisympathetic interventions remains unclear. We conclude that lung injury edema causes sympathetically mediated pulmonary venoconstriction and that antisympathetic interventions significantly reduce lung injury edema and microvascular pressure. PMID:6315774

  8. Neurogenic pulmonary edema following Cryptococcal meningoencephalitis associated with HIV infection.

    PubMed

    Kondo, Reiichiro; Sugita, Yasuo; Arakawa, Kenji; Nakashima, Shinji; Umeno, Yumi; Todoroki, Keita; Yoshida, Tomoko; Takase, Yorihiko; Kage, Masayoshi; Oshima, Koichi; Yano, Hirohisa

    2015-08-01

    Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40-year-old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Non-contrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H2 O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm(3) . The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow-Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow-Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus. PMID:25955768

  9. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats.

    PubMed

    Fernández-López, David; Pazos, M Ruth; Tolón, Rosa M; Moro, M Angeles; Romero, Julián; Lizasoain, Ignacio; Martínez-Orgado, José

    2007-09-01

    Neonatal hypoxic-ischemic encephalopathy (NHIE) is a devastating condition for which effective therapeutic treatments are still unavailable. Cannabinoids emerge as neuroprotective substances in adult animal studies; therefore, we aimed herein to test whether cannabinoids might reduce brain damage induced by hypoxiaischemia (HI) in newborn rats. Thus, 7-d-old Wistar rats (P7) were exposed to 8% O2 for 120 min after left carotid artery ligature, then received s.c. vehicle (VEH) (HI+VEH), the cannabinoid agonist WIN55212 (WIN) (0.1 mg/kg), or WIN with the CB1 or CB2 receptor antagonist SR141617 (SR1) (3 mg/kg) or SR141588 (SR2) (2 mg/kg). Brain damage was assessed by magnetic resonance imaging (MRI) at 1, 3, and 7 d after the insult. At the end of the experiment, MRI findings were corroborated by histology (Nissl staining). HI+VEH showed an area of cytotoxic and vasogenic edema at 24 h after the insult, then evolving to necrosis. HI+WIN showed a similar damaged area at 24 h after the insult, but the final necrotic area was reduced by 66%. Coadministration of either SR1 or SR2 reversed the effects of WIN. In conclusion, likely by activating CB1 and CB2 receptors, WIN afforded robust neuroprotection in newborn rats after HI. PMID:17622949

  10. Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury.

    PubMed

    Shultz, Sandy R; Wright, David K; Zheng, Ping; Stuchbery, Ryan; Liu, Shi-Jie; Sashindranath, Maithili; Medcalf, Robert L; Johnston, Leigh A; Hovens, Christopher M; Jones, Nigel C; O'Brien, Terence J

    2015-05-01

    Traumatic brain injury is a common and serious neurodegenerative condition that lacks a pharmaceutical intervention to improve long-term outcome. Hyperphosphorylated tau is implicated in some of the consequences of traumatic brain injury and is a potential pharmacological target. Protein phosphatase 2A is a heterotrimeric protein that regulates key signalling pathways, and protein phosphatase 2A heterotrimers consisting of the PR55 B-subunit represent the major tau phosphatase in the brain. Here we investigated whether traumatic brain injury in rats and humans would induce changes in protein phosphatase 2A and phosphorylated tau, and whether treatment with sodium selenate-a potent PR55 activator-would reduce phosphorylated tau and improve traumatic brain injury outcomes in rats. Ninety young adult male Long-Evans rats were administered either a fluid percussion injury or sham-injury. A proportion of rats were killed at 2, 24, and 72 h post-injury to assess acute changes in protein phosphatase 2A and tau. Other rats were given either sodium selenate or saline-vehicle treatment that was continuously administered via subcutaneous osmotic pump for 12 weeks. Serial magnetic resonance imaging was acquired prior to, and at 1, 4, and 12 weeks post-injury to assess evolving structural brain damage and axonal injury. Behavioural impairments were assessed at 12 weeks post-injury. The results showed that traumatic brain injury in rats acutely reduced PR55 expression and protein phosphatase 2A activity, and increased the expression of phosphorylated tau and the ratio of phosphorylated tau to total tau. Similar findings were seen in post-mortem brain samples from acute human traumatic brain injury patients, although many did not reach statistical significance. Continuous sodium selenate treatment for 12 weeks after sham or fluid percussion injury in rats increased protein phosphatase 2A activity and PR55 expression, and reduced the ratio of phosphorylated tau to total tau, attenuated brain damage, and improved behavioural outcomes in rats given a fluid percussion injury. Notably, total tau levels were decreased in rats 12 weeks after fluid percussion injury, and several other factors, including the use of anaesthetic, the length of recovery time, and that some brain injury and behavioural dysfunction still occurred in rats treated with sodium selenate must be considered in the interpretation of this study. However, taken together these data suggest protein phosphatase 2A and hyperphosphorylated tau may be involved in the neurodegenerative cascade of traumatic brain injury, and support the potential use of sodium selenate as a novel traumatic brain injury therapy. PMID:25771151

  11. Reduced energy utilization in the brain is a feature of an animal model of fatigue.

    PubMed

    Tanaka, Masaaki; Watanabe, Yasuyoshi

    2008-05-01

    Recently, the authors established an animal model of fatigue. The fatigued animals showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain, although their blood glucose level did not differ from that of the control animals. For further clarification, the study measured regional cerebral blood flow, ATP level, and the ability of mitochondria to produce ATP in the brain of the fatigued and control rats. The fatigued animals showed almost equal regional cerebral blood flow, a significantly higher ATP level, and almost equal mitochondria ability to produce ATP. These data suggest that decreased energy utilization in the brain is a feature of fatigue. PMID:18446584

  12. Cerebral embolism: local CFBF and edema measured by CT scanning and Xe inhalation. [Baboons

    SciTech Connect

    Meyer, J.S.; Yamamoto, M.; Hayman, L.A.; Sakai, F.; Nakajima, S.; Armstrong, D.

    1980-01-01

    Serial CT scans were made in baboons after cerebral embolization during stable Xe inhalation for measuring local values for CBF and lambda (brain-blood partition or solubility coefficients), followed by iodine infusion for detecting blood-brain barrier (BBB) damage. Persistent zones of zero flow surrounded by reduced flow were measured predominantly in subcortical regions, which showed gross and microscopic evidence of infarction at necropsy. Overlying cortex was relatively spared. Reduced lambda values attributed to edema appeared within 3 to 5 minutes and progressed up to 60 minutes. Damage to BBB with visible transvascular seepage of iodine began to appear 1 to 1 1/2 hours after embolism. In chronic animals, lambda values were persistently reduced in areas showing histologic infarction. Contralateral hemispheric CBF increased for the first 15 minutes after embolism, followed by progressive reduction after 30 minutes (diaschisis).

  13. Bone marrow derived mesenchymal stem cells alleviated brain injury via down-regulation of interleukin-1β in focal cerebral ischemic rats

    PubMed Central

    Zhao, Yansong; Wang, Xiaoli; Dong, Peng; Xu, Qinyan; Ma, Ze; Mu, Qingjie; Sun, Xihe; Jiang, Zhengchen; Wang, Xin

    2016-01-01

    Interleukin-1β (IL-1β) plays an important role in brain injury after focal ischemia, and bone marrow-derived mesenchymal stem cells (BMSCs) are capable of reducing the expression of IL-1β, we investigated the effects of BMSCs transplantation on brain edema and cerebral infarction as well as the underlying mechanisms via IL-1β. Male Sprague-Dawley rats were randomly divided into five groups: Normal + phosphate-buffered saline (PBS), middle cerebral artery occlusion (MCAO) + PBS, Normal + BMSCs, MCAO + BMSCs and MCAO + IL-1ra (an antagonist of IL-1β). BMSCs were transplanted 24 hours after MCAO, and brain edema was evaluated by Magnetic Resonance Imaging (MRI) and brain water content method after BMSCs transplantation. The expression of NeuN and AQP4 was analyzed by immunofluorescence staining. Protein level of AQP4 and IL-1β was detected by western blot analysis 48 hours after transplantation. The results showed that BMSCs transplantation reduced brain edema by measurement of brain water content and ADC Value of MRI, as well as the expression of AQP4 and IL-1β. It was also found that BMSCs transplantation could alleviate the cerebral infarction volume and neuronal damage. Both the brain edema and the cerebral infarction were associated with IL-1β expression. In conclusion, BMSCs transplantation was capable of alleviating brain edema as well as reducing cerebral infarction via down-regulation of IL-1β expression, thus repair the injured brain in focal cerebral ischemic rats.

  14. Chronic Brain Inflammation: The Neurochemical Basis for Drugs to Reduce Inflammation.

    PubMed

    Jarrott, Bevyn; Williams, Spencer J

    2016-03-01

    It is now recognised that the brain and the peripheral immune system have bidirectional communication in both health and neuronal diseases. Brain inflammation results after both acute injury and also with the appearance of mutated proteins or endogenous neurotoxic metabolites associated with slow neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and some psychiatric disorders. Microglia play a key role in brain inflammation by the release of pro-inflammatory cytokines and with ageing, microglia exhibit 'priming' leading to increased basal release of the pro-inflammatory cytokines. Neurochemical targets to reduce or slow chronic brain inflammation include cyclooxygenase enzymes, Nrf2 transcription factor, angiotensin AT1 receptors and sigma-1 receptors. Development of more selective drugs to act at these targets is occurring but large scale clinical trials to validate the drugs will take significant time. PMID:26177578

  15. N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice.

    PubMed

    Baek, Rena C; Kasperzyk, Julie L; Platt, Frances M; Seyfried, Thomas N

    2008-05-01

    Sandhoff disease involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the beta-subunit gene of beta-hexosaminidase A and B (Hexb gene). Accumulation of these glycosphingolipids (GSLs) produces progressive neurodegeneration, ultimately leading to death. Substrate reduction therapy (SRT) aims to decrease the rate of glycosphingolipid (GSL) biosynthesis to compensate for the impaired rate of catabolism. The imino sugar, N-butyldeoxygalactonojirimycin (NB-DGJ) inhibits the first committed step in GSL biosynthesis. NB-DGJ treatment, administered from postnatal day 2 (p-2) to p-5 (600 mg/kg/day)), significantly reduced total brain ganglioside and GM2 content in the Sandhoff disease (Hexb(-/-)) mice, but did not reduce the content of GA2. We also found that NB-DGJ treatment caused a slight, but significant elevation in brain sialidase activity. The drug had no adverse effects on viability, body weight, brain weight, or brain water content in the mice. No significant alterations in neutral lipids or acidic phospholipids were observed in the NB-DGJ-treated Hexb(-/-) mice. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages. PMID:18207611

  16. Dynamic repertoire of intrinsic brain states is reduced in propofol-induced unconsciousness.

    PubMed

    Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan

    2015-02-01

    The richness of conscious experience is thought to scale with the size of the repertoire of causal brain states, and it may be diminished in anesthesia. We estimated the state repertoire from dynamic analysis of intrinsic functional brain networks in conscious sedated and unconscious anesthetized rats. Functional resonance images were obtained from 30-min whole-brain resting-state blood oxygen level-dependent (BOLD) signals at propofol infusion rates of 20 and 40 mg/kg/h, intravenously. Dynamic brain networks were defined at the voxel level by sliding window analysis of regional homogeneity (ReHo) or coincident threshold crossings (CTC) of the BOLD signal acquired in nine sagittal slices. The state repertoire was characterized by the temporal variance of the number of voxels with significant ReHo or positive CTC. From low to high propofol dose, the temporal variances of ReHo and CTC were reduced by 78% 20% and 76% 20%, respectively. Both baseline and propofol-induced reduction of CTC temporal variance increased from lateral to medial position. Group analysis showed a 20% reduction in the number of unique states at the higher propofol dose. Analysis of temporal variance in 12 anatomically defined regions of interest predicted that the largest changes occurred in visual cortex, parietal cortex, and caudate-putamen. The results suggest that the repertoire of large-scale brain states derived from the spatiotemporal dynamics of intrinsic networks is substantially reduced at an anesthetic dose associated with loss of consciousness. PMID:24702200

  17. Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV.

    PubMed

    Grishchuk, Yulia; Peña, Karina A; Coblentz, Jessica; King, Victoria E; Humphrey, Daniel M; Wang, Shirley L; Kiselyov, Kirill I; Slaugenhaupt, Susan A

    2015-12-01

    Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in the MCOLN1 gene, which encodes the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1). MLIV causes impaired motor and cognitive development, progressive loss of vision and gastric achlorhydria. How loss of TRPML1 leads to severe psychomotor retardation is currently unknown, and there is no therapy for MLIV. White matter abnormalities and a hypoplastic corpus callosum are the major hallmarks of MLIV brain pathology. Here, we report that loss of TRPML1 in mice results in developmental aberrations of brain myelination as a result of deficient maturation and loss of oligodendrocytes. Defective myelination is evident in Mcoln1(-/-) mice at postnatal day 10, an active stage of postnatal myelination in the mouse brain. Expression of mature oligodendrocyte markers is reduced in Mcoln1(-/-) mice at postnatal day 10 and remains lower throughout the course of the disease. We observed reduced Perls' staining in Mcoln1(-/-) brain, indicating lower levels of ferric iron. Total iron content in unperfused brain is not significantly different between Mcoln1(-/-) and wild-type littermate mice, suggesting that the observed maturation delay or loss of oligodendrocytes might be caused by impaired iron handling, rather than by global iron deficiency. Overall, these data emphasize a developmental rather than a degenerative disease course in MLIV, and suggest that there should be a stronger focus on oligodendrocyte maturation and survival to better understand MLIV pathogenesis and aid treatment development. PMID:26398942

  18. Compliant intracortical implants reduce strains and strain rates in brain tissue in vivo

    NASA Astrophysics Data System (ADS)

    Sridharan, Arati; Nguyen, Jessica K.; Capadona, Jeffrey R.; Muthuswamy, Jit

    2015-06-01

    Objective. The objective of this research is to characterize the mechanical interactions of (1) soft, compliant and (2) non-compliant implants with the surrounding brain tissue in a rodent brain. Understanding such interactions will enable the engineering of novel materials that will improve stability and reliability of brain implants. Approach. Acute force measurements were made using a load cell in n = 3 live rats, each with 4 craniotomies. Using an indentation method, brain tissue was tested for changes in force using established protocols. A total of 4 non-compliant, bare silicon microshanks, 3 non-compliant polyvinyl acetate (PVAc)-coated silicon microshanks, and 6 compliant, nanocomposite microshanks were tested. Stress values were calculated by dividing the force by surface area and strain was estimated using a linear stress-strain relationship. Micromotion effects from breathing and vascular pulsatility on tissue stress were estimated from a 5 s interval of steady-state measurements. Viscoelastic properties were estimated using a second-order Prony series expansion of stress-displacement curves for each shank. Main results. The distribution of strain values imposed on brain tissue for both compliant nanocomposite microshanks and PVAc-coated, non-compliant silicon microshanks were significantly lower compared to non-compliant bare silicon shanks. Interestingly, step-indentation experiments also showed that compliant, nanocomposite materials significantly decreased stress relaxation rates in the brain tissue at the interface (p < 0.05) compared to non-compliant silicon and PVAc-coated silicon materials. Furthermore, both PVAc-coated non-compliant silicon and compliant nanocomposite shanks showed significantly reduced (by 4-5 fold) stresses due to tissue micromotion at the interface. Significance. The results of this study showed that soft, adaptive materials reduce strains and strain rates and micromotion induced stresses in the surrounding brain tissue. Understanding the material behavior at the site of tissue contact will help to improve neural implant design.

  19. N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis.

    PubMed

    Kasperzyk, Julie L; El-Abbadi, Mohga M; Hauser, Eric C; D'Azzo, Alessandra; Platt, Frances M; Seyfried, Thomas N

    2004-05-01

    GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid beta-galactosidase (beta-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Substrate reduction therapy aims to decrease the rate of GSL biosynthesis to counterbalance the impaired rate of catabolism. The imino sugar N-butyldeoxygalactonojirimycin (NB-DGJ) is a competitive inhibitor of the ceramide-specific glucosyltransferase that catalyzes the first step in GSL biosynthesis. Neonatal C57BL/6J (B6) and beta-gal knockout (-/-) mice were injected daily from post-natal day 2 (p-2) to p-5 with either vehicle or NB-DGJ at 600 mg or 1200 mg/kg body weight. These drug concentrations significantly reduced total brain ganglioside and GM1 content in the B6 and the beta-gal (-/-) mice. Drug treatment had no significant effect on viability, body weight, brain weight, or brain water content in the B6 and beta-gal (-/-) mice. Significant elevations in neutral lipids (GA1, ceramide, and sphingomyelin) were observed in the NB-DGJ-treated beta-gal (-/-) mice, but were not associated with adverse effects. Also, NB-DGJ treatment of B6 and beta-gal (-/-) mice from p-2 to p-5 had no subsequent effect on brain ganglioside content at p-21. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM1 content at early neonatal ages. These findings suggest that substrate reduction therapy using NB-DGJ may be an effective early intervention for GM1 gangliosidosis and possibly other GSL lysosomal storage diseases. PMID:15086521

  20. Delayed localized hypothermia reduces intracranial pressure following collagenase-induced intracerebral hemorrhage in rat.

    PubMed

    John, Roseleen F; Colbourne, Frederick

    2016-02-15

    Brain injury, such as from intracerebral hemorrhage (ICH), causes edema and raises intracranial pressure (ICP) - a potentially life-threatening complication. Clinical studies suggest that therapeutic hypothermia (TH) reduces edema and ICP after ICH. Similarly, animal studies show that TH can sometimes reduce edema, but whether ICP would be attenuated is not known. Here we tested whether 24-h delayed TH reduces edema and ICP in rats with severe striatal ICH (collagenase model). First, we showed that ICH increased epidural ICP (mean of 18 vs. 6.5mm Hg in controls), measured via telemetry. Second, we confirmed that delayed TH did not affect hematoma size at 7day (~65 vs. ~61L in controls). A cranial cooling device lowered striatal temperature to ~33C from 24 to 72h after ICH. Third, we compared normothermic rats to those with TH that were rewarmed immediately or over 6h. Both TH protocols significantly reduced average and peak ICP by the second treatment day, and benefits persisted after rewarming. However, TH with slow rewarming failed to mitigate edema at 96h (83.2% vs. 83.6% in controls) whereas rapid rewarming worsened edema (85.7%). Finally, we compared normothermic and TH rats without rewarming and found no impact on edema at 72h (~81%). In summary, it appears that 24-h delayed local TH lowers ICP by a mechanism other than edema. Rapid rewarming worsens edema after local cooling, but this did not markedly impact ICP. Thus, TH should reduce ICP in patients with severe ICH, but not necessarily through mitigating edema. PMID:26723566

  1. Cerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys

    PubMed Central

    Gonzales, Lauren A.; Benefit, Brenda R.; McCrossin, Monte L.; Spoor, Fred

    2015-01-01

    Analysis of the only complete early cercopithecoid (Old World monkey) endocast currently known, that of 15-million-year (Myr)-old Victoriapithecus, reveals an unexpectedly small endocranial volume (ECV) relative to body size and a large olfactory bulb volume relative to ECV, similar to extant lemurs and Oligocene anthropoids. However, the Victoriapithecus brain has principal and arcuate sulci of the frontal lobe not seen in the stem catarrhine Aegyptopithecus, as well as a distinctive cercopithecoid pattern of gyrification, indicating that cerebral complexity preceded encephalization in cercopithecoids. Since larger ECVs, expanded frontal lobes, and reduced olfactory bulbs are already present in the 17- to 18-Myr-old ape Proconsul these features evolved independently in hominoids (apes) and cercopithecoids and much earlier in the former. Moreover, the order of encephalization and brain reorganization was apparently different in hominoids and cercopithecoids, showing that brain size and cerebral organization evolve independently. PMID:26138795

  2. Cerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys.

    PubMed

    Gonzales, Lauren A; Benefit, Brenda R; McCrossin, Monte L; Spoor, Fred

    2015-01-01

    Analysis of the only complete early cercopithecoid (Old World monkey) endocast currently known, that of 15-million-year (Myr)-old Victoriapithecus, reveals an unexpectedly small endocranial volume (ECV) relative to body size and a large olfactory bulb volume relative to ECV, similar to extant lemurs and Oligocene anthropoids. However, the Victoriapithecus brain has principal and arcuate sulci of the frontal lobe not seen in the stem catarrhine Aegyptopithecus, as well as a distinctive cercopithecoid pattern of gyrification, indicating that cerebral complexity preceded encephalization in cercopithecoids. Since larger ECVs, expanded frontal lobes, and reduced olfactory bulbs are already present in the 17- to 18-Myr-old ape Proconsul these features evolved independently in hominoids (apes) and cercopithecoids and much earlier in the former. Moreover, the order of encephalization and brain reorganization was apparently different in hominoids and cercopithecoids, showing that brain size and cerebral organization evolve independently. PMID:26138795

  3. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease.

    PubMed

    de Hemptinne, Coralie; Swann, Nicole C; Ostrem, Jill L; Ryapolova-Webb, Elena S; San Luciano, Marta; Galifianakis, Nicholas B; Starr, Philip A

    2015-05-01

    Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons. PMID:25867121

  4. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease

    PubMed Central

    de Hemptinne, Coralie; Swann, Nicole; Ostrem, Jill L.; Ryapolova-Webb, Elena S.; Luciano, Marta San; Galifianakis, Nicholas; Starr, Philip A.

    2015-01-01

    Deep brain stimulation (DBS) is increasingly applied to the treatment of brain disorders, but its mechanism of action remains unknown. Here, we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the β rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive β phase locking of motor cortex neurons. PMID:25867121

  5. Pemetrexed-induced eyelid edema in lung cancer.

    PubMed

    Martins-Filho, Paulo Ricardo Saquete; Kameo, Simone Yuriko; Mascarenhas-Oliveira, Ana Carolina; Vieira, Nivaldo Farias; Azevedo, Eduardo

    2013-07-01

    Pemetrexed is a novel, multitargeted antifolate approved for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. Although pemetrexed is a safe drug, some adverse effects such as myelosupression and cutaneous reactions are observed. Pemetrexed-induced eyelid edema is a rare side effect of pemetrexed treatment, and until this moment few cases were reported in the medical literature. We reported a new case of pemetrexed-induced eyelid edema in a patient with adenocarcinoma of the lung with brain metastases. PMID:23851735

  6. Reversible lesions in the brain parenchyma in Wilson's disease confirmed by magnetic resonance imaging: earlier administration of chelating therapy can reduce the damage to the brain

    PubMed Central

    Kozić, Duško B.; Petrović, Igor; Svetel, Marina; Pekmezović, Tatjana; Ragaji, Aleksandar; Kostić, Vladimir S.

    2014-01-01

    The aim of this study was to evaluate the resolution of brain lesions in patients with Wilson's disease during the long-term chelating therapy using magnetic resonance imaging and a possible significance of the time latency between the initial symptoms of the disease and the introduction of this therapy. Initial magnetic resonance examination was performed in 37 patients with proven neurological form of Wilson's disease with cerebellar, parkinsonian and dystonic presentation. Magnetic resonance reexamination was done 5.7 ± 1.3 years later in 14 patients. Patients were divided into: group A, where chelating therapy was initiated < 24 months from the first symptoms and group B, where the therapy started ≥ 24 months after the initial symptoms. Symmetry of the lesions was seen in 100% of patients. There was a significant difference between groups A and B regarding complete resolution of brain stem and putaminal lesions (P = 0.005 and P = 0.024, respectively). If the correct diagnosis and adequate treatment are not established less than 24 months after onset of the symptoms, irreversible lesions in the brain parenchyma could be expected. Signal abnormalities on magnetic resonance imaging might therefore, at least in the early stages, represent reversible myelinolisis or cytotoxic edema associated with copper toxicity. PMID:25558242

  7. Passive Immunization Reduces Murine Cytomegalovirus-Induced Brain Pathology in Newborn Mice▿

    PubMed Central

    Cekinović, Đurđica; Golemac, Mijo; Pugel, Ester Pernjak; Tomac, Jelena; Čičin-Šain, Luka; Slavuljica, Irena; Bradford, Russell; Misch, Sonja; Winkler, Thomas H.; Mach, Michael; Britt, William J.; Jonjić, Stipan

    2008-01-01

    Human cytomegalovirus (HCMV) is the most frequent cause of congenital viral infections in humans and frequently leads to long-term central nervous system (CNS) abnormalities that include learning disabilities, microcephaly, and hearing loss. The pathogenesis of the CNS infection has not been fully elucidated and may arise as a result of direct damage of CMV-infected neurons or indirectly secondary to inflammatory response to infection. We used a recently established model of mouse CMV (MCMV) infection in newborn mice to analyze the contribution of humoral immunity to virus clearance from the brain. In brains of MCMV-infected newborn mice treated with immune serum, the titer of infectious virus was reduced below detection limit, whereas in the brains of mice receiving control (nonimmune) serum significant amounts of virus were recovered. Moreover, histopathological and immunohistological analyses revealed significantly less CNS inflammation in mice treated with immune serum. Treatment with MCMV-specific monoclonal antibodies also resulted in the reduction of virus titer in the brain. Recipients of control serum or irrelevant antibodies had more viral foci, marked mononuclear cell infiltrates, and prominent glial nodules in their brains than mice treated with immune serum or MCMV-specific antibodies. In conclusion, our data indicate that virus-specific antibodies have a protective role in the development of CNS pathology in MCMV-infected newborn mice, suggesting that antiviral antibodies may be an important component of protective immunological responses during CMV infection of the developing CNS. PMID:18842707

  8. Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice.

    PubMed

    Cekinović, Durdica; Golemac, Mijo; Pugel, Ester Pernjak; Tomac, Jelena; Cicin-Sain, Luka; Slavuljica, Irena; Bradford, Russell; Misch, Sonja; Winkler, Thomas H; Mach, Michael; Britt, William J; Jonjić, Stipan

    2008-12-01

    Human cytomegalovirus (HCMV) is the most frequent cause of congenital viral infections in humans and frequently leads to long-term central nervous system (CNS) abnormalities that include learning disabilities, microcephaly, and hearing loss. The pathogenesis of the CNS infection has not been fully elucidated and may arise as a result of direct damage of CMV-infected neurons or indirectly secondary to inflammatory response to infection. We used a recently established model of mouse CMV (MCMV) infection in newborn mice to analyze the contribution of humoral immunity to virus clearance from the brain. In brains of MCMV-infected newborn mice treated with immune serum, the titer of infectious virus was reduced below detection limit, whereas in the brains of mice receiving control (nonimmune) serum significant amounts of virus were recovered. Moreover, histopathological and immunohistological analyses revealed significantly less CNS inflammation in mice treated with immune serum. Treatment with MCMV-specific monoclonal antibodies also resulted in the reduction of virus titer in the brain. Recipients of control serum or irrelevant antibodies had more viral foci, marked mononuclear cell infiltrates, and prominent glial nodules in their brains than mice treated with immune serum or MCMV-specific antibodies. In conclusion, our data indicate that virus-specific antibodies have a protective role in the development of CNS pathology in MCMV-infected newborn mice, suggesting that antiviral antibodies may be an important component of protective immunological responses during CMV infection of the developing CNS. PMID:18842707

  9. Dosimetric Predictors of Laryngeal Edema

    SciTech Connect

    Sanguineti, Giuseppe . E-mail: gisangui@utmb.edu; Adapala, Prashanth; Endres, Eugene J. C; Brack, Collin; Fiorino, Claudio; Sormani, Maria Pia; Parker, Brent

    2007-07-01

    Purpose: To investigate dosimetric predictors of laryngeal edema after radiotherapy (RT). Methods and Materials: A total of 66 patients were selected who had squamous cell carcinoma of the head and neck with grossly uninvolved larynx at the time of RT, no prior major surgical operation except for neck dissection and tonsillectomy, treatment planning data available for analysis, and at least one fiberoptic examination of the larynx within 2 years from RT performed by a single observer. Both the biologically equivalent mean dose at 2 Gy per fraction and the cumulative biologic dose-volume histogram of the larynx were extracted for each patient. Laryngeal edema was prospectively scored after treatment. Time to endpoint, moderate or worse laryngeal edema (Radiation Therapy Oncology Group Grade 2+), was calculated with log rank test from the date of treatment end. Results: At a median follow-up of 17.1 months (range, 0.4- 50.0 months), the risk of Grade 2+ edema was 58.9% {+-} 7%. Mean dose to the larynx, V30, V40, V50, V60, and V70 were significantly correlated with Grade 2+ edema at univariate analysis. At multivariate analysis, mean laryngeal dose (continuum, hazard ratio, 1.11; 95% confidence interval, 1.06-1.15; p < 0.001), and positive neck stage at RT (N0-x vs. N +, hazard ratio, 3.66; 95% confidence interval, 1.40-9.58; p = 0.008) were the only independent predictors. Further stratification showed that, to minimize the risk of Grade 2+ edema, the mean dose to the larynx has to be kept {<=}43.5 Gy at 2 Gy per fraction. Conclusion: Laryngeal edema is strictly correlated with various dosimetric parameters; mean dose to the larynx should be kept {<=}43.5 Gy.

  10. Reduced Field of View Diffusion Weighted Imaging of the Brain at 7T

    PubMed Central

    von Morze, Cornelius; Kelley, Douglas A.C.; Shepherd, Timothy M.; Banerjee, Suchandrima; Xu, Duan; Hess, Christopher P.

    2010-01-01

    Ventral and rostral regions of the brain are of emerging importance for the MRI characterization of early dementia, traumatic brain injury, and epilepsy. Unfortunately, standard single shot echo planar diffusion weighted imaging of these regions at high fields is contaminated by severe imaging artifacts in the vicinity of air-tissue interfaces. To mitigate these artifacts and improve visualization of the temporal and frontal lobes at 7T, we applied a reduced field of view strategy, enabled by outer volume suppression with novel quadratic phase radiofrequency pulses, combined with partial Fourier and parallel imaging methods. The new acquisition greatly reduced the level of artifacts in six human subjects (including four patients with early symptoms of dementia). PMID:20850242

  11. Acupuncture at Baihui and Dazhui reduces brain cell apoptosis in heroin readdicts.

    PubMed

    Hou, Xiaorong; Zhang, Rongjun; Lv, Hang; Cai, Xinghui; Xie, Guangchuan; Song, Xiaoge

    2014-01-15

    Acupuncture at Baihui (GV20) and Dazhui (GV14) reduces neuronal loss and attenuates ultrastructural damage in cerebral ischemic rats. However, whether acupuncture can treat addiction and prevent readdiction through changes to brain cell ultrastructure remains unknown. In this study, cell apoptosis was observed in the hippocampus and frontal lobe of heroin readdicted rats by electron microscopy. Immunohistochemical staining displayed a reduction in Bcl-2 expression and an increase in Bax expression in the hippocampus and frontal lobe. After rats were given acupuncture at Baihui and Dazhui, the pathological damage in the hippocampus and frontal lobe was significantly reduced, Bcl-2 expression was upregulated and Bax expression was downregulated. Acupuncture exerted a similar effect with methadone, a commonly used drug for clinical treatment of drug addiction. Experimental findings suggest that acupuncture at Dazhui and Baihui can prevent brain cell apoptosis in heroin readdicted rats. PMID:25206797

  12. Neonatal neuronal overexpression of glycogen synthase kinase-3 beta reduces brain size in transgenic mice.

    PubMed

    Spittaels, K; Van den Haute, C; Van Dorpe, J; Terwel, D; Vandezande, K; Lasrado, R; Bruynseels, K; Irizarry, M; Verhoye, M; Van Lint, J; Vandenheede, J R; Ashton, D; Mercken, M; Loos, R; Hyman, B; Van der Linden, A; Geerts, H; Van Leuven, F

    2002-01-01

    Glycogen synthase kinase-3beta (GSK-3beta) is important in neurogenesis. Here we demonstrate that the kinase influenced post-natal maturation and differentiation of neurons in vivo in transgenic mice that overexpress a constitutively active GSK-3beta[S9A]. Magnetic resonance imaging revealed a reduced volume of the entire brain, concordant with a nearly 20% reduction in wet brain weight. The reduced volume was most prominent for the cerebral cortex, without however, disturbing the normal cortical layering. The resulting compacted architecture was further demonstrated by an increased neuronal density, by reduced size of neuronal cell bodies and of the somatodendritic compartment of pyramidal neurons in the cortex. No evidence for apoptosis was obtained. The marked overall reduction in the level of the microtubule-associated protein 2 in brain and in spinal cord, did not affect the ultrastructure of the microtubular cytoskeleton in the proximal apical dendrites. The overall reduction in size of the entire CNS induced by constitutive active GSK-3beta caused only very subtle changes in the psychomotoric ability of adult and ageing GSK-3beta transgenic mice. PMID:12182887

  13. Dynamic Repertoire of Intrinsic Brain States Is Reduced in Propofol-Induced Unconsciousness

    PubMed Central

    Liu, Xiping; Pillay, Siveshigan

    2015-01-01

    Abstract The richness of conscious experience is thought to scale with the size of the repertoire of causal brain states, and it may be diminished in anesthesia. We estimated the state repertoire from dynamic analysis of intrinsic functional brain networks in conscious sedated and unconscious anesthetized rats. Functional resonance images were obtained from 30-min whole-brain resting-state blood oxygen level-dependent (BOLD) signals at propofol infusion rates of 20 and 40 mg/kg/h, intravenously. Dynamic brain networks were defined at the voxel level by sliding window analysis of regional homogeneity (ReHo) or coincident threshold crossings (CTC) of the BOLD signal acquired in nine sagittal slices. The state repertoire was characterized by the temporal variance of the number of voxels with significant ReHo or positive CTC. From low to high propofol dose, the temporal variances of ReHo and CTC were reduced by 78%±20% and 76%±20%, respectively. Both baseline and propofol-induced reduction of CTC temporal variance increased from lateral to medial position. Group analysis showed a 20% reduction in the number of unique states at the higher propofol dose. Analysis of temporal variance in 12 anatomically defined regions of interest predicted that the largest changes occurred in visual cortex, parietal cortex, and caudate-putamen. The results suggest that the repertoire of large-scale brain states derived from the spatiotemporal dynamics of intrinsic networks is substantially reduced at an anesthetic dose associated with loss of consciousness. PMID:24702200

  14. Melatonin treatment reduces astrogliosis and apoptosis in rats with traumatic brain injury

    PubMed Central

    Babaee, Abdolreza; Eftekhar-Vaghefi, Seyed Hassan; Asadi-shekaari, Majid; Shahrokhi, Nader; Soltani, Samereh Dehghani; Malekpour-Afshar, Reza; Basiri, Mohsen

    2015-01-01

    Objective(s): Melatonin is known as an anti-inflammatory agent, and it has been proven to exert neuroprotection through inhibition of cell death (apoptosis) in several models of brain injury. Secondary injury following the primary traumatic brain injury (TBI) results in glial cells activation, especially astrocytes. In fact, astrocyte activation causes the production of pro-inflammatory cytokines that may lead to secondary injury. Since most TBI research studies have focused on injured neurons and paid little attention to glial cells, the aim of current study was to investigate the effects of melatonin against astrocytes activation (astrogliosis), as well as inhibition of apoptosis in brain tissue of male rats after TBI. Materials and Methods: The animals were randomly allocated into five groups: sham group, TBI+ vehicle group (1% ethanol in saline) and TBI+ melatonin groups (5 mg/kg, 10 mg/kg and 20 mg/kg). All rats were intubated and then exposed to diffuse TBI, except for the sham group. Immunohistochemical methods were conducted using glial fibrillary acidic protein (GFAP) marker and TUNEL assay to evaluate astrocyte reactivity and cell death, respectively. Results: The results showed that based on the number of GFAP positive astrocytes in brain cortex, astrogliosis was reduced significantly (P<0.05) in melatonin- treated groups (no dose dependent) compared to the vehicle group. Furthermore, based on TUNEL results, melatonin treatment considerably reduced the number of apoptotic cells (P<0.05). Conclusion: In total, the present findings suggest that melatonin treatment following TBI diminishes astrocyte reactivity and neuronal cells apoptosis in brain cortex in the rat model. PMID:26523219

  15. Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV

    PubMed Central

    Grishchuk, Yulia; Peña, Karina A.; Coblentz, Jessica; King, Victoria E.; Humphrey, Daniel M.; Wang, Shirley L.; Kiselyov, Kirill I.; Slaugenhaupt, Susan A.

    2015-01-01

    ABSTRACT Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in the MCOLN1 gene, which encodes the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1). MLIV causes impaired motor and cognitive development, progressive loss of vision and gastric achlorhydria. How loss of TRPML1 leads to severe psychomotor retardation is currently unknown, and there is no therapy for MLIV. White matter abnormalities and a hypoplastic corpus callosum are the major hallmarks of MLIV brain pathology. Here, we report that loss of TRPML1 in mice results in developmental aberrations of brain myelination as a result of deficient maturation and loss of oligodendrocytes. Defective myelination is evident in Mcoln1−/− mice at postnatal day 10, an active stage of postnatal myelination in the mouse brain. Expression of mature oligodendrocyte markers is reduced in Mcoln1−/− mice at postnatal day 10 and remains lower throughout the course of the disease. We observed reduced Perls' staining in Mcoln1−/− brain, indicating lower levels of ferric iron. Total iron content in unperfused brain is not significantly different between Mcoln1−/− and wild-type littermate mice, suggesting that the observed maturation delay or loss of oligodendrocytes might be caused by impaired iron handling, rather than by global iron deficiency. Overall, these data emphasize a developmental rather than a degenerative disease course in MLIV, and suggest that there should be a stronger focus on oligodendrocyte maturation and survival to better understand MLIV pathogenesis and aid treatment development. PMID:26398942

  16. Acute Hemorrhagic Edema of Infancy.

    PubMed

    Serra E Moura Garcia, C; Sokolova, A; Torre, M L; Amaro, C

    2016-01-01

    Acute Hemorrhagic Edema of Infancy is a small vessel leucocytoclastic vasculitis affecting young infants. It is characterized by large, target-like, macular to purpuric plaques predominantly affecting the face, ear lobes and extremities. Non-pitting edema of the distal extremities and low-grade fever may also be present. Extra-cutaneous involvement is very rare. Although the lesions have a dramatic onset in a twenty-four to forty-eight hour period, usually the child has a non-toxic appearance. In most cases there are no changes in laboratory parameters. The cutaneous biopsy reveals an inflammatory perivascular infiltrate. It is a benign and auto-limited disease, with complete resolution within two to three weeks leaving no sequelae in the majority of cases. No recurrences are described. We report a case of a 42-day old girl admitted at our hospital with Acute Hemorrhagic Edema of Infancy. PMID:26808448

  17. Reducing Traumatic Brain Injuries in Youth Sports: Youth Sports Traumatic Brain Injury State Laws, January 2009–December 2012

    PubMed Central

    2013-01-01

    Objectives. I sought to describe current state-wide youth sports traumatic brain injury (TBI) laws and their relationship to prevailing scientific understandings of youth sports TBIs, and to facilitate further research by creating an open-source data set of current laws. Methods. I used Westlaw and LexisNexis databases to create a 50-state data set of youth sports TBI laws enacted between January 2009 and December 2012. I collected and coded the text and citations of each law and developed a protocol and codebook to facilitate future research. Results. Forty-four states and Washington, DC, passed youth sports TBI laws between 2009 and 2012. No state’s youth sports TBI law focuses on primary prevention. Instead, such laws focus on (1) increasing coaches’ and parents’ ability to identify and respond to TBIs and (2) reducing the immediate risk of multiple TBIs. Conclusions. Existing youth sports TBI laws were not designed to reduce initial TBIs. Evaluation is required to assess their effectiveness in reducing the risk and consequences of multiple TBIs. Continued research and evaluation of existing laws will be needed to develop a more comprehensive youth TBI-reduction solution. PMID:23678903

  18. Pathophysiology, Evaluation, and Management of Edema in Childhood Nephrotic Syndrome

    PubMed Central

    Ellis, Demetrius

    2016-01-01

    Generalized edema is a major presenting clinical feature of children with nephrotic syndrome (NS) exemplified by such primary conditions as minimal change disease (MCD). In these children with classical NS and marked proteinuria and hypoalbuminemia, the ensuing tendency to hypovolemia triggers compensatory physiological mechanisms, which enhance renal sodium (Na+) and water retention; this is known as the “underfill hypothesis.” Edema can also occur in secondary forms of NS and several other glomerulonephritides, in which the degree of proteinuria and hypoalbuminemia, are variable. In contrast to MCD, in these latter conditions, the predominant mechanism of edema formation is “primary” or “pathophysiological,” Na+ and water retention; this is known as the “overfill hypothesis.” A major clinical challenge in children with these disorders is to distinguish the predominant mechanism of edema formation, identify other potential contributing factors, and prevent the deleterious effects of diuretic regimens in those with unsuspected reduced effective circulatory volume (i.e., underfill). This article reviews the Starling forces that become altered in NS so as to tip the balance of fluid movement in favor of edema formation. An understanding of these pathomechanisms then serves to formulate a more rational approach to prevention, evaluation, and management of such edema. PMID:26793696

  19. Frequency dependence of phase shift in edema: a theoretical study with magnetic induction.

    PubMed

    Gonzalez, Cesar; Rubinsky, Boris

    2005-01-01

    A spectroscopic distribution of induction phase shift as a function of relative volume of edema in the brain, lung and muscle was produced from available tissue data and a simple mathematical model of electromagnetic induction in tissue. The results show that the phase shift is sensitive to the relative volume of edema at frequencies higher than approximately 10 MHz. The behaviors of brain, lung and muscle tissues are substantially different from each other. Increasing the volume of tissue has the effect of lowering the frequency at which the phase shift becomes sensitive to the volume of edema. The results indicate that induction measurement of the phase shift has the potential for becoming a robust means for non-contact detection of edema in brain, lung and muscle tissues. PMID:17280983

  20. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis

    PubMed Central

    Wilkins, Heather M.; Harris, Janna L.; Carl, Steven M.; E, Lezi; Lu, Jianghua; Eva Selfridge, J.; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M.; Michaelis, Mary L.; Michaelis, Elias K.; Brooks, William M.; Swerdlow, Russell H.

    2014-01-01

    Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1–2 g/kg once per day for 1–2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. 1H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. PMID:25027327

  1. Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains.

    PubMed

    Adzovic, Linda; Lynn, Ashley E; D'Angelo, Heather M; Crockett, Alexis M; Kaercher, Roxanne M; Royer, Sarah E; Hopp, Sarah C; Wenk, Gary L

    2015-01-01

    The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain. PMID:25889938

  2. Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways.

    PubMed

    Folgueira, Cintia; Beiroa, Daniel; Callon, Aurelie; Al-Massadi, Omar; Barja-Fernandez, Silvia; Senra, Ana; Fernø, Johan; López, Miguel; Dieguez, Carlos; Casanueva, Felipe F; Rohner-Jeanrenaud, Françoise; Seoane, Luisa M; Nogueiras, Ruben

    2016-02-01

    The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity. PMID:26566631

  3. Decreased light attenuation in cerebral cortex during cerebral edema detected using optical coherence tomography

    PubMed Central

    Rodriguez, Carissa L. R.; Szu, Jenny I.; Eberle, Melissa M.; Wang, Yan; Hsu, Mike S.; Binder, Devin K.; Park, B. Hyle

    2014-01-01

    Abstract. Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema. PMID:25674578

  4. S100B inhibition reduces behavioral and pathologic changes in experimental traumatic brain injury.

    PubMed

    Kabadi, Shruti V; Stoica, Bogdan A; Zimmer, Danna B; Afanador, Lauriaselle; Duffy, Kara B; Loane, David J; Faden, Alan I

    2015-12-01

    Neuroinflammation following traumatic brain injury (TBI) is increasingly recognized to contribute to chronic tissue loss and neurologic dysfunction. Circulating levels of S100B increase after TBI and have been used as a biomarker. S100B is produced by activated astrocytes and can promote microglial activation; signaling by S100B through interaction with the multiligand advanced glycation end product-specific receptor (AGER) has been implicated in brain injury and microglial activation during chronic neurodegeneration. We examined the effects of S100B inhibition in a controlled cortical impact model, using S100B knockout mice or administration of neutralizing S100B antibody. Both interventions significantly reduced TBI-induced lesion volume, improved retention memory function, and attenuated microglial activation. The neutralizing antibody also significantly reduced sensorimotor deficits and improved neuronal survival in the cortex. However, S100B did not alter microglial activation in BV2 cells or primary microglial cultures stimulated by lipopolysaccharide or interferon gamma. Further, proximity ligation assays did not support direct interaction in the brain between S100B and AGER following TBI. Future studies are needed to elucidate specific pathways underlying S100B-mediated neuroinflammatory actions after TBI. Our results strongly implicate S100B in TBI-induced neuroinflammation, cell loss, and neurologic dysfunction, thereby indicating that it is a potential therapeutic target for TBI. PMID:26154869

  5. Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury

    PubMed Central

    Piao, Chun-Shu; Stoica, Bogdan A.; Wu, Junfang; Sabirzhanov, Boris; Zhao, Zaorui; Cabatbat, Rainier; Loane, David J.; Faden, Alan I.

    2013-01-01

    Delayed secondary biochemical and cellular changes after traumatic brain injury continue for months to years, and are associated with chronic neuroinflammation and progressive neurodegeneration. Physical activity can reduce inflammation and facilitate recovery after brain injury. Here, we investigated the time-dependent effects, and underlying mechanisms of post-traumatic exercise initiation on outcome after moderate traumatic brain injury using a well-characterized mouse controlled cortical impact model. Late exercise initiation beginning at 5 weeks after trauma, but not early initiation of exercise at 1 week, significantly reduced working and retention memory impairment at 3 months, and decreased lesion volume compared to non-exercise injury controls. Cognitive recovery was associated with attenuation of classical inflammatory pathways, activation of alternative inflammatory responses and enhancement of neurogenesis. In contrast, early initiation of exercise failed to alter behavioral recovery or lesion size, while increasing the neurotoxic pro-inflammatory responses. These data underscore the critical importance of timing of exercise initiation after trauma and its relation to neuroinflammation, and challenge the widely held view that effective neuroprotection requires early intervention. PMID:23313314

  6. Autologous Bone Marrow Mononuclear Cells Reduce Therapeutic Intensity for Severe Traumatic Brain Injury in Children

    PubMed Central

    Liao, George P.; Harting, Matthew T.; Hetz, Robert A.; Walker, Peter A.; DO, Shinil K. Shah; Corkins, Christopher J.; Hughes, Travis G.; Jimenez, Fernando; Kosmach, Steven C.; Day, Mary-Clare; Tsao, KuoJen; Lee, Dean A.; Worth, Laura L.; Baumgartner, James E.; Cox, Charles S.

    2014-01-01

    Objective The devastating effect of traumatic brain injury (TBI) is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure (ICP) due to cerebral edema. The treatment effect of cell based therapies in the acute post-TBI period has not been clinically studied although preclinical data demonstrate that bone marrow derived mononuclear cell (BMMNC) infusion downregulates the inflammatory response. Our study evaluates whether pediatric TBI patients receiving intravenous, autologous BMMNCs within 48 hours of injury experienced a reduction in therapeutic intensity directed towards managing elevated ICP relative to matched controls. Design The study was a retrospective cohort design comparing pediatric patients in a Phase I clinical trial treated with intravenous autologous BMMNCs (n=10) to a control group of age and severity matched children (n=19). Setting The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000-2008. Patients Study patients were 5-14 years with post resuscitation Glasgow Coma Scale scores of 5-8. Interventions The treatment group received 6 million autologous BMMNC/kg body weight intravenously within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our TBI management protocol, derived from American Association of Neurological Surgeons guidelines. Measurements The primary measure was the Pediatric Intensity Level of Therapy (PILOT) scale, used to quantify treatment of elevated ICP. Secondary measures included the Pediatric Logistic Organ Dysfunction (PELOD) score and days of ICP monitoring as a surrogate for length of neurointensive care. Main Results A repeated measure mixed model with marginal linear predictions identified a significant reduction in the PILOT score beginning at 24 hours post treatment through week one (P<0.05). This divergence was also reflected in the PELOD score following the first week. The duration of ICP monitoring was 8.2±1.3 days in the treated group, and 15.6±3.5 days (p=0.03) in the time matched control group. Conclusions Intravenous autologous BMMNC therapy is associated with lower treatment intensity required to manage ICP, associated severity of organ injury, and duration of neurointensive care following severe TBI. This may corroborate preclinical data that autologous BMMNC therapy attenuates the effects of inflammation in the early post TBI period. PMID:25581630

  7. Reconstruction of the arcuate fasciculus for surgical planning in the setting of peritumoral edema using two-tensor unscented Kalman filter tractography

    PubMed Central

    Chen, Zhenrui; Tie, Yanmei; Olubiyi, Olutayo; Rigolo, Laura; Mehrtash, Alireza; Norton, Isaiah; Pasternak, Ofer; Rathi, Yogesh; Golby, Alexandra J.; O'Donnell, Lauren J.

    2015-01-01

    Background Diffusion imaging tractography is increasingly used to trace critical fiber tracts in brain tumor patients to reduce the risk of post-operative neurological deficit. However, the effects of peritumoral edema pose a challenge to conventional tractography using the standard diffusion tensor model. The aim of this study was to present a novel technique using a two-tensor unscented Kalman filter (UKF) algorithm to track the arcuate fasciculus (AF) in brain tumor patients with peritumoral edema. Methods Ten right-handed patients with left-sided brain tumors in the vicinity of language-related cortex and evidence of significant peritumoral edema were retrospectively selected for the study. All patients underwent 3-Tesla magnetic resonance imaging (MRI) including a diffusion-weighted dataset with 31 directions. Fiber tractography was performed using both single-tensor streamline and two-tensor UKF tractography. A two-regions-of-interest approach was applied to perform the delineation of the AF. Results from the two different tractography algorithms were compared visually and quantitatively. Results Using single-tensor streamline tractography, the AF appeared disrupted in four patients and contained few fibers in the remaining six patients. Two-tensor UKF tractography delineated an AF that traversed edematous brain areas in all patients. The volume of the AF was significantly larger on two-tensor UKF than on single-tensor streamline tractography (p < 0.01). Conclusions Two-tensor UKF tractography provides the ability to trace a larger volume AF than single-tensor streamline tractography in the setting of peritumoral edema in brain tumor patients. PMID:26082890

  8. Progesterone reduces brain mitochondrial dysfunction after transient focal ischemia in male and female mice.

    PubMed

    Gaignard, Pauline; Frchou, Magalie; Schumacher, Michael; Thrond, Patrice; Mattern, Claudia; Slama, Abdelhamid; Guennoun, Rachida

    2016-03-01

    This study investigated the effect of intranasal administration of progesterone on the early brain mitochondrial respiratory chain dysfunction and oxidative damage after transient middle cerebral occlusion in male and female mice. We showed that progesterone (8?mg/kg at 1?h post-middle cerebral occlusion) restored the mitochondrial reduced glutathione pool and the nicotinamide adenine dinucleotide-linked respiration in both sexes. Progesterone also reversed the decrease of the flavin adenine dinucleotide-linked respiration, which was only observed in females. Our findings point to a sex difference in stroke effects on the brain respiratory chain and suggest that the actions of progesterone on mitochondrial function may participate in its neuroprotective properties. PMID:26661198

  9. Melatonin reduces traumatic brain injury-induced oxidative stress in the cerebral cortex and blood of rats

    PubMed Central

    Şenol, Nilgün; Nazıroğlu, Mustafa

    2014-01-01

    Free radicals induced by traumatic brain injury have deleterious effects on the function and antioxidant vitamin levels of several organ systems including the brain. Melatonin possesses antioxidant effect on the brain by maintaining antioxidant enzyme and vitamin levels. We investigated the effects of melatonin on antioxidant ability in the cerebral cortex and blood of traumatic brain injury rats. Results showed that the cerebral cortex β-carotene, vitamin C, vitamin E, reduced glutathione, and erythrocyte reduced glutathione levels, and plasma vitamin C level were decreased by traumatic brain injury whereas they were increased following melatonin treatment. In conclusion, melatonin seems to have protective effects on traumatic brain injury-induced cerebral cortex and blood toxicity by inhibiting free radical formation and supporting antioxidant vitamin redox system. PMID:25206769

  10. Effect of arginine vasopressin on the cortex edema in the ischemic stroke of Mongolian gerbils.

    PubMed

    Zhao, Xue-Yan; Wu, Chun-Fang; Yang, Jun; Gao, Yang; Sun, Fang-Jie; Wang, Da-Xin; Wang, Chang-Hong; Lin, Bao-Cheng

    2015-06-01

    Brain edema formation is one of the most important mechanisms of ischemia-evoked cerebral edema. It has been demonstrated that arginine vasopressin (AVP) receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. In a well-characterized animal model of ischemic stroke of Mongolian gerbils, the present study was undertaken to clear the effect of AVP on cortex edema in cerebral ischemia. The results showed that (1) occluding the left carotid artery of Mongolian gerbils not only decreased the cortex specific gravity (cortex edema) but also increased AVP levels in the ipsilateral cortex (ischemic area) including left prefrontal lobe, left parietal lobe, left temporal lobe, left occipital lobe and left hippocampus for the first 6 hours, and did not change of the cortex specific gravity and AVP concentration in the right cortex (non-ischemic area); (2) there were many negative relationships between the specific gravity and AVP levels in the ischemic cortex; (3) intranasal AVP (50 ng or 200 ng), which could pass through the blood-brain barrier to the brain, aggravated the focal cortex edema, whereas intranasal AVP receptor antagonist-D(CH2)5Tyr(ET)DAVP (2 µg) mitigated the cortex edema in the ischemic area after occluding the left carotid artery of Mongolian gerbils; and (4) either intranasal AVP or AVP receptor antagonist did not evoke that edema in the non-ischemic cortex. The data indicated that AVP participated in the process of ischemia-evoked cortex edema, and the cerebral AVP receptor might serve as an important therapeutic target for the ischemia-evoked cortex edema. PMID:25843346

  11. Brain

    MedlinePlus

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  12. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

    PubMed

    Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E; Redhi, Godfrey H; Panlilio, Leigh V; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R

    2013-11-01

    In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737

  13. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

    PubMed Central

    Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D.; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R.

    2013-01-01

    In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737

  14. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine.

    PubMed

    Wu, D; Kang, Y S; Bickel, U; Pardridge, W M

    1997-06-01

    The blood-brain barrier (BBB) permeability to morphine and morphine-6-glucuronide (M6G) is measured under identical conditions using an intravenous injection method in the rat and HPLC separation of morphine from its metabolites. The brain uptake of M6G expressed as %ID/g was 32-fold lower than that of morphine, and the BBB permeability surface area product (PS) of M6G was 57-fold lower as compared with that of morphine. Consistent with these in vivo data, the 1-octanol/buffer partition study showed the liposolubility of M6G was 187-fold lower than that of morphine. The CNS origin of M6G analgesia after peripheral administration was confirmed because the analgesia was completely blocked by naloxone, which crosses BBB, but not by naloxone methiodide, which does not enter brain from blood. In conclusion, the BBB permeability to M6G is markedly reduced as compared with morphine, consistent with the much lower lipid solubility of M6G relative to morphine. PMID:9193881

  15. Pyrazole antagonists of the CB1 receptor with reduced brain penetration.

    PubMed

    Fulp, Alan; Zhang, Yanan; Bortoff, Katherine; Seltzman, Herbert; Snyder, Rodney; Wiethe, Robert; Amato, George; Maitra, Rangan

    2016-03-01

    Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant. PMID:26827137

  16. Effect of lavender oil (Lavandula angustifolia) on cerebral edema and its possible mechanisms in an experimental model of stroke.

    PubMed

    Vakili, Abedin; Sharifat, Shaghayegh; Akhavan, Maziar Mohammad; Bandegi, Ahmad Reza

    2014-02-22

    Lavender belongs to the family Labiatae and has a variety of cosmetic uses as well as therapeutic purposes in herbal medicine. The present study was conducted to evaluate the protective effect of lavender oil against brain edema and its possible mechanisms in an experimental model of stroke. Under Laser-Doppler Flowmetry, focal cerebral ischemia was induced by the transient occlusion of the middle cerebral artery for 1h in rats. Lavender oil (100, 200, and 400 mg/kg ip (and/or vehicle was injected at the onset of ischemia. Infarct size, cerebral edema, functional outcome, and oxidative stress biomarkers were evaluated using standard methods. Western blotting was used to determine the protein expression of VEGF, Bax, and Bcl-2. Treatment with lavender oil at doses of 200 and 400 mg/kg significantly diminished infarct size, brain edema, and improved functional outcome after cerebral ischemia (P<0.001). Lavender oil (200 mg/kg) also reduced the content of malondialdehyde and increased the activities of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity (P<0.001). Although lavender oil enhanced VEGF expression (P=0.026), it could not decrease the Bax-to-Bcl-2 ratio (pro- to anti-apoptotic proteins) in the rat brain (P>0.05). The results indicated that lavender oil has neuroprotective activity against cerebral ischemia and alleviated neurological function in rats, and the mechanism may be related to augmentation in endogenous antioxidant defense, inhibiting oxidative stress, and increasing VEGF expression in the rat brain. However, lavender oil could not suppress the apoptosis pathway. PMID:24384140

  17. Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress.

    PubMed

    Xia, Huijing; de Queiroz, Thyago Moreira; Sriramula, Srinivas; Feng, Yumei; Johnson, Tanya; Mungrue, Imran N; Lazartigues, Eric

    2015-03-01

    Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. PMID:25519733

  18. Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

    PubMed Central

    de Queiroz, Thyago Moreira; Sriramula, Srinivas; Feng, Yumei; Johnson, Tanya; Mungrue, Imran N.; Lazartigues, Eric

    2014-01-01

    Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. PMID:25519733

  19. Evaluation of Peritumoral Edema in the Delineation of Radiotherapy Clinical Target Volumes for Glioblastoma

    SciTech Connect

    Chang, Eric L. . E-mail: echang@mdanderson.org; Akyurek, Serap; Avalos, Tedde C; Rebueno, Neal C; Spicer, Chris C; Garcia, John C; Famiglietti, Robin; Allen, Pamela K.; Chao, K.S. Clifford; Mahajan, Anita; Woo, Shiao Y.; Maor, Moshe H.

    2007-05-01

    Purpose: To evaluate the spatial relationship between peritumoral edema and recurrence pattern in patients with glioblastoma (GBM). Methods and Materials: Forty-eight primary GBM patients received three-dimensional conformal radiotherapy that did not intentionally include peritumoral edema within the clinical target volume between July 2000 and June 2001. All 48 patients have subsequently recurred, and their original treatment planning parameters were used for this study. New theoretical radiation treatment plans were created for the same 48 patients, based on Radiation Therapy Oncology Group (RTOG) target delineation guidelines that specify inclusion of peritumoral edema. Target volume and recurrent tumor coverage, as well as percent volume of normal brain irradiated, were assessed for both methods of target delineation using dose-volume histograms. Results: A comparison between the location of recurrent tumor and peritumoral edema volumes from all 48 cases failed to show correlation by linear regression modeling (r {sup 2} 0.0007; p = 0.3). For patients with edema >75 cm{sup 3}, the percent volume of brain irradiated to 46 Gy was significantly greater in treatment plans that intentionally included peritumoral edema compared with those that did not (38% vs. 31%; p = 0.003). The pattern of failure was identical between the two sets of plans (40 central, 3 in-field, 3 marginal, and 2 distant recurrence). Conclusion: Clinical target volume delineation based on a 2-cm margin rather than on peritumoral edema did not seem to alter the central pattern of failure for patients with GBM. For patients with peritumoral edema >75 cm{sup 3}, using a constant 2-cm margin resulted in a smaller median percent volume of brain being irradiated to 30 Gy, 46 Gy, and 50 Gy compared with corresponding theoretical RTOG plans that deliberately included peritumoral edema.

  20. Reduced calcium uptake by rat brain mitochondria and synaptosomes in response to aging.

    PubMed

    Leslie, S W; Chandler, L J; Barr, E M; Farrar, R P

    1985-03-11

    Synaptosomes were isolated from cerebral cortex of 3-, 18- and 24-month-old male, Fisher 344 rats and 45Ca2+ uptake was measured at 1, 3, 5, 15 and 30 s time periods following 65 mM KCl depolarization. Identical experiments were performed in which 5 mM KCl was added to examine age-related changes in resting 45Ca2+ accumulation by synaptosomes. Both 'fast-' and 'slow-phase' voltage-dependent 45Ca2+ uptake were significantly reduced in synaptosomes from 18- and 24- vs 3-month-old rats. No age-related change in resting (5 mM KCl) 45Ca2+ accumulation was observed. ATP-dependent and respiration-linked 45Ca2+ uptake was examined in mitochondria isolated from whole brains of 3- and 28-month-old male, hooded Long-Evans rats. Both ATP-dependent and glutamate-malate-ADP stimulated 45Ca2+ uptake by mitochondria were markedly reduced in response to aging. Respiratory control ratios were the same for 3- and 28-month-old mitochondria, suggesting that the decrement in 45Ca2+ uptake was not caused by an age-related decline in respiratory activity of mitochondria. The results of this study show that both voltage-dependent calcium entry into presynaptic nerve terminals and calcium uptake by mitochondria in brain decline with advanced aging. Age-related changes in cytosolic calcium levels could underlie, at least in part, cellular decrements in brain observed with aging. PMID:3978439

  1. β-Hydroxybutyrate supports synaptic vesicle cycling but reduces endocytosis and exocytosis in rat brain synaptosomes.

    PubMed

    Hrynevich, Sviatlana V; Waseem, Tatyana V; Hébert, Audrey; Pellerin, Luc; Fedorovich, Sergei V

    2016-02-01

    The ketogenic diet is used as a prophylactic treatment for different types of brain diseases, such as epilepsy or Alzheimer's disease. In such a diet, carbohydrates are replaced by fats in everyday food, resulting in an elevation of blood-borne ketone bodies levels. Despite clinical applications of this treatment, the molecular mechanisms by which the ketogenic diet exerts its beneficial effects are still uncertain. In this study, we investigated the effect of replacing glucose by the ketone body β-hydroxybutyrate as the main energy substrate on synaptic vesicle recycling in rat brain synaptosomes. First, we observed that exposing presynaptic terminals to nonglycolytic energy substrates instead of glucose did not alter the plasma membrane potential. Next, we found that synaptosomes were able to maintain the synaptic vesicle cycle monitored with the fluorescent dye acridine orange when glucose was replaced by β-hydroxybutyrate. However, in presence of β-hydroxybutyrate, synaptic vesicle recycling was modified with reduced endocytosis. Replacing glucose by pyruvate also led to a reduced endocytosis. Addition of β-hydroxybutyrate to glucose-containing incubation medium was without effect. Reduced endocytosis in presence of β-hydroxybutyrate as sole energy substrate was confirmed using the fluorescent dye FM2-10. Also we found that replacement of glucose by ketone bodies leads to inhibition of exocytosis, monitored by FM2-10. However this reduction was smaller than the effect on endocytosis under the same conditions. Using both acridine orange in synaptosomes and the genetically encoded sensor synaptopHluorin in cortical neurons, we observed that replacing glucose by β-hydroxybutyrate did not modify the pH gradient of synaptic vesicles. In conclusion, the nonglycolytic energy substrates β-hydroxybutyrate and pyruvate are able to support synaptic vesicle recycling. However, they both reduce endocytosis. Reduction of both endocytosis and exocytosis together with misbalance between endocytosis and exocytosis could be involved in the anticonvulsant activity of the ketogenic diet. PMID:26748385

  2. LUNG EDEMA FOLLOWING BILATERAL VAGOTOMY

    PubMed Central

    Lorber, Victor

    1939-01-01

    1. Small animals (rat and guinea pig) vagotomized in the neck die within a period of hours, the lungs showing extensive congestion and edema. 2. Tracheotomy permits appreciably longer survival with minimal lung changes approximating those seen in the control animals. 3. Intrathoracic vagotomy (sparing the recurrent laryngeal nerve) on one side, and cervical vagotomy on the other, permits almost indefinite survival (guinea pig and rabbit), unless laryngeal paralysis from the unilateral denervation produces respiratory obstruction (rat, guinea pig, and rabbit). 4. Pulmonary edema following bilateral vagotomy probably results primarily from respiratory obstruction. It is suggested that circulatory failure may also be a factor of some importance. The rle of vagotomy itself is considered in relationship to these two phenomena. 5. The reaction of smaller animals to bilateral vagotomy, with regard to lung changes, apparently differs in no way from that of the larger animals, but is less readily demonstrated because of the smaller diameters of the air passages. PMID:19870894

  3. Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury

    PubMed Central

    ZHANG, CHENGCHENG; CHEN, JIANQIANG; LU, HONG

    2015-01-01

    Aquaporin 4 (AQP4) is a widely distributed membrane protein, which is found in glial cells, ependymocytes and capillary endothelial cells in the brain, and particularly in the choroid plexus. AQP4 is a key regulator of water metabolism, and changes in its expression following brain injury are associated with pathological changes in the damaged side of the brain; however, the effects of brain injury on AQP4 and injury-induced pathological changes in the contralateral non-damaged side of the brain remain to be fully elucidated. In the present study, male Sprague-Dawley rats were subjected to traumatic brain injury (TBI) and changes in brain water content, the expression of AQP4 expression and pathological characteristics in the damaged and contralateral non-damaged sides of the brain were examined. In the damaged side of the brain, vasogenic edema appeared first, followed by cellular edema. The aggravated cellular edema in the damaged side of the brain resulted in two periods of peak edema severity. Pathological changes in the contralateral non-damaged side of the brain occurred later than those in the damaged side; cellular edema appeared first, followed by vasogenic edema, which was alleviated earlier than the cellular edema. AQP4 was downregulated during vasogenic edema, and upregulated during cellular edema. Taken together, these results suggested that the downregulation of AQP4 was a result of vasogenic edema and that the upregulation of AQP4 may have induced cellular edema. PMID:26459070

  4. CT imaging and spontaneous behavior analysis after osmotic blood-brain barrier opening in Wistar rat.

    PubMed

    Kozler, P; Riljak, V; Jandová, K; Pokorný, J

    2014-01-01

    In our previous experiments we demonstrated that osmotic opening of the blood brain barrier (BBB) in rats by administration of mannitol into the internal carotid artery leads to cerebral edema. The aim of this study was to confirm objectively the development of brain edema and determine whether it affects spontaneous locomotor activity in rats (SLA). Brain edema was verified by computer tomography (CT) examination of the brain and SLA was observed during open field test. Twenty four adult male rats were divided into four groups of six: (1) control animals (C), (2) controls with anesthesia (CA), (3) controls with sham surgery (CS), (4) experimental - osmotic opening of the BBB (MA). Osmotic BBB disruption manifested by reducing the density of brain tissue (hypodensity), suggesting a higher water content in the brain tissue. SLA was compared between C, CA, CS and MA groups and between MA and CA groups. Significant difference was found only between the control group and MA group. In the first 30 min of the examination, rats after the mannitol administration revealed a marked limitation of spontaneous locomotor activity. Experimental results demonstrated reduction of spontaneous locomotor activity in rats with induced brain edema. PMID:25669684

  5. Interstitial pulmonary edema in children and adolescents with diabetic ketoacidosis.

    PubMed

    Hoffman, W H; Locksmith, J P; Burton, E M; Hobbs, E; Passmore, G G; Pearson-Shaver, A L; Deane, D A; Beaudreau, M; Bassali, R W

    1998-01-01

    The acute complications of diabetic ketoacidosis in children and adolescents are well recognized but not completely understood. Clinical studies have focused primarily on brain edema. We have investigated the prevalence and course of interstitial pulmonary edema in patients with severe diabetic ketoacidosis all of whom had uneventful clinical courses. High resolution computed tomography scans of the lungs were analyzed by determining the Hounsfield attenuation level and then converting to physical density values. All seven patients had evidence of interstitial pulmonary edema on the first scan, which was performed within 1 h of hydration and prior to receiving insulin; six of the seven patients had increased pulmonary density 6-8 h into treatment, and all had complete resolution of the interstitial changes at discharge. Our study suggests that subclinical interstitial pulmonary edema may be a frequent occurrence in children and adolescents with severe diabetic ketoacidosis and may very well be present prior to treatment. The study also supports the philosophy of cautious rehydration and the close monitoring of children and adolescents with diabetic ketoacidosis until a more complete understanding of this pathophysiologic event is achieved. PMID:9877465

  6. Pathogenesis of optic disc edema in raised intracranial pressure.

    PubMed

    Hayreh, Sohan Singh

    2016-01-01

    Optic disc edema in raised intracranial pressure was first described in 1853. Ever since, there has been a plethora of controversial hypotheses to explain its pathogenesis. I have explored the subject comprehensively by doing basic, experimental and clinical studies. My objective was to investigate the fundamentals of the subject, to test the validity of the previous theories, and finally, based on all these studies, to find a logical explanation for the pathogenesis. My studies included the following issues pertinent to the pathogenesis of optic disc edema in raised intracranial pressure: the anatomy and blood supply of the optic nerve, the roles of the sheath of the optic nerve, of the centripetal flow of fluids along the optic nerve, of compression of the central retinal vein, and of acute intracranial hypertension and its associated effects. I found that, contrary to some previous claims, an acute rise of intracranial pressure was not quickly followed by production of optic disc edema. Then, in rhesus monkeys, I produced experimentally chronic intracranial hypertension by slowly increasing in size space-occupying lesions, in different parts of the brain. Those produced raised cerebrospinal fluid pressure (CSFP) and optic disc edema, identical to those seen in patients with elevated CSFP. Having achieved that, I investigated various aspects of optic disc edema by ophthalmoscopy, stereoscopic color fundus photography and fluorescein fundus angiography, and light microscopic, electron microscopic, horseradish peroxidase and axoplasmic transport studies, and evaluated the effect of opening the sheath of the optic nerve on the optic disc edema. This latter study showed that opening the sheath resulted in resolution of optic disc edema on the side of the sheath fenestration, in spite of high intracranial CSFP, proving that a rise of CSFP in the sheath was the essential pre-requisite for the development of optic disc edema. I also investigated optic disc edema with raised CSFP in patients, by evaluating optic disc and fundus changes by stereoscopic fundus photography and fluorescein fundus angiography. Based on the combined information from all the studies discussed above, it is clear that the pathogenesis of optic disc edema in raised intracranial pressure is a mechanical phenomenon. It is primarily due to a rise of CSFP in the optic nerve sheath, which produces axoplasmic flow stasis in the optic nerve fibers in the surface nerve fiber layer and prelaminar region of the optic nerve head. Axoplasmic flow stasis then results in swelling of the nerve fibers, and consequently of the optic disc. Swelling of the nerve fibers and of the optic disc secondarily compresses the fine, low-pressure venules in that region, resulting in venous stasis and fluid leakage; that leads to the accumulation of extracellular fluid. Contrary to the previous theories, the various vascular changes seen in optic disc edema are secondary and not primary. Thus, optic disc edema in raised CSFP is due to a combination of swollen nerve fibers and the accumulation of extracellular fluid. My studies also provided information about the pathogeneses of visual disturbances in raised intracranial pressure. PMID:26453995

  7. [Hypoxic brain damage after carbon monoxide poisoning. Visual agnosia, reduced initiative and memory and delayed sequelae].

    PubMed

    Tvedt, B; Krogstad, J M; Berstad, J

    1996-10-20

    Four patients with hypoxic brain damage caused by carbon monoxide poisoning are described. Three of these had attempted suicide with car exhaust fumes. Two patients had visual agnosia due to lesions in the parieto-occipital cortex. Three patients had temporary Parkinsonian symptoms. In two of these patients CT and MRI showed lesions in the globus pallidus. They also showed reduced initiative, and in one patient this was combined with minor tics and obsessive symptoms. One patient had impaired memory as the only symptom. The patient with the longest lasting exposure developed delayed sequelae; three weeks after the poisoning he became apathetic and confused, with failing memory, Parkinsonian symptoms, and urinary and faecal incontinence. MRI showed demyelination in the periventricular white matter. His condition started to improve two months after the accident. PMID:8975424

  8. Neural evidence that conscious awareness of errors is reduced in depression following a traumatic brain injury.

    PubMed

    Bailey, N W; Hoy, K E; Maller, J J; Upton, D J; Segrave, R A; Fitzgibbon, B M; Fitzgerald, P B

    2015-03-01

    Impaired error awareness is related to poorer outcome following traumatic brain injury (TBI). Error awareness deficits are also found in major depressive disorder (MDD), but have not been examined in the MDD that follows a TBI (TBI-MDD). This study assessed neural activity related to error awareness in TBI-MDD. Four groups completed a response inhibition task while EEG was recorded- healthy controls (N = 15), MDD-only (N = 15), TBI-only (N = 16), and TBI-MDD (N = 12). Error related EEG activity was compared using powerful randomisation statistics that included all electrodes and time points. Participants with TBI-MDD displayed less frontally distributed neural activity, suggesting reduced contribution from frontal generating sources. Neural activity during this time window is thought to reflect conscious awareness of errors. The TBI-only and MDD-only groups did not differ from controls, and early error processing was unaffected, suggesting early error detection is intact. PMID:25637786

  9. Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain

    PubMed Central

    Simpson, Tamara; Pase, Matthew; Stough, Con

    2015-01-01

    The detrimental effect of neuronal cell death due to oxidative stress and mitochondrial dysfunction has been implicated in age-related cognitive decline and neurodegenerative disorders such as Alzheimer's disease. The Indian herb Bacopa monnieri is a dietary antioxidant, with animal and in vitro studies indicating several modes of action that may protect the brain against oxidative damage. In parallel, several studies using the CDRI08 extract have shown that extracts of Bacopa monnieri improve cognitive function in humans. The biological mechanisms of this cognitive enhancement are unknown. In this review we discuss the animal studies and in vivo evidence for Bacopa monnieri as a potential therapeutic antioxidant to reduce oxidative stress and improve cognitive function. We suggest that future studies incorporate neuroimaging particularly magnetic resonance spectroscopy into their randomized controlled trials to better understand whether changes in antioxidant status in vivo cause improvements in cognitive function. PMID:26413126

  10. Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    PubMed

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID:24072071

  11. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus.

    PubMed

    Gilbert, M E; Sui, L; Walker, M J; Anderson, W; Thomas, S; Smoller, S N; Schon, J P; Phani, S; Goodman, J H

    2007-01-01

    Thyroid hormones are necessary for brain development. gamma-Amino-butyric acid (GABA)ergic interneurons comprise the bulk of local inhibitory circuitry in brain, many of which contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe postnatal hypothyroidism reduces PV immunoreactivity (IR) in rat neocortex. We examined PV-IR and GABA-mediated synaptic inhibition in the hippocampus of rats deprived of thyroid hormone from gestational d 6 until weaning on postnatal d 30. Pregnant dams were exposed to propylthiouracil (0, 3, 10 ppm) via the drinking water, which decreased maternal serum T(4) by approximately 50-75% and increased TSH. At weaning, T(4) was reduced by approximately 70% in offspring in the low-dose group and fell below detectable levels in high-dose animals. PV-IR was diminished in the hippocampus and neocortex of offspring killed on postnatal d 21, an effect that could be reversed by postnatal administration of T(4). Dose-dependent decreases in the density of PV-IR neurons were observed in neocortex and hippocampus, with the dentate gyrus showing the most severe reductions (50-75% below control counts). Altered staining persisted to adulthood despite the return of thyroid hormones to control levels. Developmental cross-fostering and adult-onset deprivation studies revealed that early postnatal hormone insufficiency was required for an alteration in PV-IR. Synaptic inhibition of the perforant path-dentate gyrus synapse evaluated in adult offspring, in vivo, revealed dose-dependent reductions in paired pulse depression indicative of a suppression of GABA-mediated inhibition. These data demonstrate that moderate degrees of thyroid hormone insufficiency during the early postnatal period permanently alters interneuron expression of PV and compromises inhibitory function in the hippocampus. PMID:17008398

  12. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment.

    PubMed

    Hatipoglu, Gökçe; Hock, Stefan W; Weiss, Ruth; Fan, Zheng; Sehm, Tina; Ghoochani, Ali; Buchfelder, Michael; Savaskan, Nicolai E; Eyüpoglu, Ilker Y

    2015-02-01

    Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients. PMID:25458015

  13. Preventing Flow-Metabolism Uncoupling Acutely Reduces Axonal Injury after Traumatic Brain Injury

    PubMed Central

    Mironova, Yevgeniya A.; Chen, Szu-Fu; Richards, Hugh K.; Pickard, John D.

    2012-01-01

    Abstract We have previously presented evidence that the development of secondary traumatic axonal injury is related to the degree of local cerebral blood flow (LCBF) and flow-metabolism uncoupling. We have now tested the hypothesis that augmenting LCBF in the acute stages after brain injury prevents further axonal injury. Data were acquired from rats with or without acetazolamide (ACZ) that was administered immediately following controlled cortical impact injury to increase cortical LCBF. Local cerebral metabolic rate for glucose (LCMRglc) and LCBF measurements were obtained 3 h post-trauma in the same rat via 18F-fluorodeoxyglucose and 14C-iodoantipyrine co-registered autoradiographic images, and compared to the density of damaged axonal profiles in adjacent sections, and in additional groups at 24 h used to assess different populations of injured axons stereologically. ACZ treatment significantly and globally elevated LCBF twofold above untreated-injured rats at 3 h (p<0.05), but did not significantly affect LCMRglc. As a result, ipsilateral LCMRglc:LCBF ratios were reduced by twofold to sham-control levels, and the density of β-APP-stained axons at 24 h was significantly reduced in most brain regions compared to the untreated-injured group (p<0.01). Furthermore, early LCBF augmentation prevented the injury-associated increase in the number of stained axons from 3–24 h. Additional robust stereological analysis of impaired axonal transport and neurofilament compaction in the corpus callosum and cingulum underlying the injury core confirmed the amelioration of β-APP axon density, and showed a trend, but no significant effect, on RMO14-positive axons. These data underline the importance of maintaining flow-metabolism coupling immediately after injury in order to prevent further axonal injury, in at least one population of injured axons. PMID:22321027

  14. Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.

    PubMed

    Fang, Qing; Yan, Xu; Li, Shaowu; Sun, Yilin; Xu, Lixin; Shi, Zhongfang; Wu, Min; Lu, Yi; Dong, Liping; Liu, Ran; Yuan, Fang; Yang, Shao-Hua

    2016-01-01

    The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented. PMID:26463954

  15. Contribution of Lethal Toxin and Edema Toxin to the Pathogenesis of Anthrax Meningitis ?

    PubMed Central

    Ebrahimi, Celia M.; Sheen, Tamsin R.; Renken, Christian W.; Gottlieb, Roberta A.; Doran, Kelly S.

    2011-01-01

    Bacillus anthracis is a Gram-positive spore-forming bacterium that causes anthrax disease in humans and animals. Systemic infection is characterized by septicemia, toxemia, and meningitis, the main neurological complication associated with high mortality. We have shown previously that B. anthracis Sterne is capable of blood-brain barrier (BBB) penetration, establishing the classic signs of meningitis, and that infection is dependent on the expression of both major anthrax toxins, lethal toxin (LT) and edema toxin (ET). Here we further investigate the contribution of the individual toxins to BBB disruption using isogenic toxin mutants deficient in lethal factor, ?LF, and edema factor, ?EF. Acute infection with B. anthracis Sterne and the ?LF mutant resulted in disruption of human brain microvascular endothelial cell (hBMEC) monolayer integrity and tight junction protein zona occludens-1, while the result for cells infected with the ?EF mutant was similar to that for the noninfected control. A significant decrease in bacterial invasion of BBB endothelium in vitro was observed during infection with the ?LF strain, suggesting a prominent role for LT in promoting BBB interaction. Further, treatment of hBMECs with purified LT or chemicals that mimic LT action on host signaling pathways rescued the hypoinvasive phenotype of the ?LF mutant and resulted in increased bacterial uptake. We also observed that toxin expression reduced bacterial intracellular survival by inducing the bulk degradative autophagy pathway in host cells. Finally, in a murine model of anthrax meningitis, mice infected with the ?LF mutant exhibited no mortality, brain bacterial load, or evidence of meningitis compared to mice infected with the parental or ?EF strains. PMID:21518787

  16. Neuroprotective effects of vagus nerve stimulation on traumatic brain injury

    PubMed Central

    Zhou, Long; Lin, Jinhuang; Lin, Junming; Kui, Guoju; Zhang, Jianhua; Yu, Yigang

    2014-01-01

    Previous studies have shown that vagus nerve stimulation can improve the prognosis of traumatic brain injury. The aim of this study was to elucidate the mechanism of the neuroprotective effects of vagus nerve stimulation in rabbits with brain explosive injury. Rabbits with brain explosive injury received continuous stimulation (10 V, 5 Hz, 5 ms, 20 minutes) of the right cervical vagus nerve. Tumor necrosis factor-α, interleukin-1β and interleukin-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured. Results showed that vagus nerve stimulation could reduce the degree of brain edema, decrease tumor necrosis factor-α and interleukin-1β concentrations, and increase interleukin-10 concentration after brain explosive injury in rabbits. These data suggest that vagus nerve stimulation may exert neuroprotective effects against explosive injury via regulating the expression of tumor necrosis factor-α, interleukin-1β and interleukin-10 in the serum and brain tissue. PMID:25368644

  17. Restraint of appetite and reduced regional brain volumes in anorexia nervosa: a voxel-based morphometric study

    PubMed Central

    2011-01-01

    Background Previous Magnetic Resonance Imaging (MRI) studies of people with anorexia nervosa (AN) have shown differences in brain structure. This study aimed to provide preliminary extensions of this data by examining how different levels of appetitive restraint impact on brain volume. Methods Voxel based morphometry (VBM), corrected for total intracranial volume, age, BMI, years of education in 14 women with AN (8 RAN and 6 BPAN) and 21 women (HC) was performed. Correlations between brain volume and dietary restraint were done using Statistical Package for the Social Sciences (SPSS). Results Increased right dorsolateral prefrontal cortex (DLPFC) and reduced right anterior insular cortex, bilateral parahippocampal gyrus, left fusiform gyrus, left cerebellum and right posterior cingulate volumes in AN compared to HC. RAN compared to BPAN had reduced left orbitofrontal cortex, right anterior insular cortex, bilateral parahippocampal gyrus and left cerebellum. Age negatively correlated with right DLPFC volume in HC but not in AN; dietary restraint and BMI predicted 57% of variance in right DLPFC volume in AN. Conclusions In AN, brain volume differences were found in appetitive, somatosensory and top-down control brain regions. Differences in regional GMV may be linked to levels of appetitive restraint, but whether they are state or trait is unclear. Nevertheless, these discrete brain volume differences provide candidate brain regions for further structural and functional study in people with eating disorders. PMID:22093442

  18. Reduced cerebral glucose metabolism and increased brain capillary permeability following high-dose methotrexate chemotherapy: a positron emission tomographic study

    SciTech Connect

    Phillips, P.C.; Dhawan, V.; Strother, S.C.; Sidtis, J.J.; Evans, A.C.; Allen, J.C.; Rottenberg, D.A.

    1987-01-01

    Regional glucose metabolic rate constants and blood-to-brain transport of rubidium were estimated using positron emission tomography in an adolescent patient with a brain tumor, before and after chemotherapy with intravenous high-dose methotrexate. Widespread depression of cerebral glucose metabolism was apparent 24 hours after drug administration, which may reflect reduced glucose phosphorylation, and the influx rate constant for /sup 82/Rb was increased, indicating a drug-induced alteration in blood-brain barrier function. Associated changes in neuropsychological performance, electroencephalogram, and plasma amino acid concentration were identified in the absence of evidence of systemic methotrexate toxicity, suggesting primary methotrexate neurotoxicity.

  19. Does Electroencephalogram Phase Variability Account for Reduced P3 Brain Potential in Externalizing Disorders?

    PubMed Central

    Burwell, Scott J.; Malone, Stephen M.; Bernat, Edward M.; Iacono, William G.

    2014-01-01

    Objective Amplitude deficits of the P3 event-related potential (ERP) are associated with externalizing psychopathology but little is known about the nature of underlying brain electrical activity that accounts for this amplitude reduction. We sought to understand if group differences in task-induced phase-locking in electroencephalographic (EEG) delta and theta frequencies may account for P3-externalizing associations. Methods Adult males (N = 410) completed a visual oddball task and frontal and parietal P3-related delta- and theta-band phase-invariant evoked energy and inter-trial phase-locking measures were investigated with respect to the externalizing spectrum, including substance dependence, adult antisociality, and childhood disruptive disorders. We hypothesized that P3-related phase-locking is weaker in externalizing-diagnosed individuals and this might mediate prior findings of reduced evoked P3energy. Results Reductions in both evoked energy and phase-locking, in both frequency bands, at both scalp sites, were associated with greater odds of externalizing diagnoses. Generally, adding phase-locking to evoked energy came with better prediction model fit. Moreover, reduced theta-band phase-locking partially mediated the effects of within-frequency evoked energy on externalizing prediction. Conclusions Inter-trial phase-locking underlying P3 appears to be an important distinction between externalizing and control subjects. Significance This cross-trial phase-variability for externalizing-diagnosed individuals might reflect deficient top-down “tuning” by neuromodulatory systems. PMID:24656843

  20. Optical imaging reveals reduced seizure spread and propagation velocities in aged rat brain in vitro.

    PubMed

    Holtkamp, M; Buchheim, K; Siegmund, H; Meierkord, H

    2003-01-01

    Old age is the most common time for patients to develop epileptic seizures, and due to their frequent unusual clinical presentation the diagnosis of epilepsy is often delayed in the elderly. It is as yet unknown if pronounced alterations in the plastic properties of aging nervous tissue contribute to these phenomena. We employed a non-lesional in vitro epilepsy model to study seizure susceptibility, spread pattern, and propagation velocities in combined hippocampal-entorhinal cortex slices of aged rats and controls using electrophysiological methods and imaging of intrinsic optical signals. In aged animals we saw a less extensive spread of seizure-like events into areas adjacent to the region of onset of activity and a decreased spread velocity in various anatomical regions. In addition, both the activity-dependent shrinkage of the extracellular space (ECS)-volume and the extracellular K(+) concentration were significantly reduced compared to controls. The results of this study are consistent with the clinical observation that epileptic seizures in the elderly have a reduced tendency to spread. In addition, our data suggest that in the absence of structural lesions seizure susceptibility in the aging brain is not increased. PMID:12498969

  1. Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities.

    PubMed

    Zhou, Ping; Qian, Liping; D'Aurelio, Marilena; Cho, Sunghee; Wang, Gang; Manfredi, Giovanni; Pickel, Virginia; Iadecola, Costantino

    2012-01-11

    Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron-microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress. PMID:22238093

  2. Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities

    PubMed Central

    Zhou, Ping; Qian, Liping; D’Aurelio, Marilena; Cho, Sunghee; Wang, Gang; Manfredi, Giovanni; Pickel, Virginia; Iadecola, Costantino

    2012-01-01

    Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene-silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress. PMID:22238093

  3. Reduced ischemic brain injury by partial rejuvenation of bone marrow cells in aged rats

    PubMed Central

    Taguchi, Akihiko; Zhu, Pengxiang; Cao, Fang; Kikuchi-Taura, Akie; Kasahara, Yukiko; Stern, David M; Soma, Toshihiro; Matsuyama, Tomohiro; Hata, Ryuji

    2011-01-01

    Circulating bone marrow-derived immature cells, including endothelial progenitor cells, have been implicated in homeostasis of the microvasculature. Decreased levels of circulating endothelial progenitor cells, associated with aging and/or cardiovascular risk factors, correlate with poor clinical outcomes in a range of cardiovascular diseases. Herein, we transplanted bone marrow cells from young stroke-prone spontaneously hypertensive rats (SHR-SP) into aged SHR-SP, the latter not exposed to radiation or chemotherapy. Analysis of recipient peripheral blood 28 days after transplantation revealed that 5% of circulating blood cells were of donor origin. Cerebral infarction was induced on day 30 posttransplantation. Animals transplanted with bone marrow from young SHR-SP displayed an increase in density of the microvasculature in the periinfarction zone, reduced ischemic brain damage and improved neurologic function. In vitro analysis revealed enhanced activation of endothelial nitric oxide synthase and reduced activation p38 microtubule-associated protein (MAP) kinase, the latter associated with endothelial apoptosis, in cultures exposed to bone marrow-derived mononuclear cells from young animals versus cells from aged counterparts. Our findings indicate that partial rejuvenation of bone marrow from aged rats with cells from young animals enhances the response to ischemic injury, potentially at the level of endothelial/vascular activation, providing insight into a novel approach ameliorate chronic vascular diseases. PMID:20859292

  4. Reexpansion pulmonary edema in children

    PubMed Central

    Rodrigues, Antonio Lucas L.; Lopes, Carlos Eduardo; Romaneli, Mariana Tresoldi das N.; Fraga, Andrea de Melo A.; Pereira, Ricardo Mendes; Tresoldi, Antonia Teresinha

    2013-01-01

    OBJECTIVE To present a case of a patient with clinical and radiological features of reexpansion pulmonary edema, a rare and potentially fatal disease. CASE DESCRIPTION An 11-year-old boy presenting fever, clinical signs and radiological features of large pleural effusion initially treated as a parapneumonic process. Due to clinical deterioration he underwent tube thoracostomy, with evacuation of 3,000 mL of fluid; he shortly presented acute respiratory insufficiency and needed mechanical ventilation. He had an atypical evolution (extubated twice with no satisfactory response). Computerized tomography findings matched those of reexpansion edema. He recovered satisfactorily after intensive care, and pleural tuberculosis was diagnosed afterwards. COMMENTS Despite its rareness in the pediatric population (only five case reports gathered), the knowledge of this pathology and its prevention is very important, due to high mortality rates. It is recommended, among other measures, slow evacuation of the pleural effusion, not removing more than 1,500 mL of fluid at once. PMID:24142327

  5. Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models

    PubMed Central

    Balducci, Claudia; Mancini, Simona; Minniti, Stefania; La Vitola, Pietro; Zotti, Margherita; Sancini, Giulio; Mauri, Mario; Cagnotto, Alfredo; Colombo, Laura; Fiordaliso, Fabio; Grigoli, Emanuele; Salmona, Mario; Snellman, Anniina; Haaparanta-Solin, Merja; Forloni, Gianluigi; Re, Francesca

    2014-01-01

    Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood–brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1–42 (−33%), assessed by ELISA, and the number and total area of plaques (−34%) detected histologically. Also, brain Aβ oligomers were reduced (−70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [11C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood–brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease. PMID:25319699

  6. Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum

    PubMed Central

    Cole, Jeffrey T.; Kean, William S.; Pollard, Harvey B.; Verma, Ajay; Watson, William D.

    2012-01-01

    Brain cells expend large amounts of energy sequestering calcium (Ca2+), while loss of Ca2+ compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P), a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum (ER) to sequester Ca2+. This led to the hypothesis that G6P regulates Ca2+ accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA). Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio-isotopic assays, 45Ca2+ accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi) coupled with Ca2+ accumulation was quantified. Addition of G6P significantly and decreased Ca2+ accumulation in a dose-dependent fashion (1–10 mM). The reduction in Ca2+ accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca2+ accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca2+ uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca2+ dystasis caused by altered G6P regulation of SERCA activity. PMID:22529775

  7. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo

    PubMed Central

    Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain. PMID:26466323

  8. Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling

    PubMed Central

    Hagmann, Patric; Deco, Gustavo

    2015-01-01

    How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model’s prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information. PMID:26317432

  9. COG1410 Improves Cognitive Performance and Reduces Cortical Neuronal Loss in the Traumatically Injured Brain

    PubMed Central

    Kaufman, Nicholas; Vitek, Michael P.; McKenna, Suzanne E.

    2009-01-01

    Abstract We have previously shown that a single dose of COG1410, a small molecule ApoE-mimetic peptide derived from the apolipoprotein E (ApoE) receptor binding region, improves sensorimotor and motor outcome following cortical contusion injury (CCI). The present study evaluated a regimen of COG1410 following frontal CCI in order to examine its preclinical efficacy on cognitive recovery. Animals were prepared with a bilateral CCI of the frontal cortex. A regimen of COG1410 (0.8 mg/kg intravenously [IV]) was administered twice, at 30 min and again at 24 h post-CCI. Starting on day 11, the animals were tested for their acquisition of a reference memory task in the Morris water maze (MWM), followed by a working memory task in the MWM on day 15. Following CCI, the animals were also tested on the bilateral tactile adhesive removal test to measure sensorimotor dysfunction. On all of the behavioral tests the COG1410 group was no different from the uninjured sham group. Administration of the regimen of COG1410 significantly improved recovery on the reference and working memory tests, as well as on the sensorimotor test. Lesion analysis revealed that COG1410 significantly reduced the size of the injury cavity. Administration of COG1410 also reduced the number of degenerating neurons, as measured by Fluoro-Jade C staining, in the frontal cortex at 48 h post-CCI. These results suggest that a regimen of COG1410 appeared to block the development of significant behavioral deficits and reduced tissue loss. These combined findings suggest that COG1410 appears to have strong preclinical efficacy when administered following traumatic brain injury (TBI). PMID:19119914

  10. Anti-tau antibody reduces insoluble tau and decreases brain atrophy

    PubMed Central

    Yanamandra, Kiran; Jiang, Hong; Mahan, Thomas E; Maloney, Susan E; Wozniak, David F; Diamond, Marc I; Holtzman, David M

    2015-01-01

    Objective We previously found a strong reduction in tau pathology and insoluble tau in P301S tau transgenic mice following intracerebroventricular infusion of the anti-tau antibody HJ8.5. We sought to determine the effects of HJ8.5 in the same model following peripheral administration. Methods The primary objective was to determine if HJ8.5 administered at a dose of 50 mg kg−1 week−1 by intraperitoneal (IP) injection to 6-month-old P301S mice for 3 months would influence phospho-tau (p-tau) accumulation, tau insolubility, and neurodegeneration. Results Treatment with HJ8.5 at 50 mg/kg showed a very strong decrease in detergent-insoluble tau. Importantly, HJ8.5 significantly reduced the loss of cortical and hippocampal tissue volumes compared to control treated mice. HJ8.5 treatment reduced hippocampal CA1 cellular layer staining with the p-tau antibody AT8 and thio-S-positive tau aggregates in piriform cortex and amygdala. Moreover, mice treated with HJ8.5 at 50 mg/kg showed a decrease in motor/sensorimotor deficits compared to vehicle-treated mice. Some effects of HJ8.5, including reduction in brain atrophy, and p-tau immunostaining were also seen with a dose of 10 mg kg−1 week−1. In BV2-microglial cells, we observed significantly higher uptake of P301S tau aggregates in the presence of HJ8.5. HJ8.5 treatment also resulted in a large dose-dependent increase of tau in the plasma. Interpretation Our results indicate that systemically administered anti-tau antibody HJ8.5 significantly decreases insoluble tau, decreases brain atrophy, and improves motor/sensorimotor function in a mouse model of tauopathy. These data further support the idea that anti-tau antibodies should be further assessed as a potential treatment for tauopathies. PMID:25815354

  11. Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease.

    PubMed

    Bang, Shraddha R; Ambavade, Shirishkumar D; Jagdale, Priti G; Adkar, Prafulla P; Waghmare, Arun B; Ambavade, Prashant D

    2015-07-01

    Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease. PMID:25931268

  12. Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat.

    PubMed

    Fredduzzi, S; Mariucci, G; Tantucci, M; Del Soldato, P; Ambrosini, M V

    2001-04-20

    The potential neuroprotective effects of the novel nitro-derivate of aspirin (NCX4016) on permanent focal cerebral ischemia in spontaneously hypertensive rats (SHRs) was investigated. Reference compounds were acetylsalicilic acid (ASA) and FK506 (tacrolimus). Ten minutes after surgery, SHRs were randomly divided into four groups of ten, pharmacologically treated and sacrificed 24 h after treatment. Brains were removed and processed to measure infarct volume, 70 kDa heat shock protein (hsp70), glial fibrillary acidic protein (GFAP) and vimentin (Vim) immunoreactivity (IR), and apoptosis using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. NCX-4016 significantly reduced total infarct volume compared to ASA (-20%, P < 0.05), FK506 (-18%, P < 0.05) and vehicle treatment (-20%, P < 0.05). Experimental groups did not differ in hsp70-IR and GFAP-IR. Conversely, hyperplastic astrocytes, measured by Vim-IR, were significantly lower in NCX-4016 than in the vehicle group (-36%, P<0.01). TUNEL assay indicated a significantly lower degree of apoptosis in NCX-4016 group than vehicle in both the homolateral (-27%, P < 0.01) and contralateral hemisphere (-29%, P < 0.05). These findings indicate that NO release associated with aspirin confers neuroprotective effects against ischemic injury. PMID:11290402

  13. Association of Reduced Folate Carrier-1 (RFC-1) Polymorphisms with Ischemic Stroke and Silent Brain Infarction

    PubMed Central

    Cho, Yunkyung; Kim, Jung O; Lee, Jeong Han; Park, Hye Mi; Jeon, Young Joo; Oh, Seung Hun; Bae, Jinkun; Park, Young Seok; Kim, Ok Joon; Kim, Nam Keun

    2015-01-01

    Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke. PMID:25659099

  14. A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo.

    PubMed

    Nuñez-Figueredo, Yanier; Ramírez-Sánchez, Jeney; Hansel, Gisele; Simões Pires, Elisa Nicoloso; Merino, Nelson; Valdes, Odalys; Delgado-Hernández, René; Parra, Alicia Lagarto; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Salbego, Christianne; Costa, Silvia L; Souza, Diogo O; Pardo-Andreu, Gilberto L

    2014-10-01

    We previously showed that JM-20, a novel 1,5-benzodiazepine fused to a dihydropyridine moiety, possessed an anxiolytic profile similar to diazepam and strong neuroprotective activity in different cell models relevant to cerebral ischemia. Here, we investigated whether JM-20 protects against ischemic neuronal damage in vitro and in vivo. The effects of JM-20 were evaluated on hippocampal slices subjected to oxygen and glucose deprivation (OGD). For in vivo studies, Wistar rats were subjected 90 min of middle cerebral artery occlusion (MCAo) and oral administration of JM-20 at 2, 4 and 8 mg/kg 1 h following reperfusion. Twenty-four hours after cerebral blood flow restoration, neurological deficits were scored, and the infarct volume, histopathological changes in cortex, number of hippocampal and striatal neurons, and glutamate/aspartate concentrations in the cerebrospinal fluid were measured. Susceptibility to brain mitochondrial swelling, membrane potential dissipation, H2O2 generation, cytochrome c release, Ca2+ accumulation, and morphological changes in the organelles were assessed 24 h post-ischemia. In vitro, JM-20 (1 and 10 μM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to OGD. In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions. JM-20 treatment also protected brain mitochondria from ischemic damage, most likely by preventing Ca2+ accumulation in organelles. Moreover, an 8-mg/kg JM-20 dose reduced glutamate and aspartate concentrations in cerebrospinal fluid and the deleterious effects of MCAo even when delivered 8 h after blood flow restoration. These results suggest that in rats, JM-20 is a robust neuroprotective agent against ischemia/reperfusion injury with a wide therapeutic window. Our findings support the further examination of potential clinical JM-20 use to treat acute ischemic stroke. PMID:24953828

  15. Molecular Mechanisms of Reduced Nerve Toxicity by Titanium Dioxide Nanoparticles in the Phoxim-Exposed Brain of Bombyx mori

    PubMed Central

    Ni, Min; Shen, Weide; Hong, Fashui; Li, Bing

    2014-01-01

    Bombyx mori (B. mori), silkworm, is one of the most important economic insects in the world, while phoxim, an organophosphorus (OP) pesticide, impact its economic benefits seriously. Phoxim exposure can damage the brain, fatbody, midgut and haemolymph of B. mori. However the metabolism of proteins and carbohydrates in phoxim-exposed B. mori can be improved by Titanium dioxide nanoparticles (TiO2 NPs). In this study, we explored whether TiO2 NPs treatment can reduce the phoxim-induced brain damage of the 5th larval instar of B. mori. We observed that TiO2 NPs pretreatments significantly reduced the mortality of phoxim-exposed larva and relieved severe brain damage and oxidative stress under phoxim exposure in the brain. The treatments also relieved the phoxim-induced increases in the contents of acetylcholine (Ach), glutamate (Glu) and nitric oxide (NO) and the phoxim-induced decreases in the contents of norepinephrine (NE), Dopamine (DA), and 5-hydroxytryptamine (5-HT), and reduced the inhibition of acetylcholinesterase (AChE), Na+/K+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase activities and the activation of total nitric oxide synthase (TNOS) in the brain. Furthermore, digital gene expression profile (DGE) analysis and real time quantitative PCR (qRT-PCR) assay revealed that TiO2 NPs pretreatment inhibited the up-regulated expression of ace1, cytochrome c, caspase-9, caspase-3, Bm109 and down-regulated expression of BmIap caused by phoxim; these genes are involved in nerve conduction, oxidative stress and apoptosis. TiO2 NPs pretreatment also inhibited the down-regulated expression of H+ transporting ATP synthase and vacuolar ATP synthase under phoxim exposure, which are involved in ion transport and energy metabolism. These results indicate that TiO2 NPs pretreatment reduced the phoxim-induced nerve toxicity in the brain of B. mori. PMID:24971466

  16. Neuronal K(ATP) channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury.

    PubMed

    Sun, Hong-Shuo; Xu, Baofeng; Chen, Wenliang; Xiao, Aijiao; Turlova, Ekaterina; Alibraham, Ammar; Barszczyk, Andrew; Bae, Christine Y J; Quan, Yi; Liu, Baosong; Pei, Lin; Sun, Christopher L F; Deurloo, Marielle; Feng, Zhong-Ping

    2015-01-01

    Neonatal hypoxic-ischemic brain injury and its related illness hypoxic-ischemic encephalopathy (HIE) are major causes of nervous system damage and neurological morbidity in children. Hypoxic preconditioning (HPC) is known to be neuroprotective in cerebral ischemic brain injury. K(ATP) channels are involved in ischemic preconditioning in the heart; however the involvement of neuronal K(ATP) channels in HPC in the brain has not been fully investigated. In this study, we investigated the role of HPC in hypoxia-ischemia (HI)-induced brain injury in postnatal seven-day-old (P7) CD1 mouse pups. Specifically, TTC (2,3,5-triphenyltetrazolium chloride) staining was used to assess the infarct volume, TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling) to detect apoptotic cells, Western blots to evaluate protein level, and patch-clamp recordings to measure K(ATP) channel current activities. Behavioral tests were performed to assess the functional recovery after hypoxic-ischemic insults. We found that hypoxic preconditioning reduced infarct volume, decreased the number of TUNEL-positive cells, and improved neurobehavioral functional recovery in neonatal mice following hypoxic-ischemic insults. Pre-treatment with a K(ATP) channel blocker, tolbutamide, inhibited hypoxic preconditioning-induced neuroprotection and augmented neurodegeneration following hypoxic-ischemic injury. Pre-treatment with a K(ATP) channel opener, diazoxide, reduced infarct volume and mimicked hypoxic preconditioning-induced neuroprotection. Hypoxic preconditioning induced upregulation of the protein level of the Kir6.2 isoform and enhanced current activities of K(ATP) channels. Hypoxic preconditioning restored the HI-reduced PKC and pAkt levels, and reduced caspase-3 level, while tolbutamide inhibited the effects of hypoxic preconditioning. We conclude that K(ATP) channels are involved in hypoxic preconditioning-induced neuroprotection in neonatal hypoxic-ischemic brain injury. K(ATP) channel openers may therefore have therapeutic effects in neonatal hypoxic-ischemic brain injury. PMID:25448006

  17. Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients

    PubMed Central

    Mojtahedzadeh, Mojtaba; Ahmadi, Arezoo; Mahmoodpoor, Ata; Beigmohammadi, Mohammad Taghi; Abdollahi, Mohammad; Khazaeipour, Zahra; Shaki, Fatemeh; Kuochaki, Bizhan; Hendouei, Narjes

    2014-01-01

    Background: Oxidative stress processes play an important role in the pathogenesis of secondary brain injury after traumatic brain injury (TBI). Hypertonic saline (HTS) has advantages as being preferred osmotic agent, but few studies investigated oxidant and antioxidant effects of HTS in TBI. This study was designed to compare two different regimens of HTS 5% with mannitol on TBI-induced oxidative stress. Materials and Methods: Thirty-three adult patients with TBI were recruited and have randomly received one of the three protocols: 125 cc of HTS 5% every 6 h as bolus, 500 cc of HTS 5%as infusion for 24 h or 1 g/kg mannitol of 20% as a bolus, repeated with a dose of 0.25-0.5 g/kg every 6 h based on patient's response for 3 days. Serum total antioxidant power (TAP), reactive oxygen species (ROS) and nitric oxide (NO) were measured at baseline and daily for 3 days. Results: Initial serum ROS and NO levels in patients were higher than control(6.86± [3.2] vs. 1.57± [0.5] picoM, P = 0.001, 14.6± [1.6] vs. 7.8± [3.9] mM, P = 0.001, respectively). Levels of ROS have decreased for all patients, but reduction was significantly after HTS infusion and mannitol (3. 08 [±3.1] to 1.07 [±1.6], P = 0.001, 5.6 [±3.4] to 2.5 [±1.8], P = 0.003 respectively). During study, NO levels significantly decreased in HTS infusion but significantly increased in mannitol. TAP Levels had decreased in all patients during study especially in mannitol (P = 0.004). Conclusion: Hypertonic saline 5% has significant effects on the oxidant responses compared to mannitol following TBI that makes HTS as a perfect therapeutic intervention for reducing unfavorable outcomes in TBI patients. PMID:25535502

  18. Normobaric hyperoxia markedly reduces brain damage and sensorimotor deficits following brief focal ischaemia.

    PubMed

    Ejaz, Sohail; Emmrich, Julius V; Sitnikov, Sergey L; Hong, Young T; Sawiak, Stephen J; Fryer, Tim D; Aigbirhio, Franklin I; Williamson, David J; Baron, Jean-Claude

    2016-03-01

    'True' transient ischaemic attacks are characterized not only clinically, but also radiologically by a lack of corresponding changes on magnetic resonance imaging. During a transient ischaemic attack it is assumed that the affected tissue is penumbral but rescued by early spontaneous reperfusion. There is, however, evidence from rodent studies that even brief focal ischaemia not resulting in tissue infarction can cause extensive selective neuronal loss associated with long-lasting sensorimotor impairment but normal magnetic resonance imaging. Selective neuronal loss might therefore contribute to the increasingly recognized cognitive impairment occurring in patients with transient ischaemic attacks. It is therefore relevant to consider treatments to reduce brain damage occurring with transient ischaemic attacks. As penumbral neurons are threatened by markedly constrained oxygen delivery, improving the latter by increasing arterial O2 content would seem logical. Despite only small increases in arterial O2 content, normobaric oxygen therapy experimentally induces significant increases in penumbral O2 pressure and by such may maintain the penumbra alive until reperfusion. Nevertheless, the effects of normobaric oxygen therapy on infarct volume in rodent models have been conflicting, although duration of occlusion appeared an important factor. Likewise, in the single randomized trial published to date, early-administered normobaric oxygen therapy had no significant effect on clinical outcome despite reduced diffusion-weighted imaging lesion growth during therapy. Here we tested the hypothesis that normobaric oxygen therapy prevents both selective neuronal loss and sensorimotor deficits in a rodent model mimicking true transient ischaemic attack. Normobaric oxygen therapy was applied from the onset and until completion of 15 min distal middle cerebral artery occlusion in spontaneously hypertensive rats, a strain representative of the transient ischaemic attack-prone population. Whereas normoxic controls showed normal magnetic resonance imaging but extensive cortical selective neuronal loss associated with microglial activation (present both at Day 14 in vivo and at Day 28 post-mortem) and marked and long-lasting sensorimotor deficits, normobaric oxygen therapy completely prevented sensorimotor deficit (P < 0.02) and near-completely Day 28 selective neuronal loss (P < 0.005). Microglial activation was substantially reduced at Day 14 and completely prevented at Day 28 (P = 0.002). Our findings document that normobaric oxygen therapy administered during ischaemia nearly completely prevents the neuronal death, microglial inflammation and sensorimotor impairment that characterize this rodent true transient ischaemic attack model. Taken together with the available literature, normobaric oxygen therapy appears a promising therapy for short-lasting ischaemia, and is attractive clinically as it could be started at home in at-risk patients or in the ambulance in subjects suspected of transient ischaemic attack/early stroke. It may also be a straightforward adjunct to reperfusion therapies, and help prevent subtle brain damage potentially contributing to long-term cognitive and sensorimotor impairment in at-risk populations. PMID:26767570

  19. Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage.

    PubMed

    Guo, Jing; Chen, Qianwei; Tang, Jun; Zhang, Jianbo; Tao, Yihao; Li, Lin; Zhu, Gang; Feng, Hua; Chen, Zhi

    2015-01-12

    Germinal matrix hemorrhage (GMH) is the most important adverse neurologic event during the newborn period. Evidence has shown that neonates with GMH and hydrocephalus have more severe damage compared to those with GMH alone. Our preliminary study demonstrated the role of iron in hydrocephalus and brain damage in adult rats following intraventricular hemorrhage. Therefore, the aim of the current study was to investigate iron accumulation and iron-handling proteins in a rat model of GMH and whether minocycline reduces iron overload after GMH and iron-induced brain injury in vivo. This study was divided into two parts. In the first part, rats received either a needle insertion or an intracerebral injection of 0.3 U of clostridial collagenase VII-S. Brain iron and brain iron handling proteins (heme oxygenase-1 and ferritin) were measured. In the second part, rats with a GMH were treated with minocycline or vehicle. Brain edema, brain cell death, hydrocephalus, iron-handling proteins and long-term motor function were examined. The result showed iron accumulation and upregulation of iron-handling proteins after GMH. Minocycline treatment significantly reduced GMH-induced brain edema, hydrocephalus and brain damage. Minocycline also suppressed upregulation of ferritin after GMH. In conclusion, the current study found that iron plays a role in brain injury following GMH and that minocycline reduces iron overload after GMH and iron-induced brain injury. PMID:25451129

  20. The Inhibitory Effect of Kakkonto, Japanese Traditional (Kampo) Medicine, on Brain Penetration of Oseltamivir Carboxylate in Mice with Reduced Blood-Brain Barrier Function

    PubMed Central

    Ohara, Kousuke; Oshima, Shinji; Fukuda, Nanami; Ochiai, Yumiko; Maruyama, Ayumi; Kanamuro, Aki; Negishi, Akio; Honma, Seiichi; Ohshima, Shigeru; Akimoto, Masayuki; Takenaka, Shingo; Kobayashi, Daisuke

    2015-01-01

    Oseltamivir phosphate (OP) is used to treat influenza virus infections. However, its use may result in central nervous system (CNS) adverse effects. In Japan, OP is used with Kampo formulations to improve clinical effectiveness. We evaluated the potential for using Kampo formulations to reduce CNS adverse effects by quantifying the CNS distribution of oseltamivir and its active metabolite oseltamivir carboxylate (OC) when administered with maoto and kakkonto. We administered lipopolysaccharide (LPS) by intraperitoneal injection to C57BL/6 mice to reduce blood-brain barrier function. Saline, maoto, and kakkonto were administered orally at the same time as LPS. OP was orally administered 4 hours after the last LPS injection and the migration of oseltamivir and OC was examined. Additionally, we examined the brain distribution of OC following intravenous administration. Changes in OC concentrations in the brain suggest that, in comparison to LPS-treated control mice, both Kampo formulations increased plasma levels of OC, thereby enhancing its therapeutic effect. Additionally, our findings suggest kakkonto may not only improve the therapeutic effect of oseltamivir but also reduce the risk of CNS-based adverse effects. Considering these findings, it should be noted that administration of kakkonto during periods of inflammation has led to increased OAT3 expression. PMID:25788966

  1. Hyaluronidase injection for the treatment of eyelid edema: a retrospective analysis of 20 patients

    PubMed Central

    2014-01-01

    Background Hyaluronidase (Hylase Dessau®) is a hyaluronic acid-metabolizing enzyme, which has been shown to loosen the extracellular matrix, thereby improving the diffusion of local anesthetics. Lower eyelid edema is a common post-interventional complication of cosmetic procedures performed in the lid region, such as the injection of hyaluronic acid fillers for tear-trough augmentation. The purpose of this study was to validate the efficacy of hyaluronidase in the management of lower eyelid edema. Methods We performed a retrospective analysis with 20 patients with lower eyelid edema. Most patients (n = 14) presented with edema following hyaluronic acid injection (tear-trough augmentation), whereas the minority (n = 6) were treated due to idiopathic edema (malar edema or malar mounds). Patients were treated by local infiltration of approximately 0.2 ml to 0.5 ml of hyaluronidase (Hylase Dessau® 20 IU to 75 IU) per eyelid. Photographs were taken prior to and seven days after infiltration. Results Hyaluronidase was found to reduce effectively and rapidly or resolve eyelid edema after a single injection. No relevant adverse effects were observed. However, it must be noted that a hyaluronidase injection may also dissolve injected hyaluronic acid fillers and may therefore negatively affect tear-trough augmentations. While the effects of a treatment for edema due to tear-trough augmentation were permanent, malar edema and malar mounds reoccurred within two to three weeks. Conclusion The infiltration of hyaluronidase is rapid, safe and currently the only effective option for the management of eyelid edema. No relevant adverse effects were observed. PMID:24886711

  2. Intravenous Treatment With Coenzyme Q10 Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Brain Ischemia in Rats.

    PubMed

    Belousova, Margarita; Tokareva, Olga G; Gorodetskaya, Evgeniya; Kalenikova, Elena I; Medvedev, Oleg S

    2016-02-01

    Coenzyme Q10 (CoQ10) crosses the blood-brain barrier when administered intravenously and accumulates in the brain. In this study, we investigated whether CoQ10 protects against ischemia-reperfusion injury by measuring neurological function and brain infarct volumes in a rat model of transient focal cerebral ischemia. In male Wistar rats, we performed transient middle cerebral artery occlusion (tMCAO) for 60 minutes, followed by reperfusion for 24 hours or 7 days. Forty-five minutes after the onset of occlusion (or 15 minutes before reperfusion), rats received a single intravenous injection of solubilized CoQ10 (30 mg·mL·kg) or saline (2 mL/kg). Sensory and motor function scores and body weights were obtained before the rats were killed by decapitation, and brain infarct volumes were calculated using tetrazolium chloride staining. CoQ10 brain levels were measured by high-performance liquid chromatography with electrochemical detection. CoQ10 significantly improved neurological behavior and reduced weight loss up to 7 days after tMCAO (P < 0.05). Furthermore, CoQ10 reduced cerebral infarct volumes by 67% at 24 hours after tMCAO and 35% at 7 days (P < 0.05). Cerebral ischemia resulted in a significant reduction in endogenous CoQ10 in both hemispheres (P < 0.05). However, intravenous injection of solubilized CoQ10 resulted in its increase in both hemispheres at 24 hours and in the contralateral hemisphere at 7 days (P < 0.05). Our results demonstrate that CoQ10 is a robust neuroprotective agent against ischemia-reperfusion brain injury in rats, improving both functional and morphological indices of brain damage. PMID:26371950

  3. Analysis of lymphatic drainage in various forms of leg edema using two compartment lymphoscintigraphy.

    PubMed

    Bräutigam, P; Földi, E; Schaiper, I; Krause, T; Vanscheidt, W; Moser, E

    1998-06-01

    The anatomical and functional status of the epifascial and subfascial lymphatic compartments was analyzed using two compartment lymphoscintigraphy in five groups of patients (total 55) with various forms of edema of the lower extremities. Digital whole body scintigraphy enabled semiquantitative estimation of radiotracer transport with comparison of lymphatic drainage between those individuals without (normal) and those with leg edema by calculating the uptake of the radiopharmaceutical transported to regional lymph nodes. A visual assessment of the lymphatic drainage pathways of the legs was also performed. In patients with cyclic idiopathic edema, an accelerated rate of lymphatic transport was detected (high lymph volume overload or dynamic insufficiency). In those with venous (phlebo) edemas, high volume lymphatic overload (dynamic insufficiency) of the epifascial compartment was scintigraphically detected by increased tracer uptake in regional nodes. In patients with deep femoral venous occlusion (post-thrombotic syndrome). subfascial lymphatic transport was uniformly markedly reduced (safety valve lymphatic insufficiency). On the other hand, in the epifascial compartment, lymph transport was accelerated. In those patients with recurrent or extensive skin ulceration, lymph transport was reduced. Patients with lipedema (obesity) scintigraphically showed no alteration in lymphatic transport. This study demonstrates that lymphatic drainage is notably affected (except in obesity termed lipedema) in various edemas of the leg. Lymphatic drainage varied depending on the specific compartment and the pathophysiologic mechanism accounting for the edema. Two compartment lymphoscintigraphy is a valuable diagnostic tool for accurate assessment of leg edema of known and unknown origin. PMID:9664268

  4. Flaxseed oil reduces oxidative stress and enhances brain monoamines release in streptozotocin-induced diabetic rats.

    PubMed

    Badawy, E A; Rasheed, W I; Elias, T R; Hussein, J; Harvi, M; Morsy, S; Mahmoud, Ya El-Latif

    2015-11-01

    This study was performed to investigate the biochemical effect of flaxseed oil on oxidative stress and brain monoamines release in streptozotocin-induced diabetic rats. Sixty male albino rats were divided into following four groups (15 for each group): control group, flaxseed oil group, diabetic group, and flaxseed oil-treated diabetic group. Serum glucose, insulin, pentosidine, plasma advanced oxidation protein products (AOPPs), and plasma total antioxidant capacity were estimated. Brain neurotransmitters, malondialdehyde (MDA), and nitric oxide (NO) were also determined. The mean values of serum pentosidine and plasma AOPP showed a significant decrease in treated diabetic group as compared to their values in the diabetic group. Also, brain neurotransmitters levels were improved after treatment with flaxseed. Brain MDA and NO were increased significantly in the diabetic group, while they were significantly decreased after treatment. Brain NO and brain MDA had a significant positive correlation with pentosidine, AOPP, and neurotransmitters. We concluded that flaxseed oil supplementation may be useful in the treatment of brain dysfunction in diabetes. PMID:25669659

  5. Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits.

    PubMed

    Chen, Jun-Hui; Yang, Li-Kun; Chen, Lei; Wang, Yu-Hai; Wu, Yun; Jiang, Bing-Jie; Zhu, Jie; Li, Pei-Pei

    2016-04-01

    The therapeutic effects of atorvastatin on early brain injury (EBI), cerebral edema and its association with aquaporin 4 (AQP4) were studied in rabbits after subarachnoid hemorrhage (SAH) using western blot analysis and the dry-wet method. Seventy-two healthy male New Zealand rabbits weighing between 2.5 and 3.2 kg were randomly divided into three groups: the SAH group (n=24), sham-operated group (n=24) and the SAH + atorvastatin group (n=24). A double SAH model was employed. The sham-operated group were injected with the same dose of saline solution, the SAH + atorvastatin group received atorvastatin 20 mg/kg/day after SAH. All rabbit brain samples were taken at 72 h after the SAH model was established successfully. Brain edema was detected using the dry-wet method after experimental SAH was induced; AQP4 and caspase-3 expression was measured by western blot analysis, and neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining at 72 h after SAH. The results indicated that brain edema and injury appeared soon after SAH, while brain edema and EBI were ameliorated and increased behavior scores were noted after prophylactic use of atorvastatin. Compared with the SAH group, the level of AQP4 and the cerebral content of water was significantly decreased (P<0.01) by atorvastatin, and TUNEL staining and studying the expression of caspase-3 showed that the apoptosis of neurons was reduced markedly both in the hippocampus and brain cortex by atorvastatin. The results suggest that atorvastatin ameliorated brain edema and EBI after SAH, which was related to its inhibition of AQP4 expression. Our findings provide evidence that atorvastatin is an effective and well-tolerated approach for treating SAH in various clinical settings. PMID:26935263

  6. Reduced serum brain-derived neurotrophic factor in patients with first onset vitiligo

    PubMed Central

    Yanik, M Emin; Erfan, Gamze; Albayrak, Yakup; Aydin, Murat; Kulac, Mustafa; Kuloglu, Murat

    2014-01-01

    Purpose Vitiligo is an acquired pigmentary skin disease that can cause serious cosmetic problems. There have been numerous and well established studies that have demonstrated the comorbidity of various psychiatric disorders in patients with vitiligo. However, to our knowledge, there have been no studies investigating whether a psychiatric biomarker, such as brain-derived neurotrophic factor (BDNF), is associated with vitiligo. Patients and methods This study was conducted in Namık Kemal University Medical Faculty, Departments of Dermatology and Psychiatry between January 2013 and September 2014. After meeting inclusion and exclusion criteria, serum BDNF levels were assayed in 57 patients with first onset vitiligo and no known current or past psychiatric disorder and compared with BDNF levels in 58 age and sex matched healthy subjects. Results The age and female/male ratios were similar between groups. The mean values of serum BDNF were 1.57±0.97 ng/dL and 2.37±1.73 ng/dL in the vitiligo group and in the healthy control group, respectively. The mean BDNF level was significantly higher in the healthy control group compared with the vitiligo group (t=2.76, P=0.007). Conclusion This is the first study to compare serum BDNF levels between patients with vitiligo and healthy subjects. The reduced level of serum BDNF in patients with vitiligo may be directly related to the etiology of vitiligo or associated with the high percentage of psychiatric disorders in that patient population. Further studies are needed to support our preliminary results. PMID:25540586

  7. Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors

    PubMed Central

    2011-01-01

    Background VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB) that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs) in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA) in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV) infection of brain endothelial cells using in vitro and in vivo approaches. Methods i) in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii) in vivo: CB1 receptor deficient mice (Cnr1-/-) infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. Results Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-), the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor exacerbated neuroinflammation. Conclusions Our results suggest that CB1 receptor dependent VCAM-1 inhibition is a novel mechanism for AEA-reduced leukocyte transmigration and contribute to a better understanding of the mechanisms underlying the beneficial role of endocannabinoid system in the Theiler's virus model of MS. PMID:21851608

  8. GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling.

    PubMed

    D'Angelo, Barbara; Ek, C Joakim; Sun, Yanyan; Zhu, Changlian; Sandberg, Mats; Mallard, Carina

    2016-02-01

    Hypoxic-ischaemic (HI) injury is an important cause of neurological morbidity in neonates. HI leads to pathophysiological responses, including inflammation and oxidative stress that culminate in cell death. Activation of glycogen synthase kinase 3β (GSK3β) and the signal transducer and activator of transcription (STAT3) promotes brain inflammation. The purpose of this study was to test whether inhibition of GSK3β signalling protects against neonatal HI brain injury. Mice were subjected to HI at postnatal day (PND) 9 and treated with a selective GSK3β inhibitor, SB216763. Brain injury and caspase-3 activation, anti-oxidant and inflammatory mRNA responses and activation of STAT3 were analysed. Our results show that HI reduced phosphorylation of GSK3β, thus promoting its kinase activity. The GSK3β inhibitor reduced caspase-3 activation and neuronal cell death elicited by HI and reverted the effects of HI on gene expression of the anti-oxidant enzyme sod2 and mitochondrial factor pgc1α. The HI insult activated STAT3 in glial cells and GSK3β inhibition attenuated STAT3 phosphorylation and its nuclear translocation following HI. Further, GSK3β inhibition reduced HI-induced gene expression of pro-inflammatory cytokines tnfα and Il-6, while promoted the anti-inflammatory factor Il-10. In summary, data show that GSK3β inhibition is neuroprotective in neonatal HI brain injury likely via reduced pro-inflammatory responses by blocking STAT3 signalling. Our study suggests that pharmacological interventions built upon GSK3β silencing strategies could represent a novel therapy in neonatal brain injury. PMID:26384655

  9. THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.

    EPA Science Inventory

    The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

  10. Elevated Intracranial Pressure and Cerebral Edema following Permanent MCA Occlusion in an Ovine Model

    PubMed Central

    Wells, Adam J.; Vink, Robert; Helps, Stephen C.; Knox, Steven J.; Blumbergs, Peter C.; Turner, Renée J.

    2015-01-01

    Introduction Malignant middle cerebral artery (MCA) stroke has a disproportionately high mortality due to the rapid development of refractory space-occupying cerebral edema. Animal models are essential in developing successful anti-edema therapies; however to date poor clinical translation has been associated with the predominately used rodent models. As such, large animal gyrencephalic models of stroke are urgently needed. The aim of the study was to characterize the intracranial pressure (ICP) response to MCA occlusion in our recently developed ovine stroke model. Materials and Methods 30 adult female Merino sheep (n = 8–12/gp) were randomized to sham surgery, temporary or permanent proximal MCA occlusion. ICP and brain tissue oxygen were monitored for 24 hours under general anesthesia. MRI, infarct volume with triphenyltetrazolium chloride (TTC) staining and histology were performed. Results No increase in ICP, radiological evidence of ischemia within the MCA territory but without space-occupying edema, and TTC infarct volumes of 7.9+/-5.1% were seen with temporary MCAO. Permanent MCAO resulted in significantly elevated ICP, accompanied by 30% mortality, radiological evidence of space-occupying cerebral edema and TTC infarct volumes of 27.4+/-6.4%. Conclusions Permanent proximal MCAO in the sheep results in space-occupying cerebral edema, raised ICP and mortality similar to human malignant MCA stroke. This animal model may prove useful for pre-clinical testing of anti-edema therapies that have shown promise in rodent studies. PMID:26121036

  11. Do Thebesian veins and arterioluminal vessels protect against myocardial edema occurrence?

    PubMed

    Kurbel, Sven; Marić, Svjetlana; Gros, Mario

    2009-07-01

    Thebesian veins, arteriosinusoidal and arterioluminal vessels drain blood from heart muscle into the chambers. Thebesian veins are reported common in atria and right ventricle, but scarce in the left ventricle. Since the left ventricle may be less prone to edema due to its intermittent cycle of perfusion, it is here proposed that Thebesian veins prevent myocardial edema. This is in concordance with reports that Thebesian veins are common at the ventricle apex and at papillary muscles base, regions prone to edema due to distance to the coronary sinus. Thebesian veins can act as local reducers of venous hydrostatic pressure that correct small differences in fluid filtration and maintain contractility. By analogy, arterioluminal and arteriosinusoidal vessels might act as regulators of local arteriolar pressure. All these vessels reduce capillary fluid filtration in otherwise healthy tissue surrounding ischemic lesions in coronary patients and other situations that lead to edema. PMID:19264425

  12. Reduced Fetal Cerebral Oxygen Consumption is Associated With Smaller Brain Size in Fetuses With Congenital Heart Disease

    PubMed Central

    Sun, Liqun; Macgowan, Christopher K; Sled, John G; Yoo, Shi-Joon; Manlhiot, Cedric; Porayette, Prashob; Grosse-Wortmann, Lars; Jaeggi, Edgar; McCrindle, Brian W; Kingdom, John; Hickey, Edward; Miller, Steven; Seed, Mike

    2015-01-01

    Background Fetal hypoxia has been implicated in the abnormal brain development seen in newborns with congenital heart disease (CHD). New magnetic resonance imaging (MRI) technology now offers the potential to investigate the relationship between fetal hemodynamics and brain dysmaturation. Methods and Results We measured fetal brain size, oxygen saturation and blood flow in the major vessels of the fetal circulation in 30 late gestation fetuses with CHD and 30 normal controls using phase contrast MRI and T2 mapping. Fetal hemodynamic parameters were calculated using a combination of MRI flow and oximetry data and fetal hemoglobin concentrations estimated from population averages. In fetuses with CHD, reductions in umbilical vein oxygen content (p<0.001), and failure of the normal streaming of oxygenated blood from the placenta to the ascending aorta were associated with a mean reduction in ascending aortic saturation of 10% (p < 0.001), while cerebral blood flow and cerebral oxygen extraction were no different from controls. This accounted for the mean 15% reduction in cerebral oxygen delivery (p = 0.08) and 32% reduction cerebral VO2 in CHD fetuses (p < 0.001), which were associated with a 13% reduction in fetal brain volume (p < 0.001). Fetal brain size correlated with ascending aortic oxygen saturation and cerebral VO2 (r = 0.37 p = 0.004). Conclusions This study supports a direct link between reduced cerebral oxygenation and impaired brain growth in fetuses with CHD and raises the possibility that in utero brain development could be improved with maternal oxygen therapy. PMID:25762062

  13. Xenon improves neurological outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury

    PubMed Central

    Luh, Clara; Gruss, Marco; Radyushkin, Konstantin; Hirnet, Tobias; Werner, Christian; Engelhard, Kristin; Franks, Nicholas P; Thal, Serge C; Dickinson, Robert

    2015-01-01

    Objectives To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury, and to determine whether application of xenon has a clinically relevant therapeutic time window. Design Controlled animal study. Setting University research laboratory. Subjects Male C57BL/6N mice (n=196) Interventions 75% xenon, 50% xenon or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact. Measurements & Main Results Outcome following trauma was measured using: 1) functional neurological outcome score, 2) histological measurement of contusion volume, 3) analysis of locomotor function and gait. Our study shows that xenon-treatment improves outcome following traumatic brain injury. Neurological outcome scores were significantly (p<0.05) better in xenon-treated groups in the early phase (24 hours) and up to 4 days after injury. Contusion volume was significantly (p<0.05) reduced in the xenon-treated groups. Xenon treatment significantly (p<0.05) reduced contusion volume when xenon was given 15 minutes after injury or when treatment was delayed 1 hour or 3 hours after injury. Neurological outcome was significantly (p<0.05) improved when xenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (p<0.05) were observed in the xenon-treated group, 1 month after trauma. Conclusions These results show for the first time that xenon improves neurological outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in brain trauma patients. PMID:25188549

  14. Perspectives on edema in childhood nephrotic syndrome.

    PubMed

    Teoh, Chia Wei; Robinson, Lisa A; Noone, Damien

    2015-10-01

    There have been two major theories surrounding the development of edema in nephrotic syndrome (NS), namely, the under- and overfill hypotheses. Edema is one of the cardinal features of NS and remains one of the principal reasons for admission of children to the hospital. Recently, the discovery that proteases in the glomerular filtrate of patients with NS are activating the epithelial sodium channel (ENaC), resulting in intrarenal salt retention and thereby contributing to edema, might suggest that targeting ENaC with amiloride might be a suitable strategy to manage the edema of NS. Other potential agents, particularly urearetics and aquaretics, might also prove useful in NS. Recent evidence also suggests that there may be other areas involved in salt storage, especially the skin, and it will be intriguing to study the implications of this in NS. PMID:26290369

  15. Pedal edema associated with atypical antipsychotics

    PubMed Central

    Munshi, Santanu; Mukherjee, Shatavisa; Saha, Indranil; Sen, Sukanta

    2016-01-01

    This study describes a patient diagnosed as a case of bipolar affective disorder complaining of bothersome incidence of pedal edema 1 month after the initiation of atypical antipsychotic regimen with risperidone and quetiapine. All hematological and biochemical profiles were found to be normal. On discontinuation of risperidone, the condition remained unresolved even after 2 weeks, and the edema progressed reaching her calves. On tapering the dose of quetiapine, she started showing gradual improvement in edematous condition. Quetiapine was slowly discontinued. No further recurrence of edema occurred, and hence, no further medication changes were implemented. Pedal edema was found to be resolved within weeks of dechallenge of the regimen. Naranjo adverse drug reaction probability scale gave a score of 7 which denotes “probable” adverse drug reaction with quetiapine.

  16. A strategy to passively reduce neuroinflammation surrounding devices implanted chronically in brain tissue by manipulating device surface permeability.

    PubMed

    Skousen, John L; Bridge, Michael J; Tresco, Patrick A

    2015-01-01

    Available evidence indicates that pro-inflammatory cytokines produced by immune cells are likely responsible for the negative sequela associated with the foreign body response (FBR) to chronic indwelling implants in brain tissue. In this study a computational modeling approach was used to design a diffusion sink placed at the device surface that would retain pro-inflammatory cytokines for sufficient time to passively antagonize their impact on the FBR. Using quantitative immunohistochemistry, we examined the FBR to such engineered devices after a 16-week implantation period in the cortex of adult male Sprague-Dawley rats. Our results indicate that thick permeable surface coatings, which served as diffusion sinks, significantly reduced the FBR compared to implants either with no coating or with a thinner coating. The results suggest that increasing surface permeability of solid implanted devices to create a diffusion sink can be used to reduce the FBR and improve biocompatibility of chronic indwelling devices in brain tissue. PMID:25310936

  17. Xylazine-induced pulmonary edema in rats.

    PubMed

    Amouzadeh, H R; Sangiah, S; Qualls, C W; Cowell, R L; Mauromoustakos, A

    1991-05-01

    Inhibitors of cytochrome P450, such as SK&F 525-A, prolong the duration of xylazine-ketamine anesthesia and cause pulmonary edema (PE) and death in rats. To determine the cause of PE, Sprague-Dawley rats were given a single dose of xylazine (21 mg/kg, im) alone or in combination with ketamine (45 mg/kg, im) and/or SK&F 525-A (50 mg/kg, ip) and percentage lung to body weight (%LW/BW) ratios (as an indicator of PE) were compared. The results indicated that xylazine caused PE which was independent of ketamine and was enhanced by SK&F 525-A. Subsequently, it was determined that 42 mg/kg xylazine, im, is an optimal edemagenic dose. Xylazine (42 mg/kg, im) increased the %LW/BW ratio as compared to control. Pleural effusion (PLE) of various amounts was observed in 75% of the animals. The pleural fluid to serum protein ratio for xylazine was similar to that obtained for alpha-naphthylthiourea (5 mg/kg, ip). Extensive serous PLE and alveolar edema with hemorrhage were found at necropsy in xylazine-treated rats. Pretreatment with yohimbine (4.2 mg/kg), prazosin (20 mg/kg), tolazoline (20 mg/kg), yohimbine (4.2 mg/kg) plus prazosin (20 mg/kg), atropine (20 mg/kg), dimethyl sulfoxide (DMSO) (7.8 g/kg), allopurinol (50 mg/kg), superoxide dismutase (20,000 U/kg), catalase (20,000 U/kg), BW755C (50 mg/kg), ibuprofen (50 mg/kg), cystathionine (100 mg/kg) plus taurine (100 mg/kg) did not affect the %LW/BW ratio. PLE was increased by yohimbine, yohimbine plus prazosin, and allopurinol, reduced by DMSO, and not changed in other groups. The results indicate that xylazine caused increased-permeability PE characterized by rapid onset, cellular damage and protein-rich pleural fluid. PE may not be mediated by adverse cardiovascular effects of xylazine and oxygen radicals are possibly involved in its etiology. PMID:1902333

  18. Transient Corneal Edema is a Predictive Factor for Pseudophakic Cystoid Macular Edema after Uncomplicated Cataract Surgery

    PubMed Central

    Do, Jae Rock; Oh, Jong-Hyun; Chuck, Roy S.

    2015-01-01

    Purpose To report transient corneal edema after phacoemulsification as a predictive factor for the development of pseudophakic cystoid macular edema (PCME). Methods A total of 150 eyes from 150 patients (59 men and 91 women; mean age, 68.0 ± 10.15 years) were analyzed using spectral domain optical coherence tomography 1 week and 5 weeks after routine phacoemulsification cataract surgery. Transient corneal edema detected 1 week after surgery was analyzed to reveal any significant relationship with the development of PCME 5 weeks after surgery. Results Transient corneal edema developed in 17 (11.3%) of 150 eyes 1 week after surgery. A history of diabetes mellitus was significantly associated with development of transient corneal edema (odds ratio [OR], 4.04; 95% confidence interval [CI], 1.41 to 11.54; p = 0.011). Both diabetes mellitus and transient corneal edema were significantly associated with PCME development 5 weeks after surgery (OR, 4.58; 95% CI, 1.56 to 13.43; p = 0.007; and OR, 6.71; CI, 2.05 to 21.95; p = 0.003, respectively). In the 8 eyes with both diabetes mellitus and transient corneal edema, 4 (50%) developed PCME 5 weeks after surgery. Conclusions Transient corneal edema detected 1 week after routine cataract surgery is a predictive factor for development of PCME. Close postoperative observation and intervention is recommended in patients with transient corneal edema. PMID:25646056

  19. Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) reduces neonatal hypoxic-ischaemic brain damage.

    PubMed

    Hristova, Mariya; Rocha-Ferreira, Eridan; Fontana, Xavier; Thei, Laura; Buckle, Rheanan; Christou, Melina; Hompoonsup, Supanida; Gostelow, Naomi; Raivich, Gennadij; Peebles, Donald

    2016-03-01

    Hypoxic-ischaemic encephalopathy is a leading cause of child death, with high mortality and morbidity, including cerebral palsy, epilepsy and cognitive disabilities. Hypoxia-ischaemia (HI) strongly up-regulates Signal Transducer and Activator of Transcription 3 (STAT3) in the immature brain. Our aim was to establish whether STAT3 up-regulation is associated with neonatal HI-brain damage and evaluate the phosphorylated STAT3-contribution from different cell types in eliciting damage. We subjected postnatal day seven mice to unilateral carotid artery ligation followed by 60 min hypoxia. Neuronal STAT3-deletion reduced cell death, tissue loss, microglial and astroglial activation in all brain regions. Astroglia-specific STAT3-deletion also reduced cell death, tissue loss and microglial activation, although not as strongly as the deletion in neurons. Systemic pre-insult STAT3-blockade at tyrosine 705 (Y705) with JAK2-inhibitor WP1066 reduced microglial and astroglial activation to a more moderate degree, but in a pattern similar to the one produced by the cell-specific deletions. Our results suggest that STAT3 is a crucial factor in neonatal HI-brain damage and its removal in neurons or astrocytes, and, to some extent, inhibition of its phosphorylation via JAK2-blockade reduces inflammation and tissue loss. Overall, the protective effects of STAT3 inactivation make it a possible target for a therapeutic strategy in neonatal HI. Current data show that neuronal and astroglial STAT3 molecules are involved in the pathways underlying cell death, tissue loss and gliosis following neonatal hypoxia-ischaemia, but differ with respect to the target of their effect. Y705-phosphorylation contributes to hypoxic-ischaemic histopathology. Protective effects of STAT3 inactivation make it a possible target for a therapeutic strategy in neonatal hypoxia-ischaemia. PMID:26669927

  20. Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

    PubMed

    Huang, Xiao-Tian; Qian, Zhong-Ming; He, Xuan; Gong, Qi; Wu, Ka-Chun; Jiang, Li-Rong; Lu, Li-Na; Zhu, Zhou-Jing; Zhang, Hai-Yan; Yung, Wing-Ho; Ke, Ya

    2014-05-01

    Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease. PMID:24332448

  1. Monoclonal nicotine-specific antibodies reduce nicotine distribution to brain in rats: dose- and affinity-response relationships.

    PubMed

    Keyler, D E; Roiko, S A; Benlhabib, E; LeSage, M G; St Peter, J V; Stewart, S; Fuller, S; Le, C T; Pentel, P R

    2005-07-01

    Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotine-specific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with K(d) values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (K(d) = 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb, NICmAb311, was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotine-specific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine. PMID:15843487

  2. Olanzapine-induced tender pitting pre-tibial edema.

    PubMed

    Mathan, Kaliaperumal; Muthukrishnan, Venkatesan; Menon, Vikas

    2015-01-01

    Antipsychotic-induced edema is uncommonly encountered in clinical practice. We report a case of tender pitting pre-tibial edema with olanzapine in a woman with no medical comorbidities. The peculiar distribution of edema resulted in diagnostic confusion necessitating specific investigations. Eventually, the edema resolved following complete stoppage of the drug, but caused distress to the patient and the caregiver. PMID:25969664

  3. Clinical neurosciences in the decade of the brain: hypotheses in neuro-oncology. VEG/PF acts upon the actin cytoskeleton and is inhibited by dexamethasone: relevance to tumor angiogenesis and vasogenic edema.

    PubMed Central

    Criscuolo, G. R.; Balledux, J. P.

    1996-01-01

    HYPOTHESIS: We have proposed that VEG/PF acts by transforming the cytoskeletal architecture of microvascular endothelial cells. BACKGROUND: Evidence supporting a pivotal role for vascular endothelial growth/permeability factor (VEG/PF) in tumor angiogenesis and edemagenesis is compelling. VEG/PF exhibits specific endothelial cell mitogenicity and is expressed by brain tumors exhibiting increased vascularity and microvascular extravasation. The mechanistic cascade that follows VEG/PF-tyrosine kinase receptor binding remains uncertain, however. Actin is a cytoskeletal protein that regulates cellular motility, shape and vesicular transport. Regulation of actin stress fibers, cell-surface focal adhesions and plasmalemmal "ruffles" is mediated by tyrosine kinase activation of GTP-binding proteins that are in turn linked to intracellular calcium flux. As VEG/PF is known to induce cytosolic calcium ion transients in endothelial cells, actin microfilaments would appear to be logical candidates for study of a cytocontractile response mediated by calcium signal transduction. METHODS: VEG/PF-induced endothelial actin cytoskeletal changes were studied using rhodamine phalloidin staining and fluorescence photomicrography. RESULTS: When exposed to VEG/PF, cultured endothelial cells from human umbilical veins and rat brain microvessels exhibited a reversible, dose-related reorganization of actin stress fibers, cell contraction and rounding, and widening of the intercellular spaces. VEG/PF perturbation also induced plasmalemmal "ruffling". All VEG/PF-induced cytoskeletal changes were inhibited by preincubating endothelial cells with dexamethasone or anti-VEG/PF IgG antibody. CONCLUSION: The findings support a role for VEG/PF-induced cytoskeletal alterations in the pathophysiology of brain tumor angiogenesis and edemagenesis. These observations are likely to be directly linked to VEG/PF-induced endothelial cytosolic calcium flux. Insight into the mechanism of dexamethasone's clinical efficacy is also provided. Images Figure 1A Figure 1B Figure 1C Figure 2 Figure 3A Figure 3B Figure 3C Figure 3D Figure 4A Figure 4B Figure 4C Figure 5 Figures 6A Figures 6B Figures 6C PMID:9273988

  4. Reduced Verbal Fluency following Subthalamic Deep Brain Stimulation: A Frontal-Related Cognitive Deficit?

    PubMed Central

    Houvenaghel, Jean-François; Le Jeune, Florence; Dondaine, Thibaut; Esquevin, Aurore; Robert, Gabriel Hadrien; Péron, Julie; Haegelen, Claire; Drapier, Sophie; Jannin, Pierre; Lozachmeur, Clément; Argaud, Soizic; Duprez, Joan; Drapier, Dominique; Vérin, Marc; Sauleau, Paul

    2015-01-01

    Objective The decrease in verbal fluency in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking. Methods To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism. Results We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency. Conclusions These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms. PMID:26448131

  5. Berry fruit and nuts: their role in reducing oxidative stress and inflammation in the aging brain

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Berry fruits and nuts are nutrient dense and contain a variety of bioactive phytochemicals, specifically polyphenols. A growing body of literature describes pre-clinical research, using both in vitro and in vivo techniques, which show beneficial effects of nut and berry consumption on the brain in ...

  6. Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts...

  7. Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats

    SciTech Connect

    Schwartz, M.W.; Figlewicz, D.F.; Kahn, S.E.; Baskin, D.G.; Greenwood, M.R.; Porte, D. Jr. )

    1990-05-01

    In order to study the role of plasma insulin in regulating the binding of insulin to the endothelium of the blood-brain barrier (BBB), insulin binding to a purified preparation of brain capillaries was measured in both genetically obese Zucker rats and lean Zucker controls. We found a reduction of 65% in brain capillary insulin binding site number in the obese compared to lean rats with no change in receptor affinity. Furthermore, specific insulin binding to brain capillaries was negatively correlated (p less than 0.05) to the plasma insulin level, suggesting a role for plasma insulin in regulating insulin binding. A similar relationship was observed between insulin receptor number in liver membranes and the plasma insulin level. We conclude that obese, hyperinsulinemic Zucker rats exhibit a reduction in the number of BBB insulin receptors, which parallels the reduction seen in other peripheral tissues. Since insulin receptors have been hypothesized to participate in the transport of insulin across the BBB, the reduction observed in the obese rats may account for the decrease in cerebrospinal fluid insulin uptake previously demonstrated in these animals.

  8. Reduced N400 Semantic Priming Effects in Adult Survivors of Paediatric and Adolescent Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Knuepffer, C.; Murdoch, B. E.; Lloyd, D.; Lewis, F. M.; Hinchliffe, F. J.

    2012-01-01

    The immediate and long-term neural correlates of linguistic processing deficits reported following paediatric and adolescent traumatic brain injury (TBI) are poorly understood. Therefore, the current research investigated event-related potentials (ERPs) elicited during a semantic picture-word priming experiment in two groups of highly functioning…

  9. An Online Family Intervention to Reduce Parental Distress Following Pediatric Brain Injury

    ERIC Educational Resources Information Center

    Wade, Shari L.; Carey, Joanne; Wolfe, Christopher R.

    2006-01-01

    This study examined whether an online problem-solving intervention could improve parental adjustment following pediatric traumatic brain injury (TBI). Families of children with moderate-to-severe TBI were recruited from the trauma registry of a large children's hospital and randomly assigned to receive online family problem solving therapy (FPS; n…

  10. Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats.

    PubMed

    Shiha, Ahmed Anis; de Cristóbal, Javier; Delgado, Mercedes; Fernández de la Rosa, Rubén; Bascuñana, Pablo; Pozo, Miguel A; García-García, Luis

    2015-02-01

    The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of GABAA receptor expression in hippocampus. PMID:25541342

  11. Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats.

    PubMed

    Ramos, Denise Barbosa; Muller, Gabriel Cardozo; Rocha, Guilherme Botter Maio; Dellavia, Gustavo Hirata; Almeida, Roberto Farina; Pettenuzzo, Leticia Ferreira; Loureiro, Samanta Oliveira; Hansel, Gisele; Horn, Ângelo Cássio Magalhães; Souza, Diogo Onofre; Ganzella, Marcelo

    2016-03-01

    In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window. PMID:26695181

  12. Action expertise reduces brain activity for audiovisual matching actions: an fMRI study with expert drummers.

    PubMed

    Petrini, Karin; Pollick, Frank E; Dahl, Sofia; McAleer, Phil; McKay, Lawrie S; McKay, Lawrie; Rocchesso, Davide; Waadeland, Carl Haakon; Love, Scott; Avanzini, Federico; Puce, Aina

    2011-06-01

    When we observe someone perform a familiar action, we can usually predict what kind of sound that action will produce. Musical actions are over-experienced by musicians and not by non-musicians, and thus offer a unique way to examine how action expertise affects brain processes when the predictability of the produced sound is manipulated. We used functional magnetic resonance imaging to scan 11 drummers and 11 age- and gender-matched novices who made judgments on point-light drumming movements presented with sound. In Experiment 1, sound was synchronized or desynchronized with drumming strikes, while in Experiment 2 sound was always synchronized, but the natural covariation between sound intensity and velocity of the drumming strike was maintained or eliminated. Prior to MRI scanning, each participant completed psychophysical testing to identify personal levels of synchronous and asynchronous timing to be used in the two fMRI activation tasks. In both experiments, the drummers' brain activation was reduced in motor and action representation brain regions when sound matched the observed movements, and was similar to that of novices when sound was mismatched. This reduction in neural activity occurred bilaterally in the cerebellum and left parahippocampal gyrus in Experiment 1, and in the right inferior parietal lobule, inferior temporal gyrus, middle frontal gyrus and precentral gyrus in Experiment 2. Our results indicate that brain functions in action-sound representation areas are modulated by multimodal action expertise. PMID:21397699

  13. The neuroprotection of hypoxic preconditioning on rat brain against traumatic brain injury by up-regulated transcription factor Nrf2 and HO-1 expression.

    PubMed

    Shu, Longfei; Wang, Chunlin; Wang, Jinbiao; Zhang, Yongming; Zhang, Xing; Yang, Yanyan; Zhuo, Jianwei; Liu, Jiachuan

    2016-01-12

    Hypoxic preconditioning (HPC) increases the inherent tolerance of brain tissue suffering from severe hypoxia or ischemia insult by stimulating the protective ability of the brain. However, little is known concerning the effect of HPC on traumatic brain injury (TBI). We designed this study to investigate the effect of HPC on TBI and explore its underlying mechanisms. We found that HPC significantly alleviates neurological dysfunction, lessens brain edema, reduces cell apoptosis, increases neuronal survival, up-regulates the expressions of Nrf2 and HO-1, and decreases the inducer of protein carbonyls, 4-hydroxy-2-nonenal, and 8-hydroxy-2-deoxyguanosine in the brain tissue of rats 24h after brain injury. However, no influence was observed in normal rats after only 3d of hypoxic training. Results further indicated that HPC protects the brain against traumatic damage. This protective effect may be achieved by up-regulating Nrf2 and HO-1 expression and alleviating oxidative stress damage. PMID:26590328

  14. Inhibition of JNK by a Peptide Inhibitor Reduces Traumatic Brain Injury-Induced Tauopathy in Transgenic Mice

    PubMed Central

    Tran, Hien T.; Sanchez, Laura; Brody, David L.

    2012-01-01

    Traumatic brain injury (TBI) is a major environmental risk factor for subsequent development of Alzheimer disease (AD). Pathological features that are common to AD and many tauopathies are neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated tau. Axonal accumulations of total and phospho-tau have been observed within hours to weeks and intracytoplasmic NFTs have been documented years following severe TBI in humans. We previously reported that controlled cortical impact TBI accelerated tau pathology in young 3×Tg-AD mice. Here, we used this TBI mouse model to investigate mechanisms responsible for increased tau phosphorylation and accumulation following brain trauma. We found that TBI resulted in abnormal axonal accumulation of several kinases that phosphorylate tau. Notably, c-Jun N-terminal kinase (JNK) was markedly activated in injured axons and colocalized with phospho-tau. We found that moderate reduction of JNK activity (40%) by a peptide inhibitor, DJNKi1, was sufficient to reduce total and phospho-tau accumulations in axons of these mice with TBI. Longer-term studies will be required to determine whether reducing acute tau pathology proves beneficial in brain trauma. PMID:22249463

  15. Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia

    PubMed Central

    Yang, Xiao; Hei, Changhun; Liu, Ping; Song, Yaozu; Thomas, Taylor; Tshimanga, Sylvie; Wang, Feng; Niu, Jianguo; Sun, Tao; Li, P. Andy

    2015-01-01

    The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage. PMID:26681922

  16. Reduced Metabolsim in Brain 'Control Networks' Following Cocaine-Cues Exposure in Female Cocaine Abusers

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Telang, F.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2011-03-01

    Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. To test this we compared brain metabolism (using PET and {sup 18}FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreased metabolism (-8.6% {+-} 10) whereas males tended to increase it (+5.5% {+-} 18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus). Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from 'control networks' (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.

  17. Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

    PubMed Central

    Reed, Bruce R.; Madison, Cindee M.; Wirth, Miranka; Marchant, Natalie L.; Kriger, Stephen; Mack, Wendy J.; Sanossian, Nerses; DeCarli, Charles; Chui, Helena C.; Weiner, Michael W.; Jagust, William J.

    2014-01-01

    Objective: The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [11C]Pittsburgh compound B–PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk. Conclusion: Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD. PMID:24907234

  18. Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

    PubMed Central

    Glahn, David C.; Kent, Jack W.; Sprooten, Emma; Diego, Vincent P.; Winkler, Anderson M.; Curran, Joanne E.; McKay, D. Reese; Knowles, Emma E.; Carless, Melanie A; Göring, Harald H. H.; Dyer, Thomas D.; Olvera, Rene L.; Fox, Peter T.; Almasy, Laura; Charlesworth, Jac; Kochunov, Peter; Duggirala, Ravi; Blangero, John

    2013-01-01

    Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18–83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging. PMID:24191011

  19. HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model

    PubMed Central

    Chen, Wanqiu; Jadhav, Vikram; Tang, Jiping; Zhang, John H.

    2008-01-01

    Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxic-ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2h of hypoxia (8% O2 at 37°C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death. PMID:18602008

  20. Partially flexible MEMS neural probe composed of polyimide and sucrose gel for reducing brain damage during and after implantation

    NASA Astrophysics Data System (ADS)

    Jeon, Myounggun; Cho, Jeiwon; Kim, Yun Kyung; Jung, Dahee; Yoon, Eui-Sung; Shin, Sehyun; Cho, Il-Joo

    2014-02-01

    This paper presents a flexible microelectromechanical systems (MEMS) neural probe that minimizes neuron damage and immune response, suitable for chronic recording applications. MEMS neural probes with various features such as high electrode densities have been actively investigated for neuron stimulation and recording to study brain functions. However, successful recording of neural signals in chronic application using rigid silicon probes still remains challenging because of cell death and macrophages accumulated around the electrodes over time from continuous brain movement. Thus, in this paper, we propose a new flexible MEMS neural probe that consists of two segments: a polyimide-based, flexible segment for connection and a rigid segment composed of thin silicon for insertion. While the flexible connection segment is designed to reduce the long-term chronic neuron damage, the thin insertion segment is designed to minimize the brain damage during the insertion process. The proposed flexible neural probe was successfully fabricated using the MEMS process on a silicon on insulator wafer. For a successful insertion, a biodegradable sucrose gel is coated on the flexible segment to temporarily increase the probe stiffness to prevent buckling. After the insertion, the sucrose gel dissolves inside the brain exposing the polyimide probe. By performing an insertion test, we confirm that the flexible probe has enough stiffness. In addition, by monitoring immune responses and brain histology, we successfully demonstrate that the proposed flexible neural probe incurs fivefold less neural damage than that incurred by a conventional silicon neural probe. Therefore, the presented flexible neural probe is a promising candidate for recording stable neural signals for long-time chronic applications.

  1. Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria.

    PubMed

    Ney, Denise M; Hull, Angela K; van Calcar, Sandra C; Liu, Xiaowen; Etzel, Mark R

    2008-02-01

    Phenylketonuria (PKU) is a genetic disorder caused by deficiency of phenylalanine hydroxylase (PAH) that requires life-long adherence to a low-phenylalanine (Phe) diet. Glycomacropeptide (GMP) is uniquely suited to the nutritional management of PKU, because pure GMP contains no Phe. Our aim was to assess how ingestion of diets containing GMP support growth and affect the concentrations of amino acids in plasma and brains of mice with a deficiency of PAH, the Pah(enu2) mouse (PKU mouse). Experiments were conducted in 4- to 6-wk-old wild-type (WT) (C57Bl/6) and PKU mice fed diets containing 20% protein from casein, amino acids, or GMP supplemented with limiting indispensable amino acids (IAA). PKU mice fed the GMP diet showed gains in body weight, feed efficiency, and a protein efficiency ratio that did not differ from the amino acid diet. The concentrations of isoleucine and threonine in plasma showed a significant 2- to 3-fold increase for WT and PKU mice fed GMP compared with casein or amino acid diets, respectively. PKU mice fed the GMP diet had decreased concentrations of Phe in plasma (11% decrease) and in 5 regions of the brain (20% decrease) compared with the amino acid diet. The concentration of Phe in the brain was inversely correlated with the concentrations of isoleucine, threonine, and valine in plasma (R2 = 0.74; P < 0.0001), suggesting competitive inhibition of Phe transport into the brain. In summary, PKU mice fed GMP showed comparable growth and reduced concentrations of Phe in plasma and the brain compared with an amino acid diet. These data support the use of GMP supplemented with IAA as an alternative source of dietary protein for individuals with PKU. PMID:18203898

  2. Administration of DHA Reduces Endoplasmic Reticulum Stress-Associated Inflammation and Alters Microglial or Macrophage Activation in Traumatic Brain Injury

    PubMed Central

    Harvey, Lloyd D.; Yin, Yan; Attarwala, Insiya Y.; Begum, Gulnaz; Deng, Julia; Yan, Hong Q.; Dixon, C. Edward

    2015-01-01

    We investigated the effects of the administration of docosahexaenoic acid (DHA) post-traumatic brain injury (TBI) on reducing neuroinflammation. TBI was induced by cortical contusion injury in Sprague Dawley rats. Either DHA (16 mg/kg in dimethyl sulfoxide) or vehicle dimethyl sulfoxide (1 ml/kg) was administered intraperitonially at 5 min after TBI, followed by a daily dose for 3 to 21 days. TBI triggered activation of microglia or macrophages, detected by an increase of Iba1 positively stained microglia or macrophages in peri-lesion cortical tissues at 3, 7, and 21 days post-TBI. The inflammatory response was further characterized by expression of the proinflammatory marker CD16/32 and the anti-inflammatory marker CD206 in Iba1+ microglia or macrophages. DHA-treated brains showed significantly fewer CD16/32+ microglia or macrophages, but an increased CD206+ phagocytic microglial or macrophage population. Additionally, DHA treatment revealed a shift in microglial or macrophage morphology from the activated, amoeboid-like state into the more permissive, surveillant state. Furthermore, activated Iba1+ microglial or macrophages were associated with neurons expressing the endoplasmic reticulum (ER) stress marker CHOP at 3 days post-TBI, and the administration of DHA post-TBI concurrently reduced ER stress and the associated activation of Iba1+ microglial or macrophages. There was a decrease in nuclear translocation of activated nuclear factor kappa-light-chain-enhancer of activated B cells protein at 3 days in DHA-treated tissue and reduced neuronal degeneration in DHA-treated brains at 3, 7, and 21 days after TBI. In summary, our study demonstrated that TBI mediated inflammatory responses are associated with increased neuronal ER stress and subsequent activation of microglia or macrophages. DHA administration reduced neuronal ER stress and subsequent association with microglial or macrophage polarization after TBI, demonstrating its therapeutic potential to ameliorate TBI-induced cellular pathology. PMID:26685193

  3. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus

    PubMed Central

    Lauderdale, Kelli; Murphy, Thomas; Tung, Tina; Davila, David; Binder, Devin K.

    2015-01-01

    Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8–20 weeks old) compared with juvenile (P15–P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space. PMID:26489684

  4. Specific blood flow reducing effects of hyperoxaemia on high flow capillaries in the pig brain.

    PubMed

    Sjberg, F; Gustafsson, U; Eintrei, C

    1999-01-01

    The mechanisms behind oxygen mediated changes in tissue blood flow remain unsettled. Today these are thought to (from experiments on separate vessels and other tissues than the brain) operate through the vessels themselves, probably by involvement of the endothelium in the distal parts of the vascular tree. The aim of this study was to investigate how hyperoxaemia affects the cerebrocortical capillary blood flow distribution in order to gain further knowledge of oxygen mediated blood flow regulating mechanisms. The experiments were performed on seven ventilated anaesthetized pigs. A multiwire Clark-type microelectrode, placed on the brain surface (motor cortex), was used for capillary blood flow (hydrogen clearance) and oxygen pressure measurements, both of which were made at normoxaemia (arterial PO2 14.4 kPa) and hyperoxaemia (arterial PO2 50.4 kPa)(the animals serving as their own control). Blood pressure, arterial PCO2 and pH remained unchanged throughout the experiments. During hyperoxaemia a 11% reduction in the cerebrocortical capillary blood flow was found (P < 0.001). This flow reduction was seen mainly in two capillary blood flow classes (6/7 animals). In parallel a heterogeneous increase in the cerebrocortical oxygen pressures from 4.5 to 10.1 kPa (mean) (P < 0.001) was found. These results show that hyperoxaemia causes a selective reduction in capillary blood flow affecting capillaries at specific flow levels. A finding that suggests, for the brain, that both the oxygen sensor and effect mechanism is situated distally, in the vascular tree. PMID:10072094

  5. Diabetic macular edema: New promising therapies

    PubMed Central

    Shamsi, Hanan N Al; Masaud, Jluwi S; Ghazi, Nicola G

    2013-01-01

    The treatment of diabetic macular edema is rapidly evolving. The era of laser therapy is being quickly replaced by an era of pharmacotherapy. Several pharmacotherapies have been recently developed for the treatment of retinal vascular diseases such as diabetic macular edema. Several intravitreal injections or sustained delivery devices have undergone phase 3 testing while others are currently being evaluated. The results of clinical trials have shown the superiority of some of these agents to laser therapy. However, with the availability of several of these newer agents, it may be difficult to individualize treatment options especially those patients respond differently to various therapies. As such, more effort is still needed in order to determine the best treatment regimen for a given patient. In this article, we briefly summarize the major new therapeutic additions for the treatment of diabetic macular edema and allude to some future promising therapies. PMID:24379924

  6. Udder edema and association with some serum biochemical measurands and dietary factors in first calving cows

    PubMed Central

    Kojouri, G. A; Mosavi Pouryeganeh, M; Nekouei, S; Nazifi, S

    2015-01-01

    The aims of this study were to determine some major biochemical alterations observed in first calving cows with udder edema during the periparturient period and to detect some associations between dietary factors and the disease. For that, the concentrations of some electrolytes (Na+, K+, Cl, Ca2+, P and Mg2+), lipid (triglycerides and cholesterol) markers and lipoproteins (HDL, LDL and VLDL) and total proteins were measured in serum samples collected from 70 first calving cows (35 with udder edema and 35 healthy ones) whereas the percentages of dry matter and crude proteins and the electrolyte (Na+, K+, Cl, Ca2+, Mg2+, P and sulphates) amounts in feed rations were determined in parallel. The total protein, the calcium and the phosphorus as well as the concentrations of lipid markers and lipoproteins (HDL and LDL) were significantly decreased in first calving cows with udder edema compared to the healthy ones and these biochemical alterations were correlated with a reduced dry matter content and an electrolyte desequilibrium mainly involving Na+ and Cl– in feed rations distributed to the cows with udder edema. To our knowledge the mechanism(s) of physiologic udder edema is uncertain and the obtained results suggest that a transient liver dysfunction (decreased total protein and LDL) probably linked to a feed ration deficient in dry matter may be involved in the aetiology of the udder edema in first calving cows. PMID:27175201

  7. Arginine-Restricted Therapy Resistant Bilateral Macular Edema Associated with Gyrate Atrophy

    PubMed Central

    Doguizi, Sibel; Sekeroglu, Mehmet Ali; Anayol, Mustafa Alpaslan; Yilmazbas, Pelin

    2015-01-01

    Introduction. Gyrate atrophy is a rare genetical metabolic disorder affecting vision. Here, we report a 9-year-old boy with gyrate atrophy associated with bilateral macular edema at the time of diagnosis and the effect of long term metabolic control on macular edema. Case Presentation. A 9-year-old boy presented with a complaint of low visual acuity (best corrected visual acuity: 20/80 in both eyes, refractive error: −12.00 D). Dilated fundus examination revealed multiple bilateral, sharply defined, and scalloped chorioretinal atrophy areas in the midperipheral and peripheral zone. Spectral-domain optical coherence tomography revealed bilateral cystoid macular edema in both eyes. Serum ornithine level was high (622 μmol/L). An arginine-restricted diet reduced serum ornithine level (55 μmol/L). However, visual findings including macular edema remained unchanged in 2 years of follow-up. Conclusion. Arginine-restricted diet did not improve macular edema in our patient with gyrate atrophy. A more comprehensive understanding of the underlying factors for macular edema will lead to the development of effective therapies. PMID:26770854

  8. Clinical review: post-extubation laryngeal edema and extubation failure in critically ill adult patients.

    PubMed

    Wittekamp, Bastiaan H J; van Mook, Walther N K A; Tjan, Dave H T; Zwaveling, Jan Harm; Bergmans, Dennis C J J

    2009-01-01

    Laryngeal edema is a frequent complication of intubation. It often presents shortly after extubation as post-extubation stridor and results from damage to the mucosa of the larynx. Mucosal damage is caused by pressure and ischemia resulting in an inflammatory response. Laryngeal edema may compromise the airway necessitating reintubation. Several studies show that a positive cuff leak test combined with the presence of risk factors can identify patients with increased risk for laryngeal edema. Meta-analyses show that pre-emptive administration of a multiple-dose regimen of glucocorticosteroids can reduce the incidence of laryngeal edema and subsequent reintubation. If post-extubation edema occurs this may necessitate medical intervention. Parenteral administration of corticosteroids, epinephrine nebulization and inhalation of a helium/oxygen mixture are potentially effective, although this has not been confirmed by randomized controlled trials. The use of non-invasive positive pressure ventilation is not indicated since this will delay reintubation. Reintubation should be considered early after onset of laryngeal edema to adequately secure an airway. Reintubation leads to increased cost, morbidity and mortality. PMID:20017891

  9. The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    NASA Astrophysics Data System (ADS)

    (Jay Chen, Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-08-01

    Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069-77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days) is longer than that of 131Cs (9.7 days), because the advantage of the longer 103Pd decay half-life was negated by the lower effective energy of the photons it emits (~21 keV compared to ~30.4 keV for 131Cs). In addition, the impact of edema could be reduced or enhanced by differences in the tumor characteristics (e.g. potential tumor doubling time or the α/β ratio), and the effect of these factors varied for the different radioactive sources. There is a clear need to consider the effects of prostate edema during the planning and evaluation of permanent interstitial brachytherapy treatments for prostate cancer.

  10. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke.

    PubMed

    Kono, Syoichiro; Kurata, Tomoko; Sato, Kota; Omote, Yoshio; Hishikawa, Nozomi; Yamashita, Toru; Deguchi, Kentaro; Abe, Koji

    2015-03-01

    Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke. PMID:25534368

  11. Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU).

    PubMed

    Chakraborty, Goutam; Magagna-Poveda, Alejandra; Parratt, Carolyn; Umans, Jason G; MacLusky, Neil J; Scharfman, Helen E

    2012-03-01

    Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy. PMID:22253429

  12. Molecular Signatures of Reduced Nerve Toxicity by CeCl3 in Phoxim-exposed Silkworm Brains

    PubMed Central

    Wang, Binbin; Li, Fanchi; Ni, Min; Zhang, Hua; Xu, Kaizun; Tian, Jianghai; Hu, Jingsheng; Shen, Weide; Li, Bing

    2015-01-01

    CeCl3 can reduce the damage caused by OP pesticides, in this study we used the brain of silkworms to investigate the mechanism of CeCl3 effects on pesticide resistance. The results showed that phoxim treatments led to brain damages, swelling and death of neurons, chromatin condensation, and mitochondrial damage. Normal nerve conduction was severely affected by phoxim treatments, as revealed by: increases in the contents of neurotransmitters Glu, NO, and ACh by 63.65%, 61.14%, and 98.54%, respectively; decreases in the contents of 5-HT and DA by 53.19% and 43.71%, respectively; reductions in the activities of Na+/K+-ATPase, Ca2+/Mg2+-ATPase, and AChE by 85.27%, 85.63%, and 85.63%, respectively; and increase in the activity of TNOS by 22.33%. CeCl3 pretreatment can significantly reduce such damages. Results of DGE and qRT-PCR indicated that CeCl3 treatments significantly upregulated the expression levels of CYP4G23, cyt-b5, GSTs-σ1, ace1, esterase-FE4, and β-esterase 2. Overall, phoxim treatments cause nerve tissue lesions, neuron death, and nerve conduction hindrance, but CeCl3 pretreatments can promote the expression of phoxim resistance-related genes in silkworm brains to reduce phoxim-induced damages. Our study provides a potential new method to improve the resistance of silkworms against OP pesticides. PMID:26227613

  13. Reduced Hippocampal Brain-Derived Neurotrophic Factor (BDNF) in Neonatal Rats after Prenatal Exposure to Propylthiouracil (PTU)

    PubMed Central

    Chakraborty, Goutam; Magagna-Poveda, Alejandra; Parratt, Carolyn; Umans, Jason G.; MacLusky, Neil J.

    2012-01-01

    Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy. PMID:22253429

  14. Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice

    PubMed Central

    Copin, Jean-Christophe; da Silva, Rafaela F; Fraga-Silva, Rodrigo A; Capettini, Luciano; Quintao, Silvia; Lenglet, Sébastien; Pelli, Graziano; Galan, Katia; Burger, Fabienne; Braunersreuther, Vincent; Schaller, Karl; Deruaz, Maud; Proudfoot, Amanda E; Dallegri, Franco; Stergiopulos, Nikolaos; Santos, Robson A S; Gasche, Yvan; Mach, François; Montecucco, Fabrizio

    2013-01-01

    Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a ‘cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes. PMID:23250107

  15. Reducing Inhomogeneity Artifacts in Functional MRI of Human Brain Activation—Thin Sections vs Gradient Compensation

    NASA Astrophysics Data System (ADS)

    Merboldt, Klaus-Dietmar; Finsterbusch, Jürgen; Frahm, Jens

    2000-08-01

    We evaluated two methods for correcting inhomogeneity-induced signal losses in magnetic resonance gradient-echo imaging that either use gradient compensation or simply acquire thin sections. The strategies were tested in the human brain in terms of achievable quality of T2*-weighted images at the level of the hippocampus and of functional activation maps of the visual cortex. Experiments were performed at 2.0 T and based on single-shot echo-planar imaging at 2.0 × 2.0 mm2 resolution, 4 mm section thickness, and 2.0 s temporal resolution. Gradient compensation involved a sequential 16-step variation of the refocusing lobe of the slice-selection gradient (TR/TE = 125/53 ms, flip angle 15°), whereas thin sections divided the 4-mm target plane into either four 1-mm or eight 0.5-mm interleaved multislice acquisitions (TR/TE = 2000/54 ms, flip angle 70°). Both approaches were capable of alleviating the inhomogeneity problem for structures in the base of the brain. When compared to standard 4-mm EPI, functional mapping in the visual cortex was partially compromised because of a lower signal-to-noise ratio of inhomogeneity-corrected images by either method. Relative to each other, consistently better results were obtained with the use of contiguous thin sections, in particular for a thickness of 1 mm. Multislice acquisitions of thin sections require minimal technical adjustments.

  16. Human induced pluripotent stem cells improve stroke outcome and reduce secondary degeneration in the recipient brain.

    PubMed

    Polentes, Jérôme; Jendelova, Pavla; Cailleret, Michel; Braun, Holger; Romanyuk, Nataliya; Tropel, Philippe; Brenot, Marion; Itier, Valerie; Seminatore, Christine; Baldauf, Kathrin; Turnovcova, Karolina; Jirak, Daniel; Teletin, Marius; Côme, Julien; Tournois, Johana; Reymann, Klaus; Sykova, Eva; Viville, Stéphane; Onteniente, Brigitte

    2012-01-01

    Human induced pluripotent stem cells (hiPSCs) are a most appealing source for cell replacement therapy in acute brain lesions. We evaluated the potential of hiPSC therapy in stroke by transplanting hiPSC-derived neural progenitor cells (NPCs) into the postischemic striatum. Grafts received host tyrosine hydroxylase-positive afferents and contained developing interneurons and homotopic GABAergic medium spiny neurons that, with time, sent axons to the host substantia nigra. Grafting reversed stroke-induced somatosensory and motor deficits. Grafting also protected the host substantia nigra from the atrophy that follows disruption of reciprocal striatonigral connections. Graft innervation by tyrosine hydoxylase fibers, substantia nigra protection, and somatosensory functional recovery were early events, temporally dissociated from the slow maturation of GABAergic neurons in the grafts and innervation of substantia nigra. This suggests that grafted hiPSC-NPCs initially exert trophic effects on host brain structures, which precede integration and potential pathway reconstruction. We believe that transplantation of NPCs derived from hiPSCs can provide useful interventions to limit the functional consequences of stroke through both neuroprotective effects and reconstruction of impaired pathways. PMID:22889472

  17. Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

    PubMed Central

    Lin, Li-Chun; Sibille, Etienne

    2013-01-01

    Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders. PMID:24058344

  18. Baifuzi reduces transient ischemic brain damage through an interaction with the STREX domain of BKCa channels

    PubMed Central

    Chi, S; Cai, W; Liu, P; Zhang, Z; Chen, X; Gao, L; Qi, J; Bi, L; Chen, L; Qi, Z

    2010-01-01

    Stroke is a long-term disability and one of the leading causes of death. However, no successful therapeutic intervention is available for the majority of stroke patients. In this study, we explored a traditional Chinese medicine Baifuzi (Typhonium giganteum Engl.). We show, at first, that the ethanol extract of Baifuzi exerts neuroprotective effects against brain damage induced by transient global or focal cerebral ischemia in rats and mice. Second, the extract activated large-conductance Ca2+-activated K+ channel (BKCa) channels, and BKCa channel blockade suppressed the neuroprotection of the extract, suggesting that the BKCa is the molecular target of Baifuzi. Third, Baifuzi cerebroside (Baifuzi-CB), purified from its ethanol extract, activated BKCa channels in a manner similar to that of the extract. Fourth, the stress axis hormone-regulated exon (STREX) domain of the BKCa channel directly interacted with Baifuzi-CB, and its deletion suppressed channel activation by Baifuzi-CB. These results indicate that Baifuzi-CB activated the BKCa channel through its direct interaction with the STREX domain of the channel and suggests that Baifuzi-CB merits exploration as a potential therapeutic agent for treating brain ischemia. PMID:21364615

  19. Serum brain-derived neurotrophic factor levels were reduced during methamphetamine early withdrawal.

    PubMed

    Chen, Pao-Huan; Huang, Ming-Chi; Lai, Ying-Ching; Chen, Po-Yu; Liu, Hsing-Cheng

    2014-05-01

    Methamphetamine (METH) abuse is an increasing public health problem worldwide. Many of the METH-induced physical and mental problems are associated with the neurotoxic effects of METH. Animal studies have shown that brain-derived neurotrophic factor (BDNF) decreased after repeated amphetamine administration and increased at 30 and 90 days from psychostimulant withdrawal, suggesting that there might be a psychostimulant-induced neuroprotective dysfunction followed by a neuroadaptive process in the brain. However, current research on the role of BDNF in human METH addiction is limited, particularly during early withdrawal. The aim of this study was to assess the serum BDNF levels in METH abusers during the early withdrawal stage. Two groups of subjects were enrolled: (1) 59 DSM-IV METH abusers confirmed by board-certified psychiatrists during the first 3 weeks of withdrawal; (2) 59 age- and sex-matched healthy controls. We found that serum BDNF levels were significantly and constantly lower in the METH abusers during early withdrawal than those of the healthy controls. This indicates that METH abusers might have severe BDNF dysfunction and an impaired neuroprotective function after repetitive METH misuse. PMID:22458544

  20. CDC grand rounds: reducing severe traumatic brain injury in the United States.

    PubMed

    2013-07-12

    A traumatic brain injury (TBI) is caused by a bump, blow, jolt, or penetrating wound to the head that disrupts the normal functioning of the brain. In 2009, CDC estimated that at least 2.4 million emergency department visits, hospitalizations, or deaths were related to a TBI, either alone or in combination with other injuries. Approximately 75% of TBIs are mild, often called concussions. Children, adolescents, and older adults are most likely to sustain a TBI. Nearly one third (30.5%) of all injury deaths included a diagnosis of TBI. In addition, an estimated 5.3 million U.S. residents are living with TBI-related disabilities, including long-term cognitive and psychologic impairments. A severe TBI not only affects a person's life and family, but also has a large societal and economic toll. The economic costs of TBIs in 2010 were estimated at $76.5 billion, including $11.5 billion in direct medical costs and $64.8 billion in indirect costs (e.g., lost wages, lost productivity, and nonmedical expenditures). These data underestimate the national burden because they include neither TBIs managed in nonhospital settings nor >31,000 military personnel diagnosed with TBI and treated in the U.S. Department of Defense or Veterans Administration medical systems in 2010. PMID:23842444

  1. Preservation of the Blood Brain Barrier and Cortical Neuronal Tissue by Liraglutide, a Long Acting Glucagon-Like-1 Analogue, after Experimental Traumatic Brain Injury

    PubMed Central

    Hakon, Jakob; Ruscher, Karsten; Tomasevic, Gregor

    2015-01-01

    Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 μg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI. PMID:25822252

  2. Diabetic papillopathy with macular edema treated with intravitreal ranibizumab

    PubMed Central

    Kim, Moosang; Lee, Jang-Hun; Lee, Seung-Jun

    2013-01-01

    We report a case of diabetic papillopathy that demonstrated a resolution of optic disk swelling and rapid visual recovery when intravitreal ranibizumab was administered. A 51-year-old male presented with acute painless visual loss in his right eye. His vision was 20/320 in the right eye and 20/50 in the left eye. Fundus examination of the right eye showed nonproliferative diabetic retinopathy with macular edema and a swollen optic disk. Fluorescein angiography showed dye leakage from the right optic disk. Optical coherent tomography revealed a significant increase in retinal nerve fiber-layer thickness. Magnetic resonance imaging of the brain was normal. The patient received a single intravitreal ranibizumab (0.5 mg) injection. Two weeks following injection, there was marked regression of the disk swelling and improvement of macular edema, with vision improving to 20/100. Three months following injection, there was complete resolution of the optic disk swelling. No further treatment was required. PMID:24348012

  3. Low-power hardware implementation of movement decoding for brain computer interface with reduced-resolution discrete cosine transform.

    PubMed

    Minho Won; Albalawi, Hassan; Xin Li; Thomas, Donald E

    2014-01-01

    This paper describes a low-power hardware implementation for movement decoding of brain computer interface. Our proposed hardware design is facilitated by two novel ideas: (i) an efficient feature extraction method based on reduced-resolution discrete cosine transform (DCT), and (ii) a new hardware architecture of dual look-up table to perform discrete cosine transform without explicit multiplication. The proposed hardware implementation has been validated for movement decoding of electrocorticography (ECoG) signal by using a Xilinx FPGA Zynq-7000 board. It achieves more than 56× energy reduction over a reference design using band-pass filters for feature extraction. PMID:25570284

  4. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice.

    PubMed

    Chan, Yin-Ching; Hosoda, Kazuaki; Tsai, Chin-Ju; Yamamoto, Shigeru; Wang, Ming-Fu

    2006-08-01

    The present study was carried out to explore the effects of oolong and green teas on improving the memory deficits and brain pathological changes in senescence accelerated-prone mice P8 (SAMP8). Six-month-old mice were supplied with oolong tea, green tea or water as the sole drinking fluid for 16 wk. The memory ability of mice was evaluated by passive and active avoidance tests, while the extent of the brain degeneration was measured by the spongiosis grades and the lipofuscin percentage in the hippocampus. The total grading score and serum biochemical levels were also measured. The results indicated that the mice supplemented with the oolong and green tea drinks reversed the cognitive impairment, lessened the spongy degeneration and lipofuscin, and increased the serum Trolox equivalent antioxidant capacity more than the control group. The total grading score of the oolong tea group was lower than that of the control group in male mice, whereas it did not differ among female groups. No differentiations in the concentrations of total cholesterol. triglyceride, glucose, iron or hemoglobin were observed among three drink groups. In conclusion, oolong and green teas could reduce the deteriorations of cognitive ability, brain degenerative changes and aging process in SAMP8, probably through the potent antioxidative activity of the tea. PMID:17087053

  5. Topical Nonsteroidal Anti-Inflammatory Drugs for Macular Edema

    PubMed Central

    Parmeggiani, Francesco; Romano, Mario R.; dell'Omo, Roberto

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are nowadays widely used in ophthalmology to reduce eye inflammation, pain, and cystoid macular edema associated with cataract surgery. Recently, new topical NSAIDs have been approved for topical ophthalmic use, allowing for greater drug penetration into the vitreous. Hence, new therapeutic effects can be achieved, such as reduction of exudation secondary to age-related macular degeneration or diabetic maculopathy. We provide an updated review on the clinical use of NSAIDs for retinal diseases, with a focus on the potential future applications. PMID:24227908

  6. Hypothalamic Deep Brain Stimulation Reduces Weight Gain in an Obesity-Animal Model

    PubMed Central

    Melega, William P.; Lacan, Goran; Gorgulho, Alessandra A.; Behnke, Eric J.; De Salles, Antonio A. F.

    2012-01-01

    Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS. Female Göttingen minipigs were used because of their dietary habits, physiologic characteristics, and brain structures that resemble those of primates. Further, these animals become obese on extra-feeding regimens. DBS electrodes were first bilaterally implanted into the VMH of the animals (n = 8) which were then maintained on a restricted food regimen for 1 mo following the surgery. The daily amount of food was then doubled for the next 2 mo in all animals to produce obesity associated with extra calorie intake, with half of the animals (n = 4) concurrently receiving continuous low frequency (50 Hz) VMH-DBS. Adverse motoric or behavioral effects were not observed subsequent to the surgical procedure or during the DBS period. Throughout this 2 mo DBS period, all animals consumed the doubled amount of daily food. However, the animals that had received VMH-DBS showed a cumulative weight gain (6.1±0.4 kg; mean ± SEM) that was lower than the nonstimulated VMH-DBS animals (9.4±1.3 kg; p<0.05), suggestive of a DBS-associated increase in metabolic rate. These results in a porcine obesity model demonstrate the efficacy and behavioral safety of a low frequency VMH-DBS application as a potential clinical strategy for modulation of body weight. PMID:22295102

  7. Establishment and evaluation of an experimental animal model of high altitude cerebral edema.

    PubMed

    Guo, Ping; Luo, Han; Fan, Yong; Luo, Yongjun; Zhou, Qiquan

    2013-06-28

    The aim of our study was to develop a model of high altitude cerebral edema (HACE) using an acute, hypobaric hypoxia environment combined with exhaustive exercise. Forty healthy male Sprague-Dawley rats were randomly divided into a plains control group (PC group) and a plateau altitude hypoxia group (AH group). After 2 days of treadmill adaptation under normoxic conditions, the AH group was housed in hypobaric conditions (simulating 4000 m above sea level) for 2 days while performing exhaustive exercise. The simulated altitude was then increased to 8000 m for 3 days of simple hypobaric hypoxia exposure. Compared with the PC group, the AH group showed significantly greater (P<0.01) water content and Evans blue staining in their brain tissue. Furthermore, the hippocampal formation was seriously damaged, and the number of pyramidal cells decreased. In addition, the brain structure was altered into a loose state with notable edema, which was demonstrated by the leakage of lanthanum nitrate particles from brain microvessels into the surrounding tissue through widened tight junctions. Some neurons and glial cell organelles were swollen and some nerve fibers were demyelinated as well. We have shown that acute hypobaric hypoxia exposure with exhaustive exercise increases the permeability of the blood-brain barrier and leads to cerebral edema, making this a valid animal model of HACE. PMID:23680461

  8. Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells*

    PubMed Central

    Lee, Jae W.; Fang, Xiaohui; Dolganov, Gregory; Fremont, Richard D.; Bastarache, Julie A.; Ware, Lorraine B.; Matthay, Michael A.

    2009-01-01

    Most patients with acute lung injury (ALI) have reduced alveolar fluid clearance that has been associated with higher mortality. Several mechanisms may contribute to the decrease in alveolar fluid clearance. In this study, we tested the hypothesis that pulmonary edema fluid from patients with ALI might reduce the expression of ion transport genes responsible for vectorial fluid transport in primary cultures of human alveolar epithelial type II cells. Following exposure to ALI pulmonary edema fluid, the gene copy number for the major sodium and chloride transport genes decreased. By Western blot analyses, protein levels of ?ENaC, ?1Na,K-ATPase, and cystic fibrosis transmembrane conductance regulator decreased as well. In contrast, the gene copy number for several inflammatory cytokines increased markedly. Functional studies demonstrated that net vectorial fluid transport was reduced for human alveolar type II cells exposed to ALI pulmonary edema fluid compared with plasma (0.020.05 versus 1.310.56 ?l/cm2/h, p<0.02). An inhibitor of p38 MAPK phosphorylation (SB202190) partially reversed the effects of the edema fluid on net fluid transport as well as gene and protein expression of the main ion transporters. In summary, alveolar edema fluid from patients with ALI induced a significant reduction in sodium and chloride transport genes and proteins in human alveolar epithelial type II cells, effects that were associated with a decrease in net vectorial fluid transport across human alveolar type II cell monolayers. PMID:17580309

  9. Edema - Multiple Languages: MedlinePlus

    MedlinePlus

    ... XYZ List of All Topics All Edema - Multiple Languages To use the sharing features on this page, please enable JavaScript. French (français) Russian (Русский) Somali (af Soomaali) Spanish (español) ...

  10. Current status in diabetic macular edema treatments.

    PubMed

    Romero-Aroca, Pedro

    2013-10-15

    Diabetes is a serious chronic condition, which increase the risk of cardiovascular diseases, kidney failure and nerve damage leading to amputation. Furthermore the ocular complications include diabetic macular edema, is the leading cause of blindness among adults in the industrialized countries. Today, blindness from diabetic macular edema is largely preventable with timely detection and appropriate interventional therapy. The treatment should include an optimized control of glycemia, arterial tension, lipids and renal status. The photocoagulation laser is currently restricted to focal macular edema in some countries, but due the high cost of intravitreal drugs, the use of laser treatment for focal and diffuse diabetic macular edema (DME), can be valid as gold standard in many countries. The intravitreal anti vascular endothelial growth factor drugs (ranibizumab and bevacizumab), are indicated in the treatment of all types of DME, but the correct protocol for administration should be defined for the different Retina Scientific Societies. The corticosteroids for diffuse DME, has a place in pseudophakic patients, but its complications restricted the use of these drugs for some patients. Finally the intravitreal interface plays an important role and its exploration is mandatory in all DME patients. PMID:24147200

  11. INTRAVITREAL CORTICOSTEROIDS IN DIABETIC MACULAR EDEMA

    PubMed Central

    Bailey, Clare; Loewenstein, Anat; Massin, Pascale

    2015-01-01

    Purpose: To review the relationship between kinetics, efficacy, and safety of several corticosteroid formulations for the treatment of diabetic macular edema. Methods: Reports of corticosteroid use for the treatment of diabetic macular edema were identified by a literature search, which focused on the pharmacokinetics, efficacy, and safety of these agents in preclinical animal models and clinical trials. Results: Available corticosteroids for diabetic macular edema treatment include intravitreal triamcinolone acetonide, dexamethasone, and fluocinolone acetonide. Because of differences in solubility and bioavailability, various delivery mechanisms are used. Bioerodible delivery systems achieve higher maximum concentrations than nonbioerodible formulations. There is a relationship between visual gains and drug persistence in the intravitreal compartment. Safety effects were more complex; level of intravitreal triamcinolone acetonide exposure is related to development of elevated intraocular pressure and cataract; this does not seem to be the case for dexamethasone, where two different doses showed similar mean intraocular pressure and incidence of cataract surgery. With fluocinolone acetonide, rates of intraocular pressure elevations requiring surgery seem to be dose related; rates of cataract extraction were similar regardless of dose. Conclusion: Available corticosteroids for diabetic macular edema exhibit different pharmacokinetic profiles that impact efficacy and adverse events and should be taken into account when developing individualized treatment plans. PMID:26352555

  12. Intraoperative lung edema monitoring by microwave reflectometry.

    PubMed

    Nowak, Kai; Gross, Wolfgang; Nicksch, Kathrin; Hanusch, Christine; Helbig, Marko; Hohenberger, Peter; Gebhard, Martha M; Schaefer, Michael

    2011-04-01

    Microwave reflectometry might be a suitable tool for the thoracic surgeon to monitor edema formation of the lung during lung surgery. A new setup of microwave reflectometry for lung water measurements was developed and tested for clinical application. Three lung models were used for the microwave reflectometry tests: 1) the model of an ex vivo isolated perfused rat lung to investigate lung edema formation during ischemia-reperfusion (n=6), 2) the in situ lung of a human patient to demonstrate the feasibility of lung water monitoring during a surgical operation, 3) the model of an ex vivo isolated perfused human lung to investigate edema formation during postischemic reperfusion and to investigate the changes in water content in the region of a tumor. During human lung operation, significant changes in water content occurred in different lung areas. During isolated perfusion, a significant increase in lung water was measured in models 1) and 3) (P=0.03). Water content of tumor tissue was higher than in the surrounding healthy lung tissue. Microwave reflectometry offers a non-invasive approach to monitor lung edema formation in experimental models and during thoracic surgery. PMID:21172949

  13. Interstitial lung edema triggered by marathon running.

    PubMed

    Zavorsky, Gerald S; Milne, Eric N C; Lavorini, Federico; Rienzi, Joseph P; Lavin, Kaleen M; Straub, Allison M; Pistolesi, Massimo

    2014-01-01

    The purpose of this study was to determine whether marathon running causes lung edema, and if so, to determine its effects on runners. Posterior/anterior (PA) radiographs were taken one day before the marathon and at 19, 55, and 98min post-marathon in 26 runners. The pre and post exercise radiographs of each runner were collated, and then read simultaneously. Two physicians interpreted the images independently in a blinded fashion. The PA radiographs were viewed together at each time-point and findings suggestive for interstitial lung edema were rated as 'mild,' 'moderate,' or 'severe' based on four different radiological criteria. Forty-six percent of the runners presented radiographic findings suggestive of mild to severe interstitial lung edema. Radiographic findings persisted until 98-min post-marathon, with at least moderate degree increases found more frequently in women (55%) than men (6%) (p<0.01). In conclusion, about half of the runners developed interstitial lung edema of varying degrees post-exercise with the incidence being higher in women compared to men. PMID:24369923

  14. Etoricoxib-induced pretibial erythema and edema

    PubMed Central

    Kumar, Pramod

    2015-01-01

    Cyclooxygenase inhibitors were developed in the quest of enhanced analgesic efficacy devoid of gastric side effects. Etoricoxib is a second-generation cox-2 inhibitor and as its use increases so do the reports of side effects. We report a case of extoricoxib-induced pretibial erythema and edema; and review the literature. PMID:26904451

  15. A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease.

    PubMed

    Kalinin, Sergey; Richardson, Jill C; Feinstein, Douglas L

    2009-10-01

    Agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARdelta), which is expressed at higher levels in the brain than PPARgamma, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARdelta agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARgamma agonists, PPARdelta agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance. PMID:19874267

  16. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease.

    PubMed

    Jordão, Jessica F; Ayala-Grosso, Carlos A; Markham, Kelly; Huang, Yuexi; Chopra, Rajiv; McLaurin, JoAnne; Hynynen, Kullervo; Aubert, Isabelle

    2010-01-01

    Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Abeta), which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Abeta plaque pathology. Therefore, delivering anti-Abeta antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB), allowing intravenously administered therapeutics to enter the brain. Our goal was to establish that anti-Abeta antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) can reduce plaque pathology. To test this, TgCRND8 mice received intravenous injections of MRI and FUS contrast agents, as well as anti-Abeta antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Abeta plaques in targeted cortical areas. Four days post-treatment, Abeta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Abeta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology. PMID:20485502

  17. Anti-inflammatory effect of laser acupuncture in ST36 (Zusanli) acupoint in mouse paw edema.

    PubMed

    Erthal, Vanessa; Maria-Ferreira, Daniele; Werner, Maria Fernanda de Paula; Baggio, Cristiane Hatsuko; Nohama, Percy

    2016-02-01

    Low-level laser therapy (LLLT) in acupuncture is a low-power laser applied to acupoints for providing luminous energy, capable to produce photobiological induction that results in biochemical, bioelectric, and bioenergetic effects. ST36 (Zusanli) is a point of acupuncture commonly used for treatment of several pathological alterations, such as inflammation, acute pain, and gastrointestinal disorders. In this study, we evaluated the anti-inflammatory effect of LLLT (830 nm, 4 J/cm(2)) in ST36 acupoint through the model of carrageenan-induced paw edema in mice and the possible mechanisms involved. Female Swiss mice were treated with LLLT in ST36 before the paw edema induction, which was measured by means of a digital micrometer and the temperature through a high-resolution digital thermograph. After this, the levels of reactive oxygen species (ROS), lipid hydroperoxides (LOOH), and reduced glutathione (GSH) were quantified. In another set of experiments, the paw edema was induced by bradykinin, histamine, and prostaglandin E2 (PGE2). LLLT in ST36 acupoint significantly inhibited the edema formation for 4 h after the carrageenan injection and reduced the paw temperature in 10 %. Furthermore, LLLT also reduced the levels of ROS (55 %) and LOOH (50 %) but, however, did not alter the GSH levels. LLLT in ST36 reduced the paw edema induced by bradykinin (30 min, 6 %, 60 min, 7 %), histamine (30 min, 11 %), and PGE2 (90 min, 10 %, 120 min, 16 %). In conclusion, these results prove that LLLT in ST36 acupoint produces a relevant anti-inflammatory effect, reducing edema, temperature, and free radicals levels in mice paw. PMID:26738499

  18. MAP training: combining meditation and aerobic exercise reduces depression and rumination while enhancing synchronized brain activity

    PubMed Central

    Alderman, B L; Olson, R L; Brush, C J; Shors, T J

    2016-01-01

    Mental and physical (MAP) training is a novel clinical intervention that combines mental training through meditation and physical training through aerobic exercise. The intervention was translated from neuroscientific studies indicating that MAP training increases neurogenesis in the adult brain. Each session consisted of 30 min of focused-attention (FA) meditation and 30 min of moderate-intensity aerobic exercise. Fifty-two participants completed the 8-week intervention, which consisted of two sessions per week. Following the intervention, individuals with major depressive disorder (MDD; n=22) reported significantly less depressive symptoms and ruminative thoughts. Typical healthy individuals (n=30) also reported less depressive symptoms at follow-up. Behavioral and event-related potential indices of cognitive control were collected at baseline and follow-up during a modified flanker task. Following MAP training, N2 and P3 component amplitudes increased relative to baseline, especially among individuals with MDD. These data indicate enhanced neural responses during the detection and resolution of conflicting stimuli. Although previous research has supported the individual beneficial effects of aerobic exercise and meditation for depression, these findings indicate that a combination of the two may be particularly effective in increasing cognitive control processes and decreasing ruminative thought patterns. PMID:26836414

  19. CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.

    PubMed

    Shiina, Satoshi; Ohno, Masasuke; Ohka, Fumiharu; Kuramitsu, Shunichiro; Yamamichi, Akane; Kato, Akira; Motomura, Kazuya; Tanahashi, Kuniaki; Yamamoto, Takashi; Watanabe, Reiko; Ito, Ichiro; Senga, Takeshi; Hamaguchi, Michinari; Wakabayashi, Toshihiko; Kaneko, Mika K; Kato, Yukinari; Chandramohan, Vidyalakshmi; Bigner, Darell D; Natsume, Atsushi

    2016-03-01

    Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM. Cancer Immunol Res; 4(3); 259-68. ©2016 AACR. PMID:26822025

  20. Luteolin Reduces Alzheimer’s Disease Pathologies Induced by Traumatic Brain Injury

    PubMed Central

    Sawmiller, Darrell; Li, Song; Shahaduzzaman, Md; Smith, Adam J.; Obregon, Demian; Giunta, Brian; Borlongan, Cesar V.; Sanberg, Paul R.; Tan, Jun

    2014-01-01

    Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI. PMID:24413756

  1. MAP training: combining meditation and aerobic exercise reduces depression and rumination while enhancing synchronized brain activity.

    PubMed

    Alderman, B L; Olson, R L; Brush, C J; Shors, T J

    2016-01-01

    Mental and physical (MAP) training is a novel clinical intervention that combines mental training through meditation and physical training through aerobic exercise. The intervention was translated from neuroscientific studies indicating that MAP training increases neurogenesis in the adult brain. Each session consisted of 30 min of focused-attention (FA) meditation and 30 min of moderate-intensity aerobic exercise. Fifty-two participants completed the 8-week intervention, which consisted of two sessions per week. Following the intervention, individuals with major depressive disorder (MDD; n=22) reported significantly less depressive symptoms and ruminative thoughts. Typical healthy individuals (n=30) also reported less depressive symptoms at follow-up. Behavioral and event-related potential indices of cognitive control were collected at baseline and follow-up during a modified flanker task. Following MAP training, N2 and P3 component amplitudes increased relative to baseline, especially among individuals with MDD. These data indicate enhanced neural responses during the detection and resolution of conflicting stimuli. Although previous research has supported the individual beneficial effects of aerobic exercise and meditation for depression, these findings indicate that a combination of the two may be particularly effective in increasing cognitive control processes and decreasing ruminative thought patterns. PMID:26836414

  2. Methylene Blue Attenuates Traumatic Brain Injury-Associated Neuroinflammation and Acute Depressive-Like Behavior in Mice

    PubMed Central

    Fenn, Ashley M.; Skendelas, John P.; Moussa, Daniel N.; Muccigrosso, Megan M.; Popovich, Phillip G.; Lifshitz, Jonathan

    2015-01-01

    Abstract Traumatic brain injury (TBI) is associated with cerebral edema, blood brain barrier breakdown, and neuroinflammation that contribute to the degree of injury severity and functional recovery. Unfortunately, there are no effective proactive treatments for limiting immediate or long-term consequences of TBI. Therefore, the objective of this study was to determine the efficacy of methylene blue (MB), an antioxidant agent, in reducing inflammation and behavioral complications associated with a diffuse brain injury. Here we show that immediate MB infusion (intravenous; 15–30 minutes after TBI) reduced cerebral edema, attenuated microglial activation and reduced neuroinflammation, and improved behavioral recovery after midline fluid percussion injury in mice. Specifically, TBI-associated edema and inflammatory gene expression in the hippocampus were significantly reduced by MB at 1 d post injury. Moreover, MB intervention attenuated TBI-induced inflammatory gene expression (interleukin [IL]-1β, tumor necrosis factor α) in enriched microglia/macrophages 1 d post injury. Cell culture experiments with lipopolysaccharide-activated BV2 microglia confirmed that MB treatment directly reduced IL-1β and increased IL-10 messenger ribonucleic acid in microglia. Last, functional recovery and depressive-like behavior were assessed up to one week after TBI. MB intervention did not prevent TBI-induced reductions in body weight or motor coordination 1–7 d post injury. Nonetheless, MB attenuated the development of acute depressive-like behavior at 7 d post injury. Taken together, immediate intervention with MB was effective in reducing neuroinflammation and improving behavioral recovery after diffuse brain injury. Thus, MB intervention may reduce life-threatening complications of TBI, including edema and neuroinflammation, and protect against the development of neuropsychiatric complications. PMID:25070744

  3. Deep brain stimulation reduces Tic-related neural activity via temporal locking with stimulus pulses.

    PubMed

    McCairn, Kevin W; Iriki, Atsushi; Isoda, Masaki

    2013-04-10

    A neurosurgical intervention that has shown potential for treating basal ganglia (BG) mediated motor tics involves high-frequency deep brain stimulation (HF-DBS) targeted to the output nucleus of the BG: the globus pallidus internus (GPi). This study used a nonhuman primate (Macaca fuscata) model of BG-meditated motor tics, and investigated the short-term neuronal mechanism that might underlie the beneficial effects of GPi-HF-DBS. In parallel with behavioral tic expressions, phasic alterations of neuronal activity emerged in the pallidum following focal disinhibition of the striatum with bicuculline. We delivered HF-DBS in the GPi in such a way that on-stimulation and off-stimulation conditions alternated every 30 s. Analysis of electromyographic (EMG) records showed that during on-stimulation, there were significant reductions in tic-related EMG amplitude. Analysis of pallidal activity showed that GPi-HF-DBS induced both sustained and transient patterns of excitation and inhibition in both segments of the GP. Population-scale firing rates were initially raised relative to baseline, but were not significantly different by the time stimulation ceased. Modulation of behavior and neuronal firing rates were associated with the reduction of tic-related phasic activity in pallidal cells. Examination of short-latency responses showed that firing rate changes were strongly associated with locking of the cells' activity with the HF-DBS pulse. This temporal locking often induced multiphasic changes of firing rates in individual cells, which dynamically changed across the stimulation period. These results support clinical studies that reported success in treating motor tics with GPi-HF-DBS, and demonstrate that the underlying local mechanism within the GP is suppression of tic-related activity through temporal locking with the stimulation pulse. PMID:23575855

  4. Bax inhibiting peptide reduces apoptosis in neonatal rat hypoxic-ischemic brain damage

    PubMed Central

    Sun, Meng-Ya; Cui, Kai-Jie; Yu, Mao-Min; Zhang, Hui; Peng, Xiang-Li; Jiang, Hong

    2015-01-01

    Neonatal hypoxic ischemic encephalopathy (HIE) has been reported to induce apoptosis in neonates. We, therefore, analyzed the ability of Bax-inhibiting peptide (BIP) to provide neuroprotective effects during hypoxic-ischemic brain damage (HIBD). Seven-day-old wistar rat pups (n = 198) were randomly divided into a sham-operated group (Group S, n = 18), saline group (Group C, n = 90) and BIP group (Group B, n = 90). Pathological changes in the cerebral tissues of rat pups were analyzed using hematoxylin and eosin stain, TUNEL and Western blot. The expression of cytochrome c and caspase-3 was determined using western blot technique. Rat pups demonstrated neurobehavioral alteration in Groups C and B. TUNEL-positive cells in the left hippocampus were significantly increased in Group C and Group B after HIBD (P < 0.01) when compared with Group S. There was a marked reduction in TUNEL positive cells in subgroups B1 through B4 when compared with the respective subgroups C1 through C5. Compared with Group S, the expression of caspase-3 and cytochrome c was significantly increased in Groups C and B (P < 0.01). The difference in expression of caspase-3 and cytochrome c between subgroups B1 through B4 and C1 through C4 was significant (P < 0.01). In conclusions, the neuro-protective effect of BIP was due to a reduction of nerve cell apoptosis in our neonatal HIE rat model. We propose that BIP has potential as a neuro-protective drug in neonatal HIE cases. PMID:26823794

  5. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

    PubMed

    Steele, J W; Ju, S; Lachenmayer, M L; Liken, J; Stock, A; Kim, S H; Delgado, L M; Alfaro, I E; Bernales, S; Verdile, G; Bharadwaj, P; Gupta, V; Barr, R; Friss, A; Dolios, G; Wang, R; Ringe, D; Protter, A A; Martins, R N; Ehrlich, M E; Yue, Z; Petsko, G A; Gandy, S

    2013-08-01

    Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities. PMID:22869031

  6. Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

    PubMed Central

    Stefani, Alessandro; Fedele, Ernesto; Pierantozzi, Mariangela; Galati, Salvatore; Marzetti, Francesco; Peppe, Antonella; Pastore, Francesco Saverio; Bernardi, Giorgio; Stanzione, Paolo

    2011-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy. PMID:21519387

  7. Reduced glucose uptake and Aβ in brain regions with hyperintensities in connected white matter

    PubMed Central

    Rusinek, H.; Tsui, W.; Mosconi, L.; Li, Y.; Osorio, R.S.; Williams, S.; Randall, C.; Spector, N.; McHugh, P.; Murray, J.; Pirraglia, E.; Vallabhajosula, S.; Raj, A.; de Leon, M.J.

    2014-01-01

    Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDGPET) in connected GM. WML masks from 72 cognitively normal (age 61.7±9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r=0.20, p<0.05 corrected) and lower PiB uptake (r=0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (β=0.045) and FDG-PET (β=0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition. PMID:24999038

  8. Multimodal MR imaging of acute and subacute experimental traumatic brain injury: Time course and correlation with cerebral energy metabolites

    PubMed Central

    Maegele, Marc; Hoeffgen, Alexander; Uhlenkueken, Ulla; Mautes, Angelika; Schaefer, Nadine; Lippert-Gruener, Marcela; Schaefer, Ute; Hoehn, Mathias

    2015-01-01

    Background Traumatic brain injury (TBI) is one of the leading causes of death and permanent disability world-wide. The predominant cause of death after TBI is brain edema which can be quantified by non-invasive diffusion-weighted magnetic resonance imaging (DWI). Purpose To provide a better understanding of the early onset, time course, spatial development, and type of brain edema after TBI and to correlate MRI data and the cerebral energy state reflected by the metabolite adenosine triphosphate (ATP). Material and Methods The spontaneous development of lateral fluid percussion-induced TBI was investigated in the acute (6 h), subacute (48 h), and chronic (7 days) phase in rats by MRI of quantitative T2 and apparent diffusion coefficient (ADC) mapping as well as perfusion was combined with ATP-specific bioluminescence imaging and histology. Results An induced TBI led to moderate to mild brain damages, reflected by transient, pronounced development of vasogenic edema and perfusion reduction. Heterogeneous ADC patterns indicated a parallel, but mixed expression of vasogenic and cytotoxic edema. Cortical ATP levels were reduced in the acute and subacute phase by 13% and 27%, respectively, but were completely normalized at 7 days after injury. Conclusion The partial ATP reduction was interpreted to be partially caused by a loss of neurons in parallel with transient dilution of the regional ATP concentration by pronounced vasogenic edema. The normalization of energy metabolism after 7 days was likely due to infiltrating glia and not to recovery. The MRI combined with metabolite measurement further improves the understanding and evaluation of brain damages after TBI. PMID:25610615

  9. Activation of liver X receptor reduces global ischemia brain injury by reduction of nuclear factor-κB

    PubMed Central

    Cheng, Oumei; Ostrowski, Robert P.; Liu, Wenwu; Zhang, John H.

    2010-01-01

    Recent studies have found that liver X receptors (LXRs) agonists decrease inflammation and possess neuroprotective properties. The aim of this study was to examine the mechanisms of liver X receptor agonist GW3965 on brain injury following global cerebral ischemia in the rat. The 48 male SD rats were randomly partitioned into three groups: sham, global ischemia (4-vessel occlusion for 15 minutes; 4VO) treated with vehicle and global ischemia treated with GW3965 (20mg/kg, via i.p at 10 minutes after reperfusion). The functional outcome was determined by neurological evaluation at 24 hours post ischemia and by testing rats in T maze at 3 and 7 days after reperfusion. The rats' daily body weight, incidence of seizures and 72 hours mortality were also determined. After Nissl staining and TUNEL in coronal brain sections, the numbers of intact and damaged cells were counted in the CA1 sector of the hippocampus. The expression of phosphorylated inhibitor of κB (p-IκBα), Nuclear Factor-κB (NF-κB) subunit p65, and cyclo-oxygenase-2 (COX-2) were analyzed with Western blot at 12 hours after reperfusion. GW3965 tended to reduce 72 hours mortality and the incidence of post-ischemic seizures. GW3965-treated rats showed an improved neuronal survivability in CA1 and a significant increase in the percentage of spontaneous alternations detected in T-maze on day 7 after ischemia. GW3965-induced neuroprotection was associated with a significant reduction in nuclear translocation of NF-kB p65 subunit and a decrease in the hippocampal expression of NF-kB target gene, COX-2. LXR receptor agonist protects against neuronal damage following global cerebral ischemia. The mechanism of neuroprotection may include blockade of NF-κB activation and the subsequent suppression of COX-2 in the post ischemic brain. PMID:20096333

  10. Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

    PubMed Central

    White, Sarah J.; Hendrickson, Howard P.; Atchley, William T.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Williams, D. Keith; Owens, S. Michael

    2014-01-01

    We hypothesized that treatment of pregnant rat dams with a dual reactive monoclonal antibody (mAb4G9) against (+)-methamphetamine [METH; equilibrium dissociation rate constant (KD) = 16 nM] and (+)-amphetamine (AMP; KD = 102 nM) could confer maternal and fetal protection from brain accumulation of both drugs of abuse. To test this hypothesis, pregnant Sprague-Dawley rats (on gestational day 21) received a 1 mg/kg i.v. METH dose, followed 30 minutes later by vehicle or mAb4G9 treatment. The mAb4G9 dose was 0.56 mole-equivalent in binding sites to the METH body burden. Pharmacokinetic analysis showed baseline METH and AMP elimination half-lives were congruent in dams and fetuses, but the METH volume of distribution in dams was nearly double the fetal values. The METH and AMP area under the serum concentration-versus-time curves from 40 minutes to 5 hours after mAb4G9 treatment increased >7000% and 2000%, respectively, in dams. Fetal METH serum did not change, but AMP decreased 23%. The increased METH and AMP concentrations in maternal serum resulted from significant increases in mAb4G9 binding. Protein binding changed from ∼15% to > 90% for METH and AMP. Fetal serum protein binding appeared to gradually increase, but the absolute fraction bound was trivial compared with the dams. mAb4G9 treatment significantly reduced METH and AMP brain values by 66% and 45% in dams and 44% and 46% in fetuses (P < 0.05), respectively. These results show anti-METH/AMP mAb4G9 therapy in dams can offer maternal and fetal brain protection from the potentially harmful effects of METH and AMP. PMID:24839971

  11. Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most devastating neurological problem of premature infants. Current treatment strategies are ineffective and brain injury is unpreventable. Insulin-like growth factor 1 (IGF-1) is an endogenous protein shown to have multiple neuroprotective properties. We therefore hypothesized that IGF-1 would reduce brain injury after GMH. Neonatal rats (P7 age) received stereotactic collagenase into the right ganglionic eminence. The following groups were studied: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal IGF-1. Three days later, the animals were evaluated using the righting-reflex (early neurobehavior), Evans blue dye leakage (blood-brain barrier (BBB) permeability), brain water content (edema), and hemoglobin assay (extent of bleeding). Three weeks later, juvenile rats were tested using a water maze (delayed neurobehavior), and then were sacrificed on day 28 for assessment of hydrocephalus (ventricular size). Intranasal IGF-1 treated animals had improved neurological function, and amelioration of BBB permeability, edema, and re-bleeding. IGF-1 may play a part in protective brain signaling following GMH, and our observed protective effect may offer new promise for treatment targeting this vulnerable patient population. PMID:26463950

  12. Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis

    PubMed Central

    Karim, Rushmia; Sykakis, Evripidis; Lightman, Susan; Fraser-Bell, Samantha

    2013-01-01

    Background Uveitic macular edema is the major cause of reduced vision in eyes with uveitis. Objectives To assess the effectiveness of interventions in the treatment of uveitic macular edema. Search strategy Cochrane Central Register of Controlled Trials, Medline, and Embase. There were no language or data restrictions in the search for trials. The databases were last searched on December 1, 2011. Reference lists of included trials were searched. Archives of Ophthalmology, Ophthalmology, Retina, the British Journal of Ophthalmology, and the New England Journal of Medicine were searched for clinical trials and reviews. Selection criteria Participants of any age and sex with any type of uveitic macular edema were included. Early, chronic, refractory, or secondary uveitic macular edema were included. We included trials that compared any interventions of any dose and duration, including comparison with another treatment, sham treatment, or no treatment. Data collection and analysis Best-corrected visual acuity and central macular thickness were the primary outcome measures. Secondary outcome data including adverse effects were collected. Conclusion More results from randomized controlled trials with long follow-up periods are needed for interventions for uveitic macular edema to assist in determining the overall long-term benefit of different treatments. The only intervention with sufficiently robust randomized controlled trials for a meta-analysis was acetazolamide, which was shown to be ineffective in improving vision in eyes with uveitic macular edema, and is clinically now rarely used. Interventions showing promise in this disease include dexamethasone implants, immunomodulatory drugs and anti-vascular endothelial growth-factor agents. When macular edema has become refractory after multiple interventions, pars plana vitrectomy could be considered. The disease pathophysiology is uncertain and the course of disease unpredictable. As there are no clear guidelines from the literature, interventions should be tailored to the individual patient. PMID:23807831

  13. Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis

    PubMed Central

    HAJEK, TOMAS; KOPECEK, MILOSLAV; HÖSCHL, CYRIL

    2012-01-01

    Objectives Converging evidence suggests that the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects brain structure. Yet the majority of studies have shown no effect of this polymorphism on hippocampal volumes, perhaps due to small effect size. Methods We performed a meta-analysis of studies investigating the association between Val66Met BDNF polymorphism and hippocampal volumes in healthy subjects by combining standardized differences between means (SDM) from individual studies using random effect models. Results Data from 399 healthy subjects (255 Val-BDNF homozygotes and 144 carriers of at least one Met-BDNF allele) in seven studies were meta-analysed. Both the left and right hippocampi were significantly larger in Val-BDNF homozygotes than in carriers of at least one Met-BDNF allele (SDM = 0.41, 95% Confidence Interval = 0.20; 0.62, z = 3.86, P = 0.0001; SDM = 0.41; 95% Confidence Interval = 0.20; 0.61, z = 3.81, P = 0.0001, respectively), with no evidence of publication bias. Conclusions Healthy carriers of BDNF gene Val66Met polymorphism show bilateral hippocampal volume reduction. The effect size was small, but the same direction of effect was seen in all meta-analyzed studies. The association with the BDNF gene Val66Met polymorphism makes hippocampal volume a potential candidate for an endophenotype of disorders presenting with reduced hippocampal volumes. PMID:21722019

  14. Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain.

    PubMed

    Baulch, Janet E; Acharya, Munjal M; Allen, Barrett D; Ru, Ning; Chmielewski, Nicole N; Martirosian, Vahan; Giedzinski, Erich; Syage, Amber; Park, Audrey L; Benke, Sarah N; Parihar, Vipan K; Limoli, Charles L

    2016-04-26

    Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment. PMID:27044087

  15. Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

    PubMed Central

    Baulch, Janet E.; Acharya, Munjal M.; Allen, Barrett D.; Ru, Ning; Chmielewski, Nicole N.; Martirosian, Vahan; Giedzinski, Erich; Syage, Amber; Park, Audrey L.; Benke, Sarah N.; Parihar, Vipan K.; Limoli, Charles L.

    2016-01-01

    Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment. PMID:27044087

  16. Neurons in Vulnerable Regions of the Alzheimer's Disease Brain Display Reduced ATM Signaling.

    PubMed

    Shen, Xuting; Chen, Jianmin; Li, Jiali; Kofler, Julia; Herrup, Karl

    2016-01-01

    Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer's disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function-nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity-appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals. PMID:27022623

  17. Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123

    PubMed Central

    Shen, Xuting; Chen, Jianmin; Li, Jiali; Kofler, Julia

    2016-01-01

    Abstract Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals. PMID:27022623

  18. High Serum MiR-130a Levels Are Associated with Severe Perihematomal Edema and Predict Adverse Outcome in Acute ICH.

    PubMed

    Wang, Meng-Die; Wang, Yong; Xia, Yuan-Peng; Dai, Jing-Wen; Gao, Lin; Wang, Si-Qi; Wang, Hai-Jun; Mao, Ling; Li, Man; Yu, Shi-Meng; Tu, Yan; He, Quan-Wei; Zhang, Guo-Peng; Wang, Lei; Xu, Guo-Zheng; Xu, Hai-Bo; Zhu, Ling-Qiang; Hu, Bo

    2016-03-01

    The development and/or progression of perihematomal edema (PHE) in patients with acute spontaneous intracerebral hemorrhage (ICH) vary substantially with different individuals. Although hematoma volume is a useful indicator for predicting PHE, its predictive power was not good at the early stage of ICH. Better predictors are urgently needed. In this study, we found that miR-130a was elevated in the serum of ICH patients and was an independent indicator positively associated with PHE volume within the first 3 days after onset. The R (2) was further evaluated when it is used in combination with hematoma mass. Serum miR-130a levels were associated with clinical outcome (National Institute of Health Stroke Scale (NIHSS) scores at day 14 and modified Rankin Scale (mRS) scores at day 90) only in patients with deep hematoma. Moreover, miR-130a was significantly increased in rat serum and perihematomal tissues and was in line with the change in brain edema. MiR-130a inhibitors reduced brain edema, blood-brain barrier (BBB) permeability, and increased neurological deficit scores, and miR-130a mimics increased monolayer permeability. Thrombin-stimulated brain microvascular endothelial cells (BMECs) were a main source of miR-130a under ICH. In the experimental model, the elevated miR-130a level was accompanied by the decreased caveolin-1 and increased matrix metalloproleinase (MMP)-2/9. Meanwhile, caveolin-1 (cav-1) was reduced by miR-130a mimics, accompanied by an increase in MMP-2/9 expression. The upregulated MMP-2/9 was then downregulated by cavtratin, a cav-1 scaffolding domain peptide. This regulation mechanism was authenticated in a thrombin-induced cellular ICH model. Our results suggest that serum miR-130a may serve as a useful early biomarker for monitoring post-ICH PHE and predicting prognosis and may be helpful in the decision-making of individualized therapy. PMID:25631713

  19. Testing the Neurovascular Hypothesis of Alzheimer’s Disease: LRP-1 Antisense Reduces Blood-Brain Barrier Clearance, Increases Brain Levels of Amyloid-β Protein, and Impairs Cognition

    PubMed Central

    Jaeger, Laura B.; Dohgu, Shinya; Hwang, Mark C.; Farr, Susan A.; Murphy, M. Paul; Fleegal-DeMotta, Melissa A.; Lynch, Jessica L.; Robinson, Sandra M.; Niehoff, Michael L.; Johnson, Steven N.; Kumar, Vijaya B.; Banks, William A.

    2009-01-01

    Decreased clearance is the main reason amyloid-β protein (Aβ) in increased in the brains of patients with Alzheimer’s disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Aβ at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Aβ42, increased brain levels of Aβ42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Aβ could increase and AD would be promoted. PMID:19433890

  20. Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study

    PubMed Central

    2011-01-01

    Background The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS). Methods Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR. Results CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD. Conclusions These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid. PMID:21244691

  1. Noopept reduces the postischemic functional and metabolic disorders in the brain of rats with different sensitivity to hypoxia.

    PubMed

    Zarubina, I V; Shabanov, P D

    2009-03-01

    Chronic cerebral ischemia was induced by ligation of both common carotid arteries in Wistar rats, divided by sensitivity to hypoxia into highly sensitive and low-sensitive. Noopept (peptide preparation), injected (0.5 mg/kg) during 7 days after occlusion of the carotid arteries, reduced the neurological disorders in rats with high and low sensitivity to hypoxia and improved their survival during the postischemic period. Noopept normalized behavior disordered by cerebral ischemia (according to the open field and elevated plus maze tests), prevented accumulation of LPO products and inhibition of antioxidant systems in the brain of rats with high and low sensitivity to hypoxia. Hence, noopept exhibited a neuroprotective effect in cerebral ischemia. PMID:19529857

  2. Increased release of brain serotonin reduces vulnerability to ventricular fibrillation in the cat

    NASA Technical Reports Server (NTRS)

    Lehnert, Hendrik; Lombardi, Federico; Raeder, Ernst A.; Lorenzo, Antonio V.; Verrier, Richard L.; Lown, Bernard; Wurtman, Richard J.

    1987-01-01

    The effect of administering the serotonin precursor 5-l-hydroxytryptophan, in conjunction with a monamine oxidase inhibitor phenelzine and a l-amino acid decarboxylase inhibitor carbidopa, on neurochemical changes in the concentrations of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of the cat were investigated. Results showed that this drug regimen led to increases of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid by 330 and 830 percent, respectively. Concomitantly, the threshold of ventricular fibrillation was found to be elevated by 42 percent and the effective refractory period was prolonged by 7 percent; the efferent sympathetic neural activity was suppressed in the normal heart. The results indicate that the enhancement of central serotoninergic neurotransmission can reduce the susceptibility of the heart to ventricular fibrillation mediated through a decline in sympathetic neural traffic to the heart.

  3. Emotional graphic cigarette warning labels reduce the electrophysiological brain response to smoking cues.

    PubMed

    Wang, An-Li; Romer, Dan; Elman, Igor; Turetsky, Bruce I; Gur, Ruben C; Langleben, Daniel D

    2015-03-01

    There is an ongoing public debate about the new graphic warning labels (GWLs) that the Food and Drug Administration (FDA) proposes to place on cigarette packs. Tobacco companies argued that the strongly emotional images FDA proposed to include in the GWLs encroached on their constitutional rights. The court ruled that FDA did not provide sufficient scientific evidence of compelling public interest in such encroachment. This study's objectives were to examine the effects of the GWLs on the electrophysiological and behavioral correlates of smoking addiction and to determine whether labels rated higher on the emotional reaction (ER) scale are associated with greater effects. We studied 25 non-treatment-seeking smokers. Event-related potentials (ERPs) were recorded while participants viewed a random sequence of paired images, in which visual smoking (Cues) or non-smoking (non-Cues) images were preceded by GWLs or neutral images. Participants reported their cigarette craving after viewing each pair. Dependent variables were magnitude of P300 ERPs and self-reported cigarette craving in response to Cues. We found that subjective craving response to Cues was significantly reduced by preceding GWLs, whereas the P300 amplitude response to Cues was reduced only by preceding GWLs rated high on the ER scale. In conclusion, our study provides experimental neuroscience evidence that weighs in on the ongoing public and legal debate about how to balance the constitutional and public health aspects of the FDA-proposed GWLs. The high toll of smoking-related illness and death adds urgency to the debate and prompts consideration of our findings while longitudinal studies of GWLs are underway. PMID:24330194

  4. Emotional graphic cigarette warning labels reduce the electrophysiological brain response to smoking cues

    PubMed Central

    Wang, An-Li; Romer, Dan; Elman, Igor; Turetsky, Bruce I.; Gur, Ruben C.; Langleben, Daniel D.

    2015-01-01

    There is an ongoing public debate about the new graphic warning labels (GWLs) that the Food and Drug Administration (FDA) proposes to place on cigarette packs. Tobacco companies argued that the strongly emotional images FDA proposed to include in the GWLs encroached on their constitutional rights. The court ruled that FDA did not provide sufficient scientific evidence of compelling public interest in such encroachment. This study’s objectives were to examine the effects of the GWLs on the electrophysiological and behavioral correlates of smoking addiction and to determine whether labels rated higher on the emotional reaction (ER) scale are associated with greater effects. We studied 25 non-treatment-seeking smokers. Event-related potentials (ERPs) were recorded while participants viewed a random sequence of paired images, in which visual smoking (Cues) or non-smoking (non-Cues) images were preceded by GWLs or neutral images. Participants reported their cigarette craving after viewing each pair. Dependent variables were magnitude of P300 ERPs and self-reported cigarette craving in response to Cues. We found that subjective craving response to Cues was significantly reduced by preceding GWLs, whereas the P300 amplitude response to Cues was reduced only by preceding GWLs rated high on the ER scale. In conclusion, our study provides experimental neuroscience evidence that weighs in on the ongoing public and legal debate about how to balance the constitutional and public health aspects of the FDA-proposed GWLs. The high toll of smoking-related illness and death adds urgency to the debate and prompts consideration of our findings while longitudinal studies of GWLs are underway. PMID:24330194

  5. Management of pseudophakic cystoid macular edema.

    PubMed

    Guo, Suqin; Patel, Shriji; Baumrind, Ben; Johnson, Keegan; Levinsohn, Daniel; Marcus, Edward; Tannen, Brad; Roy, Monique; Bhagat, Neelakshi; Zarbin, Marco

    2015-01-01

    Pseudophakic cystoid macular edema (PCME) is a common complication following cataract surgery. Acute PCME may resolve spontaneously, but some patients will develop chronic macular edema that affects vision and is difficult to treat. This disease was described more than 50 years ago, and there are multiple options for clinical management. We discuss mechanisms, clinical efficacy, and adverse effects of these treatment modalities. Topical non-steroidal anti-inflammatory agents and corticosteroids are widely used and, when combined, may have a synergistic effect. Intravitreal corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) agents have shown promise when topical medications either fail or have had limited effects. Randomized clinical studies evaluating anti-VEGF agents are needed to fully evaluate benefits and risks. When PCME is either refractory to medical therapy or is associated with significant vitreous involvement, pars plana vitrectomy has been shown to improve outcomes, though it is associated with additional risks. PMID:25438734

  6. Influenza leaves a TRAIL to pulmonary edema.

    PubMed

    Brauer, Rena; Chen, Peter

    2016-04-01

    Influenza infection can cause acute respiratory distress syndrome (ARDS), leading to poor disease outcome with high mortality. One of the driving features in the pathogenesis of ARDS is the accumulation of fluid in the alveoli, which causes severe pulmonary edema and impaired oxygen uptake. In this issue of the JCI, Peteranderl and colleagues define a paracrine communication between macrophages and type II alveolar epithelial cells during influenza infection where IFNα induces macrophage secretion of TRAIL that causes endocytosis of Na,K-ATPase by the alveolar epithelium. This reduction of Na,K-ATPase expression decreases alveolar fluid clearance, which in turn leads to pulmonary edema. Inhibition of the TRAIL signaling pathway has been shown to improve lung injury after influenza infection, and future studies will be needed to determine if blocking this pathway is a viable option in the treatment of ARDS. PMID:26999598

  7. Emerging Pharmacotherapies for Diabetic Macular Edema

    PubMed Central

    Javey, Golnaz; Schwartz, Stephen G.; Flynn, Harry W.

    2012-01-01

    Diabetic macular edema (DME) remains an important cause of visual loss in patients with diabetes mellitus. Although photocoagulation and intensive control of systemic metabolic factors have been reported to achieve improved outcomes in large randomized clinical trials (RCTs), some patients with DME continue to lose vision despite treatment. Pharmacotherapies for DME include locally and systemically administered agents. We review several agents that have been studied for the treatment of DME. PMID:22474425

  8. An unusual cause of pulmonary edema.

    PubMed

    Chong, Adrian; Wahi, Sudhir; Harvey, Ryan; Finn, Chris; Shah, Pallav; Gould, Paul

    2014-03-01

    Primary cardiac tumors are rare malignancies. Patients may present with congestive cardiac failure due to intracavitary obstruction to blood flow, valvular dysfunction, embolic phenomena, local invasion resulting in arrhythmias, pericardial involvement, constitutional symptoms, or paraneoplastic syndromes. We describe the case of a previously fit 79-year-old woman who presented with acute pulmonary edema due to a large left atrial pleomorphic sarcoma causing severe functional mitral stenosis. She underwent palliative debulking surgery with good symptomatic relief. PMID:24585913

  9. Reexpansion pulmonary edema: review of pediatric cases.

    PubMed

    Kira, Shinichiro

    2014-03-01

    Reexpansion pulmonary edema (RPE) is an increased permeability pulmonary edema that usually occurs in the reexpanded lung after several days of lung collapse. This condition is recognized to occur more frequently in patients under the age of 40 years, but there has been no detailed analysis of reported pediatric cases of RPE to date. For this review, PubMed literature searches were performed using the following terms: 're(-)expansion pulmonary (o)edema' AND ('child' OR 'children' OR 'infant' OR 'boy' OR 'girl' OR 'adolescent'). The 22 pediatric cases of RPE identified were included in this review. RPE was reported in almost the entire pediatric age range, and as in adult cases, the severity ranged from subclinical to lethal. No specific treatment for RPE was identified, and treatment was administered according to the clinical features of each patient. Of the 22 reported cases, 10 occurred during the perioperative period, but were not related to any specific surgical procedures or anesthetic techniques, or to the duration of lung collapse. Pediatric anesthesiologists should be aware that pediatric RPE can occur after reexpansion of any collapsed lung and that some invasive therapies can be useful in severe cases. PMID:24224467

  10. High altitude pulmonary edema in mountain climbers.

    PubMed

    Korzeniewski, Krzysztof; Nitsch-Osuch, Aneta; Guzek, Aneta; Juszczak, Dariusz

    2015-04-01

    Every year thousands of ski, trekking or climbing fans travel to the mountains where they stay at the altitude of more than 2500-3000m above sea level or climb mountain peaks, often exceeding 7000-8000m. High mountain climbers are at a serious risk from the effects of adverse environmental conditions prevailing at higher elevations. They may experience health problems resulting from hypotension, hypoxia or exposure to low temperatures; the severity of those conditions is largely dependent on elevation, time of exposure as well as the rate of ascent and descent. A disease which poses a direct threat to the lives of mountain climbers is high altitude pulmonary edema (HAPE). It is a non-cardiogenic pulmonary edema which typically occurs in rapidly climbing unacclimatized lowlanders usually within 2-4 days of ascent above 2500-3000m. It is the most common cause of death resulting from the exposure to high altitude. The risk of HAPE rises with increased altitude and faster ascent. HAPE incidence ranges from an estimated 0.01% to 15.5%. Climbers with a previous history of HAPE, who ascent rapidly above 4500m have a 60% chance of illness recurrence. The aim of this article was to present the relevant details concerning epidemiology, pathophysiology, clinical symptoms, prevention, and treatment of high altitude pulmonary edema among climbers in the mountain environment. PMID:25291181

  11. Evidence-based review of diabetic macular edema management: Consensus statement on Indian treatment guidelines

    PubMed Central

    Das, Taraprasad; Aurora, Ajay; Chhablani, Jay; Giridhar, Anantharaman; Kumar, Atul; Raman, Rajiv; Nagpal, Manish; Narayanan, Raja; Natarajan, Sundaram; Ramasamay, Kim; Tyagi, Mudit; Verma, Lalit

    2016-01-01

    The purpose of the study was to review the current evidence and design a diabetic macular edema (DME) management guideline specific for India. The published DME guidelines from different organizations and publications were weighed against the practice trends in India. This included the recently approved drugs. DME management consisted of control of diabetes and other associated systemic conditions, such as hypertension and hyperlipidemia, and specific therapy to reduce macular edema. Quantification of macular edema is precisely made with the optical coherence tomography and treatment options include retinal laser, intravitreal anti-vascular endothelial growth factors (VEGF), and implantable dexamethasone. Specific use of these modalities depends on the presenting vision and extent of macular involvement. Invariable eyes with center-involving macular edema benefit from intravitreal anti-VEGF or dexamethasone implant therapy, and eyes with macular edema not involving the macula center benefit from retinal laser. The results are illustrated with adequate case studies and frequently asked questions. This guideline prepared on the current published evidence is meant as a guideline for the treating physicians. PMID:26953019

  12. Monensin and the prevention of tryptophan-induced acute bovine pulmonary edema and emphysema.

    PubMed

    Hammond, A C; Carlson, J R; Breeze, R G

    1978-07-14

    3-Methylindole, a ruminal fermentation product of tryptophan, induces acute pulmonary edema and emphysema in cattle, and 3-methylindole is present in the ruminal fluid and blood of cows with a natually occurring form of this disease. Monensin, a polyether antibiotic and widely used feed additive for beef cattle, prevented tryptophan-induced acute bovine pulmonary edema and emphysema. Monensin acted by reducing the ruminal conversion of L-tryptophan to 3-methylindole both in vitro and in vivo. Lasalocid, also a polyether antibiotic, showed similar effects in vitro. These results provide a promising approach to prevention of this major respiratory disease of cattle. PMID:663643

  13. Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology

    SciTech Connect

    Testylier, Guy . E-mail: guytestylier@crssa.net; Lahrech, Hana; Montigon, Olivier; Foquin, Annie; Delacour, Claire; Bernabe, Denis; Segebarth, Christoph; Dorandeu, Frederic; Carpentier, Pierre

    2007-04-15

    Purpose: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. Methods: Three hours and 24 h after the intoxication with soman (172 {mu}g/kg), the mice were anesthetized with an isoflurane/N{sub 2}O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. Results: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication and was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. Conclusions: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into Brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures.

  14. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

    PubMed Central

    Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

    2012-01-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

  15. Intravitreal ketorolac for the treatment of chronic cystoid macular edema after cataract surgery

    PubMed Central

    Tsilimbaris, Miltiadis K; Tsika, Chrysanthi; Kymionis, George D

    2016-01-01

    Purpose To report two cases of chronic postoperative cystoid macular edema, resistant to topical therapy, treated with consecutive intravitreal injections of ketorolac tromethamine. Methods Four daily intravitreal injections of 500 μg/0.05 mL of ketorolac were given to each patient. Complete clinical examination and OCT were performed before every injection, 1, 2, 3 weeks, and 1, 3, and 6 months after the last injection. Fluorescein angiography was performed at baseline examination, 1, 3, and 6 months after the last injection. Results In both cases, the edema regressed and visual acuity increased. At 6 months after the last injection, the leakage was significantly reduced at the fluorescein angiography. Discussion Both cases responded favorably to the consecutive intravitreal administration of ketorolac tromethamine. The long-lasting remission of the macular edema in these chronic cases underlines the therapeutic potential of these agents when delivered intravitreally. PMID:26929630

  16. Alveolar Edema Fluid Clearance and Acute Lung Injury

    PubMed Central

    Berthiaume, Yves; Matthay, Michael A.

    2009-01-01

    Although lung-protective ventilation strategies have substantially reduced mortality of acute lung injury patients there is still a need for new therapies that can further decrease mortality in patients with acute lung injury. Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding potential new therapies for acute lung injury. Overall, there is convincing evidence that the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance and the resolution of acute lung injury. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. Vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance. The general paradigm is that active Na+ and Cl? transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. Although these transport processes can be impaired in severe lung injury, multiple experimental studies suggest that upregulation of Na+ and Cl? transport might be an effective therapy in acute lung injury. We will review mechanisms involved in pharmacological modulation of ion transport in lung injury with a special focus on the use of ?-adrenergic agonists which has generated considerable interest and is a promising therapy for clinical acute lung injury. PMID:17604701

  17. Rhodiola crenulata Extract Alleviates Hypoxic Pulmonary Edema in Rats

    PubMed Central

    Li, Min-Hui; Shi, Li-Shian; Ho, Cheng-Wen

    2013-01-01

    Sudden exposure of nonacclimatized individuals to high altitude can easily lead to high altitude illnesses. High altitude pulmonary edema (HAPE) is the most lethal form of high altitude illness. The present study was designed to investigate the ability of Rhodiola crenulata extract (RCE), an herbal medicine traditionally used as an antiacute mountain sickness remedy, to attenuate hypoxia-induced pulmonary injury. Exposure of animals to hypobaric hypoxia led to a significant increase in pathological indicators for pulmonary edema, including the lung water content, disruption of the alveolar-capillary barrier, and protein-rich fluid in the lungs. In addition, hypobaric hypoxia also increased oxidative stress markers, including (ROS) production, (MDA) level, and (MPO) activity. Furthermore, overexpression of plasma (ET-1), (VEGF) in (BALF), and (HIF-1α) in lung tissue was also found. However, pretreatment with RCE relieved the HAPE findings by curtailing all of the hypoxia-induced lung injury parameters. These findings suggest that RCE confers effective protection for maintaining the integrity of the alveolar-capillary barrier by alleviating the elevated ET-1 and VEGF levels; it does so by reducing hypoxia-induced oxidative stress. Our results offer substantial evidence to support arguments in favor of traditional applications of Rhodiola crenulata for antihigh altitude illness. PMID:23710233

  18. Reduced intestinal brain-derived neurotrophic factor increases vagal sensory innervation of the intestine and enhances satiation.

    PubMed

    Biddinger, Jessica E; Fox, Edward A

    2014-07-30

    Brain-derived neurotrophic factor (BDNF) is produced by developing and mature gastrointestinal (GI) tissues that are heavily innervated by autonomic neurons and may therefore control their development or function. To begin investigating this hypothesis, we compared the morphology, distribution, and density of intraganglionic laminar endings (IGLEs), the predominant vagal GI afferent, in mice with reduced intestinal BDNF (INT-BDNF(-/-)) and controls. Contrary to expectations of reduced development, IGLE density and longitudinal axon bundle number in the intestine of INT-BDNF(-/-) mice were increased, but stomach IGLEs were normal. INT-BDNF(-/-) mice also exhibited increased vagal sensory neuron numbers, suggesting that their survival was enhanced. To determine whether increased intestinal IGLE density or other changes to gut innervation in INT-BDNF(-/-) mice altered feeding behavior, meal pattern and microstructural analyses were performed. INT-BDNF(-/-) mice ate meals of much shorter duration than controls, resulting in reduced meal size. Increased suppression of feeding in INT-BDNF(-/-) mice during the late phase of a scheduled meal suggested that increased satiation signaling contributed to reduced meal duration and size. Furthermore, INT-BDNF(-/-) mice demonstrated increases in total daily intermeal interval and satiety ratio, suggesting that satiety signaling was augmented. Compensatory responses maintained normal daily food intake and body weight in INT-BDNF(-/-) mice. These findings suggest a target organ-derived neurotrophin suppresses development of that organ's sensory innervation and sensory neuron survival and demonstrate a role for BDNF produced by peripheral tissues in short-term controls of feeding, likely through its regulation of development or function of gut innervation, possibly including augmented intestinal IGLE innervation. PMID:25080597

  19. Reduced Intestinal Brain-Derived Neurotrophic Factor Increases Vagal Sensory Innervation of the Intestine and Enhances Satiation

    PubMed Central

    Biddinger, Jessica E.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is produced by developing and mature gastrointestinal (GI) tissues that are heavily innervated by autonomic neurons and may therefore control their development or function. To begin investigating this hypothesis, we compared the morphology, distribution, and density of intraganglionic laminar endings (IGLEs), the predominant vagal GI afferent, in mice with reduced intestinal BDNF (INT-BDNF−/−) and controls. Contrary to expectations of reduced development, IGLE density and longitudinal axon bundle number in the intestine of INT-BDNF−/− mice were increased, but stomach IGLEs were normal. INT-BDNF−/− mice also exhibited increased vagal sensory neuron numbers, suggesting that their survival was enhanced. To determine whether increased intestinal IGLE density or other changes to gut innervation in INT-BDNF−/− mice altered feeding behavior, meal pattern and microstructural analyses were performed. INT-BDNF−/− mice ate meals of much shorter duration than controls, resulting in reduced meal size. Increased suppression of feeding in INT-BDNF−/− mice during the late phase of a scheduled meal suggested that increased satiation signaling contributed to reduced meal duration and size. Furthermore, INT-BDNF−/− mice demonstrated increases in total daily intermeal interval and satiety ratio, suggesting that satiety signaling was augmented. Compensatory responses maintained normal daily food intake and body weight in INT-BDNF−/− mice. These findings suggest a target organ-derived neurotrophin suppresses development of that organ's sensory innervation and sensory neuron survival and demonstrate a role for BDNF produced by peripheral tissues in short-term controls of feeding, likely through its regulation of development or function of gut innervation, possibly including augmented intestinal IGLE innervation. PMID:25080597

  20. Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats

    PubMed Central

    BAI, YONGSHENG; XU, GUANGHUI; XU, MENGXUE; LI, QI; QIN, XINYUE

    2014-01-01

    The disruption of the blood-brain barrier (BBB) caused by cerebral ischemia determines the extent of injury and patient prognosis. Inhibitors of Src can markedly minimize the infarct size and preserve neurological function. The Src protein tyrosine kinase (PTK) inhibitor, PP2, protects the rat brain against ischemic injury, possibly through the reduction of vascular endothelial growth factor A (VEGFA) expression and the upregulation of claudin-5 expression, which preserves the integrity of the BBB. In this study, the expression levels of phosphorylated (p)-Src, VEGFA and claudin-5 were determined to investigate the changes occurring in the levels of these proteins and to determine the benefits of PP2 treatment following cerebral ischemia/reperfusion (I/R). Our study included a sham-operated group, an I/R group, a vehicle-treated group (V) and a PP2-treated group (PP2). We found that the rats in the PP2 group exhibited greater preservation of neurological function and reduced VEGFA and p-Src protein expression compared with the rats in the I/R and V groups. Moreover, the mRNA and protein levels of claudin-5 were markedly higher in the PP2 group than in the I/R group or the V group after 3 days of reperfusion. Immunofluorescence staining revealed that the co-localized immunostaining of fibrinogen and claudin-5 was reduced in the PP2 group, which suggests that the exudation of fibrinogen in this group was less than that in the I/R and V groups. Furthermore, the reduced co-localization of immunostaining of glial fibrillary acidic protein (GFAP) and claudin-5 indicated that the rats in the PP2 group had only a slight disruption of the BBB. These findings suggested that PP2 treatment attenuated the disruption of the BBB following ischemia and minimized the neurological deficit; these effects were associated with a decreased VEGFA expression and an increased claudin-5 expression. Members of the Src PTK family may be critical targets for the protection of the BBB following cerebral ischemia. PMID:25269821

  1. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism.

    PubMed

    Anderson, Collin J; Sheppard, Daylan T; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A; Dorval, Alan D

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms. PMID:26217192

  2. Chlorella vulgaris reduces the impact of stress on hypothalamic-pituitary-adrenal axis and brain c-fos expression.

    PubMed

    Souza Queiroz, Julia; Marín Blasco, Ignacio; Gagliano, Humberto; Daviu, Nuria; Gómez Román, Almudena; Belda, Xavier; Carrasco, Javier; Rocha, Michelle C; Palermo Neto, João; Armario, Antonio

    2016-03-01

    Predominantly emotional stressors activate a wide range of brain areas, as revealed by the expression of immediate early genes, such as c-fos. Chlorella vulgaris (CV) is considered a biological response modifier, as demonstrated by its protective activities against infections, tumors and stress. We evaluated the effect of acute pretreatment with CV on the peripheral and central responses to forced swimming stress in adult male rats. Pretreatment with CV produced a significant reduction of stress-related hypothalamic-pituitary-adrenal activation, demonstrated by decreased corticotrophin releasing factor gene expression in the hypothalamic paraventricular nucleus (PVN) and lower ACTH response. Hyperglycemia induced by the stressor was similarly reduced. This attenuated neuroendocrine response to stress occurred in parallel with a diminished c-fos expression in most evaluated areas, including the PVN. The data presented in this study reinforce the usefulness of CV to diminish the impact of stressors, by reducing the HPA response. Although our results suggest a central effect of CV, further studies are necessary to understand the precise mechanisms underpinning this effect. PMID:26685709

  3. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism

    PubMed Central

    Anderson, Collin J.; Sheppard, Daylan T.; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A.; Dorval, Alan D.

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson’s disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms. PMID:26217192

  4. Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice.

    PubMed

    Robert, Jérôme; Stukas, Sophie; Button, Emily; Cheng, Wai Hang; Lee, Michael; Fan, Jianjia; Wilkinson, Anna; Kulic, Iva; Wright, Samuel D; Wellington, Cheryl L

    2016-05-01

    Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26454209

  5. The administration of food supplemented with cocoa powder during nutritional recovery reduces damage caused by oxidative stress in rat brain.

    PubMed

    Barragán Mejía, Gerardo; Calderón Guzmán, David; Juárez Olguín, Hugo; Hernández Martínez, Nancy; García Cruz, Edna; Morales Ramírez, Aline; Labra Ruiz, Norma; Esquivel Jiménez, Gabriela; Osnaya Brizuela, Norma; García Álvarez, Raquel; Ontiveros Mendoza, Esperanza

    2011-12-01

    Malnutrition contributes to the development of oxidative damage in the central nervous system. The selective administration of nutrients tends to show positive results in individuals who have suffered from malnutrition. To determine the effect of the administration of cocoa powder on the peroxidation of lipids and glutathione level during the nutritional recovery in brain, rats of 21 days old were subjected to a protocol that resembles malnutrition (MN) by feeding them with 60% of the daily food consumption of the control group (WN) and later to nutritional recovery with regular rodent feed (RFR) or added with cocoa (10 g of cocoa powder/kg of regular rodent feed) (CCR). Animals fed with regular rodent food showed significant reduction in brain glutathione: RFR (84.18 ± 6.38 ng/mg protein) vs. CCR (210.61 ± 50.10 ng/mg protein) and WN (186.55 ± 33.18 ng/mg protein), but with similar level to that of MN (92.12 ± 15.60 ng/mg protein). On the contrary, lipid peroxidation in RFR-fed animals increased RFR (1.32 ± 0.2 μM malondialdehyde/g of tissue), CCR (0.86 ± 0.07 μM malondialdehyde/g of tissue), WN (0.89 ± 0.09 μM malondialdehyde/g of tissue), but their thiobarbituric acid reactive substances concentration is similar to that of MN group (1.50 ± 0.2 μM malondialdehyde/g of tissue). Consumption of cocoa powder as a source of antioxidants favors the restoration of the concentration of glutathione and reduces the damage caused by oxidative stress during nutritional recovery in rat brain. PMID:21826449

  6. Wharton's Jelly Transplantation Improves Neurologic Function in a Rat Model of Traumatic Brain Injury.

    PubMed

    Cheng, Tian; Yang, Bo; Li, Dongpeng; Ma, Shanshan; Tian, Yi; Qu, Ruina; Zhang, Wenjin; Zhang, Yanting; Hu, Kai; Guan, Fangxia; Wang, Jian

    2015-07-01

    Traumatic brain injury (TBI), which can lead to disability, dysfunction, and even death, is a prominent health problem worldwide. Effective therapy for this serious and debilitating condition is needed. Human umbilical cord matrix, known as Wharton's jelly (WJ), provides a natural, interface scaffold that is enriched in mesenchymal stem cells. In this study, we tested the efficacy of WJ tissue transplantation in a weight-drop model of TBI in rats. WJ tissue was cultured and transplanted into the injury site 24 h after TBI. The modified neurologic severity score, body weight, brain edema, and lesion volume were evaluated at various time points after TBI. Cognitive behavior was assessed by the novel object recognition test and the Morris water maze test. Expression of brain-derived neurotrophic factor (BDNF) in the perilesional brain area was measured at day 14 after TBI. We found that WJ tissue transplantation lessened TBI-induced brain edema (day 3), reduced lesion volume (day 28), improved neurologic function (days 21-28), and promoted memory and cognitive recovery. Additionally, expression of BDNF mRNA and protein was higher in WJ tissue-treated rats than in sham-operated or vehicle-treated rats. These data suggest that WJ tissue transplantation can reduce TBI-induced brain injury and may have therapeutic potential for the treatment of TBI. PMID:25638565

  7. Traumatic brain injury: pathophysiology for neurocritical care.

    PubMed

    Kinoshita, Kosaku

    2016-01-01

    Severe cases of traumatic brain injury (TBI) require neurocritical care, the goal being to stabilize hemodynamics and systemic oxygenation to prevent secondary brain injury. It is reported that approximately 45 % of dysoxygenation episodes during critical care have both extracranial and intracranial causes, such as intracranial hypertension and brain edema. For this reason, neurocritical care is incomplete if it only focuses on prevention of increased intracranial pressure (ICP) or decreased cerebral perfusion pressure (CPP). Arterial hypotension is a major risk factor for secondary brain injury, but hypertension with a loss of autoregulation response or excess hyperventilation to reduce ICP can also result in a critical condition in the brain and is associated with a poor outcome after TBI. Moreover, brain injury itself stimulates systemic inflammation, leading to increased permeability of the blood-brain barrier, exacerbated by secondary brain injury and resulting in increased ICP. Indeed, systemic inflammatory response syndrome after TBI reflects the extent of tissue damage at onset and predicts further tissue disruption, producing a worsening clinical condition and ultimately a poor outcome. Elevation of blood catecholamine levels after severe brain damage has been reported to contribute to the regulation of the cytokine network, but this phenomenon is a systemic protective response against systemic insults. Catecholamines are directly involved in the regulation of cytokines, and elevated levels appear to influence the immune system during stress. Medical complications are the leading cause of late morbidity and mortality in many types of brain damage. Neurocritical care after severe TBI has therefore been refined to focus not only on secondary brain injury but also on systemic organ damage after excitation of sympathetic nerves following a stress reaction. PMID:27123305

  8. Use of Electrical Impedance Tomography to Monitor Regional Cerebral Edema during Clinical Dehydration Treatment

    PubMed Central

    Hu, Shi-Jie; Li, Xia; Xu, Can-Hua; Wang, Bing; Yang, Bin; Tang, Meng-Xing; Dong, Xiu-Zhen; Fei, Zhou; Shi, Xue-Tao

    2014-01-01

    Objective Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content. Design a prospective study. Setting In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank. Patients 23 patients with brain edema. Interventions The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes. Measurement and Main Results Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients' responses to such treatment. Conclusions EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients. PMID:25474474

  9. Pulmonary edema as a complication of interleukin-2 therapy.

    PubMed

    Conant, E F; Fox, K R; Miller, W T

    1989-04-01

    Eight patients underwent IV bolus therapy with recombinant interleukin-2 (Cetus Corporation, Emeryville, CA) for treatment of metastatic melanoma or renal cell carcinoma. The patients were randomized to receive interleukin-2 alone or interleukin-2 in combination with lymphokine-activated killer cells. Radiographs showed pulmonary edema in five of the eight patients. The changes ranged from mild interstitial edema (two patients) to frank pulmonary edema (three patients). The edema generally resolved within 4 days after the termination of therapy (four patients), however, one patient developed edema and arrhythmias approximately 7 days after interleukin-2 therapy ended. Seven of the eight patients had either cardiac arrythmias or angina. The mechanisms that contribute to the pathogenesis of these cardiac complications with interleukin-2 therapy remain unclear. The development of pulmonary edema is thought to be caused by capillary leakage and cardiac pulmonary edema due to cardiac toxicity of the drug. The radiologic appearances of these types of pulmonary edema were indistinguishable from one another and from other causes of pulmonary edema. Our study shows that interleukin-2 can cause pulmonary edema, cardiac arrhythmias, and unstable angina. The severity of these conditions is unrelated to dose. PMID:2784257

  10. GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury.

    PubMed

    Almeida-Suhett, Camila P; Prager, Eric M; Pidoplichko, Volodymyr; Figueiredo, Taiza H; Marini, Ann M; Li, Zheng; Eiden, Lee E; Braga, Maria F M

    2015-11-01

    Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region. We investigated whether mTBI induces morphological and pathophysiological alterations in the CA1 using the controlled cortical impact (CCI) model. Seven days after CCI, animals subjected to mTBI showed cognitive impairment in the passive avoidance test and deficits to long-term potentiation (LTP) of synaptic transmission. Deficiencies in inducing or maintaining LTP were likely due to an observed reduction in the activation of NMDA but not AMPA receptors. Significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs) were also observed 7 days after CCI. Design-based stereology revealed that although the total number of neurons was unaltered, the number of GABAergic interneurons is significantly reduced in the CA1 region 7 days after CCI. Additionally, the surface expression of α1, ß2/3, and γ2 subunits of the GABAA receptor were reduced, contributing to a reduced mIPSC frequency and amplitude, respectively. Together, these results suggest that mTBI causes a significant reduction in GABAergic inhibitory transmission and deficits to NMDA receptor mediated currents in the CA1, which may contribute to changes in hippocampal excitability and subsequent cognitive impairments after mTBI. PMID:26238734

  11. DKA with Severe Hypertriglyceridemia and Cerebral Edema in an Adolescent Boy: A Case Study and Review of the Literature

    PubMed Central

    Saengkaew, Tansit; Sahakitrungruang, Taninee; Wacharasindhu, Suttipong; Supornsilchai, Vichit

    2016-01-01

    A 13-year-old adolescent boy with type 1 diabetes mellitus (1b) presented with diabetic ketoacidosis (DKA) and cerebral edema. Grossly lipemic serum and lipemia retinals due to extremely high triglyceride (TG) level were observed without evidence of xanthoma or xanthelasma. Cerebral edema was treated by appropriate ventilation and mannitol administration. Normal saline was carefully given and regular insulin was titrated according to blood sugar levels. Triglyceride levels were reduced from 9,800 mg/dL to normal range within 9 days after conventional treatment was commenced without antilipid medication. Based on our review of the literature, this is the first reported case of confirmed pediatric DKA with severe hypertriglyceridemia and cerebral edema. In patients with DKA and hypertriglyceridemia, clinicians should be mindful of the possibility of associated acute pancreatitis and cerebral edema. PMID:26904318

  12. DKA with Severe Hypertriglyceridemia and Cerebral Edema in an Adolescent Boy: A Case Study and Review of the Literature.

    PubMed

    Saengkaew, Tansit; Sahakitrungruang, Taninee; Wacharasindhu, Suttipong; Supornsilchai, Vichit

    2016-01-01

    A 13-year-old adolescent boy with type 1 diabetes mellitus (1b) presented with diabetic ketoacidosis (DKA) and cerebral edema. Grossly lipemic serum and lipemia retinals due to extremely high triglyceride (TG) level were observed without evidence of xanthoma or xanthelasma. Cerebral edema was treated by appropriate ventilation and mannitol administration. Normal saline was carefully given and regular insulin was titrated according to blood sugar levels. Triglyceride levels were reduced from 9,800 mg/dL to normal range within 9 days after conventional treatment was commenced without antilipid medication. Based on our review of the literature, this is the first reported case of confirmed pediatric DKA with severe hypertriglyceridemia and cerebral edema. In patients with DKA and hypertriglyceridemia, clinicians should be mindful of the possibility of associated acute pancreatitis and cerebral edema. PMID:26904318

  13. CD11d integrin blockade reduces the systemic inflammatory response syndrome after traumatic brain injury in rats

    PubMed Central

    Weaver, Lynne C.; Bao, Feng; Dekaban, Gregory A.; Hryciw, Todd; Shultz, Sandy R.; Cain, Donald P.; Brown, Arthur

    2015-01-01

    Traumatic CNS injury triggers a systemic inflammatory response syndrome (SIRS), in which circulating inflammatory cells invade body organs causing local inflammation and tissue damage. We have shown that the SIRS caused by spinal cord injury is greatly reduced by acute intravenous treatment with an antibody against the CD11d subunit of the CD11d/CD18 integrin expressed by neutrophils and monocyte/macrophages, a treatment that reduces their efflux from the circulation. Traumatic brain injury (TBI) is a frequently occurring injury after motor vehicle accidents, sporting and military injuries, and falls. Our studies have shown that the anti-CD11d treatment diminishes brain inflammation and oxidative injury after moderate or mild TBI, improving neurological outcomes. Accordingly, we examined the impact of this treatment on the SIRS triggered by TBI. The anti-CD11d treatment was given at 2 h after a single moderate (2.5–3.0 atm) or 2 and 24 h after each of three consecutive mild (1.0–1.5 atm) fluid percussion TBIs. Sham-injured, saline-treated rats served as controls. At 24 h, 72 h, and 4 or 8 weeks after the single TBI and after the third of three TBIs, lungs of rats were examined histochemically, immunocytochemically and biochemically for downstream effects of SIRS including inflammation, tissue damage and expression of oxidative enzymes. Lung sections revealed that both the single moderate and repeated mild TBI caused alveolar disruption, thickening of inter-alveolar tissue, hemorrhage into the parenchyma and increased density of intra-and peri-alveolar macrophages. The anti-CD11d treatment decreased the intrapulmonary influx of neutrophils and the density of activated macrophages and the activity of myeloperoxidase after these TBIs. Moreover, Western blotting studies showed that the treatment decreased lung protein levels of oxidative enzymes gp91phox, inducible nitric oxide synthase and cyclooxygenase-2, as well as the apoptotic pathway enzyme caspase-3 and levels of 4-hydroxynonenal-bound proteins (an indicator of lipid peroxidation). Decreased expression of the cytoprotective transcription factor Nrf2 reflected decreased lung oxidative stress. Anti-CD11d treatment also diminished the lung concentration of free radicals and tissue aldehydes. In conclusion, the substantial lung component of the SIRS after single or repeated TBIs is significantly decreased by a simple, minimally invasive and short-lasting anti-inflammatory treatment. PMID:26169930

  14. Effect of glycerol on ischemic cerebral edema assessed by magnetic resonance imaging.

    PubMed

    Sakamaki, Masanori; Igarashi, Hironaka; Nishiyama, Yutaka; Hagiwara, Hiroshi; Ando, Jun; Chishiki, Tetsurou; Curran, Brian C; Katayama, Yasuo

    2003-05-15

    The aim of this study is to assess the anticerebral edema effect of glycerol on a large cerebral infarction with magnetic resonance imaging (MRI). Glycerol, which is widely used as an osmotic agent against cerebral edema, could exacerbate brain tissue shift, since it has been suggested that glycerol might shrink a noninfarcted hemisphere and worsen the mass effect after a large hemispheric cerebral infarction. To investigate these issues, changes in a large hemispheric infarction with cerebral edema were studied using MRI before and after glycerol administration. Infarct volumes, normal brain tissue volumes and lateral ventricle volumes, in addition to signal intensities of T(2)-weighted images, were measured in six patients before and after administration of 300 ml of glycerol. Ventricle volumes were significantly increased (p=0.0015) and the T(2) signal intensity of the post-treatment ischemic region decreased after glycerol administration. In contrast, no significant differences in either cerebral volume or T(2) signal intensity were seen in the noninfarcted hemisphere before and after administration. Our data suggest that glycerol does not exacerbate the mass effect on a large hemispheric infarction. PMID:12686405

  15. Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur.

    PubMed

    Pifferi, Fabien; Dorieux, Olène; Castellano, Christian-Alexandre; Croteau, Etienne; Masson, Marie; Guillermier, Martine; Van Camp, Nadja; Guesnet, Philippe; Alessandri, Jean-Marc; Cunnane, Stephen; Dhenain, Marc; Aujard, Fabienne

    2015-08-01

    Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze. Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. PMID:26063461

  16. Subclinical pulmonary edema in endurance athletes.

    PubMed

    Bussotti, M; Di Marco, S; Marchese, G; Agostoni, P G

    2012-06-01

    Strenuous exercise may cause progressive and proportional haemodynamic overload damage to the alveolar membrane, even in athletes. Despite the high incidence of arterial desaturation reported in endurance athletes has been attributed, into other factors, also to the damage of the alveolar-capillary membrane this evidence is equivocal. Some studies demonstrated flood of the interstitial space and consequent increase in pulmonary water content, but most of them were able to show this through indirect signs of interstitial oedema. The present review illustrates the literature's data in favour or against pulmonary interstitial edema due to intense exercise in athletes. PMID:23193844

  17. 3-Nitropropionic acid-induced ischemia tolerance in the rat brain is mediated by reduced metabolic activity and cerebral blood flow

    PubMed Central

    Bracko, Oliver; Di Pietro, Valentina; Lazzarino, Giacomo; Amorini, Angela M; Tavazzi, Barbara; Artmann, Judith; Wong, Eric C; Buxton, Richard B; Weller, Michael; Luft, Andreas R; Wegener, Susanne

    2014-01-01

    Tissue tolerance to ischemia can be achieved by noxious stimuli that are below a threshold to cause irreversible damage (preconditioning'). Understanding the mechanisms underlying preconditioning may lead to the identification of novel therapeutic targets for diseases such as stroke. We here used the oxidative chain inhibitor 3-nitropropionic acid (NPA) to induce ischemia tolerance in a rat middle cerebral artery occlusion (MCAO) stroke model. Cerebral blood flow (CBF) and structural integrity were characterized by longitudinal magnetic resonance imaging (MRI) in combination with behavioral, histologic, and biochemical assessment of NPA-preconditioned animals and controls. Using this approach we show that the ischemia-tolerant state is characterized by a lower energy charge potential and lower CBF, indicating a reduced baseline metabolic demand, and therefore a cellular mechanism of neural protection. Blood vessel density and structural integrity were not altered by NPA treatment. When subjected to MCAO, preconditioned animals had a characteristic MRI signature consisting of enhanced CBF maintenance within the ischemic territory and intraischemic reversal of the initial cytotoxic edema, resulting in reduced infarct volumes. Thus, our data show that tissue protection through preconditioning occurs early during ischemia and indicate that a reduced cellular metabolism is associated with tissue tolerance to ischemia. PMID:24938399

  18. Fecal Impaction Causing Pelvic Venous Compression and Edema

    PubMed Central

    Naramore, Sara; Aziz, Faisal; Alexander, Chandran Paul; Methratta, Sosamma; Cilley, Robert; Rocourt, Dorothy

    2015-01-01

    Chronic constipation is a common condition which may result in fecal impaction. A 13-year-old male with chronic constipation and encopresis presented with fecal impaction for three weeks. The impaction caused abdominal pain, distension, encopresis, and decreased oral intake. He was found in severe distress with non-pitting edema of his feet and ankles along with perineal edema. The pedal edema worsened after receiving a fluid bolus, so concern arose for venous compression or a thrombus. A Duplex Ultrasound demonstrated changes in the venous waveforms of the bilateral external iliac and common femoral veins without thrombosis. Manual disimpaction and polyethylene glycol 3350 with electrolytes resolved the pedal and perineal edema. Four months later, he had soft bowel movements without recurrence of the edema. A repeat Duplex Ultrasound was normal. We present a child in whom severe fecal impaction caused pelvic venous compression resulting in bilateral pedal and perineal edema. PMID:26500749

  19. Effects of atorvastatin on pathological changes in brain tissue and plasma MMP-9 in rats with intracerebral hemorrhage.

    PubMed

    Cui, Jing-Jing; Wang, Dong; Gao, Fei; Li, Yue-Rong

    2012-01-01

    To explore the effects of atorvastatin on hydrocephalus, neurocyte apoptosis, and the level of plasma matrix metalloproteinase-9 (MMP-9) after intracerebral hemorrhage (ICH) in rats. A rat model of ICH was established by intracerebral injection of collagenase. The brain water content was determined by the wet/dry weight ratio, ultrastructural changes in brain tissue were observed by electron microscopy, and the level of plasma MMP-9 was quantified by ELISA. Atorvastatin showed significant effects in reducing the brain water content, blocking neuron apoptosis, and decreasing plasma MMP-9 in rats with ICH. There was a positive linear correlation between plasma MMP-9 and the brain water content. Atorvastatin can significantly relieve brain edema, decrease the brain injury caused by MMP-9 and protect neurons in rats with ICH. PMID:22006254

  20. Diffusion tensor-based tumor infiltration index cannot discriminate vasogenic edema from tumor-infiltrated edema.

    PubMed

    Kinoshita, Manabu; Goto, Tetsu; Okita, Yoshiko; Kagawa, Naoki; Kishima, Haruhiko; Hashimoto, Naoya; Yoshimine, Toshiki

    2010-02-01

    Diffusion tensor imaging (DTI) by magnetic resonance imaging (MRI) is now used not only for delineating white matter fiber tracts, but also for assessing the histological characteristics of pathological tissues. Among these uses, predicting the extent or existence of tumor cell invasion into white matter by DTI is under extensive investigation. The previously reported tumor infiltration index (TII) holds great potential for the discrimination of pure vasogenic edema from tumor-infiltrated edema. However, conflicting data are being reported questioning the clinical value of TII. The present investigation reevaluated the utility of TII in patients with meningioma or glioma. We found that TII was unable to discriminate vasogenic from tumor-infiltrated edema. Conversely, detailed voxel-by-voxel comparison of TII and (11)C-methionie PET in the T2-hyperintense area of gliomas showed that TII and (11)C-methionie PET has a positive correlation, suggesting that, although TII is unable to discriminate the cause of edema, the extent of tumor cell invasion into white matter is depicted in gliomas by TII. These data suggest that TII involves both vasogenic and tumor-infiltrated factors, rather than only a single factor. A more intensive investigation is required to reach a complete understanding of TII. PMID:19696968

  1. Angular Impact Mitigation System for Bicycle Helmets to Reduce Head Acceleration and Risk of Traumatic Brain Injury

    PubMed Central

    Hansen, Kirk; Dau, Nathan; Feist, Florian; Deck, Caroline; Willinger, Rémy; Madey, Steven M.; Bottlang, Michael

    2013-01-01

    Angular acceleration of the head is a known cause of traumatic brain injury (TBI), but contemporary bicycle helmets lack dedicated mechanisms to mitigate angular acceleration. A novel Angular Impact Mitigation (AIM) system for bicycle helmets has been developed that employs an elastically suspended aluminum honeycomb liner to absorb linear acceleration in normal impacts as well as angular acceleration in oblique impacts. This study tested bicycle helmets with and without AIM technology to comparatively assess impact mitigation. Normal impact tests were performed to measure linear head acceleration. Oblique impact tests were performed to measure angular head acceleration and neck loading. Furthermore, acceleration histories of oblique impacts were analyzed in a computational head model to predict the resulting risk of TBI in the form of concussion and diffuse axonal injury (DAI). Compared to standard helmets, AIM helmets resulted in a 14% reduction in peak linear acceleration (p < 0.001), a 34% reduction in peak angular acceleration (p < 0.001), and a 22% to 32% reduction in neck loading (p < 0.001). Computational results predicted that AIM helmets reduced the risk of concussion and DAI by 27% and 44%, respectively. In conclusion, these results demonstrated that AIM technology could effectively improve impact mitigation compared to a contemporary expanded polystyrene-based bicycle helmet, and may enhance prevention of bicycle-related TBI. Further research is required. PMID:23770518

  2. Exogenous brain-derived neurotrophic factor relieves pain symptoms of diabetic rats by reducing excitability of dorsal root ganglion neurons.

    PubMed

    Li, Lei; Yu, Ting; Yu, Liling; Li, Haijun; Liu, Yongjuan; Wang, Dongqin

    2016-08-01

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking of effective treatments. Enhanced excitability of dorsal root ganglion (DRG) neuron plays a crucial role in the progression of diabetic neuropathic hyperalgesia. Brain-derived neurotrophic factor (BDNF) is known as a neuromodulator of nociception, but whether and how BDNF modulates the excitability of DRG neurons in the development of DPN remain to be clarified. This study investigated the role of exogenous BDNF and its high-affinity tropomyosin receptor kinase B (TrkB) in rats with streptozotocin-induced diabetic neuropathic pain. The results showed that continued intrathecal administration of BDNF to diabetic rats dramatically alleviated mechanical and thermal hyperalgesia, as well as inhibited hyperexcitability of DRG neurons. These effects were blocked by pretreatment with TrkB Fc (a synthetic fusion protein consisting of the extracellular ligand-binding domain of the TrkB receptor). The expression of BDNF and TrkB was upregulated in the DRG of diabetic rats. Intrathecal administration of BDNF did not affect this upregulation. These data provide novel information that exogenous BDNF relieved pain symptoms of diabetic rats by reducing hyperexcitability of DRG neurons and might be the potential treatment of painful diabetic neuropathy. PMID:26441011

  3. Towards reducing impact-induced brain injury: lessons from a computational study of army and football helmet pads.

    PubMed

    Moss, William C; King, Michael J; Blackman, Eric G

    2014-01-01

    We use computational simulations to compare the impact response of different football and U.S. Army helmet pad materials. We conduct experiments to characterise the material response of different helmet pads. We simulate experimental helmet impact tests performed by the U.S. Army to validate our methods. We then simulate a cylindrical impactor striking different pads. The acceleration history of the impactor is used to calculate the head injury criterion for each pad. We conduct sensitivity studies exploring the effects of pad composition, geometry and material stiffness. We find that (1) the football pad materials do not outperform the currently used military pad material in militarily relevant impact scenarios; (2) optimal material properties for a pad depend on impact energy and (3) thicker pads perform better at all velocities. Although we considered only the isolated response of pad materials, not entire helmet systems, our analysis suggests that by using larger helmet shells with correspondingly thicker pads, impact-induced traumatic brain injury may be reduced. PMID:23244512

  4. Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats.

    PubMed

    Todtenkopf, Mark S; O'Neill, Krystal S; Kriksciukaite, Kristina; Turncliff, Ryan Z; Dean, Reginald L; Ostrovsky-Day, Irina; Deaver, Daniel R

    2009-09-01

    Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone. PMID:19489752

  5. Pathogenetic Mechanisms of Neurogenic Pulmonary Edema.

    PubMed

    Šedý, Jiří; Kuneš, Jaroslav; Zicha, Josef

    2015-08-01

    Neurogenic pulmonary edema (NPE) is a life-threatening complication of central nervous system (CNS) injuries. This review summarizes current knowledge about NPE etiology and pathophysiology with an emphasis on its experimental models, including our spinal cord compression model. NPE may develop as a result of activation of specific CNS trigger zones located in the brainstem, leading to a rapid sympathetic discharge, rise in systemic blood pressure, baroreflex-induced bradycardia, and enhanced venous return resulting in pulmonary vascular congestion characterized by interstitial edema, intra-alveolar accumulation of transudate, and intra-alveolar hemorrhages. The potential etiological role of neurotransmitter changes in NPE trigger zones leading to enhanced sympathetic nerve activity is discussed. Degree of anesthesia is a crucial determinant for the extent of NPE development in experimental models because of its influence on sympathetic nervous system activity. Sympathetic hyperactivity is based on the major activation of either ascending spinal pathways by spinal cord injury or NPE trigger zones by increased intracranial pressure. Attenuation of sympathetic nerve activity or abolition of reflex bradycardia completely prevent NPE development in our experimental model. Suggestions for future research into NPE pathogenesis as well as therapeutic potential of particular drugs and interventions are discussed. PMID:25496372

  6. A multimodal approach to diabetic macular edema.

    PubMed

    Au, Adrian; Singh, Rishi P

    2016-04-01

    Diabetic retinopathy is a common complication of uncontrolled diabetes. A complication is diabetic macular edema, which is the leading cause of blindness in patients with diabetic retinopathy. Historically, management of these conditions was laser photocoagulation with regulation of blood pressure, blood sugar, and cholesterol. The initial studies demonstrated that this treatment regimen prevented further visual deterioration but did not improve visual acuity. Novel studies identifying the presence of vascular endothelial growth factor (VEGF) in the eye with accompanying elucidation of diabetic pathophysiology allowed for the development of alternative therapies, namely antibodies against VEGF and corticosteroids. These two therapies revolutionized the management of diabetic macular edema by not only preventing vision loss, but also improving overall vision. In this review, we outline the major breakthroughs and underlying thought processes of the paradigm shifts that have occurred in management of these conditions. Further, we present how the evolving role of anti-inflammatory and anti-VEGF therapies, in a combinatorial approach, may provide further permutations to optimize treatment. PMID:26853628

  7. New Compton densitometer for measuring pulmonary edema

    SciTech Connect

    Loo, B.W.; Goulding, F.S.; Simon, D.S.

    1985-10-01

    Pulmonary edema is the pathological increase of extravascular lung water found most often in patients with congestive heart failure and other critically ill patients who suffer from intravenous fluid overload. A non-invasive lung density monitor that is accurate, easily portable, safe and inexpensive is needed for clinical evaluation of pulmonary edema. Other researchers who have employed Compton scattering techniques generally used systems of extended size and detectors with poor energy resolution. This has resulted in significant systematic biases from multiply-scattered photons and larger errors in counting statistics at a given radiation dose to the patient. We are proposing a patented approach in which only backscattered photons are measured with a high-resolution HPGe detector in a compact system geometry. By proper design and a unique data extraction scheme, effects of the variable chest wall on lung density measurements are minimized. Preliminary test results indicate that with a radioactive source of under 30 GBq, it should be possible to make an accurate lung density measurement in one minute, with a risk of radiation exposure to the patient a thousand times smaller than that from a typical chest x-ray. The ability to make safe, frequent lung density measurements could be very helpful for monitoring the course of P.E. at the hospital bedside or outpatient clinics, and for evaluating the efficacy of therapy in clinical research. 6 refs., 5 figs.

  8. The Curious Question of Exercise-Induced Pulmonary Edema

    PubMed Central

    Bates, Melissa L.; Farrell, Emily T.; Eldridge, Marlowe W.

    2011-01-01

    The question of whether pulmonary edema develops during exercise on land is controversial. Yet, the development of pulmonary edema during swimming and diving is well established. This paper addresses the current controversies that exist in the field of exercise-induced pulmonary edema on land and with water immersion. It also discusses the mechanisms by which pulmonary edema can develop during land exercise, swimming, and diving and the current gaps in knowledge that exist. Finally, this paper discusses how these fields can continue to advance and the areas where clinical knowledge is lacking. PMID:21660232

  9. Effect of ethanol and/or reduced caloric intake during pregnancy on brain weight and synaptic membranes of mothers and their newborn

    SciTech Connect

    Breen, M.; Weinsxein, H.G.

    1986-03-05

    Pregnant female rats were divided into five groups and fed as follows: - Ad libitum (AD), 20% of calories as ethanol (ED20), pair fed to ED20 (CD20), 36% of calories as ethanol (ED36), pair to ED36( CD36). New-born rats were obtained from these groups and labelled:- AN, EN20, CN20, EN36, CN36. The brains were removed and a synaptic membrane enriched fraction isolated which was analyzed for protein, sialic acid and the marker enzymes:- acetylcholinesterase (AC) and Na/K ATPase. Caloric intake was reduced by ethanol to 85% (ED20) and 68% (ED36) of the ad libitum fed (AD). Brain wt. of the neonate was reduced by the lower caloric intake of the dam but ethanol ingestion reduced the brain weight of the neonate even more significantly, CN36 vs. ED36 (p<0.05). The amount of synaptic membranes (syn.mem), in the brain was 5 to 7 times greater in the dam than their corresponding neonates, but there was no significant difference in the sialic acid (SA) content of the syn. mem. of dams and their corresponding neonates; however, the levels of both enzyme markers were negligible in the neonate. The reduced caloric and/or ethanol ingestion by the dam increased the levels of SA in the syn. mem. of both dam and neonate, and the marker enzymes in the dam.

  10. Brain Volume Determination in Subarachnoid Hemorrhage Using Rats.

    PubMed

    Lekic, Tim; Hardy, Maurice; Fujii, Mutsumi; McBride, Devin W; Zhang, John H

    2016-01-01

    Brain edema is routinely measured using the wet-dry method. Volume, however, is the sum total of all cerebral tissues, including water. Therefore, volumetric change following injury may not be adequately quantified using percentage of edema. We thus tested the hypothesis that dried brains can be reconstituted with water and then re-measured to determine the actual volume. Subarachnoid hemorrhage (SAH) was induced by endovascular perforation in adult male Sprague-Dawley rats (n = 30). Animals were euthanized at 24 and 72 h after evaluation of neurobehavior for determination of brain water content. Dried brains were thereafter reconstituted with equal parts of water (lost from brain edema) and centrifuged to remove air bubbles. The total volume was quantified using hydrostatic (underwater) physics principles that 1 ml water (mass) = 1 cm(3) (volume). The amount of additional water needed to reach a preset level marked on 2-ml test tubes was added to that lost from brain edema, and from the brain itself, to determine the final volume. SAH significantly increased both brain water and volume while worsening neurological function in affected rats. Volumetric measurements demonstrated significant brain swelling after SAH, in addition to the brain edema approach. This modification of the "wet-dry" method permits brain volume determination using valuable post hoc dried brain tissue. PMID:26463930

  11. Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease.

    PubMed

    Meek, Stephen; Thomson, Alison J; Sutherland, Linda; Sharp, Matthew G F; Thomson, Julie; Bishop, Valerie; Meddle, Simone L; Gloaguen, Yoann; Weidt, Stefan; Singh-Dolt, Karamjit; Buehr, Mia; Brown, Helen K; Gill, Andrew C; Burdon, Tom

    2016-01-01

    Lesch-Nyhan disease (LND) is a severe neurological disorder caused by loss-of-function mutations in the gene encoding hypoxanthine phosphoribosyltransferase (HPRT), an enzyme required for efficient recycling of purine nucleotides. Although this biochemical defect reconfigures purine metabolism and leads to elevated levels of the breakdown product urea, it remains unclear exactly how loss of HPRT activity disrupts brain function. As the rat is the preferred rodent experimental model for studying neurobiology and diseases of the brain, we used genetically-modified embryonic stem cells to generate an HPRT knock-out rat. Male HPRT-deficient rats were viable, fertile and displayed normal caged behaviour. However, metabolomic analysis revealed changes in brain biochemistry consistent with disruption of purine recycling and nucleotide metabolism. Broader changes in brain biochemistry were also indicated by increased levels of the core metabolite citrate and reduced levels of lipids and fatty acids. Targeted MS/MS analysis identified reduced levels of dopamine in the brains of HPRT-deficient animals, consistent with deficits noted previously in human LND patients and HPRT knock-out mice. The HPRT-deficient rat therefore provides a new experimental platform for future investigation of how HPRT activity and disruption of purine metabolism affects neural function and behaviour. PMID:27185277

  12. Autoradiographic localization of a non-reducible somatostatin analog (/sup 125/I-CGP 23996) binding sites in the rat brain: comparison with membrane binding

    SciTech Connect

    Epelbaum, J.; Dussaillant, M.; Enjalbert, A.; Kordon, C.; Rostene, W.

    1985-07-01

    The regional distribution of somatostatin binding sites in the rat brain was determined by quantitative autoradiography, using /sup 125/I-CGP 23996, a non-reducible somatostatin analog. In preliminary experiments, kinetic properties of /sup 125/I-CGP 23996 binding to rat brain membranes and slide mounted frozen brain sections were compared and found similar. In addition, distribution of /sup 125/I-CGP 23996 and /sup 125/I-N-Tyr-SRIF14 binding sites on membrane prepared from 10 different rat brain structures were closely correlated (r = 0.91, 2 p less than 0.01), indicating that the non-reducible analog recognizes the same binding site as the Tyr-extended native peptide. Highest levels of /sup 125/I-CGP 23996 binding sites were found in anterior temporal, frontal and cingular cortex as well as hippocampus. Moderate levels were found in the remaining part of the limbic system including amygdala, olfactory tubercles and bed nucleus of the stria terminalis. In the brain stem, nuclei involved in the auditory system such as the ventral cochlear nucleus and the superior olive nucleus, contained high levels of /sup 125/I-CGP 23996 binding sites. The distribution of /sup 125/I-CGP 23996 binding sites roughly correlated with that of the endogenous peptide in most structures, except in the mediobasal hypothalamus.

  13. The role of rhynchophylline in alleviating early brain injury following subarachnoid hemorrhage in rats.

    PubMed

    Zhang, Yan; Sun, Juan; Zhu, Shijie; Xu, Ting; Lu, Jianfei; Han, Hongbin; Zhou, Changman; Yan, Junhao

    2016-01-15

    Rhynchophylline (Rhy) has been demonstrated protective effects on some neurological diseases. However, the roles of Rhy in the subarachnoid hemorrhage (SAH) are still to be cleared. In the present study, the effects of Rhy on attenuation of early brain injury (EBI) after SAH have been evaluated. The adult male Sprague-Dawley rats (280-300g) were used to establish the SAH models using endovascular perforation method. Rhy was administered by intraperitoneal injection immediately following SAH. Brain edema was assessed by magnetic resonance imaging (MRI) at 24h after SAH. Neurological deficits, brain water content, malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) content in hippocampus were also evaluated. Immunofluorescence and western blot were used to explore the underlying protective mechanism of Rhy. The results showed that, following 10mg/kg Rhy treatment, the brain edema and neurological deficits, and blood-brain barrier (BBB) disruption were significantly attenuated at 24h after SAH. Additionally, in hippocampus, MDA concentration, MPO activity and ROS content were markedly decreased. Meanwhile, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO-1) were increased, while the expressions of p-p53, cleaved-caspase-3 and tumor necrosis factor-α (TNF-α) were significantly decreased. Our results indicated that Rhy could attenuate early brain injury by reducing inflammation and apoptosis in hippocampus after SAH. PMID:26631843

  14. Resolution of Pulmonary Edema. Thirty Years of Progress

    PubMed Central

    2014-01-01

    In the last 30 years, we have learned much about the molecular, cellular, and physiological mechanisms that regulate the resolution of pulmonary edema in both the normal and the injured lung. Although the physiological mechanisms responsible for the formation of pulmonary edema were identified by 1980, the mechanisms that explain the resolution of pulmonary edema were not well understood at that time. However, in the 1980s several investigators provided novel evidence that the primary mechanism for removal of alveolar edema fluid depended on active ion transport across the alveolar epithelium. Sodium enters through apical channels, primarily the epithelial sodium channel, and is pumped into the lung interstitium by basolaterally located Na/K-ATPase, thus creating a local osmotic gradient to reabsorb the water fraction of the edema fluid from the airspaces of the lungs. The resolution of alveolar edema across the normally tight epithelial barrier can be up-regulated by cyclic adenosine monophosphate (cAMP)-dependent mechanisms through adrenergic or dopamine receptor stimulation, and by several cAMP-independent mechanisms, including glucocorticoids, thyroid hormone, dopamine, and growth factors. Whereas resolution of alveolar edema in cardiogenic pulmonary edema can be rapid, the rate of edema resolution in most patients with acute respiratory distress syndrome (ARDS) is markedly impaired, a finding that correlates with higher mortality. Several mechanisms impair the resolution of alveolar edema in ARDS, including cell injury from unfavorable ventilator strategies or pathogens, hypoxia, cytokines, and oxidative stress. In patients with severe ARDS, alveolar epithelial cell death is a major mechanism that prevents the resolution of lung edema. PMID:24881936

  15. Improved perioperative neurological monitoring of coronary artery bypass graft patients reduces the incidence of postoperative delirium: the Haga Brain Care Strategy

    PubMed Central

    Palmbergen, Wijnand A.C.; van Sonderen, Agnes; Keyhan-Falsafi, Ali M.; Keunen, Ruud W.M.; Wolterbeek, Ron

    2012-01-01

    OBJECTIVES Postoperative delirium is a major cause of morbidity and mortality after cardiovascular surgery. Risk factors for postoperative delirium include poor cerebral haemodynamics and perioperative cerebral desaturations. Our aim was to reduce the postoperative delirium rate by using a new prevention strategy called the Haga Brain Care Strategy. This study evaluates the efficacy of the implementation of the Haga Brain Care Strategy to reduce the postoperative delirium rate after elective coronary artery bypass graft (CABG) procedures. The primary endpoint was the postoperative delirium rate, and the secondary endpoint was the length of stay in the intensive care unit. METHODS The Haga Brain Care Strategy consisted of the conventional screening protocol for delirium with the addition of preoperative transcranial Doppler examinations, perioperative cerebral oximetry, modified Rankin score, delirium risk score and (if indicated) duplex examination of the carotid arteries. In case of poor preoperative haemodynamics, the cerebral blood flow was optionally optimized by angioplasty or the patient was operated on under mild hypothermic conditions. Perioperative cerebral desaturations >20% outside the normal range resulted in intervention to restore cerebral oxygenation. Cerebral oximetry was discontinued when patients regained consciousness. Patients undergoing elective CABG procedures in 2010 were compared with patients scheduled for coronary bypass graft procedures in 2009 who had not been exposed to additional Haga Brain Care Strategy assessment. RESULTS A total of 233 and 409 patients were included in 2009 and 2010, respectively. The number of patients subjected in 2010 to transcranial Doppler examinations, cerebral oximetry or both (Haga Brain Care Strategy) were 262 (64.1%), 201 (49.1%) and 139 (34.0%), respectively. The overall rate of postoperative delirium decreased from 31 (13.3%) in 2009 to 30 (7.3%) in 2010 (P = 0.019). A binary logistic regression model showed that the Haga Brain Care Strategy was an independent predictor of a reduced risk of developing a postoperative delirium (odd ratio = 0.37, P = 0.021). CONCLUSIONS With the implementation of the Haga Brain Care Strategy in 2010, a reduction of the incidence of postoperative delirium in patients undergoing elective CABG procedures was observed. In addition, the length of stay in the intensive care unit showed an overall tendency to decline. The limited number of observations and the current study design do not allow a full evaluation of the Haga Brain Care Strategy but the data support the idea that a sophisticated preoperative assessment of cerebral haemodynamics and perioperative monitoring of cerebral oximetry reduce the incidence of the postoperative delirium in CABG surgery. PMID:22778141

  16. Reduced GABAergic Inhibition in the Basolateral Amygdala and the Development of Anxiety-Like Behaviors after Mild Traumatic Brain Injury

    PubMed Central

    Almeida-Suhett, Camila P.; Prager, Eric M.; Pidoplichko, Volodymyr; Figueiredo, Taiza H.; Marini, Ann M.; Li, Zheng; Eiden, Lee E.; Braga, Maria F. M.

    2014-01-01

    Traumatic brain injury (TBI) is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA); hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified. We assessed the functional alterations in inhibitory synaptic transmission in the BLA and one mechanism that modulates excitatory synaptic transmission, the α7 containing nicotinic acetylcholine receptor (α7-nAChR), after mTBI, to shed light on the mechanisms that contribute to increased anxiety-like behaviors. Seven and 30 days after a mild controlled cortical impact (CCI) injury, animals displayed significantly greater anxiety-like behavior. This was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs). Decreases in the mIPSC amplitude were associated with reduced surface expression of α1, β2, and γ2 GABAA receptor subunits. However, significant increases in the surface expression and current mediated by α7-nAChR, were observed, signifying increases in the excitability of principal neurons within the BLA. These results suggest that mTBI causes not only a significant reduction in inhibition in the BLA, but also an increase in neuronal excitability, which may contribute to hyperexcitability and the development of anxiety disorders. PMID:25047645

  17. Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects☆☆☆

    PubMed Central

    Ewers, Michael; Brendel, Matthias; Rizk-Jackson, Angela; Rominger, Axel; Bartenstein, Peter; Schuff, Norbert; Weiner, Michael W.

    2013-01-01

    Brain changes reminiscent of Alzheimer disease (AD) have been previously reported in a substantial portion of elderly cognitive healthy (HC) subjects. The major aim was to evaluate the accuracy of MRI assessed regional gray matter (GM) volume, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and neuropsychological test scores to identify those HC subjects who subsequently convert to mild cognitive impairment (MCI) or AD dementia. We obtained in 54 healthy control (HC) subjects a priori defined region of interest (ROI) values of medial temporal and parietal FDG-PET and medial temporal GM volume. In logistic regression analyses, these ROI values were tested together with neuropsychological test scores (free recall, trail making test B (TMT-B)) as predictors of HC conversion during a clinical follow-up between 3 and 4 years. In voxel-based analyses, FDG-PET and MRI GM maps were compared between HC converters and HC non-converters. Out of the 54 HC subjects, 11 subjects converted to MCI or AD dementia. Lower FDG-PET ROI values were associated with higher likelihood of conversion (p = 0.004), with the area under the curve (AUC) yielding 82.0% (95% CI = (95.5%, 68.5%)). The GM volume ROI was not a significant predictor (p = 0.07). TMT-B but not the free recall tests were a significant predictor (AUC = 71% (95% CI = 50.4%, 91.7%)). For the combination of FDG-PET and TMT-B, the AUC was 93.4% (sensitivity = 82%, specificity = 93%). Voxel-based group comparison showed reduced FDG-PET metabolism within the temporo-parietal and prefrontal cortex in HC converters. In conclusion, medial temporal and-parietal FDG-PET and executive function show a clinically acceptable accuracy for predicting clinical progression in elderly HC subjects. PMID:24286024

  18. Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats.

    PubMed

    Pravetoni, M; Raleigh, M D; Le Naour, M; Tucker, A M; Harmon, T M; Jones, J M; Birnbaum, A K; Portoghese, P S; Pentel, P R

    2012-06-29

    Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)(4) linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components. PMID:22583811

  19. Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats.

    PubMed

    Klampfl, Stefanie M; Neumann, Inga D; Bosch, Oliver J

    2013-09-01

    The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour. PMID:23742269

  20. Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats

    PubMed Central

    Pravetoni, M; Raleigh, MD; Le Naour, M; Tucker, AM; Harmon, TM; Jones, JM; Birnbaum, AK; Portoghese, PS; Pentel, PR

    2012-01-01

    Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)4 linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components. PMID:22583811

  1. ETB receptor-mediated MMP-9 activation induces vasogenic edema via ZO-1 protein degradation following status epilepticus.

    PubMed

    Kim, J Y; Ko, A-R; Hyun, H-W; Kang, T-C

    2015-09-24

    The blood-brain barrier (BBB) is formed by the endothelial cells with specialized tight junctions (TJs) lining the blood vessels and astroglial endfeet surrounding the blood vessels. Although BBB disruption during brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process, little is known about the molecular and physiological events concerning vasogenic edema formation. In the present study, status epilepticus (SE) changed the expressions and subcellular localizations of TJ proteins (claudin-5, occludin and zonula occludens-1 (ZO-1)) in endothelial cells of the rat piriform cortex. Among TJ proteins, the alteration in ZO-1 expression was relevant to endothelin B (ETB) receptor-mediated endothelial nitric oxide synthase (eNOS) activation, which increased matrix metalloproteinase-9 (MMP-9) activity. Indeed, BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced vasogenic edema by inhibiting eNOS-mediated MMP-9 activation and ZO-1 protein degradation in endothelial cells, although astroglial endfeet were detached from endothelial cells. Therefore, we suggest that SE-induced ETB receptor/eNOS-mediated MMP-9 activation may lead to impairments of endothelial cell function via TJ protein degradation, which are involved in vasogenic edema formation independent of perivascular astroglial functions. PMID:26232046

  2. Pharmacological approach to diabetic macular edema.

    PubMed

    Bandello, F; Casalino, G; Loewenstein, A; Goldstein, M; Pelayes, D; Battaglia Parodi, M

    2014-01-01

    Diabetic macular edema (DME) is a highly prevalent cause of vision loss and has a remarkable impact on public health, and on the quality of life of diabetic patients. Even though laser photocoagulation has been the standard of care for decades, a substantial group of patients are unresponsive and fail to improve after laser treatment. Recently, new pharmacological approaches based on the use of intravitreal drugs, such as corticosteroids and anti-vascular endothelial growth factor, have revolutionized the treatment of DME. The use of intravitreal drugs is supported by the improvement in visual acuity reported by several clinical trials and can limit the potentially destructive effects of the laser treatment. Encouraging results also emerged from studies evaluating the use of a combination therapy, or the association of intravitreal drugs and laser treatment. This review aims at providing a brief synopsis of the main investigations regarding the current pharmacological approach to DME. PMID:24356667

  3. Serotonin syndrome presenting as pulmonary edema.

    PubMed

    Shah, Nilima Deepak; Jain, Ajay B

    2016-01-01

    Serotonin syndrome (SS) is a potentially life-threatening condition resulting from excessive central and peripheral serotonergic activity. Clinically, it is a triad of mental-status changes, neuromuscular abnormalities, and autonomic disturbances. It can be caused by intentional self-poisoning, overdose, or inadvertent drug interactions. We report the case of a 58-year-old male with type 2 diabetes mellitus and obsessive compulsive disorder who developed pulmonary edema as a possible complication of SS. SS was caused by a combination of three specific serotonin re-uptake inhibitors (fluoxetine, fluvoxamine, and sertraline), linezolid, and fentanyl. The hospital course was further complicated by difficult weaning from the ventilator. SS was identified and successfully treated with cyproheptadine and lorazepam. The case highlights the importance of effective consultation-liaison and prompt recognition of SS as the presentation may be complex in the presence of co-morbid medical illness. PMID:26997733

  4. Serotonin syndrome presenting as pulmonary edema

    PubMed Central

    Shah, Nilima Deepak; Jain, Ajay B.

    2016-01-01

    Serotonin syndrome (SS) is a potentially life-threatening condition resulting from excessive central and peripheral serotonergic activity. Clinically, it is a triad of mental-status changes, neuromuscular abnormalities, and autonomic disturbances. It can be caused by intentional self-poisoning, overdose, or inadvertent drug interactions. We report the case of a 58-year-old male with type 2 diabetes mellitus and obsessive compulsive disorder who developed pulmonary edema as a possible complication of SS. SS was caused by a combination of three specific serotonin re-uptake inhibitors (fluoxetine, fluvoxamine, and sertraline), linezolid, and fentanyl. The hospital course was further complicated by difficult weaning from the ventilator. SS was identified and successfully treated with cyproheptadine and lorazepam. The case highlights the importance of effective consultation-liaison and prompt recognition of SS as the presentation may be complex in the presence of co-morbid medical illness. PMID:26997733

  5. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection.

    PubMed

    Peteranderl, Christin; Morales-Nebreda, Luisa; Selvakumar, Balachandar; Lecuona, Emilia; Vadász, István; Morty, Rory E; Schmoldt, Carole; Bespalowa, Julia; Wolff, Thorsten; Pleschka, Stephan; Mayer, Konstantin; Gattenloehner, Stefan; Fink, Ludger; Lohmeyer, Juergen; Seeger, Werner; Sznajder, Jacob I; Mutlu, Gökhan M; Budinger, G R Scott; Herold, Susanne

    2016-04-01

    Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury. PMID:26999599

  6. Oxygen-deficient metabolism and corneal edema

    PubMed Central

    Leung, B.K.; Bonanno, J.A.; Radke, C.J.

    2014-01-01

    Wear of low-oxygen-transmissible soft contact lenses swells the cornea significantly, even during open eye. Although oxygen-deficient corneal edema is well-documented, a self-consistent quantitative prediction based on the underlying metabolic reactions is not available. We present a biochemical description of the human cornea that quantifies hypoxic swelling through the coupled transport of water, salt, and respiratory metabolites. Aerobic and anaerobic consumption of glucose, as well as acidosis and pH buffering, are incorporated in a seven-layer corneal model (anterior chamber, endothelium, stroma, epithelium, postlens tear film, contact lens, and prelens tear film). Corneal swelling is predicted from coupled transport of water, dissolved salts, and especially metabolites, along with membrane-transport resistances at the endothelium and epithelium. At the endothelium, the Na+/K+ - ATPase electrogenic channel actively transports bicarbonate ion from the stroma into the anterior chamber. As captured by the Kedem–Katchalsky membrane-transport formalism, the active bicarbonate-ion flux provides the driving force for corneal fluid pump-out needed to match the leak-in tendency of the stroma. Increased lactate-ion production during hypoxia osmotically lowers the pump-out rate requiring the stroma to swell to higher water content. Concentration profiles are predicted for glucose, water, oxygen, carbon dioxide, and hydronium, lactate, bicarbonate, sodium, and chloride ions, along with electrostatic potential and pressure profiles. Although the active bicarbonate-ion pump at the endothelium drives bicarbonate into the aqueous humor, we find a net flux of bicarbonate ion into the cornea that safeguards against acidosis. For the first time, we predict corneal swelling upon soft-contact-lens wear from fundamental biophysico-chemical principles. We also successfully predict that hypertonic tear alleviates contact-lens-induced edema. PMID:21820076

  7. Smoke aldehyde component influences pulmonary edema

    SciTech Connect

    Hales, C.A.; Musto, S.W.; Janssens, S.; Jung, W.; Quinn, D.A.; Witten, M. , Massachusetts General Hospital, Boston )

    1992-02-01

    The pulmonary edema of smoke inhalation is caused by the toxins of smoke and not the heat. We investigated the potential of smoke consisting of carbon in combination with either acrolein or formaldehyde (both common components of smoke) to cause pulmonary edema in anesthetized sheep. Seven animals received acrolein smoke, seven animals received a low-dose formaldehyde smoke, and five animals received a high-dose formaldehyde smoke. Pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output were not affected by smoke in any group. Peak airway pressure increased after acrolein (14 +/- 1 to 21 +/- 2 mmHg; P less than 0.05) and after low- and high-dose formaldehyde (14 +/- 1 to 21 +/- 1 and 20 +/- 1 mmHg, respectively; both P less than 0.05). The partial pressure of O2 in arterial blood fell sharply after acrolein (219 +/- 29 to 86 +/- 9 (SE) Torr; P less than 0.05) but not after formaldehyde. Only acrolein resulted in a rise in lung lymph flow (6.5 +/- 2.2 to 17.9 +/- 2.6 ml/h; P less than 0.05). Lung lymph-to-plasma protein ratio was unchanged for all three groups, but clearance of lymph protein was increased after acrolein. After acrolein, the blood-free extravascular lung water-to-lung dry weight ratio was elevated (P less than 0.05) compared with both low- and high-dose formaldehyde groups (4.8 +/- 0.4 to 3.3 +/- 0.2 and 3.6 +/- 0.2, respectively). Lymph clearance (ng/h) of thromboxane B2, leukotriene B4, and the sulfidopeptide leukotrienes was elevated after acrolein but not formaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Lung Edema Clearance: Relevance to Patients with Lung Injury.

    PubMed

    Azzam, Zaher S; Sznajder, Jacob I

    2015-01-01

    Pulmonary edema clearance is necessary for patients with lung injury to recover and survive. The mechanisms regulating edema clearance from the lungs are distinct from the factors contributing edema formation during injury. Edema clearance is effected via vectorial transport of Na(+) out of the airspaces which generates an osmotic gradient causing water to follow the gradient out of the cells. This Na(+) transport across the alveolar epithelium is mostly effected via apical Na(+) and chloride channels and basolateral Na,K-ATPase. The Na,K-ATPase pumps Na(+) out of the cell and K(+) into the cell against their respective gradients in an ATP-consuming reaction. Two mechanisms contribute to the regulation of the Na,K-ATPase activity:recruitment of its subunits from intracellular compartments into the basolateral membrane, and transcriptional/translational regulation. Na,K-ATPase activity and edema clearance are increased by catecholamines, aldosterone, vasopressin, overexpression of the pump genes, and others. During lung injury, mechanisms regulating edema clearance are inhibited by yet unclear pathways. Better understanding of the mechanisms that regulate pulmonary edema clearance may lead to therapeutic interventions that counterbalance the inhibition of edema clearance during lung injury and improve the lungs' ability to clear fluid, which is crucial for patient survival. PMID:26241220

  9. Elephantoid eyelid edema associated with continuous positive airway pressure treatment.

    PubMed

    Chiam, Patrick J T; Hubbard, Alan D

    2013-01-01

    A man with rosacea developed bilateral eyelid edema from wearing a continuous positive airway pressure nasal mask daily. The edema was refractory to steroid, diuretics, and lymphatic drainage massage. The effect may be related to cumulative venous congestion and lymphostasis due to the continuous positive airway pressure treatment. PMID:23128530

  10. Lung Edema Clearance: Relevance to Patients with Lung Injury

    PubMed Central

    Azzam, Zaher S.; Sznajder, Jacob I.

    2015-01-01

    Pulmonary edema clearance is necessary for patients with lung injury to recover and survive. The mechanisms regulating edema clearance from the lungs are distinct from the factors contributing edema formation during injury. Edema clearance is effected via vectorial transport of Na+ out of the airspaces which generates an osmotic gradient causing water to follow the gradient out of the cells. This Na+ transport across the alveolar epithelium is mostly effected via apical Na+ and chloride channels and basolateral Na,K-ATPase. The Na,K-ATPase pumps Na+ out of the cell and K+ into the cell against their respective gradients in an ATP-consuming reaction. Two mechanisms contribute to the regulation of the Na,K-ATPase activity:recruitment of its subunits from intracellular compartments into the basolateral membrane, and transcriptional/translational regulation. Na,K-ATPase activity and edema clearance are increased by catecholamines, aldosterone, vasopressin, overexpression of the pump genes, and others. During lung injury, mechanisms regulating edema clearance are inhibited by yet unclear pathways. Better understanding of the mechanisms that regulate pulmonary edema clearance may lead to therapeutic interventions that counterbalance the inhibition of edema clearance during lung injury and improve the lungs ability to clear fluid, which is crucial for patient survival. PMID:26241220

  11. [Diabetic macular edema--modern diagnostics and treatment].

    PubMed

    Wylegała, Edward; Mańkowski, Wojciech; Pilat, Jarosław; Teper, Sławomir; Skupień-Mańkowska, Hanna

    2010-07-01

    Diabetic macular edema is very important medical and social problem and major cause of severe and permanent visual acuity depression in the working-age population. Rapid diagnostics with optical coherence tomography, color fundus photography, fluorescein angiography and appropriate treatment in patients with diabetes stops or retards progress of diabetic macular edema. PMID:20712253

  12. Augmentation of M-Type (KCNQ) Potassium Channels as a Novel Strategy to Reduce Stroke-Induced Brain Injury

    PubMed Central

    Bierbower, Sonya M.; Choveau, Frank S.; Lechleiter, James D.

    2015-01-01

    Cerebral ischemic stroke is a worldwide cause of mortality/morbidity and thus an important focus of research to decrease the severity of brain injury. Therapeutic options for acute stroke are still limited. In neurons throughout the brain, “M-type” K+ currents, underlain by KCNQ subunits 2–5, play dominant roles in control over excitability, and are thus implicated in myriad neurological and psychiatric disorders. Although KCNQ channel openers, such as retigabine, have emerged as anti-epilepsy drugs, their effects on ischemic injury remain unknown. Here, we investigated the protective effects of M-channel openers on stroke-induced brain injury in mouse photothrombotic and middle cerebral artery occlusion (MCAo) models. Both photothrombosis and MCAo led to rapid, predictable, and consistently sized necrotic brain lesions, inflammatory responses, and behavioral deficits. Administration of three distinct M-channel openers at 0–6 h after ischemic injury significantly decreased brain infarct size and inflammation, and prevented neurological dysfunction, although they were more effective when administered 0–3 h poststroke. Thus, we show beneficial effects against stroke-induced brain injury and neuronal death through pharmacological regulation of ion channels that control neuronal excitability. PMID:25653366

  13. Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

    PubMed Central

    Stamatovic, Svetlana M; Keep, Richard F; Andjelkovic, Anuska V

    2008-01-01

    The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption (“opening”) can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer’s disease, Parkinson’s disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB “opening”. PMID:19506719

  14. P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline.

    PubMed

    Grauer, Markus T; Uhr, Manfred

    2004-03-01

    P-glycoprotein (P-gp) is a 170-kDa membrane protein and the gene product of the multiple drug resistance (MDR1 or ABCB1) gene. It constitutes an important part of the blood-brain barrier and actively exports a number of molecules across the blood-brain barrier back into the vascular space, subsequently reducing central nervous system (CNS) bioavailability of these substances. The aim of the present study was to investigate the pharmacokinetics of amitriptyline and its metabolites in P-gp (also called mdr1ab or abcb1ab) knockout mice and controls after a long-term adminstration for 10 days. Knockout mice and controls received s.c. injections of amitriptyline (10 microg/g bodyweight) twice daily for 10 days. After 10 days, the animals were sacrificed and the concentrations of amitriptyline and nortriptyline and both their E-10-OH and Z-10-OH metabolites were measured with high-performance liquid chromatography in the cerebrum, plasma, spleen, kidney, testes, lung, liver, muscle and fat. Except for amitriptyline, the brain concentrations of all other examined substances were significantly higher in the P-gp knockout mice. Compared to controls, concentrations of nortriptyline were 2.6-fold higher, E-10-OH-nortriptyline 10-fold higher, Z-10-OH-nortriptyline seven-fold higher, E-10-OH-amitriptyline two-fold higher and Z-10-OH-amitriptyline five-fold higher. The present study confirms that P-gp plays an important role in the interaction between CNS drugs and the blood-brain barrier. Without P-gp at the blood-brain barrier, the brain concentrations of the substances were up to 10-fold higher, showing that P-gp plays an active role in exporting CNS drugs out of the brain. Recent clinical studies showing different side-effects in patients with P-gp polymorphisms confirm the clinical importance of these findings. PMID:15107187

  15. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease

    PubMed Central

    Zhu, H; Wang, X; Wallack, M; Li, H; Carreras, I; Dedeoglu, A; Hur, J-Y; Zheng, H; Li, H; Fine, R; Mwamburi, M; Sun, X; Kowall, N; Stern, R A; Qiu, W Q

    2015-01-01

    Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood–brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD. PMID:24614496

  16. Matrix Metalloproteinase Expression in Contusional Traumatic Brain Injury: A Paired Microdialysis Study

    PubMed Central

    Carpenter, Keri L.H.; Helmy, Adel; Pickard, John D.; Menon, David K.; Hutchinson, Peter J.A.

    2015-01-01

    Abstract Matrix metalloproteinases (MMPs) are extracellular enzymes that have been implicated in the pathophysiology of blood–brain barrier (BBB) breakdown, contusion expansion, and vasogenic edema after traumatic brain injury (TBI). Specifically, in focal injury models, increased MMP-9 expression has been observed in pericontusional brain, and MMP-9 inhibitors reduce brain swelling and final lesion volume. The aim of this study was to examine whether there is a similarly localized increase of MMP concentrations in patients with contusional TBI. Paired microdialysis catheters were inserted into 12 patients with contusional TBI (with or without associated mass lesion) targeting pericontusional and radiologically normal brain defined on admission computed tomography scan. Microdialysate was pooled every 8 h and analyzed for MMP-1, -2, -7, -9, and -10 using a multiplex immunoassay. Concentrations of MMP-1, -2, and -10 were similar at both monitoring sites and did not show discernible temporal trends. Overall, there was a gradual increase in MMP-7 concentrations in both normal and injured brain over the monitoring period, although this was not consistent in every patient. MMP-9 concentrations were elevated in pericontusional, compared to normal, brain, with the maximal difference at the earliest monitoring times (i.e., <24 h postinjury). Repeated-measures analysis of variance showed that MMP-9 concentrations were significantly higher in pericontusional brain (p=0.03) and within the first 72 h of injury, compared with later in the monitoring period (p=0.04). No significant differences were found for the other MMPs assayed. MMP-9 concentrations are increased in pericontusional brain early post-TBI and may represent a potential therapeutic target to reduce hemorrhagic progression and vasogenic edema. PMID:25858502

  17. Spontaneous remission of edema and regranulation of goblet cells in rat tracheae after capsaicin-induced acute inflammation.

    PubMed

    Guo, Jin-Jang; Wang, Di-Seng; Huang, Hung-Tu

    2003-03-01

    Previous studies have investigated the short-term effect of capsaicin on edema formation and goblet-cell secretion in the trachea. The present study sought to investigate the long-term effect of a high dose of capsaicin (90 micro g/ml/kg), administered intravenously, on changes in the formation of endothelial gaps among venular endothelial cells, mucosal tissue edema and the secretory activity of goblet cells, including the number and size of goblet cells, and the mucus score and secretory ratio of goblet-cell mucus secretion in the trachea of rats. The tracheal whole mounts with silver staining, those stained with chloroacetate esterase reagent and Alcian blue and tracheal tissue sections stained with Alcian blue and periodic acid-Schiff reagent were used for evaluation. Formation of endothelial gaps occurred a few min after administration of capsaicin, and gaps almost closed within 12 min after capsaicin injection. Five min after capsaicin, the leaky blood vessels were numerous and the subepithelial edema ratio (% of length of edema along the inner circumference of tracheal cross section) was found to be 57.8+/-3.0% ( n=6). The number of Alcian blue-positive goblet cells (1,090+/-220 per mm(2) of mucosal surface) was reduced to half the number of goblet cells in the vehicle-treated rats (2,200+/-230). The mucus score of goblet cell secretion was not changed. The secretory ratio was greatly increased. One day after capsaicin, the edema ratio remained large and the number of Alcian blue-positive goblet cells was also small. The mucus score was also not changed. The secretory ratio was still large. On day 3, the edema ratio remained large, but the number of Alcian blue-positive goblet cells was increased to the level of the controls. The mucus score and secretory ratio returned to the control level. On day 5, the edema ratio was greatly decreased, but it was still significantly larger than that of the controls. The mucus score and secretory ratio remained at the baseline level. Seven days after capsaicin, the edema ratio was similar to the controls. The number of goblet cells was even larger than controls. It is concluded that capsaicin-induced acute inflammation in the rat trachea involves formation of endothelial gaps, extensive plasma extravasation and edema formation, and depletion of goblet-cell secretory granules. Spontaneous gradual remission of edema was accompanied by regranulation of goblet cells with gradual mucogenesis for several days. PMID:12649728

  18. Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer

    PubMed Central

    McGowan, Patricia M.; Simedrea, Carmen; Ribot, Emeline J.; Foster, Paula J.; Palmieri, Diane; Steeg, Patricia S.; Allan, Alison L.; Chambers, Ann F.

    2011-01-01

    Brain metastasis from breast cancer is an increasingly important clinical problem. Here we assessed the role of CD44hi/CD24lo cells and pathways that regulate them, in an experimental model of brain metastasis. Notch signaling (mediated by γ-secretase) has been shown to contribute to maintenance of the cancer stem cell (CSC) phenotype. Cells sorted for a reduced stem-like phenotype had a reduced ability to form brain metastases compared to unsorted or CD44hi/CD24lo cells (p<0.05; Kruskal Wallis). To assess the effect of γ-secretase inhibition, cells were cultured with DAPT and the CD44/CD24 phenotypes quantified. 231-BR cells with a CD44hi/CD24lo phenotype was reduced by ~15 % in cells treated with DAPT compared to DMSO-treated or untreated cells (p = 0.001, ANOVA). In vivo, mice treated with DAPT developed significantly fewer micro and macrometastases compared to vehicle treated or untreated mice (p = 0.011, Kruskal Wallis). Notch1 knockdown reduced the expression of CD44hi/CD24lo phenotype by ~20%. In vitro, Notch1 shRNA resulted in a reduction in cellular growth at 24 hour, 48 hour and 72 hour time points (p = 0.033, p = 0.002 and p = 0.009, ANOVA) and a ~60% reduction in Matrigel™ invasion was observed (p < 0.001, ANOVA). Cells transfected with shNotch1 formed significantly fewer macrometastases and micrometastases compared to scrambled shRNA or untransfected cells (p < 0.001; Kruskal Wallis). These data suggest that the CSC phenotype contributes to the development of brain metastases from breast cancer, and this may arise in part from increased Notch activity. PMID:21665937

  19. NTCP Modeling of Subacute/Late Laryngeal Edema Scored by Fiberoptic Examination

    SciTech Connect

    Rancati, Tiziana; Fiorino, Claudio; Sanguineti, Giuseppe

    2009-11-01

    Purpose: Finding best-fit parameters of normal tissue complication probability (NTCP) models for laryngeal edema after radiotherapy for head and neck cancer. Methods and Materials: Forty-eight patients were considered for this study who met the following criteria: (1) grossly uninvolved larynx, (2) no prior major surgery except for neck dissection and tonsillectomy, (3) at least one fiberoptic examination of the larynx within 2 years from radiotherapy, (4) minimum follow-up of 15 months. Larynx dose-volume histograms (DVHs) were corrected into a linear quadratic equivalent one at 2 Gy/fr with alpha/beta = 3 Gy. Subacute/late edema was prospectively scored at each follow-up examination according to the Radiation Therapy Oncology Group scale. G2-G3 edema within 15 months from RT was considered as our endpoint. Two NTCP models were considered: (1) the Lyman model with DVH reduced to the equivalent uniform dose (EUD; LEUD) and (2) the Logit model with DVH reduced to the EUD (LOGEUD). The parameters for the models were fit to patient data using a maximum likelihood analysis. Results: All patients had a minimum of 15 months follow-up (only 8/48 received concurrent chemotherapy): 25/48 (52.1%) experienced G2-G3 edema. Both NTCP models fit well the clinical data: with LOGEUD the relationship between EUD and NTCP can be described with TD50 = 46.7 +- 2.1 Gy, n = 1.41 +- 0.8 and a steepness parameter k = 7.2 +- 2.5 Gy. Best fit parameters for LEUD are n = 1.17 +- 0.6, m = 0.23 +- 0.07 and TD50 = 47.3 +- 2.1 Gy. Conclusions: A clear volume effect was found for edema, consistent with a parallel architecture of the larynx for this endpoint. On the basis of our findings, an EUD <30-35 Gy should drastically reduce the risk of G2-G3 edema.

  20. Painless transient bone marrow edema syndrome in a pediatric patient.

    PubMed

    Joshi, Vivek; Hermann, George; Balwani, Manisha; Simpson, William L

    2014-11-01

    Transient regional migratory osteoporosis, considered to be part of the spectrum of bone marrow edema syndrome, is a rare condition with an unknown etiology. Patients usually present with lower extremity pain, most commonly in the 4th-5th decades of life. We describe a 15-year-old male patient with type 1 Gaucher disease who presented with transient bone marrow edema syndrome with features most closely resembling regional migratory osteoporosis. The patient presented with bone marrow edema of the lateral tibial epiphysis of his right knee that was incidentally seen on routine surveillance MRI that was performed as protocol for patients with type 1 Gaucher disease on enzyme replacement therapy. At this time, the patient had no pain and physical examination was normal. Follow-up MRI of the right knee 4 months afterward showed complete resolution of the signal abnormality in the right tibial epiphysis, and repeat study 8 months later displayed a new focus of painless migratory edema of the medial tibial epiphysis of the same knee. These changes completely resolved as well. Marrow signal abnormalities in children with Gaucher disease can have a broad differential, including infection, marrow infiltration, trauma, osteonecrosis, and bone marrow edema syndrome, amongst others. Correct diagnosis of bone marrow edema syndrome is critical, as this disease process most often resolves on conservative measures. The unusual presentation of transient bone marrow edema syndrome with regional migratory osteoporosis features in a young patient with Gaucher disease is described. PMID:24893724

  1. Exercise-Induced Pulmonary Edema in a Triathlon.

    PubMed

    Yamanashi, Hirotomo; Koyamatsu, Jun; Nobuyoshi, Masaharu; Murase, Kunihiko; Maeda, Takahiro

    2015-01-01

    Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID:26229538

  2. Synthetic smoke with acrolein but not HCl produces pulmonary edema

    SciTech Connect

    Hales, C.A.; Barkin, P.W.; Jung, W.; Trautman, E.; Lamborghini, D.; Herrig, N.; Burke, J.

    1988-03-01

    The chemical toxins in smoke and not the heat are responsible for the pulmonary edema of smoke inhalation. We developed a synthetic smoke composed of carbon particles (mean diameter of 4.3 microns) to which toxins known to be in smoke, such as HCl or acrolein, could be added one at a time. We delivered synthetic smoke to dogs for 10 min and monitored extravascular lung water (EVLW) accumulation thereafter with a double-indicator thermodilution technique. Final EVLW correlated highly with gravimetric values (r = 0.93, P less than 0.01). HCl in concentrations of 0.1-6 N when added to heated carbo